Solvent-free synthesis of thio-alkylxanthines from alkylxanthines using microwave irradiation

Article abstract of DOI:10.3987/COM-00-9003

An expeditious, solvent-free procedure for the conversion of the xanthine bases theophylline, 8-methyltheophylline, caffeine, and theobromine to the corresponding 6-thio and 2,6-dithio derivatives using Lawesson's reagent under microwave irradiation is proposed.

Full text of DOI:10.3987/COM-00-9003

HETEROCYCLES, Vol. 53, No10, 2000, pp. 2275 - 2278, Received, 10th July, 2000
SOLVENT-FREE SYNTHESIS OF THIO-ALKYLXANTHINES FROM
ALKYLXANTHINES USING MICROWAVE IRRADIATION
a
a
a
Rodrigo Rico-Gómez,* Francisco Nájera, Juan Manuel López-Romero, and
b
Pedro Cañada-Rudner
a) Departamento de Química Orgánica. Universidad de Málaga. E-29071, Spain
b) Departamento de Química Analítica. Universidad de Málaga. E-29071, Spain
Abstract-An expeditious, solvent-free procedure for the conversion of the
xanthine bases theophylline, 8-methyltheophylline, caffeine, and theobromine
to the corresponding 6-thio and 2,6-dithio derivatives using Lawesson’s
reagent under microwave irradiation is proposed.
The synthesis of 1,3-disubstituted 6-thioxanthines has received considerable attention on account of their
1
～4
biological activity.
The usual approach involves the transformation of the 6-oxo group into its 6-thio
5
analogue with phosphorus pentasulfide in pyridine. On the other hand, non-enolizable 1,3,7-
trialkylxanthines such as caffeine (1a) fail to react and yield 6-thiocaffeine (1b) under the same
6
7
conditions, and has been directly synthesized from 1a using various reagents and/or conditions, or by
6
,8
an indirect approach. The synthesis of 2,6-dithio-alkylxanthines has been less deeply studied because
replacing the 2-oxygen atom of alkylxanthines with sulfur is more difficult. In fact, 2,6-dithiotheophylline
(
2c) has been prepared from 2-thiotheophylline (2b), previously obtained from 4,5-diamino-1,3-dimethyl-
9
2
-thiouracil using Traube's method. Only three instances of direct synthesis of 2,6-dithio-alkylxanthine
7
b,7c,10
have so far been reported.
Most of these procedures, however, require a long time and drastic
reaction conditions, in addition to the use of dry solvents; also, they occasionally afford modest yields.
Me
N
Me
N
Me
N
Me
N
2
Y
Y
Y
Y
N
N
N
N
N
N
N
a, X=Y=O
b, X=S, Y=O
c, X=Y=S
H
H
Me
H
6
N
N
N
N
7N
Me
Me
H
Me
1
Me
H
Me
H
X
X
X
X
1
2
3
4
Lawesson’s reagent has been used for the conversion of a wide variety of carbonyl compounds to their
1
1
thiocarbonyl analogues. However, this method usually requires an excess of reagent, a long reaction
1
2
time, a dry hydrocarbon solvent at a high temperature, and generates unwanted side products.

