Adamantylation of hydantoin

Full text of DOI:10.1134/S1070428016060257

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2016, Vol. 52, No. 6, pp. 906–908. © Pleiades Publishing, Ltd., 2016.
Original Russian Text © D.V. Osipov, M.R. Demidov, V.A. Osyanin, M.Yu. Skomorokhov, Yu.N. Klimochkin, 2016, published in Zhurnal Organicheskoi
Khimii, 2016, Vol. 52, No. 6, pp. 911–913.
SHORT
COMMUNICATIONS
Adamantylation of Hydantoin
D. V. Osipov, M. R. Demidov, V. A. Osyanin,* M. Yu. Skomorokhov, and Yu. N. Klimochkin
Samara State Technical University, ul. Molodogvardeiskaya 244, Samara, 443100 Russia
*e-mail: vosyanin@mail.ru
Received April 19, 2016
DOI: 10.1134/S1070428016060257
Cage compounds, in particular adamantane deriva-
tives, exhibit a broad spectrum of biological activity
[1–9]. Many adamantane derivatives are used as
medicines with various therapeutic effects. Saxagliptin
has recently been marketed under the trade name
Onglyza as highly selective and efficient dipeptidyl
peptidase-4 (DDP-4) inhibitor [10] for the treatment of
type II diabetes. The key intermediate products in the
synthesis of saxagliptin are (S)-(+)-(adamantan-1-yl)-
glycin and its derivatives. Most known procedures for
their preparation require the use of expensive and/or
highly toxic reagents (such as oxalyl chloride, thionyl
chloride, rhodium and palladium compounds, etc.) and
are multistep and experimentally difficult [11–15].
lactam) failed to react. The reaction of adamantan-1-ol
with hydantoin on heating in 90% H2SO4 gave 39% of
2, the main by-product being adamantane resulting
from intermolecular hydride transfer [25–27].
The formation of just 3-(adamantan-1-yl)imidazoli-
dine-2,4-dione (2) rather than isomeric 1-(adamantan-
1-yl)imidazolidine-2,4-dione follows from the absence
of a cross peak corresponding to coupling of C1 of the
adamantane fragment with methylene protons of hy-
1
dantoin in the two-dimensional heteronuclear H–13C
HMBC spectrum. The alkylation of hydantoin at the
less basic nitrogen atom (N3) may be rationalized
assuming electrophilic addition of adamantyl cation to
more stable lactim tautomer of hydantoin (A)
(Scheme 2). This reaction is likely to be the first
example of N-alkylation of hydantoin in acid medium.
Herein, we propose a convenient method for the
synthesis of racemic 2-(adamantan-1-yl)-2-aminoace-
tic acid (1) from accessible adamantane or adamantan-
1-ol and hydantoin. In continuation of our studies on
adamantylation of nitrogen-containing substrates
[16–23], we tried to introduce an adamantyl substituent
into hydantoin molecule. Hydantoin derivatives are
precursors to α-amino acids, and they also possess
various biological activities [24].
In order to suppress hydride transfer processes,
more concentrated sulfuric acid was used. Under these
conditions, 3-(adamantan-1-yl)imidazolidine-2,4-dione
(2) underwent partial rearrangement into thermody-
namically more stable 5-(adamantan-1-yl)imidazoli-
dine-2,4-dione (3). Presumably, the reaction involves
protonated form of hydantoin, which follows from
a longer time required for the formation of 3 and com-
plete isomerization of 2 in 98% sulfuric acid. Thus,
compound 3 can be obtained from both hydantoin and
directly from adamantan-1-ol and hydantoin without
Hydantoin was subjected to adamantylation in two
ways. The first of these involved oxidation of ada-
mantane with fuming nitric acid, followed by addition
of hydantoin (Scheme 1). In this way, 3-(adamantan-1-
yl)imidazolidine-2,4-dione (2) was obtained in 71%
yield [23]. The reaction required a large amount of
hydantoin (5 equiv) because its considerable part
underwent nitrosation and thorough control of the
reaction conditions due to gas evolution in the course
of decomposition of hydantoin in nitric acid.
Scheme 1.
(1) HNO3
HN
(2)
, 70°C
O
O
O
N
H
N
NH
N-Adamantylation of acetamide, oxamide, and car-
bamates was accomplished under analogous conditions
[17, 18]; however, cyclic amides (such as ɛ-capro-
O
2
906

