Peculiar Features of the Willgerodt–Kindler Reaction of 1-Adamantylpropan-2-one and Its Derivatives

Article abstract of DOI:10.1134/S1070363217120027

The Willgerodt–Kindler reaction of 1-(1-adamantyl)propan-2-one and its derivatives was studied by gas chromatography–mass spectrometry. The reaction time was found to be 3–4 times longer than in the case of alkyl aryl ketones due to considerable steric hindrances in the molecules of adamantyl ketones. The use of diglyme as solvent and sodium butyl xanthate as catalyst significantly shortened the reaction time and improved the yield to 92%.

Full text of DOI:10.1134/S1070363217120027

ISSN 1070-3632, Russian Journal of General Chemistry, 2017, Vol. 87, No. 12, pp. 2762–2765. © Pleiades Publishing, Ltd., 2017.
Original Russian Text © I.A. Novakov, B.S. Orlinson, E.N. Savel’ev, E.A. Potaenkova, O.V. Vostrikova, D.P. Tarakanov, M.A. Nakhod, 2017, published in
Zhurnal Obshchei Khimii, 2017, Vol. 87, No. 12, pp. 1942–1946.
Peculiar Features of the Willgerodt–Kindler Reaction
of 1-Adamantylpropan-2-one and Its Derivatives
I. A. Novakov, B. S. Orlinson, E. N. Savel’ev, E. A. Potaenkova*, O. V. Vostrikova,
D. P. Tarakanov, and M. A. Nakhod
Volgograd State Technical University, pr. Lenina 28, Volgograd, 400005 Russia
*e-mail: potaoynkova@vstu.ru
Received June 26, 2017
Abstract—The Willgerodt–Kindler reaction of 1-(1-adamantyl)propan-2-one and its derivatives was studied by
gas chromatography–mass spectrometry. The reaction time was found to be 3–4 times longer than in the case of
alkyl aryl ketones due to considerable steric hindrances in the molecules of adamantyl ketones. The use of
diglyme as solvent and sodium butyl xanthate as catalyst significantly shortened the reaction time and
improved the yield to 92%.
Keywords: Willgerodt–Kindler reaction, 1-adamantylpropan-2-one, 3-(1-adamantyl)propanoic acid, sodium
butyl xanthate
DOI: 10.1134/S1070363217120027
The Willgerodt–Kindler reaction is widely known
as the method of synthesis of thioamides from alkyl
aryl ketones [1–4], arylalkenes, and alkynes [5, 6].
Aliphatic ketones and aldehydes can also be involved
in this reaction [7]. The reaction of acetophenone with
morpholine and sulfur with formation of thiomor-
pholide has been studied most thoroughly [8, 9].
However, there are no published data on Willgerodt–
Kindler reactions with ketones containing an
adamantyl fragment. Therefore, we have studied the
possibility of using this reaction to obtain ada-
mantylcarboxylic acids as an alternative to the existing
methods that are multistage, experimentally complex,
and expensive. For example, a seven-stage procedure
for the synthesis of 3-(1-adamantyl)propanoic acid
from adamantan-1-ol has been described in [10].
Posterma et al. [11] proposed an analogous procedure
with the use of adamantane-1-carbaldehyde as starting
material. Nicolaou et al. [12] reported a two-stage
method for the synthesis of adamantanecarboxylic
acids via reaction of 1-bromoadamantane with methyl
acrylate in the presence of azobis(isobutyronitrile) and
tributyltin hydride, followed by hydrolysis. The main
drawback of this method is high cost of tributyltin
hydride. The procedures described in [13, 14] utilized
sodium cyanide in the penultimate stage, which also
restricts the application of these methods. Therefore,
development of methods for the synthesis of 3-(1-
adamantyl)propanoic acid by the Willgerodt–Kindler
reaction of adamantylacetone is an important problem.
The Willgerodt–Kindler reaction of 1-(1-ada-
mantyl)propan-2-ones 1a–1c with sulfur and mor-
pholine afforded the corresponding thiomorpholides
which were hydrolyzed to obtain target 3-(1-ada-
mantyl)propanoic acids 2a–2c in 92–95% yield. It
should be noted that in the reaction with compound 1c
after 16 h the reaction mixture contained a con-
siderable amount (25%) of 3-[3-(morpholin-4-yl)-3-
sulfanylidenepropyl]adamantan-1-ol. Therefore, the
latter was subjected to alkaline hydrolysis to complete
the transformation of the bromo derivative to the
corresponding hydroxy derivative (Scheme 1).
We examined the effects of temperature, reaction
time, and reactant ratio on the yield of 3-(1-adamantyl)-
propanoic acids with a view to obtaining target
compounds in acceptable yield and purity. The
maximum conversion was attained with 2.2 equiv of
morpholine and sulfur with respect to initial 1-(1-
adamantyl)propan-2-one. The reaction required
prolonged heating. After heating for 40 h at 160°C, the
concentration of thiomorpholide in the reaction
mixture was 62%, the conversion of 1 being 65%.
Increase of the reaction time to 45 h did not raise the
2762

