(R)-n-menth-4-en-3-one and its derivatives in reactions with N-containing reagents

Article abstract of DOI:10.1007/s10600-014-0929-5

The reactions of (R)-n-menth-4-en-3-one and its derivatives with N-containing reagents were studied. New menthane-type acetamides were synthesized.

Full text of DOI:10.1007/s10600-014-0929-5

Chemistry of Natural Compounds, Vol. 50, No. 2, May, 2014 [Russian original No. 2, March–April, 2014]
(R)-n-MENTH-4-EN-3-ONE AND ITS DERIVATIVES IN
REACTIONS WITH N-CONTAINING REAGENTS
1,2*
2
1
G. Yu. Ishmuratov,
V. S. Tukhvatshin, M. P. Yakovleva,
1
2
2
R. R. Muslukhov, A. V. Allagulova, and G. R. Talipova
The reactions of (R)-n-menth-4-en-3-one and its derivatives with N-containing reagents were studied. New
menthane-type acetamides were synthesized.
Keywords: (R)-n-menth-4-en-3-one and its derivatives, nitrosation, Ritter reaction, menthane-type acetamides.
We determined earlier that (R)-n-menth-4-en-3-one (1) was less reactive than ordinary cyclic ꢀ,ꢁ-unsaturated ketones
in conjugated addition of organometallic reagents, Michael addition, and pyrazoline-formation reactions [1].
In continuation of studies on the elaboration of the synthetic potential of 1, we studied the behavior of its anti-oxime
(2) [2], epoxide (3) [3], (1R,3R)-n-menthen-3-ol (4) [4], and acetate (5) [5] in reactions with N-containing reagents. The
transformations studied herein also had practical application because it is known [6] that N-containing derivatives of
monoterpenoids exhibit various types of biological activity.
It was found that nitrosation of 2 by NaNO –AcOH in MeOH or CHCl did not give the expected unsaturated
2
3
nitroacetate (6) [6], like (–)-carvone oxime [7]. Regeneration of starting 1 was observed.
a or b
a or b
46 or 53%
OH
O N
2
OAc
N
O
6
2
1
a. NaNO , AcOH, CHCl , 20°C; b. NaNO , AcOH, MeOH, 20°C
2
3
2
The reaction of 3 with NH OH4HCl in the presence of NaOAc formed an aromatic acetamide (8) and not the proposed
2
1,2-dioxopyrazole derivative (7), like (S)-pulegone [8]. Evidently, this was due to the steric influence of the i-Pr group and the
lower reactivity of the endocyclic double bond in 1. Compound 8 was probably formed by the following scheme. Ketoalcohol
10 was dehydrated through sequential steps to enone 1, reaction of which with NH OH4HCl gave oxime 2 and then its O-acyl
2
derivative 9. The last underwent Semmler–Wolf conversion to amine 11 with further acylation to the desired acetamide 8 [2].
b
a
c
N
O
2
N
1
-AcOH
-H O
2
NOAc
O
O
HO
O
HO
7
3
10
9
+
+
H
+ H
- H
N
H
H
66%
N
NH
NHAc
2
H
11
a. NH OH4HCl, AcONa, H O, ꢂ; b. NH OH4HCl; c. AcONa
8
2
2
2
1) Institute of Organic Chemistry, Ufa Scientific Center, RussianAcademy of Sciences, 450054, Ufa, Prosp. Oktyabrya, 71,
e-mail: insect@anrb.ru; 2) Bashkir State University, 450074, Ufa, Ul. Z. Validi, 32, e-mail: vadimtukhvatshin@yandex.ru.
Translated from Khimiya Prirodnykh Soedinenii, No. 2, March–April, 2014, pp. 241–243. Original article submitted October
9, 2013.
©
272
0009-3130/14/5002-0272 2014 Springer Science+Business Media New York

