Synthesis of novel 3,7-dihydro-purine-2,6-Dione derivatives

Article abstract of DOI:10.1080/00397910903097260

Forty-six novel 3,7-dihydro-purine-2,6-dione derivatives (substituted xanthines) with great structural diversity were synthesized for biological activity screening. Three series of substituted xanthine analogs have been prepared in moderate to excellent y

Full text of DOI:10.1080/00397910903097260

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Synthesis of Novel 3,7-Dihydro-
purine-2,6-dione Derivatives
Gang Liu a , P. S. Murali Mohan Reddy a , Jack R. Barber a , Shi Chung
Ng a & Yuefen Zhou a
a CytRx Corporation, San Diego, California, USA
Version of record first published: 23 Apr 2010.
To cite this article: Gang Liu , P. S. Murali Mohan Reddy , Jack R. Barber , Shi Chung Ng & Yuefen
Zhou (2010): Synthesis of Novel 3,7-Dihydro-purine-2,6-dione Derivatives, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 40:10, 1418-1436
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Synthetic Communications1, 40: 1418–1436, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903097260
SYNTHESIS OF NOVEL 3,7-DIHYDRO-PURINE-2,6-
DIONE DERIVATIVES
Gang Liu, P. S. Murali Mohan Reddy, Jack R. Barber,
Shi Chung Ng, and Yuefen Zhou
CytRx Corporation, San Diego, California, USA
Forty-six novel 3,7-dihydro-purine-2,6-dione derivatives (substituted xanthines) with
great structural diversity were synthesized for biological activity screening. Three series
of substituted xanthine analogs have been prepared in moderate to excellent yields.
Keywords: Analog synthesis for biological screening; 3,7-dihydro-purine-2,6-dione derivatives; substituted
xanthines; xanthine derivatives
3,7-Dihydro-purine-2,6-dione derivatives (also known as substituted xanthines)
constitute an important class of pharmacologically active compounds with well-
known activities as phosphodiesterase inhibitors, cystic fibrosis transmembrane con-
ductance regulator (CFTR) chloride channel activators, and adenosine receptor
antagonists.[1] In recent years, the spectrum of clinical applications of the xanthines
has continued to widen and presently includes their use as anticonvulsants,[2] nootro-
pics,[3] oral drugs for treating asthma,[4] DPP-4 inhibitors for treatment of type 2 dia-
betes,[5] and therapeutics for the treatment of migraines and illnesses where
underactivation of the HM74A receptor contributes to the disease.[6] In addition,
they are also found in nature, such as theobromine in cocoa and caffeine in coffee
and tea.[4] Therefore, novel xanthine analog synthesis continues to attract scientists’
interest in the drug discovery field.
In the course of our research to develop novel small-molecule chaperone ampli-
fiers to treat neurodegenerative diseases, we became very interested in the design and
synthesis of a large number of novel analogs of 3,7-dihydro-purine-2,6-dione deriva-
tives (1) (Fig. 1) for our high-throughput biological screening to identify initial hits.
There are a number of reported methods to prepare xanthine derivatives 1.[7–9]
We used modified literature methods (Schemes 1–3) to synthesize a variety of 3,7-
dihydro-purine-2,6-dione derivatives (Tables 1 and 2). To the best of our knowledge,
the majority of these analogs (46 out of 54) are novel compounds.
The first series of xanthine analogs we synthesized are the ones containing
substituents at N-1, N-3, and N-7 positions where R1 ¼ R2 by applying the method
Received March 26, 2009.
Address correspondence to Yuefen Zhou, CytRx Corporation, 3030 Bunker Hill Street, Suite 101,
San Diego, CA 92109, USA. E-mail: yuefen.zhou@gmail.com
1418

SYNTHESIS OF NOVEL XANTHINE DERIVATIVES
1419
Figure 1. 3,7-Dihydro-purine-2,6-dione derivatives.
Scheme 1. Synthesis of 3,7-dihydro-purine-2,6-dione derivatives 4.
Scheme 2. Synthesis of 3,7-dihydro-purine-2,6-dione derivatives 10.

1420
G. LIU ET AL.
described in Scheme 1. The commercially available 1,3-dialkyl-5,6-diaminouracils 2
were treated with triethylorthoformate (also as solvent) under heating to provide the
key intermediates 3 in good yields.[10,11] Alkylation of the key intermediates 3 at N-7
or N-5 positions by treatment with alkyl halides in the presence of a base gave
the desired 3,7-dihydro-purine-2,6-dione derivatives 4 with good yields (Table 1).
Overall, the synthesis was very straightforward with good yields, and the majority
of the analogs in this series are novel compounds.
Another series of xanthine analogs substituents at N-1, N-5, and C-6 positions
(compounds 10) as shown in Scheme 2. In this case, the commercially available
6-chloro-3-methyluracil (5) was used as a common starting material. The analog
syntheses were routinely carried out first with nucleophilic displacement of the
chlorine in 5 by primary amines (excess) under heating in sealed tubes[12] to form
6, followed by the nitroso formation with the treatment of NaNO2 in acidic
conditions at room temperature to afford the key intermediates 7 in good yields
for both steps.[7,8,13] To reduce the nitroso moiety to an amino group, we first tried
hydrogenation using Pd=C catalyst (method A), which worked for the majority of
the substrates with good yields.[8,12] However, this method failed for some of the
substrates of 7 where R3 ¼ cyclopropylmethylene, 3,3-dimethylbutyl, benzyl, or 3-
dimethylaminopropyl groups. Instead, we found that Na2S2O4 could successfully
reduce the nitroso moiety present in these substrates 7 to an amino group, affording
desired products 8 in fairly good yields (method B).[9] The next step, imine forma-
tion, occurred selectively at the nonsubstituted amino group, leading to 9 with the
treatment of aldehydes under heating. Finally, the cyclization in the presence of
diethyl azodicarboxylate (DEAD) (40% in toluene) at high temperature completed
the synthesis to give the desired xanthine derivatives 10.[9] The overall isolated yields
for the last two steps were 30–50% (10a1–10g3, Table 2).
We followed a reaction sequence similar to the previous one and used 11 as the
starting material to assemble the xanthine derivatives 14 substituted at N-1, N-3, and
C-6 positions (Scheme 3).[9] The yields for the synthesis of 14 (14a–c) were similar to
those of 10, as shown in Table 2. Finally, alkylation of 14 at N-5 or N-7 by alkyl
Scheme 3. Synthesis of 3,7-dihydro-purine-2,6-dione derivatives 14 and 1.

