Preparative synthesis of veratraldehydeoxime esters

Article abstract of DOI:10.1007/s10600-009-9198-0

Preparative syntheses of veratraldehydeoxime esters 6-24, available fragrances produced from vanillin (1), in 82-92% yield from veratraldehydeoxime (3) were developed.

Full text of DOI:10.1007/s10600-009-9198-0

Chemistry of Natural Compounds, Vol. 44, No. 6, 2008
PREPARATIVE SYNTHESIS OF VERATRALDEHYDEOXIME
ESTERS
N. A. Zhukovskaya,1 E. A. Dikusar,1*
and O. G. Vyglazov2
UDC 547.92+547.574.2+547.362+547.288.4
6 24
1
Preparative syntheses of veratraldehydeoxime esters - , available fragrances produced from vanillin ( ),
3
in 82-92% yield from veratraldehydeoxime ( ) were developed.
vanillin, veratraldehyde, oxime, carboxylic acids, anhydrides, acid chlorides, esters, aroma analysis.
Key words:
Veratraldehyde (3,4-dimethoxybenzaldehyde, ) occurs in small quantities in essential oil of
2
Cymbopogon javanensis
and has a persistent pleasant woody aroma with hints of vanilla and heliotrope. Veratraldehyde is used in several perfumes,
deodorants, and food additives and is employed as an intermediate in the synthesis of certain drugs [1].
The goal of our work was to develop a preparative synthesis of esters of veratraldehydeoxime - based on the
6 24
available industrial starting material vanillin ( ) [2, 3]. Veratraldehyde ( ) was prepared bymethylation of vanillin byMe SO
1
2
2
4
in the presence of KOH by the Schotten—Baumann reaction. We developed a more convenient and simple synthetic method
than that described in the literature [4]. It produced in high purityand 90% yield. Reaction of with hydroxylamine produced
2
2
veratraldehydeoxime ( ) in 92% yield by a method analogous to the published one [5].
3
CHO
CHO
CH NOH
CH NOC(O)R
(CH ) SO
[RC(O)] O
2
3 2
4
HONH ⋅ HCl
2
NaHCO
KOH
RC(O)Cl
3
OCH
OCH
OCH
OCH
3
3
3
3
OH
OCH
OCH
OCH
3
3
3
6 - 24
1
2
3
R = Me ( ), Et ( ), Pr ( ), MeCH ( ), Bu ( ), MeCHCH ( ), Me(CH ) ( ), Me(CH ) ( ), Me(CH ) ( ), Me(CH ) ( ), Me(CH )
6
7
8
9
10
11
12
13
14
15
2
2 4
2 5
2 6
2 7
2 8
(
), Me(CH ) ) ( ), cyclo-C H
17
(
), C H ( ), C H (CH ) ( ), C H MeCHCH ( ), trans-C H CH=CH ( ), MeO ( ), EtO (
)
16
18
19 20 21 22 23
24
2 11
6
11
6
5
6
5
2 2
6
5
2
6 5
Esters of veratraldehydeoxime - were prepared by reaction of with alkylcarboxylic acid anhydrides
6 24
-
4a d
in
3
anhydrous benzene in the presence of catalytic amounts of HClO or with alkyl- and arylcarboxylic acid chlorides - in the
5a o
4
presence of pyridine by our method for synthesizing analogous compounds [6]. The synthesis was carried out at 20-23°C for
24-36 h, consisted of simple mixing of the appropriate reagents, and occurred without special cooling or stirring. Esters of
veratraldehydeoxime - were obtained in 82-92% yieldandwerecolorless viscous oils or crystalline compounds (crystallizing
6 24
from a benzene:hexane mixture). The esters did not required additional purification; did not contain impurities of starting
compounds, benzene, and pyridine; and were suitable for direct use in the perfumery and food industries [7]. The purity of the
products according to PMR spectroscopywas 97-98%. Esters - were stable on storage at +5°C in the absence ofair and light.
6 24
Thestructuresof - wereconfirmedbyelemental analysis, cryoscopicmolecular-weight determination, PMRspectra,
6 24
and IR spectra. Analytical results and molecular-weight determinations of all synthesized compounds agreed with those
1) Institute of Physical Organic Chemistry, National Academy of Sciences of Belarus, 220072, Minsk, ul. Surganova,
13, e-mail: evgen_58@mail.ru; 2) OOO Tereza-Inter, Russia, 129110, Moscow, Olimpiiskii prosp., 22, e-mail:
ilb_chuiko@mail.ru. Translated from Khimiya Prirodnykh Soedinenii, No. 6, pp. 558-560, November-December, 2008.
Original article submitted February 12, 2008.
0009-3130/08/4406-0688 ©2008 Springer Science+Business Media, Inc.
688