a or b
or
+
OH
CH CO Et
NHAc
NHAc
2
2
12a
a. MeCN, H SO , 20ꢄC; b. MeCN, BF 4OEt , 80ꢄC
12b
4
5
2
4
3
2
The Ritter reaction involving terpene derivatives is a convenient and common synthetic method for potentially
biologically and pharmacologically active acetamides [9]. Therefore, the behavior of (1R,3R)-n-menthen-3-ol (4) and acetate
5 in this reaction was studied. Capillary GC and PMR showed that alcohol 4 formed mixtures of acetamides 12a and b in
ratios of 55:45 and 69:31 if H SO and BF 4Et O, respectively, were used as catalysts. However, 5 with H SO catalyst was
2
4
3
2
2
4
transformed into a 57:43 mixture of these same stereoisomers with 12b dominating. Apparently, this was due to simultaneous
occurrence of S 1 and S i substitution mechanisms.
N
N
a or b
OH
C
4
12a
Me
O
N
C
Me
O
C
Me
NH
NH
14
13
15a
a. MeCN, H SO , 20ꢄC; b. MeCN, BF 4OEt , 80°C
2
4
3
2
a
O
O
OH
C Me
5
12b
- EtOAc
Me
- EtOH
CH
C
CH
C
2
N
2
Me
CH
N
CH
N
16
17
a. MeCN, H SO , 20ꢄC
15b
2
4
Thus, a mixture of equal amounts of acetamides 12a and b formed according to the S 1 mechanism. The enrichment
N
of the mixture with the 12a stereomer for 4 or 12b, for acetate 5, was obviously due to occurrence of the S i mechanism [10,
N
11], according to which adduct 13 formed initially from alcohol 4 and then dissociated to form contact ion pair 14, which
decomposed through unstable 15a into the 12a isomer.
Acetamide 12b was formed analogously via an S i mechanism from acetate 5. The ethoxy group in 5 was replaced by
N
–N=CHMe in product 16, which converted to contact ion pair 17 and eliminated ethylacetate to form 15b.
Thus, a Ritter reaction involving (1R,3R)-n-menthen-3-ol (4) or its Claisen orthoester rearrangement product 5 under
H SO or BF 4Et O catalysis occurred simultaneously according to S 1 and S i mechanisms to form an enriched mixture of
2
4
3
2
N
N
acetamides 12a and b. The S i substitution mechanism dominated to produce diastereomeric acetamides (12a and b) if a
N
Lewis acid (BF 4Et O) was used as the catalyst rather than a protic acid (H SO ).
3
2
2
4
EXPERIMENTAL
IR spectra were recorded from thin layers on a Prestige-21 instrument (Shimadzu). NMR spectra were obtained in
CDCl with TMS internal standard on a Bruker Avance III 500 spectrometer (operating frequency 500.13 MHz for PMR and
3
13
13
125.20 MHz for C NMR). PMR and C NMR spectra were analyzed and resonances were assigned by two-dimensional
correlation spectroscopy COSY (H–H), HSQC, and HMBC. Chromatographic analysis was performed on Chrom-5 [column
length 1.2 m, stationary phase silicone SE-30 (5%) + OV-225 (3%) on Chromaton N-AW-DMCS (0.16–0.20 mm), operating
temperature 50–300°C] and GC-9A [Shimadzu, quartz capillary column length 25 m, stationary phase OV-101, operating
temperature 80–280°C] instruments with He carrier gas. Optical rotation was measured on a PerkinElmer 241-MC polarimeter.
Column chromatography was carried out over silica gel L (60–200 ꢃm, Sorbfil, Russia). TLC used Sorbfil plates (Russia).
Mass spectra were taken on a 2010 EV LC MS instrument (Shimadzu, syringe injection, sample solution in MeCN at flow rate
273