SYNTHESIS OF NOVEL XANTHINE DERIVATIVES
1421
Table 1. Synthesis of 3,7-dihydro-purine-2,6-dione derivatives (3a, 4a–p)
Compound
R1
R2
R3
Yield (%)a
3a
4a
4b
n-Pr
n-Pr
n-Pr
n-Pr
n-Pr
n-Pr
H
Me
Et
86
90
89
4c
4d
n-Pr
n-Pr
n-Pr
n-Pr
85
95
4e
4f
n-Pr
n-Pr
n-Pr
n-Pr
n-Pr
n-Pr
95
90
90
4g
4h
n-Pr
n-Pr
84
4i
4j
n-Pr
n-Pr
n-Pr
n-Pr
80
82
4k
4l
n-Pr
Me
n-Pr
Me
90
85
95
4m
Me
Me
4n
4o
Me
Me
Me
Me
80
80
(Continued )

1422
G. LIU ET AL.
Table 1. Continued
Compound
R1
R2
R3
Yield (%)a
4p
Me
Me
75
aIsolated yield for the last step.
Table 2. Synthesis of 3,7-dihydro-purine-2,6-dione derivatives (10, 14, and 1)
Compound
R1
R2
H
R3
Et
R4
Yield (%)a
45
10a1
Me
10a2
10a3
10b1
10b2
10b3
10b4
Me
Me
Me
Me
Me
Me
H
H
H
H
H
H
Et
47
40
40
43
38
42
Et
n-Pr
n-Pr
n-Pr
n-Pr
10b5
Me
H
n-Pr
35
(Continued )

SYNTHESIS OF NOVEL XANTHINE DERIVATIVES
1423
Table 2. Continued
Compound
R1
R2
H
R3
R4
Yield (%)a
44
10b6
Me
n-Pr
10b7
10b8
Me
Me
H
H
n-Pr
n-Pr
46
42
10b9
10c1
10c2
Me
Me
Me
H
H
H
n-Pr
n-Bu
n-Bu
45
42
40
10c3
10c4
Me
Me
H
H
n-Bu
n-Bu
39
42
10c5
Me
H
n-Bu
34
10c6
10c7
10c8
Me
Me
Me
H
H
H
n-Bu
n-Bu
n-Bu
30
32
35
10d1
10d2
10d3
Me
Me
Me
H
H
H
50
34
42
(Continued )

1424
G. LIU ET AL.
Table 2. Continued
Compound
R1
R2
H
R3
R4
Yield (%)a
44
10d4
Me
10e1
10e2
Me
Me
H
H
46
48
10f1
10f2
Me
Me
H
H
41
42
10f3
10f4
10g1
Me
Me
Me
H
H
H
45
39
32
10g2
10g3
14a
Me
Me
H
H
30
35
44
n-Pr
n-Pr
H
14b
14c
1a
n-Pr
n-Pr
n-Pr
n-Pr
n-Pr
n-Pr
H
H
39
45
79
n-Bu
aIsolated yield for the last two steps.

SYNTHESIS OF NOVEL XANTHINE DERIVATIVES
1425
bromides in the presence of cesium carbonate led to the fully substituted xanthines 1
in good yields as shown in Scheme 3.
In conclusion, three series of 3,7-dihydro-purine-2,6-dione derivatives includ-
ing partially or fully substituted analogs (substituted xanthines) have been made in
moderate to good yields using three different methods. The majority of these
substituted xanthines are novel compounds. The substituents at C-6 can vary quite
bit, including alkyl, phenyl, and heterocycle moieties, yet they do not seem to affect
the yields, indicating potentially broad applications of the synthetic methods. These
novel compounds described here, along with their ease in synthesis, could be of
interest to the scientists working in drug discovery research.
EXPERIMENTAL
Unless otherwise stated, all reactions were performed under an inert atmos-
phere with anhydrous reagents, solvents, and oven-dried glassware. All starting
materials were purchased from Aldrich, Sigma, Fisher, or Lancaster and were used
as received. Anhydrous solvents purchased from EMD were used directly without
additional treatment. Preparative thin-layer chromatography (TLC) was performed
using Merck (0.25, 0.5, or 1 mm) coated silica-gel Kieselgel 60 F254 plates. 1H
NMR spectra were recorded on Bruker AMX-500 (500-MHz) or AMX-400
(400-MHz) spectrometers, and chemical shifts are reported in parts per million
(d) using internal solvent signals as references. Coupling constants are reported
in hertz (Hz).
Synthesis of 1,3-Dipropyl-1H-purine-2,6(3H,7H)-dione (3a)[14]
1,3-Dipropyl-5,6-diaminouracil (2a, R1 ¼ n-Pr) (2 g, 8.83 mmol) was dissolved
in triethylorthoformate (15 mL), and the mixture was heated to 100 ꢀC for 3 h.
The solvent was concentrated in vacuo to furnish 1,3-dipropylxanthine as key
1
intermediate 3a (R1 ¼ n-Pr) (1.8 g, 86%). H NMR (500 MHz, CDCl3): d 0.96 (t,
J ¼ 6.9 Hz, 6H), 1.64–1.70 (m, 2H), 1.74–1.84 (m, 2H), 4.05 (t, J ¼ 8.0 Hz, 2H),
4.12 (t, J ¼ 8.0 Hz, 2H), 7.79 (s, 1H), 12.60 (s, 1H,). LC-MS (ESIþ) m=z ¼ 237.2
[M þ H]þ.
Synthesis of 7-Methyl-1,3-dipropyl-3,7-dihydro-purine-2,6-dione (4a)[15]
K2CO3 (0.207 mg, 1.5 mmol) was added to a solution of 1,3-dipropyl-1H-
purine-2,6(3H,7H)-dione (3a) (118 mg, 0.5 mmol) in dimethylformamide (DMF),
followed by methyl iodide (78 mg, 0.55 mmol), and the reaction mixture was heated
at 100 ꢀC for 12 h. The solid (K2CO3) was filtered off, concentrated in vacuo, purified
by normal phase chromatography on silica gel (with an automated system: ISCO)
using a gradient (EtOAc=hexane ¼ 1:3) to afford the methylated derivative 4a
(113 mg, 90%). Mp ¼ 114–116 ꢀC; 1H NMR (500 MHz, CDCl3): d 0.96 (t, J ¼ 7.4 Hz,
6H); 1.62–1.71 (m, 2H), 1.74–1.80 (m, 2H), 3.94–3.97 (m, 5H), 4.05 (t, J ¼ 8.1 Hz,
2H), 7.48 (s, 1H). LC-MS (ESIþ) m=z ¼ 251.2 [M þ H]þ.
The following compounds were prepared according to the method described
for the synthesis of compound 4a using appropiate starting materials.