calculated. The molecular weight could not be determined from the molecular ion in mass spectra because of the low thermal
stability of 6-24, which was consistent with previous results [8].
IR spectra of 6-24 contained absorption bands (CH ) at 3100-3000 cm−1; (CH ), 3000-2800; (C=O), 1770-1730;
Ar
Alk
(C=N), 1675-1665; (Ar), 1600-1360; (C–O), 1300-1000; and (CH ), 880-620.
Ar
PMR spectra of 6-24 showed resonances for methoxyl protons that appeared as two singlets at 3.90-4.10 ppm; for
aromatic protons as a multiplet at 6.70-7.50; and for the HC=N proton as a singlet at 8.20-8.30. The PMR spectra of 6-24
contained resonances characteristic of the ester groups [2, 3, 6].
The organoleptic properties of the synthesized veratraldehydeoxime (3) and its esters 6-24 were evaluated bythe Taste
Committee of the Accredited Monitoring Analytical Laboratory OOO Teresa-Inter (Moscow). The statistical average taste
aromas of the pure products are given below:
Product
Aroma
vanilla-berry, woody hint
vanilla-woody with berry-flower hint
vanilla-creamy
buttery with vanilla-woody hint
berry with sweet cranberry hint
berry with citrus and powdery hints
berry with sweet hint of viburnum
berry-buttery with cheese hint
milk with vanilla-berry hint
milk-vanilla with freshness hint
Product
Aroma
3
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
creamy-vanilla with dust hint
creamy-vanilla with spicy hint
vanilla-spice with woody hint
clove-woody
clove-creamy
clove-creamy with berry hint
clove-woody with grapefruit hint
clove-flowery with vanilla hint
clove-vanilla
vanilla-clove with creamy-berry hint.
The synthesized compounds had unique aromas with various hints and could be used to create berry, milk-creamy,
vanilla, and woody-spice fragrances. It was interesting that the fragrance depended on the ester structure. Increasing the
aliphatic radical in esters 6-17 changed the aroma from vanilla-woodyto milk-creamywith berryhints. Changing the aliphatic
acid moiety to a cyclic one in esters 18-21 produced a pronounced clove aroma with various hints.
EXPERIMENTAL
IR spectra of the synthesized compounds in a thin layer or KBr were recorded on a Protege-460 Nicolet IR-Fourier
spectrometer. PMR spectra in CDCl solutions (5%) were obtained on a BS-587A spectrometer (100 MHz, Tesla). Chemical
3
shifts were determined relative to TMS internal standard. Molecular weight (MW) was determined by cryoscopy in benzene.
The physicochemical properties ofthe synthesized veratraldehyde (2) and veratraldehydeoxime (3) agreed with those published
[1, 4, 5, 9].
Veratraldehyde (2). KOH (14 g, 90%) was dissolved in water (210 mL), cooled to 20-23°C, stirred vigorously, and
treated with vanillin (1, 0.2 mol). After the vanillin was completely dissolved, the solution was treated in one portion with
Me SO (22 mL), stirred for 6 h at 20-23°C, cooled to 5°C without stirring, and left for 10-12 h. The resulting crystalline
2
4
precipitate of veratraldehyde (2) was filtered on a porous glass filter, washed with a small amount of water, and dried in air.
Yield, 90%.
Veratraldehydeoxime (3). Veratraldehyde (2, 0.21 mol), hydroxylamine hydrochloride (0.27 mol), NaHCO
3
(0.28 mol), and ethanol (75 mL, 96%) were refluxed for 1 h, poured into a beaker with water (300 mL), cooled to 5°C, and left
for 10-12 h. The resulting crystalline precipitate of veratraldehydeoxime (3) was filtered on a porous glass filter, washed with
a small amount of water, and dried in air. Yield, 92%.
Esters of Veratraldehydeoxime 6-9. Veratraldehydeoxime (3, 0.01 mol) and the anhydride of the appropriate acid
(4a-d, 0.011 mol) were dissolved in anhydrous benzene (20 mL), treated with HClO (1 drop, 47%), shaken, left at 20-23°C
4
for 24-36 h, diluted with water, and extracted with benzene. The organic layer was separated, washed with water and NaHCO
3
689