PECULIAR FEATURES OF THE WILLGERODT–KINDLER REACTION
2763
Scheme 1.
O
+S8,
N
S
H
H2O, HCl
R1
R1
R1
COOH
N
O
O
R2
R2
1a_1c
R2
2a_2c
1a, 2a, R1 = R2 = H; 1b, 2b, R1 = R2 = Me; 1c, R1 = H, R2 = Br; 2c, R1 = H, R2 = OH.
conversion of ketone 1, but the concentration of both thio-
morpholide and intermediate compound 3 decreased;
as result, the number and amount of by-products
increased. This problem was solved by proper choice
of the catalyst. Using sodium xanthate as catalyst, we
succeeded in shortening the reaction time to a
considerable extent and minimizing formation of by-
products.
does not affect the reactivity of adamantyl alkyl
ketones to an appreciable extent. Presumably, the
reaction is low sensitive to electronic properties of sub-
stituents in the adamantyl fragment. A more important
factor is likely to be the position of the carbonyl
oxygen atom with respect to the adamantyl fragment.
Sterically hindered 1-(1-adamantyl)propan-1-one showed
very low reactivity: after 20 h, only 11% of thio-
morpholide was formed. It is steric factor that is
responsible for the low reactivity of 1-(1-adamantyl)-
propan-1-one in this reaction.
O
N
O
The mechanism of the Willgerodt–Kindler reaction
was the subject of numerous studies; however, there is
still no consensus on this topic. On the basis of
S
3
We also found that the conversion of 1-(1-ada-
mantyl)propan-2-one can be increased to ~68% by
carrying out the reaction in the absence of a solvent
(16 h). Further increase of the reaction time (to 25 h)
did not improve the conversion to an appreciable
extent because of considerable thickening of the
reaction mixture. Therefore, to improve the conversion
of the initial adamantyl ketones, all reactions were
subsequently carried out in diglyme at 160°C using
butyl xanthate as catalyst.
Composition of the reaction mixturesa according to the GC/
MS data
Concentration, wt %
Conversion of
1-(1-adamantyl)-
propan-2-one, %
thiomorpholide enamine
3
2
4
20.0
40.0
58.0
70.0
75.0
85.0
92.0
98.0
99.0
99.5
18.0
32.0
42.0
55.0
58.0
71.0
88.0
91.0
94.0
98.0
0.5
0.8
1.5
1.5
2.0
2.0
0.9
0.8
0.5
0.2
6.0
10.0
12.0
13.5
15.0
8.8
The effect of the reaction time on the yield of the
corresponding thiomorpholide was studied by GC/MS
(see table). It should be noted that the Willgerodt–
Kindler reaction with 1-adamantylpropan-2-ones takes,
on the average, 3–4 times more time than analogous
reactions with alkyl aryl ketones. After 8 h, the
concentration of thiomorpholide was 55%. The other
substituted adamantylpropan-2-ones behaved similarly.
Most probably, this is related to reduced reactivity of
1-(1-adamantyl)propan-2-one in the Willgerodt–
Kindler reaction, which strongly depends on spatial
accessibility of the carbonyl group. The presence of a
substituent in position 3 of the adamantyl fragment
6
8
10
16
24
32
40
45
6.3
5.3
4.2
0.2
a
The reaction was carried out in the presence of 0.5 wt % of
sodium butyl xanthate in diglyme.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 87 No. 12 2017