1426
G. LIU ET AL.
7-Ethyl-1,3-dipropyl-3,7-dihydro-purine-2,6-dione (4b)
ISCO purification gradient: 40% EtOAc in hexane; a white solid; yield: 89%;
1H NMR (500 MHz, CDCl3): d 0.93–0.98 (m, 6H), 1.53 (t, J ¼ 6.4 Hz, 3H),
1.64–1.70 (m, 2H), 1.78–1.81 (m, 2H), 3.96 (t, J ¼ 8.2 Hz, 2H), 4.05 (t, J ¼ 8.1 Hz,
2H), 4.34 (t, J ¼ 8.2 Hz, 2H), 7.53 (s, 1H). LC-MS (ESIþ) m=z ¼ 265.2 [M þ H]þ.
7-Allyl-1,3-dipropyl-3,7-dihydro-purine-2,6-dione (4c)[15]
ISCO purification gradient: 35% EtOAc in hexane; a yellow solid; yield: 85%;
mp ¼ 58–61 ꢀC; 1H NMR (500 MHz, CDCl3): d 0.87–0.98 (m, 6H), 1.53 (t,
J ¼ 7.8 Hz, 3H), 1.64–1.69 (m, 2H), 1.75–1.81 (m, 2H), 3.96 (t, J ¼ 8.2 Hz, 2H),
4.05 (t, J ¼ 7.9 Hz, 2H), 4.34 (t, J ¼ 8.2 Hz, 2H), 4.93 (d, J ¼ 6.8 Hz, 2H), 5.24–5.30
(m, 2H), 6.01–6.08 (m, 1H), 7.54 (s, 1H). LC-MS (ESIþ) m=z ¼ 277.2 [M þ H]þ.
7-Cyclopropylmethyl-1,3-dipropyl-3,7-dihydro-purine-2,6-dione (4d)
ISCO purification gradient: 35% EtOAc in hexane; a yellow solid; yield: 95%;
1
mp ¼ 95–99 ꢀC; H NMR (500 MHz, CDCl3): d 0.41–0.44 (m, 2H), 0.63–0.67 (m,
2H), 0.87–0.99 (m, 6H), 1.37–1.42 (m, 1H), 1.62–1.70 (m, 2H), 1.71–1.83 (m, 2H),
3.96 (t, J ¼ 7.8 Hz, 2H), 4.06 (t, J ¼ 8.1 Hz, 2H), 4.16 (d, J ¼ 6.8 Hz, 2H), 7.62 (s,
1H). LC-MS (ESIþ) m=z ¼ 291.1 [M þ H]þ.
7-Benzyl-1,3-dipropyl-3,7-dihydro-purine-2,6-dione (4e)[16]
ISCO purification gradient: 35% EtOAc in hexane; a yellow solid; yield: 95%;
1
mp ¼ 96–98 ꢀC; H NMR (500 MHz, CDCl3): d 0.85–0.99 (m, 6H), 1.64–1.70 (m,
2H), 1.74–1.81 (m, 2H), 3.96 (t, J ¼ 7.8 Hz, 2H), 4.09 (t, J ¼ 7.9 Hz, 2H), 5.54 (s,
2H), 7.20–7.41 (m, 5H), 7.83 (s, 1H). LC-MS (ESIþ) m=z ¼ 327.2 [M þ H]þ.
7-(4-Trifluoromethylbenzyl)-1,3-dipropyl-3,7-dihydro-
purine-2,6-dione (4f)
ISCO purification gradient: 25% EtOAc in hexane; a yellow solid; yield: 90%;
1
mp ¼ 128–130 ꢀC; H NMR (500 MHz, CDCl3): d 0.87–1.00 (m, 6H), 1.62–1.67 (m,
2H), 1.76–1.81 (m, 2H), 3.94 (t, J ¼ 7.8 Hz, 2H), 4.10 (t, J ¼ 7.6 Hz, 2H), 5.60
(s, 2H), 7.51 (d, J ¼ 6.8 Hz, 2H), 7.62 (d, J ¼ 6.4 Hz, 2H), 7.97 (s, 1H). LC-MS (ESIþ)
m=z ¼ 395.2 [M þ H]þ.
7-(4-Trifluoromethoxybenzyl)-1,3-dipropyl-3,7-dihydro-
purine-2,6-dione (4g)
ISCO purification gradient: 25% EtOAc in hexane; a yellow solid; yield: 90%;
mp ¼ 132–134 ꢀC; 1H NMR (500 MHz, CDCl3): d 0.87–0.99 (m, 6H), 1.63–1.69
(m, 2H), 1.75–1.82 (m, 2H), 3.95 (t, J ¼ 7.9 Hz, 2H), 4.06 (t, J ¼ 7.8 Hz, 2H), 5.51
(s, 2H), 7.25 (d, J ¼ 6.8 Hz, 2H), 7.47 (d, J ¼ 6.8 Hz, 2H), 7.78 (s, 1H). LC-MS (ESIþ)
m=z ¼ 411.1 [M þ H]þ.

