Reaction of 1-Allyl(methallyl)theobromine with Halogens

Article abstract of DOI:10.1134/S1070363219040091

The reactions of bromine and iodine with 1-allyltheobromine and 1-methallyltheobromine were studied. Depending on the nature of the halogen and the initial theobromine, the reaction can lead to the formation of the adducts at the double bond, oxazolopurines or complex compounds.

Full text of DOI:10.1134/S1070363219040091

ISSN 1070-3632, Russian Journal of General Chemistry, 2019, Vol. 89, No. 4, pp. 697–700. © Pleiades Publishing, Ltd., 2019.
Russian Text © The Authors(s), 2019, published in Zhurnal Obshchei Khimii, 2019, Vol. 89, No. 4, pp. 561–565.
Reaction of 1-Allyl(methallyl)theobromine with Halogens
K. Yu. Petrovaa*, D. G. Kima, O. S. Eltsovb, and T. D. Eremenkoa
a National Research University (NPU), pr. Lenina 76, Chelyabinsk, 454080 Russia
*e-mail: osheko_kseniya@mail.ru
b Ural Federal University, Yekaterinburg, Russia
Received September 6, 2018; revised September 16, 2018; accepted September 17, 2018
Abstract—The reactions of bromine and iodine with 1-allyltheobromine and 1-methallyltheobromine were
studied. Depending on the nature of the halogen and the initial theobromine, the reaction can lead to the
formation of the adducts at the double bond, oxazolopurines or complex compounds.
Keywords: theobromine, 1-methallyltheobromine, oxazolopurine, allyltheobromine
DOI: 10.1134/S1070363219040091
Theobromine derivatives are known to possess
antihypoxic activity [1]. At the same time, there are no
data on oxazolopurinium species, which may have
high biological activity.
The reactions of allyltheobromines 1a and 1b with
bromine can proceed in different ways: the
halogenation followed by cyclization into [1,3]oxazolo
[2,3-i]purinium systems or by the addition of bromine
to the double bond. It was found that the reaction of
theobromine 1a with bromine in chloroform leads to
the formation of 1-(2,3-dibromopropyl)theobromine 2
Aiming to obtain new fused oxazolopurinium
derivatives, we studied the reactions of 1-allyltheo-
bromine 1a and 1-methallyltheobromine 1b with
bromine and iodine.
1
(Scheme 3). The H NMR spectrum of compound 2
contains two multiplets of CH2Br group in the 3.95–
4.05 ppm region; the signals of NCH2 group are
recorded at 4.25 and 4.43 ppm. The proton of CHBr
moiety appears at 4.68 ppm, which closely matches the
signals of similar protons in N-(2,3-dibromopropyl)isatin
[7].
Previously, synthesis of compound 1a has been per-
formed by alkylation of theobromine with allyl bromide
in DMF or isopropyl alcohol in the presence of a base
(i-BuONa, NaOH or K2CO3) [2–6]. We obtained
theobromine 1a in the presence of K2CO3 in DMF. The
1H NMR data and melting point of compound 1a
coincide closely with those reported earlier [2].
The reaction of methallyltheobromine 1b with
bromine in acetic acid and dichloromethane afforded a
mixture of two isomers, namely 6-(bromomethyl)-
1,4,6-trimethyl-9-oxo-3a,4,6,7,9,9a-hexahydro-1H-oxa-
zolo[3,2-a]purinium 3 and 8-(bromomethyl)-1,4,8-
trimethyl-5-oxo-3a,4,5,7,8,9b-hexahydro-1H-oxazolo-
[2,3-i]purinium 4 bromides in the ratio of 1 : 0.63 in
acetic acid and 1 : 0.95 in dichloromethane (Scheme 4).
The mass spectrum of allyltheobromine 1a contains
the molecular ion [M]+• peak with an intensity of 82%,
and a peak with m/z 205 caused by the detachment of
the methyl radical, which has a maximum intensity
(Scheme 1). In our opinion, a high signal intensity
indicates the formation of stable tricyclic systems A or
B. For allyltheobromine 1a fragmentation, elimination
of allyl isocyanate and further liberation of CO are
characteristic (peaks with m/z 137 and 109,
respectively).
1
The H NMR spectra of bromides 3 and 4 are very
close, and the H8 proton signal is shifted to a weak
field with respect to the initial compound 1b (7.88 →
8.45–8.80 ppm), which is due to the appearance of a
positive charge in the system. In the case of a linear
structure 3, the proton signal of the imidazole ring is in
a weaker field than the signal of the same proton in the
case of 4.
Methallyltheobromine 1b was obtained for the first
time by alkylation of theobromine with methallyl
chloride in DMF in the presence of anhydrous
potassium carbonate (Scheme 2).
697