2764
NOVAKOV et al.
experimental data, mechanisms involving enamines,
thioketones, thiols, and unsaturated hydrocarbons as
intermediates were proposed [1, 15–21]. In order to
elucidate the transformation path we used GC/MS
data. The chromatograms of the reaction mixture
contained four major peaks corresponding to initial
1-adamantylpropan-2-one, two intermediate compounds,
and final thiomorpholide. The intermediate compounds
were identified as enamine (retention time 8.9 min)
whose concentration ranged from 2 to 0.9% and
(assumingly) compound 3 (m/z 307).
mixture was stirred for 0.5 h, 44 mL (40 g, 0.42 mol)
of isopropenyl acetate was added over a period of 2 h,
and the mixture was stirred for 0.5 h, poured onto
200 g of ice, and made weakly alkaline reaction by
adding sodium carbonate (106 g, 1 mol) and sodium
metabisulfite (38 g, 0.2 mol). The organic layer was
separated, and the aqueous layer was extracted with
methylene chloride (3×50 mL). The extracts were
combined with the organic phase, the solvent was
distilled off, and the residue was distilled under
reduced pressure. Yield 31.9 g (83%), bp 110–112°C
(4 mm). 1H NMR spectrum (DMSO-d6), δ, ppm: 1.50–
1.80 m (12H, CH2), 1.94 s (3H, CH), 2.10 s (3H, CH3),
2.16 s (2H, CH2CO).
In order to confirm the above assumption, the
Willgerodt–Kindler reaction of 1-(1-adamantyl)propan-
2-one was carried out at a temperature not exceeding
130°C. After hydrolysis, the reaction mixture con-
tained 20% of 1-adamantylacetic acid, which suggests
intermediate formation of compound 3 with a high
degree of probability. The concentration of enamine in
the reaction mixture did not exceed 2%, while the
concentration of 3 reached its maximum value (13.5%)
after 8 h and then dropped down to 0.2% (after 45 h).
These findings conform to the classical Willgerodt–
Kindler reaction scheme proposed in [15]. The reaction
begins with the formation of enamine which rapidly
takes up sulfur. Another version implies migration of
the oxygen atom to the methyl group and subsequent
addition of morpholine and sulfur to form intermediate 3.
1-(3,5-Dimethyladamantan-1-yl)propan-2-one (1b)
was synthesized in a similar way from 48.6 g (0.2 mol)
of 1-bromo-3,5-dimethyladamantane. Yield 37.1 g
1
(91%), bp 125–127°C (4 mm). H NMR spectrum
(DMSO-d6), δ, ppm: 0.83 s (6H, CH3), 1.51–1.82 m
(12H, CH2), 1.94 s (3H, CH), 2.11 s (3H, CH3), 2.15 s
(2H, CH2CO).
1-(3-Bromoadamantan-1-yl)propan-2-one (1c)
was synthesized in a similar way from 58.8 g (0.2 mol)
of 1,3-dibromoadamantane. Yield 41.1 g (76%), bp
155–156°C (4 mm), nD20 = 1.5360. H NMR spectrum
1
(DMSO-d6), δ, ppm: 1.48–2.08 m (14H, CH2, CH),
2.31 s [2H, CH2C(O)CH3], 2.26 s [3H, CH2C(O)CH3].
In summary, we have studied the Willgerodt–
Kindler reaction of 1-adamantylpropan-2-one and its
derivatives and shown the possibility of using this
reaction to obtain 3-(1-adamantyl)propanoic acids.
3-(1-Adamantyl)propanoic acid (2a). A mixture
of 19.2 g (0.1 mol) of 1-(1-adamantyl)propan-2-one,
6.4 g (0.2 mol) of sulfur, 17.4 g (0.2 mol) of mor-
pholine, 50 mL of diglyme, and 0.5 g (0.0029 mol) of
sodium butyl xanthate was stirred for 45 h at 160°C.
The solvent was distilled off, the residue was cooled
and poured into 200 mL of water, and the precipitate
was filtered off. The resulting thiomorpholide was
hydrolyzed by heating for 20 h in concentrated
aqueous HCl. The mixture was cooled, 30 g of sodium
hydroxide was added, the mixture was extracted with
benzene to remove impurities, and aqueous HCl was
then added to pH 1–3. The product was extracted with
diethyl ether, the solvent was removed from the
extract, and the residue was distilled under reduced
pressure. Yield 19.8 g (95%), bp 175–178°C (4 mm),
mp 151°C. IR spectrum, ν, cm–1: 904, 988, 1029, 1107,
1148, 1187, 1216, 1244, 1304, 1336, 1713 (COOH),
EXPERIMENTAL
The mass spectra were recorded on a Varian Saturn-
2100 GC/MS instrument. The IR spectra were
measured on a Thermo Electron Nicolet-6700 spec-
1
trometer with Fourier transform. The H NMR spectra
were recorded on a Varian Mercury Plus BB spec-
trometer (300 MHz) relative to hexamethyldisiloxane
as internal standard.
Morpholine and diglyme were dried over potassium
hydroxide and then distilled. 1-Adamantylpropan-2-
ones 1a–1c were synthesized according to the proce-
dure developed by us previously [22].
1
2850 (CH), 2914, 3434 (OH). H NMR spectrum
1-(1-Adamantyl)propan-2-one (1a). A solution of
43 g (0.2 mol) of 1-bromoadamantane in 260 mL of
methylene chloride was cooled to –10°C, and 61.9 g
(0.23 mol) of aluminum bromide was added. The
(DMSO-d6), δ, ppm: 1.22–1.45 m (14H, CH2,
CH2CH2COOH), 2.16–2.22 t (4H, CH, CH2CH2COOH,
J = 8.3 Hz), 11.90 br.s (1H, COOH). Mass spectrum
(EI, 70 eV), m/z (Irel, %): 208 (2) [M]+, 206 (2), 190
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 87 No. 12 2017