SYNTHESIS OF NOVEL XANTHINE DERIVATIVES
1427
7-(2,6-Difluorobenzyl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione (4h)
ISCO gradient: 25% EtOAc in hexane; a white solid; yield: 84%; mp ¼ 156–
159 ꢀC; 1H NMR (500 MHz, CDCl3): d 0.88–0.99 (m, 6H), 1.64–1.71 (m, 2H),
1.75–1.82 (m, 2H), 3.98 (t, J ¼ 7.9 Hz, 2H), 4.07 (t, J ¼ 7.9 Hz, 2H), 5.68 (s, 2H),
6.95 (t, J ¼ 6.4 Hz, 1H), 7.43 (d, J ¼ 6.8 Hz, 2H), 7.54 (s, 1H). LC-MS (ESIþ)
m=z ¼ 363.2 [M þ H]þ.
7-((1H-Benzo[d][1,2,3]triazol-1-yl)methyl)-1,3-dipropyl-1H-purine-
2,6(3H,7H)-dione (4i)
ISCO purification gradient: 50% EtOAc in hexane; a yellow solid; yield: 80%;
mp ¼ 179–181 ꢀC; 1H NMR (500 MHz, CDCl3): d 0.80–0.99 (m, 6H), 1.60–1.69
(m, 2H), 1.76–1.80 (m, 2H), 3.90 (t, J ¼ 7.9 Hz, 2H), 4.10 (t, J ¼ 7.9 Hz, 2H), 5.60
(s, 2H), 6.99 (t, J ¼ 6.4 Hz, 2H), 7.40 (d, J ¼ 7.4 Hz, 2H), 7.50 (s, 1H). LC-MS (ESIþ)
m=z ¼ 368.2 [M þ H]þ.
7-((1H-Benz[d]imidazo-Yl)methyl)-1,3-dipropyl-1H-purine-
2,6(3H,7h)-dione (4j)[17]
ISCO purification gradient: 50% EtOAc in hexane; a yellow solid; yield: 82%;
1H NMR (500 MHz, CDCl3): d 0.86 (t, J ¼ 7.6 Hz, 3H), 0.99 (t, J ¼ 7.9 Hz, 3H),
1.70–1.78 (m, 4H), 4.03–4.10 (m, 4H), 5.66 (s, 2H), 7.02 (t, J ¼ 6.2 Hz, 2H), 7.42
(d, J ¼ 7.2 Hz, 2H), 7.56 (s, 1H). LC-MS (ESIþ) m=z ¼ 367.2 [M þ H]þ.
7-(2-(Piperidine-1yl)ethyl)-1,3-dipropyl-3,7-dihydro-purine-2,6-
dione (4k)[16]
ISCO purification gradient: 40% EtOAc in hexane; a yellow solid; yield: 90%;
1H NMR (500 MHz, CDCl3): d 0.84–0.99 (m, 6H), 1.63–2.20 (m, 10H), 2.60–2.67 (m,
4H), 2.91–2.97 (m, 2H), 3.95 (t, J ¼ 7.8 Hz, 2H), 4.06 (t, J ¼ 7.5 Hz, 2H), 4.60 (t,
J ¼ 7.6 Hz, 2H), 7.67 (s, 1H). LC-MS (ESIþ) m=z ¼ 348.3 [M þ H]þ.
7-(2-(Piperidine-1yl)ethyl)-1,3-dimethyl-3,7-dihydro-purine-2,6-
dione (4l)
ISCO purification gradient: 45% EtOAc in hexane; a yellow solid; yield: 85%;
1H NMR (500 MHz, CDCl3): d 1.41–1.59 (m, 10H), 2.74 (t, J ¼ 6.8 Hz, 2H), 3.39 (s,
3H), 3.57 (s, 3H), 4.42 (t, J ¼ 7.8 Hz, 2H), 7.69 (s, 1H). LC-MS (ESIþ) m=z ¼ 292.2
[M þ H]þ.
7-Benzyl-1,3-dimethyl-3,7-dihydro-purine-2,6-dione (4m)[15]
ISCO purification gradient: 35% EtOAc in hexane; a white solid; yield: 95%;
1
mp ¼ 154–157 ꢀC; H NMR (500 MHz, CDCl3): d 3.41 (s, 3H), 3.61 (s, 3H), 5.52
(s, 2H), 7.33–7.39 (m, 5H), 7.66 (s, 1H). LC-MS (ESIþ) m=z ¼ 271.1 [M þ H]þ.

1428
G. LIU ET AL.
7-((1H-Benz[d]imidazo-yl)methyl)-1,3-dimethyl-1H-purine-
2,6(3H,7H)-dione (4n)
ISCO purification gradient: 45% EtOAc in hexane; a white solid; yield: 80%; 1H
NMR (500 MHz, CDCl3): d 3.50 (s, 3H), 3.57 (s, 3H), 6.07 (s, 2H), 7.44 (t, J ¼ 6.2 Hz,
2H), 7.72 (d, J ¼ 7.4 Hz, 2H), 8.26 (s, 1H). LC-MS (ESIþ) m=z ¼ 311.2 [M þ H]þ.
7-((1H-Benzo[d][1,2,3]triazol-1-yl)methyl)-1,3-dimethyl-1H-purine-
2,6(3H,7H)-dione (4o)
ISCO purification gradient: 45% EtOAc in hexane; a white solid; yield: 80%;
1
mp ¼ 158–162 ꢀC; H NMR (500 MHz, CDCl3): d 3.21 (s, 3H), 3.39 (s, 3H), 6.00
(s, 2H), 7.46 (t, J ¼ 7.6 Hz, 1H), 7.66 (t, J ¼ 6.4 Hz, 1H), 8.07 (d, J ¼ 7.4 Hz, 1H),
8.13 (d, J ¼ 7.6 Hz, 1H), 8.53 (s, 1H), LC-MS (ESIþ) m=z ¼ 312.0 [M þ H]þ.
7-((2-Oxobenzo[d]thiazol-3(2H)-yl)methyl)-1,3-dimethyl-3,7-dihydro-
purine-2,6-dione (4p)
ISCO purification gradient: 50% EtOAc in hexane; a yellow solid; yield: 75%;
1H NMR (500 MHz, CDCl3): d 3.26 (s, 3H), 3.41 (s, 3H), 6.45 (s, 2H), 7.25 (t,
J ¼ 6.4 Hz, 2H), 7.39 (d, J ¼ 7.4 Hz, 1H), 7.70 (d, J ¼ 6.4 Hz, 1H), 8.16 (s, 1H),
LC-MS (ESIþ) m=z ¼ 344.0 [M þ H]þ.
General Procedure for the Synthesis of Compounds 6
An amine (R3-NH2, 30 mmol) [3 eq. of diisopropylethyl amine (DIPEA)
needed if R3-NH2 ꢁ HCl was used] was added to a solution of 6-chloro-3-methyluracil
(5) (10 mmol) in ethanol (15 mL) in a sealed tube. The mixture was stirred at room
temperature for 10 min, and then heated to 100–110 ꢀC with stirring overnight. The
reaction mixture was cooled to room temperature, concentrated, treated with water,
filtered, washed with 50% MeOH in water, and dried under high vacuum to give 6 as
a solid. All the desired products were confirmed by liquid chromatography–mass
spectrometry (LC-MS) analysis. Isolated yields were 85–95%.
General Procedure for the Synthesis of Compounds 7
NaNO2 (11 mmol in 10 mL H2O) was slowly added to a solution of compound
6 (10 mmol) in 50% of CH3COOH in H2O (40 mL for R3 ¼ alkyl group, 100 mL for
R3 ¼ aryl group) over 30 min. The mixture was stirred at room temperature for 3–6 h.
The reaction mixture turned to orange, then red, and a precipitation formed, which
was filtered, washed with water, dried, treated with methanol, and filtered to give 7
(yield: 60–80%). All the desired products were confirmed by LC-MS analysis.
Compounds 12 were made in a similar way.
General Procedure for the Synthesis of Compounds 8
Method A. Compound 7 (2 g) (for R3 ¼ H, Et, n-Pr, i-Pr, n-Bu) was dissolved
in methanol (200 mL), and 10% Pd=C (0.2 g) was added under an N2 atmosphere.