698
PETROVA et al.
Scheme 1.
+
O
O
O
O
N
N
N
N
N
N
N
N
N
N
−AllNCO
−CH3
N
O
N
N
O
N
O
N
1a
A
m/z 137
m/z 220
m/z 205
−CO
O
O
N
N
N
N
N
N
O
N
−CH3
N
N
O
N
N
m/z 109
B
m/z 205
Scheme 2.
O
O
O
Cl
N
N
N
N
Br
N
HN
N
N
N
O
N
O
N
O
N
1b
1a
1
After the separation of bromides 3 and 4, in the
solution of acetic acid the product of the bromine
addition at the double bond, 1-(2,3-dibromo-2-methyl-
propyl)theobromine 5, was found (Scheme 4). As in
dark powdery substance. The H NMR spectrum of
complex 6 contains the signals of allyl group.
Methallyltheobromine 1b reacts with iodine dif-
ferently: as a result of the reaction, 6-(iodomethyl)-
1,4,6-trimethyl-9-oxo-3a,4,6,7,9,9a-hexahydro-1H-oxa-
zolo[3,2-a]purinium triiodide powder was isolated.
When reacting with sodium iodide in acetone, it was
converted to 6-(iodomethyl)-1,4,6-trimethyl-9-oxo-
3a,4,6,7,9,9a-hexahydro-1H-oxazolo[3,2-a]purinium
1
the case of adduct 2, in the H NMR spectrum of
compound 5, the H8 proton appears as a singlet in the
same region as in the case of the starting 1b.
During the reaction of theobromine 1a with iodine,
a complex of iodine with 1-allyltheobromine 6 was
formed (Scheme 5), which was isolated as a stable
1
iodide 7 (Scheme 7). In the H NMR spectrum, the
Scheme 3.
Br
N
Br
Br
O
N
O
Br2
Br
N
N
N
N
1a
N
O
O
N
2
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699
REACTION OF 1-ALLYL(METHALLYL)THEOBROMINE WITH HALOGENS
Scheme 4.
Br
Br−
Br
Br
Br−
O
O
O
N
+
Br2
N
N
+
N
N
N
N
N
N
1b
N
+
+
O
N
O
O
N
Br
3
4
5
Scheme 5.
Scheme 6.
O
O
+
N
N
N
N
I2
I2
N
I−
R
1b
* I2
1a
O
N
I
N
O
N
6
7
proton of imidazole ring appears at 8.75 ppm, which
indicates the formation of a linear oxazolopurinium
system.
1-Methallylteobromine (1b). To a solution of
360 mg (2 mmol) of theobromine in 10 mL of DMF
was added 276 mg (2 mmol) of anhydrous potassium
carbonate, and the mixture was heated on a water bath
for 30 min. A solution of 0.19 mL (2 mmol) of
methallyl chloride in 1 mL of DMF was added to the
mixture. The resulting mixture was heated on a water
bath for 5 h. The precipitate was filtered off, the filtrate
was evaporated, the obtained residue was washed with
water and dried. Yield 384 mg (82%), gray powder,
In conclusion, bromine reacts with 1-allyltheo-
bromine to form the adduct at the double bond. In the
case of 1-methallyltheobromine, a mixture of oxazolo-
purines and 1-(2,3-dibromo-2-methylpropyl)theo-
bromine was obtained. The reaction of 1-allyltheo-
bromine with iodine leads to the formation of a
complex, and methallyltheobromine reacts with iodine
to furnish linear oxazolopurine.
1
mp 68–72°C. Н NMR spectrum, δ, ppm: 1.76 s (3Н,
CH3), 3.39 s (3H, N3CH3), 3.94 s (3H, N7CH3), 4.39 s
(2Н, NСН2), 4.59 s (1H, СH2), 4.75 s (1Н, СH2), 7.88
s (1Н, Н8). Found, %: С 56.42; H 5.99;N 23.90.
C11H14N4O2. Calculated, %: С 56.40; H 6.02; N 23.92.
M 234.25.
EXPERIMENTAL
1H NMR spectra (400 MHz) were registered on a
Bruker AVANCE II instrument from DMSO-d6
solutions relative to internal TMS. Mass spectrum was
registered on a GCMS-QP2010 Ultra, Shimadzu gas