PECULIAR FEATURES OF THE WILLGERODT–KINDLER REACTION
2765
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(3), 189 (2), 135 (10), 134 (100), 106 (12), 105 (4), 93
(12), 91 (9), 79 (12), 45 (4), 41 (3).
3-(3,5-Dimethyladamantan-1-yl)propanoic acid (2b)
was synthesized in a similar way from 20.8 g
(0.1 mol) of 1-(3,5-dimethyladamantan-1-yl)propan-2-
one. Yield 22.0 g (93%), mp 84–87°C. IR spectrum, ν,
cm–1: 902, 980, 1034, 1107, 1148, 1187, 1216, 1244,
1304, 1336, 1718 (COOH), 2850 (CH), 2915, 3438
1
(OH). H NMR spectrum (DMSO-d6), δ, ppm: 0.85 s
(6H, CH3), 1.23–1.51 m (14H, CH2, CH2CH2COOH),
2.02–2.10 m (4H, CH, CH2CH2COOH), 11.95 br.s
(1H, COOH). Mass spectrum (EI, 70 eV), m/z (Irel, %):
237 (47) [M]+, 236 (100), 163 (49), 162 (18), 149 (26),
133 (10), 122 (6), 121 (24), 107 (21), 105 (8), 95 (15),
93 (14), 91 (11), 45 (10), 41 (9).
3-(3-Hydroxyadamantan-1-yl)propanoic acid (2c)
was synthesized in a similar way from 20.8 g (0.1 mol)
of 1-(3-hydroxyadamantan-1-yl)propan-2-one. The
hydrolysis of thiomorpholide was carried out in the
presence of sulfuric acid. Yield 20.6 g (92%), mp 175–
178°C. IR spectrum, ν, cm–1: 902, 980, 1034, 1107,
1148, 1187, 1216, 1244, 1304, 1336, 1713 (COOH),
2849 (CH), 2915, 3435 (OH). 1H NMR spectrum (DMSO-
d6), δ, ppm: 1.22–1.45 m (14H, CH2, CH2CH2COOH),
2.01–2.10 m (4H, CH, CH2CH2COOH), 4.36 s (1H,
OH), 11.90 br.s (1H, COOH). Mass spectrum (EI,
70 eV), m/z (Irel, %): 224 (23) [M]+, 208 (14), 207
(100), 206 (18), 151 (49), 150 (18), 149 (70), 133 (10),
122 (6), 121 (24), 107 (21), 105 (8), 95 (15), 93 (14),
91 (11), 45 (10), 41 (9).
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ACKNOWLEDGMENTS
This study was performed under financial support
by the Russian Science Foundation (project no. 16-13-
00100) using the equipment of the Shared Use Center
of the Volgograd State Technical University.
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