SYNTHESIS OF NOVEL XANTHINE DERIVATIVES
1429
The mixture was stirred under H2 via an H2 balloon overnight. The reaction mixture
turned to a clear solution, which was filtered quickly through celite, washed with
methanol, concentrated under reduced pressure, and dried under high vacuum to
give 8 (yield > 90%). All the products were confirmed by LC-MS analysis. Com-
pounds 13 were made in a similar way.
Method B. Na2S2O4 (3eq.) was added to a mixture of compound 7 (2 g) (for
R3 ¼ 3,3-dimethylpropyl, 3-dimethylaminopropyl, cyclopropylmethylene, benzyl) in
10% NH3 in H2O (40 mL). The reaction mixture was heated to 65 ꢀC for 3 h. After
removal of the solvent, dichloromethane (DCM) and water were added, and then
the separated organic layer was washed with brine, dried over Na2SO4, concentrated
under reduced pressure, and dried under high vacuum to give 8 (yield: 60–70%). All
the products were confirmed by LC-MS analysis.
General Procedure for the Synthesis of Compounds 9 and 10
An aldehyde (R4-CHO, 1.5 eq.) was added to a mixture of compound 8
(150 mg) in toluene (1 mL). The resulting mixture was heated to 110 ꢀC with stirring
in a sealed tube for 1 h to form imine intermediate 9. The mixture containing 9 was
cooled to room temperature, and 40% DEAD in toluene (3 eq.) was added. The reac-
tion mixture was heated to 120–130 ꢀC for 3–4 h. After cooling to room temperature,
the precipitate (for R4 ¼ Ar) was filtered, washed with methanol, and dried to give 10
(crude yield: 60–70% for two steps), which was further purified by recrystalization
from DMF=ethanol to give pure 10 (isolated yield for two steps: 30–50%; purity:
>90%). Compounds 14 were made in a similar way.
Procedure for the Synthesis of Compound 1a
Compound 14a (55 mg, 0.15 mmol) was dissolved in DMF (0.5 mL) in a sealed
tube. Cs2CO3 (97.5 g, 0.3 mmol) and BuBr (62 mg, 0.45 mmol) were added. The mix-
ture was heated at 100 ꢀC for 3 h. TLC confirmed the completion of the reaction.
Methylene chloride was added, then washed with water and brine. The separated
organic layer was dried over anhydrous Na2SO4, concentrated, and recrystallized
1
from EtOH to give 1a (50 mg, 79% yield). H NMR (DMSO-d6): d 0.87 (t, 3H,
J ¼ 6.0 Hz), 0.92 (m, 6H), 1.38 (m, 2H), 1.57 (m, 2H), 1.74 (m, 2H), 1.84 (m, 2H),
3.85 (t, 2H, J ¼ 6.0 Hz), 3.98 (t, 2H, J ¼ 6.0 Hz), 4.98 (t, 2H, J ¼ 6.0 Hz), 7.54 (t,
1H, J ¼ 5.6 Hz), 7.60 (t, 1H, J ¼ 5.6 Hz), 8.10 (d, 1H, J ¼ 6.4 Hz), 8.18 (d, 1H,
J ¼ 6.4 Hz). LC-MS (ESIþ) m=z ¼ 426 [M þ H]þ.
The following compounds were prepared according to the method described
for the synthesis of compounds 10 using appropiate starting materials.
8-(Benzo[d]thiazol-2-yl)-9-ethyl-1-methyl-1H-purine-2,6(3H,9H)-
dione (10a1)
1H NMR (DMSO-d6): d 1.39 (t, 3H, J ¼ 6.0 Hz), 3.23 (s, 3H), 4.74 (dd, 2H,
J ¼ 6.0 Hz), 7.50 (t, 1H, J ¼ 7.0 Hz), 7.57 (t, 1H, J ¼ 7.0 Hz), 8.04 (d, 1H, J ¼ 6.4 Hz),
8.16 (d, 1H, J ¼ 6.4 Hz), 12.6 (s, 1H). LC-MS (ESIþ) m=z ¼ 328.2 [M þ H]þ.