The chemical potential of microwaves for efficient transformation of functional groups under solvent-free
1
3
conditions has aroused much interest lately. Recently, thioketons, thioesters, thiolactones and thioamides
have been prepared by reaction of their oxo analogues with Lawesson's reagent under microwave
1
4
irradiation conditions.
In this paper, we report the synthesis of 6-thiocaffeine (1b), 6-thiotheophylline (2b), 8-methyl-6-
thiotheophylline (3b), 6-thiotheobromine (4b), 2,6-thiocaffeine (1c), 2,6-dithiotheophylline (2c), 8-
methyl-2,6-dithiotheophylline (3c) and 2,6-dithiotheobromine (4c) by reaction of the corresponding
xanthine bases with Lawesson’s reagent under microwave irradiation. All reactions were carried out under
1
5
atmospheric pressure in a focused microwave reactor in the absence of solvent. The reaction conditions
were optimized to obtain the best possible yield (Table 1).
The reaction of 1 mmol of alkylxanthine with 0.5 mmol of Lawesson’s reagent (Entries 1, 3, 5 and 7,
Table 1) yielded 6-thio derivatives selectively. When the reaction was conducted at a 1:1.1 substrate-
reagent mmol ratio (Entries 2, 4, 6 and 8, Table 1), 2,6-dithioxanthines were obtained almost
quantitatively. It should be noted that, although this procedure resulted in decreased reactivity of the
oxygen atom at position 2, thionation at positions 6 and 2 only occurred if the mole ratio of Lawesson’s
reagent to xanthines was increased from 0.5:1 to 1.1:1.
Table 1. Solvent-free synthesis of thioxanthine derivatives using microwave irradiation.
a
b
Entry
Substrate
Xanthine/LR
mole ratio
1:0.5
MW Irradiation
Product
Yield
(%)
92
mp
c
Time/power
(ºC)
1
2
3
4
5
6
7
8
Caffeine, 1a
6 min / 60 W
6 min / 60 W
10 min / 60 W
10 min / 60 W
5 min / 60 W
5 min / 60 W
7 min / 60 W
7 min / 60 W
1b
1c
245-246
228-230
314-316
254-256
289-291
249-251
--
1a
1:1.1
98
Theophylline, 2a
1:0.5
2b
95
2a
1:1.1
2c
93
8-Methyltheophylline, 3a
1:0.5
3b
90
3a
Theobromine, 4a
4a
1:1.1
3c
96
1:0.5
4b + (4c)
4c
99
1:1.1
92
293-295
a) Lawesson's reagent; b) microwave; c) the temperature of the alumina at the start of irradiation was 120 ºC.
With theobromine (4a, Entry 7) a mixture of 6-thio derivative (4b) (60%), 2,6-dithio derivative 4c (20%)
1
and (4a) (20%) was obtained ( H-NMR). This result can be explained assuming that, if 0.4 eq. of
Lawesson’s reagent are required to yield 20% of 4c and 0.6 equiv produce 60% of 4b, 20% of the starting
material, 4a, must be recovered. The obtainment of 2,6-dithio derivatives can be ascribed to an increased
reactivity at position 2 in 4a. This is consistent with the fact that N-1 bears no alkyl substituent, so both
the C-6 and the C-2 carbonyl groups are enolizable, and the substitution of the oxygen by a sulfur atom is
not so regioselective as in the other alkylxanthines.
In a typical experiment, a mixture of xanthine bases (1a, 2a, 3a or 4a) (1 mmol) and Lawesson’s reagent
(
0.5 mmol or 1.1 mmol) was placed in a glass tube and mixed thoroughly with a spatula. The open glass
tube was then placed inside a microwave vessel containing alumina (40 g) and exposed to microwave

irradiation at the power and for the time stated in Table 1. After irradiation, the mixture was cooled to rt.
For isolation of the products, the reaction mixture was extracted with dichloromethane and filtered off to
1
6
obtain the corresponding thioxanthines (yields are given in Table 1), which were purified by
crystallization or silica gel flash column chromatography (CH Cl and CH Cl /CH OH 20:0.5).
In conclusion, we have developed a simple, rapid, highly efficient method for the synthesis of 2-thio- and
,6-dithio-alkylxanthines from the corresponding oxo derivatives using Lawesson’s reagent in a solvent-
2
2
2
2
3
2
free microwave-assisted reaction. Further investigation on the synthesis of 6-thiopurine nucleosides is
now in progress.
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1
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5. For irradiation, a Prolabo TX-32 microwave oven was used.
6. All products (8-methyldithiotheophylline (3c) excepted) are known compounds and were
characterized by NMR, IR and UV spectroscopies, EIMS and mp. Data for 3c: red crystals (CHCl
3
);
-1
mp 249-251 ºC; UV (CHCl
3
) λmax nm (log ε) 360 (3.87), 304 (4.03), 260 (3.89); IR (KBr) cm 3307,
1
1
2
1
605, 1111, 1062 (νC=S); H-NMR (CDCl
3
+CD
+CD OD) ppm 173.4, 173.2 (2xC=S), 154.2 (C8), 142.3 (C4),
), 14.5 (CH C8). Anal. Calcd for C : C, 42.46; H, 4.45;
3 3 3
OD) ppm 4.17 (s, 3H, NCH ), 3.88 (s, 3H, NCH ),
1
3
.43 (s, 3H, CH
3
C8); C-NMR (CDCl
), 37.8 (NCH
3
3
22.9 (C5), 42.2 (NCH
3
3
3
8 10 4 2
H N S
N, 24.74; S, 28.33. Found: C, 42.75; H, 4.67; N, 24.22; S, 28.75.