chromatography mass spectrometer (EI, 70 eV).
1-(2,3-Dibromopropyl)theobromine (2). To a
solution of 0.052 mL (1 mmol) of bromine in 5 mL of
chloroform was added 0.110 g (0.5 mmol) of 1-allyl-
theobromine. After 48 h the solvent was evaporated.
1-Allyltheobromine (1a) was synthesized according
to the procedure described in [5]. Yield 80%, white
powder, mp 147–148°С (mp 142–143°С [2], 143°С
[6]). Mass spectrum, m/z (Irel, %): 220 (82.5) [M]+, 219
(20.0) [M – H]+, 205 (100) [M – СH3]+, 203 (20.0)
[M – OH]+, 191 (7.5), 175 (5.0), 165 (5.0), 150 (7.4),
138 (15.0), 137 (6.4) [M – СH2=CHCH2NCO]•+, 136
(12.5) [M – СH2=CHCH2NCO – H]+, 109 (37.5) [M –
СH2=CHCH2NCO – CO]+, 82 (24.5), 70 (13.5), 67
(37.0), 56 (9.9), 55 (24.4), 42 (22.5), 40 (25).
1
Yield 0.137 g (72%), oil. Н NMR spectrum, δ, ppm:
3.41 s (3Н, N3CH3), 3.89 s (3H, N7CH3), 3.95 m and
4.02 m (2Н, CH2Br), 4.44 m and 4.27 m (2Н, NCH2),
4.69 m (1Н, CHBr), 8.07 s (1Н, Н8). Found, %: С
31.57; H 3.17; N 14.77. C10H12Br2N4O2. Calculated,
%: С 31.60; H 3.18; N 14.74. M 380.04.
Reaction of 1-methallylthebromine with bromine.
a. To a solution of 0.052 mL (1 mmol) of bromine in
5 mL of acetic acid was added 0.118 g (0.5 mmol) of
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PETROVA et al.
1-methallyltheobromine. After 48 h the precipitate was
filtered off. The filtrate was evaporated, the oily
residue is 1-(2,3-dibromo-2-methylpropyl)theobromine.
The precipitate was treated with acetone and filtered to
give a mixture of 0.069 g (yield 35%) of 6-(bromo-
methyl)-1,4,6-trimethyl-9-oxo-3a,4,6,7,9,9a-hexahydro-
1H-oxazolo[3,2-a]purinium bromide and 8-(bromo-
methyl)-1,4,8-trimethyl-5-oxo-3a,4,5,7,8,9b-hexahydro-
1H-oxazolo[2,3-i]purinium bromide in a ratio of 1.57 : 1.
brown precipitate of 6-(iodomethyl)-1,4,6-trimethyl-9-
oxo-3a,4,6,7,9,9a-hexahydro-1H-oxazolo[3,2-a]purinium
triiodide was filtered off, dried, then dissolved in acetone.
To the solution was added NaI, and the resulting pale
yellow precipitate was filtered off. Yield 0.146 g
1
(60%), mp 97–98°C. Н NMR spectrum, δ, ppm: 1.96
s (3Н, N6CH3), 3.65 s (3Н, N4CH3), 3.95 s (3H,
N1CH3), 3.40 m and 3.76 m (2Н, NCH2), 4.42 m (2Н,
CH2Br), 8.75 s (1Н, Н2).
b. To a solution of 0.052 mL (1 mmol) of bromine
in 5 mL of dichloromethane was added 0.118 g
(0.5 mmol) of 1-methallyltheobromine. After 48 h the
formed precipitate was filtered off, dried, then treated
with acetone and filtered to give a mixture of 0.138 g
(70% yield) of 6-(bromomethyl)-1,4,6-trimethyl-9-oxo-
3a,4,6,7,9,9a-hexahydro-1H-oxazolo[3,2-a]purinium
bromide and 8-(bromomethyl)-1,4,8-trimethyl-5-oxo-
3a,4,5,7,8,9b-hexahydro-1H-oxazolo[2,3-i]purinium
bromide in a ratio of 1 : 0.95.
FUNDING
This work was financially supported by the
Government of the Russian Federation (Decree no.
211, March 16, 2013, agreement no. 02.A03.21.0011)
and the Ministry of Education and Science of the
Russian Federation as part of the governmental task
(no. 4.9665.2017/8.9).
CONFLICT OF INTEREST
No conflict of interest was declared by the authors.
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