1430
G. LIU ET AL.
9-Ethyl-1-methyl-8-(4-methylthiazol-2-yl)-1H-purine-2,6(3H,9H)-
dione (10a2)
1H NMR (DMSO-d6): d 1.31 (t, 3H, J ¼ 6.0 Hz), 2.43 (s, 3H), 3.21 (s, 3H), 4.74
(t, 2H, J ¼ 5.6 Hz), 7.42 (s, 1H), 12.5 (s, 1H). LC-MS (ESIþ) m=z ¼ 292.2 [M þ H]þ.
8-(Benzo[d]oxazol-2-yl)-9-ethyl-1-methyl-1H-purine-2,6(3H,9H)-
dione (10a3)
1H NMR (DMSO-d6): d 1.39 (t, 3H, J ¼ 6.0 Hz), 3.22 (s, 3H), 4.74 (dd, 2H,
J ¼ 5.6 Hz), 7.48 (m, 2H), 7.82 (d, 1H, J ¼ 6.4 Hz), 7.87 (d, 1H, J ¼ 6.4 Hz), 12.62
(s, 1H). LC-MS (ESIþ) m=z ¼ 312.2 [M þ H]þ.
8-(Benzo[d]oxazol-2-yl)-1-methyl-9-propyl-1H-purine-2,6(3H,9H)-
dione (10b1)
1H NMR (DMSO-d6): d 0.92 (t, 3H, J ¼ 6.0 Hz), 1.81 (m, 2H), 3.23 (s, 3H),
4.60 (t, 2H, J ¼ 6.0 Hz), 7.48 (m, 2H), 7.85 (m, 2H), 12.63 (s, 1H). LC-MS (ESIþ)
m=z ¼ 326.5 [M þ H]þ.
8-(Benzo[d]thiazol-2-yl)-1-methyl-9-propyl-1H-purine-2,6(3H,9H)-
dione (10b2)
1H NMR (DMSO-d6): d 0.92 (t, 3H, J ¼ 6.0 Hz), 1.81 (m, 2H), 3.22 (s, 3H),
4.65 (t, 2H, J ¼ 6.0 Hz), 7.54 (m, 2H), 8.04 (d, 1H, J ¼ 6.3 Hz), 8.16 (d, 1H,
J ¼ 6.3 Hz), 12.60 (s, 1H). LC-MS (ESIþ) m=z ¼ 342.2 [M þ H]þ.
8-(Benzo[b]thiophen-2-yl)-1-methyl-9-propyl-1H-purine-2,6(3H,9H)-
dione (10b3)
1H NMR (DMSO-d6): d 0.92 (t, 3H, J ¼ 6.0 Hz), 1.73 (m, 2H), 3.22 (s, 3H),
4.32 (t, 2H, J ¼ 6.0 Hz), 7.42 (m, 2H), 7.85 (s, 1H), 7.95 (m, 1H), 8.00 (m, 1H),
12.43 (s, 1H). LC-MS (ESIþ) m=z ¼ 341.2 [M þ H]þ.
8-(Benzofuran-2-yl)-1-methyl-9-propyl-1H-purine-2,6(3H,9H)-
dione (10b4)
1H NMR (DMSO-d6): d 0.90 (t, 3H, J ¼ 6.0 Hz), 1.73 (m, 2H), 3.22 (s, 3H),
4.34 (t, 2H, J ¼ 6.0 Hz), 7.31 (t, 1H, J ¼ 5.6 Hz), 7.41 (t, 1H, J ¼ 5.6 Hz), 7.46 (s,
1H), 7.66 (d, 1H, J ¼ 6.0 Hz), 7.74 (d, 1H, J ¼ 6.0 Hz), 12.43 (s, 1H). LC-MS (ESIþ)
m=z ¼ 325.2 [M þ H]þ.
1-Methyl-8-(1-methyl-1H-benzo[d]imidazol-2-yl)-9-propyl-1H-purine-
2,6(3H,9H)-dione (10b5)
1H NMR (DMSO-d6): d 0.85 (t, 3H, J ¼ 6.0 Hz), 1.75 (m, 2H), 3.22 (s, 3H),
4.17 (s, 3H), 4.61 (t, 2H, J ¼ 6.0 Hz), 7.29 (t, 1H, J ¼ 6.0 Hz), 7.37 (t, 1H, J ¼ 6.0 Hz),

SYNTHESIS OF NOVEL XANTHINE DERIVATIVES
1431
7.66 (t, 1H, J ¼ 6.0 Hz), 7.72 (d, 1H, J ¼ 6.3 Hz), 12.52 (s, 1H). LC-MS (ESIþ)
m=z ¼ 339.2 [M þ H]þ.
1-Methyl-9-propyl-8-(thiophen-2-yl)-1H-purine-2,6(3H,9H)-
dione (10b6)
1H NMR (DMSO-d6): d 0.85 (t, 3H, J ¼ 6.0 Hz), 1.67 (m, 2H), 3.20 (s, 3H),
4.20 (t, 2H, J ¼ 6.0 Hz), 7.20 (t, 1H, J ¼ 7.2 Hz), 7.51 (d, 1H, J ¼ 3.0 Hz), 7.72 (d,
1H, J ¼ 4.0 Hz), 12.37 (s, 1H). LC-MS (ESIþ) m=z ¼ 291.1 [M þ H]þ.
1-Methyl-8-(5-methylthiophen-2-yl)-9-propyl-1H-purine-2,6(3H,9H)-
dione (10b7)
1H NMR (DMSO-d6): d 0.85 (t, 3H, J ¼ 6.0 Hz), 1.66 (m, 2H), 2.50 (s, 3H),
3.20 (s, 3H), 4.17 (t, 2H, J ¼ 6.0 Hz), 6.89 (d, 1H, J ¼ 2.4 Hz), 7.30 (d, 1H,
J ¼ 2.0 Hz), 12.33 (s, 1H). LC-MS (ESIþ) m=z ¼ 305.1 [M þ H]þ.
1-Methyl-9-propyl-8-(thiazol-2-yl)-1H-purine-2,6(3H,9H)-dione (10b8)
1H NMR (DMSO-d6): d 0.86 (t, 3H, J ¼ 6.0 Hz), 1.73 (m, 2H), 3.20 (s, 3H),
4.54 (t, 2H, J ¼ 6.0 Hz), 7.87 (d, 1H, J ¼ 2.8 Hz), 7.98 (d, 1H, J ¼ 2.8 Hz), 12.51 (s,
1H). LC-MS (ESIþ) m=z ¼ 292.1 [M þ H]þ.
1-Methyl-8-(4-methylthiazol-2-yl)-9-propyl-1H-purine-2,6(3H,9H)-
dione (10b9)
1H NMR (DMSO-d6): d 0.87 (t, 3H, J ¼ 6.0 Hz), 1.73 (m, 2H), 2.43 (s, 3H),
3.21 (s, 3H), 4.52 (t, 2H, J ¼ 6.0 Hz), 7.14 (s, 1H), 12.49 (s, 1H). LC-MS (ESIþ)
m=z ¼ 306.2 [M þ H]þ.
8-(Benzo[d]thiazol-2-yl)-9-butyl-1-methyl-1H-purine-2,6(3H,9H)-
dione (10c1)
1H NMR (DMSO-d6): d 0.92 (t, 3H, J ¼ 6.0 Hz), 1.38 (m, 2H), 1.75 (m, 2H),
3.14 (s, 3H), 4.69 (t, 2H, J ¼ 6.0 Hz), 7.53 (m, 2H), 8.02 (d, 1H, J ¼ 6.3 Hz), 8.16
(d, 1H, J ¼ 6.3 Hz), 12.60 (s, 1H). LC-MS (ESIþ) m=z ¼ 356.1 [M þ H]þ.
8-(Benzo[d]oxazol-2-yl)-9-butyl-1-methyl-1H-purine-2,6(3H,9H)-
dione (10c2)
1H NMR (DMSO-d6): d 0.92 (t, 3H, J ¼ 6.0 Hz), 1.35 (m, 2H), 1.75 (m, 2H),
3.23 (s, 3H), 4.65 (t, 2H, J ¼ 6.0 Hz), 7.49 (m, 2H), 7.85 (t, 2H, J ¼ 6.4 Hz), 12.63
(s, 1H). LC-MS (ESIþ) m=z ¼ 340.1 [M þ H]þ.