solution (5%), and dried over CaCl . Solvent was removed at reduced pressure (p = 10-15 mm Hg) keeping the temperature
2
below 25-30°C.
The following compounds were prepared by this method:
N-Acetyloximino-3,4-dimethoxyphenylmethane (6). Yield 88%, mp 43-44°C, C H NO , found MW 218.6,
11 13
4
calcd 223.
N-Propionyloximino-3,4-dimethoxyphenylmethane (7). Yield 85%, mp 61-62°C, C H NO , found MW 226.0,
12 15
4
calcd 237.
N-Butyryloximino-3,4-dimethoxyphenylmethane (8). Yield 87%, mp 63-64°C, C H NO , found MW 240.8,
13 17
4
calcd 251.
N-iso-Butyryloximino-3,4-dimethoxyphenylmethane (9). Yield 86%, mp 50-51°C, C H NO , found MW 242.3,
13 17
4
calcd 251.
Esters of Veratraldehydeoxime 10-24. Veratraldehydeoxime (3, 0.01 mol) was dissolved in anhydrous benzene
(50 mL), treated with anhydrous pyridine (0.01 mol), cooled to 15°C, mixed by careful shaking, treated with the appropriate
acid chloride (5a-o, 0.01 mol), left at 20-23°C for 24-36 h, and treated with water. The product was extracted by benzene. The
organic layer was separated, washed with water and NaHCO solution (5%), and dried over CaCl . Solvent was removed at
3
2
reduced pressure (10-15 mm Hg) keeping the temperature below 25-30°C.
The following compounds were prepared by this method:
N-Valeroyloxyimino-3,4-dimethoxyphenylmethane (10). Yield 82%, mp 62-63°C, C H NO , found MW 253.7,
14 19
4
calcd 265.
20
20
N-iso-Valeroyloxyimino-3,4-dimethoxyphenylmethane (11). Yield 84%, d
1.0813, n
1.5480, C H NO ,
14 19 4
20
D
found MW 255.1, calcd 265.
N-Caproyloxyimino-3,4-dimethoxyphenylmethane (12). Yield 88%, mp 41-42°C, C H NO , found MW 266.2,
15 21
4
calcd 279.
N-Enanthyloxyimino-3,4-dimethoxyphenylmethane (13). Yield 86%, mp 44-45°C, C H NO , found MW 281.4,
16 23
4
calcd 293.
N-Caprylyloxyimino-3,4-dimethoxyphenylmethane (14). Yield 84%, mp 47-48°C, C H NO , found MW 290.5,
17 25
4
calcd 307.
N-Pelargonyloxyimino-3,4-dimethoxyphenylmethane (15). Yield85%, mp40-41°C, C H NO , foundMW309.6,
18 27
4
calcd 321.
N-Capryloxyimino-3,4-dimethoxyphenylmethane (16). Yield 85%, mp 42-43°C, C H NO , found MW 329.4,
19 29
4
calcd 335.
N-Tridecanoyloxyimino-3,4-dimethoxyphenylmethane (17). Yield 87%, mp 56-57°C, C H NO , found MW
22 35
4
360.8, calcd 377.
N-Cyclohexylmethanoyloxyimino-3,4-dimethoxyphenylmethane (18). Yield88%, mp50-51°C, C H NO , found
16 21
4
MW 283.4, calcd 291.
N-Benzoyloxyimino-3,4-dimethoxyphenylmethane (19). Yield86%, mp110-111°C, C H NO , foundMW280.0,
16 15
4
calcd 285.
N-(3-Phenylpropionyloxyimino)-3,4-dimethoxyphenylmethane (20). Yield 88%, mp 55-56°C, C H NO , found
18 19
4
MW 302.7, calcd 313.
20
20
N-(3-Phenylbutyryloxyimino)-3,4-dimethoxyphenylmethane (21). Yield 87%, d
1.1692, n
1.0484, n
1.5795,
20
D
C H NO , found MW 318.3, calcd 327.
19 21
4
20
20
N-trans-Cinnamoyloxyimino-3,4-dimethoxyphenylmethane (22). Yield 87%, d
1.6110,
20
D
C H NO , found MW 303.8, calcd 311.
18 17
4
N-3,4-Dimethoxyphenylmethaneiminomethylcarbonate (23). Yield 84%, mp 49-50°C, C H NO , found MW
11 13
5
230.9, calcd 239.
N-3,4-Dimethoxyphenylmethaneiminoethylcarbonate (24). Yield85%, mp54-55°C, C H NO , foundMW246.2,
12 15
5
calcd 253.
690

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