60 ꢃL/min) using electrospray ionization (ESI) with simultaneous recording of positive and negative ions at capillary potentials
of 4.5 and 3.5 kV, respectively. The capillary interface temperature was 230°C; nebulizer gas (dry N ) at flow rate 1.5 L/min.
2
Petroleum ether (PE, bp 40–70°C) was used for chromatography. Solvents were dried by standard methods. Elemental
analyses of newly synthesized compounds agreed with those calculated.
Transformation of (R)-4-Menthen-3-oneAntioxime (2) under Nitrosation Reaction Conditions. a)Asuspension
of oxime 2 (0.50 g, 3.0 mmol) and NaNO (0.71 g, 10.3 mmol) in anhydrous CHCl (10 mL) was treated dropwise with
2
3
stirring at room temperature with glacial HOAc (1.5 mL), stirred for 2 h, diluted with H O (10 mL), and extracted with EtOAc
2
(3 ꢅ 30 mL). The combined organic layer was washed successively with saturated solutions of Na CO (3 ꢅ 5 mL) and NaCl
2
3
(2 ꢅ 5 mL), dried over MgSO , and evaporated. The solid (0.33 g) was chromatographed (SiO , PE–EtOAc, 30:1) to afford 1
4
2
21
25
13
(0.21 g, 46%), [ꢀ] –66.9° (c 4.95, CHCl ) {lit. [12], [ꢀ] –67.5° (c 5.3, CHCl )}. The IR, PMR, and C NMR spectral data
D
3
D
3
were identical to those published earlier [12].
b) A suspension of oxime 2 (0.50 g, 3.0 mmol) and NaNO (0.71 g, 10.3 mmol) in anhydrous MeOH (12 mL) was
2
treated dropwise with stirring at room temperature with glacial HOAc (1.4 mL), stirred for 5 h, and evaporated in vacuo. The
solid was diluted with H O (10 mL) and extracted with EtOAc (3 ꢅ 30 mL). The combined organic layer was washed
2
successively with saturated solutions of Na CO (3 ꢅ 5 mL) and NaCl (2 ꢅ 5 mL), dried over MgSO , and evaporated. The
2
3
4
solid (0.38 g) was chromatographed (SiO , PE–EtOAc, 30:1) to afford 1 (0.24 g, 53%) that was identical to that obtained in a).
2
Transformation of 3 under Oximation Reaction Conditions. Epoxide 3 (1.50 g, 8.9 mmol) was dissolved in
MeOH (8 mL); treated sequentially with NH OH4HCl (7.50 g, 107.9 mmol), NaOAc (15.0 g, 182.9 mmol), and H O (23 mL);
2
2
refluxed for 2 h, cooled to room temperature, and extracted with EtOAc (3 ꢅ 90 mL). The combined organic layer was washed
with saturated NaCl solution (2 ꢅ 15 mL), dried over Na SO , and evaporated. The solid (1.50 g) was chromatographed
2
4
13
(SiO , PE–EtOAc, 20:1) to afford 8 (1.12 g, 66%), R 0.51 (PE–EtOAc, 2:1). The IR, PMR, and C NMR spectral data were
2
f
identical to those published earlier [2].
Transformations of 4 and 5 in a Ritter Reaction. Enol 4 (0.46 g, 3.0 mmol) or acetate 5 (0.67 g, 3.0 mmol) was
dissolved in MeCN (12 mL), cooled to 0°C, stirred, and treated with BF 4Et O (0.4 mL) or conc. H SO (0.8 g, 7.7 mmol).