1432
G. LIU ET AL.
9-Butyl-1-methyl-8-(thiophen-2-yl)-1H-purine-2,6(3H,9H)-dione(10c3)
1H NMR (DMSO-d6): 0.85 (t, 3H, J ¼ 6.0 Hz), 1.28 (m, 2H), 1.60 (m, 2H), 3.20
(s, 3H), 4.23 (t, 2H, J ¼ 6.0 Hz), 7.20 (t, 1H, J ¼ 3.2 Hz), 7.51 (d, 1H, J ¼ 2.1 Hz), 7.72
(d, 1H, J ¼ 3.2 Hz), 12.36 (s, 1H). LC-MS (ESIþ) m=z ¼ 305.1 [M þ H]þ.
9-Butyl-1-methyl-8-(5-methylthiophen-2-yl)-1H-purine-2,6(3H,9H)-
dione (10c4)
1H NMR (DMSO-d6): d 0.85 (t, 3H, J ¼ 6.0 Hz), 1.28 (m, 2H), 1.60 (m, 2H),
2.40 (s, 3H), 3.20 (s, 3H), 4.20 (t, 2H, J ¼ 6.0 Hz), 6.89 (d, 1H, J ¼ 1.8 Hz), 7.30 (d,
1H, J ¼ 1.9 Hz), 12.33 (s, 1H). LC-MS (ESIþ) m=z ¼ 319.1 [M þ H]þ.
9-Butyl-1-methyl-8-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)-1H-
purine-2,6(3H,9H)-dione (10c5)
1H NMR (DMSO-d6): d 0.89 (t, 3H, J ¼ 6.0 Hz), 1.31 (m, 2H), 1.68 (m, 2H),
1.82 (m, 4H), 2.73 (m, 2H), 2.82 (m, 2H), 3.20 (s, 3H), 4.20 (t, 2H, J ¼ 6.0 Hz),
12.33 (s, 1H). LC-MS (ESIþ) m=z ¼ 360.2 [M þ H]þ.
9-Butyl-8-(4-fluorophenyl)-1-methyl-1H-purine-2,6(3H,9H)-
dione (10c6)
1H NMR (DMSO-d6): d 0.72 (t, 3H, J ¼ 6.0 Hz), 1.08 (m, 2H), 1.47 (m, 2H),
3.21 (s, 3H), 4.10 (t, 2H, J ¼ 6.0 Hz), 7.37 (m, 2H), 7.72 (m, 2H), 12.33 (s, 1H).
LC-MS (ESIþ) m=z ¼ 317.2 [M þ H]þ.
9-Butyl-8-cyclopropyl-1-methyl-1H-purine-2,6(3H,9H)-dione (10c7)
1H NMR (DMSO-d6): d 0.87 (m, 5H), 0.93 (m, 2H), 1.29 (m, 2H), 1.63 (m,
2H), 2.01 (m, 1H), 3.16 (s, 3H), 4.10 (t, 2H, J ¼ 6.0 Hz), 12.15 (s, 1H). LC-MS (ESIþ)
m=z ¼ 263.2 [M þ H]þ.
9-Butyl-1-methyl-8-(4-(trifluoromethyl)phenyl)-1H-purine-
2,6(3H,9H)-dione (10c8)
1H NMR (DMSO-d6): d 0.73 (t, 3H, J ¼ 6.0 Hz), 1.10 (m, 2H), 1.49 (m, 2H),
3.22 (s, 3H), 4.16 (t, 2H, J ¼ 6.0 Hz), 7.90 (m, 4H), 12.40 (s, 1H). LC-MS (ESIþ)
m=z ¼ 367.2 [M þ H]þ.
8-(Benzo[d]thiazol-2-yl)-9-(cyclopropylmethyl)-1-methyl-1H-purine-
2,6(3H,9H)-dione (10d1)
1H NMR (DMSO-d6): d 0.48 (d, 4H, J ¼ 5.2 Hz), 1.45 (m, 1H), 3.23 (s, 3H),
4.65 (d, 2H, J ¼ 6.0 Hz), 7.54 (m, 2H), 8.06 (d, 1H, J ¼ 6.4 Hz), 8.17 (d, 1H,
J ¼ 6.0 Hz), 12.56 (s, 1H). LC-MS (ESIþ) m=z ¼ 354.1 [M þ H]þ.