ADAMANTYLATION OF HYDANTOIN
907
Scheme 2.
HN
O
HO
O
, ∆
N
A
N
NH
O
2
H2SO4
HN
OH
O
O
N
O
H
NaOH, H2O
150°C
COOH
NH2
98% H2SO4
NH
HN
O
3
1
isolation of 2. Compound 3 can be used to obtain inter-
H 7.76; N 11.92. C13H18N2O2. Calculated, %: C 66.64;
H 7.74; N 11.96.
mediate products for the synthesis of saxagliptin [28].
1
b. Hydantoin, 6.58 g (65.8 mmol), was added to
52 mL of 90% sulfuric acid, the mixture was heated to
70°C, and 10 g (65.8 mmol) of adamantan-1-ol was
added under stirring. The product was isolated as
described above in a. Yield 6 g (39%).
In the H NMR spectrum of 2, methylene protons
on C5 of the imidazole ring resonated at δ 3.96 ppm.
1
In the H NMR spectrum of 3, the 5-H signal was
observed in a stronger field (δ 3.49 ppm) due to
shielding by the adamantane fragment. The C5 signal
of 2 was located at δC 48.7 ppm in the 13C NMR spec-
trum, and the corresponding signal of 3 appeared at
δC 66.7 ppm (in DMSO-d6).
5-(Adamantan-1-yl)imidazolidine-2,4-dione (3).
Hydantoin, 22.2 g (0.222 mol), was added under
stirring to 250 mL of 98% sulfuric acid. The mixture
was heated to 70°C until it became homogeneous, and
33.74 g (0.222 mol) of adamantan-1-ol was added in
portions under stirring at that temperature. The mixture
was stirred for 3 h at 70°C, and the brown homo-
geneous solution was cooled to room temperature and
poured with stirring onto 1 kg of ice. The precipitate
was filtered off, washed with water until neutral
washings, and dried in air. Yield 37.4 g (72%).
An analytical sample was obtained by recrystallization
from DMF. Colorless crystals, mp >250°C (sublimes).
IR spectrum, ν, cm–1: 3356, 3163, 3055, 2905, 2851,
Hydrolysis of 3 with 6% aqueous sodium hydroxide
at 150°C under pressure afforded 75% of α-adamantyl-
glycine 1 (Scheme 2).
Thus, we have developed an efficient procedure for
the synthesis of adamantylglycine via adamantylation
of hydantoin.
3-(Adamantan-1-yl)imidazolidine-2,4-dione (2).
a. A 100-mL three-necked flask equipped with
a mechanical stirrer and thermometer was charged
with 15 mL of fuming nitric acid, and 5 g (36.8 mmol)
of adamantane was added in portions at a temperature
not exceeding 30°C. After dissolution of adamantane,
12 g (0.12 mol) of hydantoin was added to the mixture
on cooling with ice. The mixture was heated for 1 h at
70–80°C, cooled, and poured onto 100 g of ice, and the
precipitate was filtered off, washed, and dried. Yield
6.5 g (71%), colorless crystals, mp >250°C (from
DMF‒i-PrOH). IR spectrum, ν cm–1: 3167, 3048,
2909, 2851, 2766, 1771, 1690, 1443, 1227, 1130, 760,
1
1763, 1701, 1420, 1288, 1196, 733, 640. H NMR
spectrum (DMSO-d6), δ, ppm: 1.40‒1.68 m (12H),
1.90 s (3H), 3.49 s (1H), 7.85 s (1H), 10.49 s (1H).
13C NMR spectrum (DMSO-d6), δC, ppm: 27.9, 36.3,
36.8, 37.6, 66.7, 158.2, 174.8. Mass spectrum, m/z
(Irel, %): 234 (1) [M]+, 135 (100) [Ad]+, 107 (10), 93
(22), 79 (34). Found, %: C 66.72; H 7.75; N 11.91.
C13H18N2O2. Calculated, %: C 66.64; H 7.74; N 11.96.
2-(Adamantan-1-yl)-2-aminoacetic acid (1).
A 1-L high-pressure reactor was charged with 40 g
(0.171 mol) of compound 3 and 700 mL of 6% aque-
ous sodium hydroxide. The mixture was stirred for 6 h
at 150°C, the resulting solution was neutralized, and
the precipitate was filtered off, washed with water, and
dried. Yield 26.8 g (75%), colorless crystals,
1
741. H NMR spectrum (DMSO-d6), δ, ppm: 1.58 br.s
(6H), 1.99 br.s (9H), 3.96 s (2H), 10.54 s (1H).
13C NMR spectrum (DMSO-d6), δC, ppm: 29.4, 36.2,
39.8, 48.7, 54.2, 156.3, 172.3. Mass spectrum, m/z
(Irel, %): 234 (12) [M]+, 177 (34), 107 (10), 106 (30),
91 (32), 79 (49), 77 (40), 55 (36). Found, %: C 66.70;
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 52 No. 6 2016

OSIPOV et al.
908
1
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mp >250°C. H NMR spectrum (CD3OD containing
a drop of DCl/D2O), δ, ppm: 1.61‒1.82 m (12H),
2.02 br.s (3H), 3.52 s (1H). 13C NMR spectrum
(CD3OD containing a drop of DCl/D2O), δC, ppm:
28.2, 34.4, 36.0, 37.9, 62.2, 169.1. Found, %: C 68.90;
H 9.17; N 6.68. C12H19NO2. Calculated, %: C 68.87;
H 9.15; N 6.69.
The IR spectra were recorded in KBr on
a Shimadzu IR Affinity-1 spectrometer. The 1H and 13C
NMR spectra, including DEPT spectra, were measured
on a JEOL JNM-ECX400 spectrometer at 400 and
100 MHz, respectively, using TMS as internal stan-
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Vector EA-3000 automated CHNS analyzer. The melt-
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OptiMelt MPA100 melting point apparatus.
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