3
2
2
4
The reaction mixture was held at 20°C (for H SO ) or 80°C (for BF 4Et O) for 12 h, poured into cold (0°C) H O (15 mL),
2
4
3
2
2
washed with NaOH solution (15%, 3 ꢅ 5 mL), and extracted with EtOAc (3 ꢅ 30 mL). The combined organic layer was
washed with saturated NaCl solution (2 ꢅ 5 mL), dried over Na SO , and evaporated. The solid was purified by column
2
4
chromatography (SiO , PE–EtOAc, 20:1) to afford diastereomeric acetamides 12a and b. For enol 4, yield 0.41 g (70%) of a
2
mixture (55:45) of 12a and b (H SO ); 0.27 g (46%) of a mixture (69:31) of 12a and b (BF 4Et O). For acetate 5, yield
2
4
3
2
–1
0.45 g (77%) of a mixture (43:57) of 12a and b (H SO ). R 0.27 (PE–EtOAc 2:1). IR spectrum (KBr, , cm ): 1539 (NÍAc),
1620 (Ñ=Ñ), 1651 (Ñ=O), 3350–3196 (NÍ). ESI mass spectrum ESI, m/z (I , %), MeCN – H O 95:5, (Scan ): 410.0
(2[Ì + H] + H O], 37.5), 196.0 ([Ì + H] , 100.0), 137.0 ([M – NHCOMe] , 12.5).
2
4
f
+
rel
2
+
+
+
2
N-[(1R,5R)-2-(1-Methylethyl)-5-methyl-2-cyclohexenyl]acetamide (12a) from a Mixture with 12b. PMR spectrum
(500.13 MHz, CD OD, ꢆ, ppm, J/Hz): 0.96 (3Í, d, J = 6.6, ÑÍ -5ꢇ), 0.98 (3Í, d, J = 6.9, Í-3ꢇꢇ), 1.04 (3Í, d, J = 6.9, Í-2ꢇꢇ),
3
3
2
3
1.31 (1Í, dd, J = 13.3, J = 4.7, Í -4ꢇ), 1.52–1.60 (1Í, m, Í-5ꢇ), 1.59 (1Í, d, J = 12.4, Í -6ꢇ), 1.79 (1Í, d, J = 13.3, Í -4ꢇ),
1.92 (3Í, s, NÍÑOCH ), 2.12 (1Í, dd, J = 12.4, J = 4.1, Í -6ꢇ), 2.19 (1Í, sept, J = 6.9, Í-1ꢇꢇ), 4.75 (1Í, m, Í -1ꢇ), 5.54 (1H,
d, J = 2.0, H-3ꢇ), 7.93 (1Í, br.s, NÍÑOCH ). C NMR spectrum (125.20 MHz, CDCl , ꢆ, ppm): 21.16 (q, Ñ-3ꢇꢇ), 21.71
a
a
e
2
3
3
e
à
13
3
3
(q, Ñ-2ꢇꢇ), 22.90 (q, ÑH -5ꢇ), 23.51 (d, Ñ-5ꢇ), 23.95 (s, NÍÑOCH ), 31.56 (d, Ñ-1ꢇꢇ), 33.86 (t, Ñ-4ꢇ), 38.00 (t, Ñ-6ꢇ), 45.62 (d,
3
3
Ñ-1ꢇ), 123.65 (d, Ñ-3ꢇ), 142.70 (s, Ñ-2ꢇ), 169.19 (s, C-1).
N-[(1S,5R)-2-(1-Methylethyl)-5-methyl-2-cyclohexenyl]acetamide (12b) from a Mixture with 12a. PMR spectrum
(500.13 MHz, CD OD, ꢆ, ppm, J/Hz): 0.96 (3Í, d, J = 6.6, ÑÍ -5ꢇ), 0.98 (3Í, d, J = 6.9, Í-3ꢇꢇ), 1.04 (3Í, d, J = 6.9, Í-2ꢇꢇ),
3
3
2
3
1.31 (1Í, dd, J = 13.3, J = 4.7, Í -4ꢇ), 1.52–1.60 (1Í, m, Í-5ꢇ), 1.59 (1Í, d, J = 12.4, Í -6ꢇ), 1.79 (1Í, d, J = 13.3, Í -4ꢇ),
1.92 (3Í, s, NÍÑOCH ), 2.12 (1Í, dd, J = 12.4, J = 4.1, Í -6ꢇ), 2.19 (1Í, sept, J = 6.9, Í-1ꢇꢇ), 4.52 (1Í, m, Í -1ꢇ), 5.61 (1H,
d, J = 4.5, H-3ꢇ), 8.07 (1Í, br.s, NÍÑOCH ). C NMR spectrum (125.20 MHz, CDCl , ꢆ, ppm): 21.16 (q, Ñ-3ꢇꢇ), 21.71
a
a
e
2
3
3
e
e
13
3
3
(q, Ñ-2ꢇꢇ), 22.90 (q, ÑH -5ꢇ), 23.51 (d, Ñ-5ꢇ), 23.95 (s, NÍÑOCH ), 31.56 (d, Ñ-1ꢇꢇ), 33.98 (t, Ñ-4ꢇ), 40.08 (t, Ñ-6ꢇ), 47.87 (d,
3
3
Ñ-1ꢇ), 121.85 (d, Ñ-3ꢇ), 143.42 (s, Ñ-2ꢇ), 169.58 (s, C-1).
274

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