SYNTHESIS OF NOVEL XANTHINE DERIVATIVES
1433
9-(Cyclopropylmethyl)-1-methyl-8-(4,5,6,7-
tetrahydrobenzo[d]thiazol-2-yl)-1H-purine-2,6(3H,9H)-dione (10d2)
1H NMR (DMSO-d6): d 0.41 (m, 4H), 1.34 (m, 1H), 1.82 (m, 4H), 2.72 (m,
2H), 2.80 (m, 2H), 3.20 (s, 3H), 4.49 (d, 2H, J ¼ 6.0 Hz), 12.56 (s, 1H). LC-MS
(ESIþ) m=z ¼ 358.1 [M þ H]þ.
9-(Cyclopropylmethyl)-1-methyl-8-(4-methylthiazol-2-yl)-1H-purine-
2,6(3H,9H)-dione (10d3)
1H NMR (DMSO-d6): d 0.42 (m, 4H), 1.37 (m, 1H), 2.43 (s, 3H), 3.21 (s, 3H), 4.52
(d, 2H, J ¼ 6.0 Hz), 7.42 (s, 1H), 12.56 (s, 1H). LC-MS (ESIþ) m=z ¼ 318.1 [M þ H]þ.
9-(Cyclopropylmethyl)-1-methyl-8-(5-methylthiophen-2-yl)-1H-
purine-2,6(3H,9H)-dione (10d4)
1H NMR (DMSO-d6): d 0.28 (m, 2H), 0.42 (m, 2H), 1.11 (m, 1H), 2.49 (s, 3H),
3.20 (s, 3H), 4.20 (d, 2H, J ¼ 6.0 Hz), 6.90 (s, 1H), 7.40 (d, 1H, J ¼ 2.8 Hz), 12.24 (s,
1H). LC-MS (ESIþ) m=z ¼ 317.1 [M þ H]þ.
8-(Benzo[d]thiazol-2-yl)-9-benzyl-1-methyl-1H-purine-
2,6(3H,9H)-dione (10e1)
1H NMR (DMSO-d6): d 3.23 (s, 3H), 6.04 (s, 2H), 7.21 (m, 3H), 7.31 (m, 2H),
7.50 (m, 2H), 7.99 (d, 1H, J ¼ 6.4 Hz), 8.14 (d, 1H, J ¼ 6.0 Hz), 12.50 (s, 1H). LC-MS
(ESIþ) m=z ¼ 390.1 [M þ H]þ.
9-Benzyl-1-methyl-8-(4-methylthiazol-2-yl)-1H-purine-
2,6(3H,9H)-dione (10e2)
1H NMR (DMSO-d6): d 2.36 (s, 3H), 3.23 (s, 3H), 5.93 (s, 2H), 7.14 (d, 2H,
J ¼ 6.0 Hz), 7.23 (t, 1H, J ¼ 4.0 Hz), 7.31 (m, 2H), 7.37 (s, 1H), 12.50 (s, 1H). LC-MS
(ESIþ) m=z ¼ 354.1 [M þ H]þ.
9-Isopentyl-1-methyl-8-(4-methylthiazol-2-yl)-1H-purine-2,6(3H,9H)-
dione (10f1)
1H NMR (DMSO-d6): d 0.87 (d, 6H, J ¼ 4.2 Hz), 1.55 (m, 2H), 1.70 (m, 1H),
2.41 (s, 3H), 3.20 (s, 3H), 4.60 (m, 2H), 7.40 (s, 1H), 12.50 (s, 1H). LC-MS (ESIþ) m=
z ¼ 334.2 [M þ H]þ.
9-Isopentyl-1-methyl-8-(5-methylthiophen-2-yl)-1H-purine-
2,6(3H,9H)-dione (10f2)
1H NMR (DMSO-d6): d 0.87 (d, 6H, J ¼ 4.2 Hz), 1.50 (m, 2H), 1.60 (m, 1H),
2.49 (s, 3H), 3.20 (s, 3H), 4.20 (d, 2H, J ¼ 6.4 Hz), 6.80 (d, 1H, J ¼ 2.8 Hz) 7.28 (d,
1H, J ¼ 2.8 Hz), 12.38 (s, 1H). LC-MS (ESIþ) m=z ¼ 333.2 [M þ H]þ.

1434
G. LIU ET AL.
8-(Benzo[d]thiazol-2-yl)-9-isopentyl-1-methyl-1H-purine-
2,6(3H,9H)-dione (10f3)
1H NMR (DMSO-d6): d 1.00 (d, 6H, J ¼ 4.2 Hz), 1.65 (m, 2H), 1.74 (m, 1H),
3.23 (s, 3H), 4.72 (d, 2H, J ¼ 6.0 Hz), 7.51 (t, 1H, J ¼ 5.6 Hz), 7.59 (t, 1H, J ¼ 5.6 Hz),
7.99 (d, 1H, J ¼ 5.6 Hz), 8.17 (d, 1H, J ¼ 6.0 Hz), 12.64 (s, 1H). LC-MS (ESIþ)
m=z ¼ 370.1 [M þ H]þ.
8-(Benzo[d]oxazol-2-yl)-9-isopentyl-1-methyl-1H-purine-
2,6(3H,9H)-dione (10f4)
1H NMR (DMSO-d6): d 0.97 (d, 6H, J ¼ 4.2 Hz), 1.65 (m, 2H), 1.70 (m, 1H),
3.23 (s, 3H), 4.72 (d, 2H, J ¼ 6.0 Hz), 7.49 (m, 2H), 7.83 (t, 2H, J ¼ 6.0 Hz), 12.67 (s,
1H). LC-MS (ESIþ) m=z ¼ 354.2 [M þ H]þ.
8-(Benzo[d]thiazol-2-yl)-9-(3-(dimethylamino)propyl)-1-methyl-1H-
purine-2,6(3H,9H)-dione (10g1)
1H NMR (DMSO-d6): d 2.23 (m, 2H), 2.78 (s, 6H), 3.08 (m, 2H), 3.23 (s, 3H),
4.66 (t, 2H, J ¼ 5.6 Hz), 7.50 (t, 1H, J ¼ 6.0 Hz), 7.57 (t, 1H, J ¼ 6.0 Hz), 8.05 (d, 1H,
J ¼ 6.4 Hz), 8.15 (d, 1H, J ¼ 6.4 Hz). LC-MS (ESIþ) m=z ¼ 385.1 [M þ H]þ.
9-(3-(Dimethylamino)propyl)-1-methyl-8-(4-methylthiazol-2-yl)-1H-
purine-2,6(3H,9H)-dione (10g2)
1H NMR (DMSO-d6): d 2.14 (m, 2H), 2.49 (s, 3H), 2.77 (s, 6H), 3.06 (m, 2H),
3.21 (s, 3H), 4.56 (t, 2H, J ¼ 5.6 Hz), 7.42 (s, 1H). LC-MS (ESIþ) m=z ¼ 349.1
[M þ H]þ.
9-(3-(Dimethylamino)propyl)-1-methyl-8-(5-methylthiophen-2-
yl)-1H-purine-2,6(3H,9H)-dione (10g3)
1H NMR (DMSO-d6): d 1.99 (m, 2H), 2.48 (s, 3H), 2.50 (s, 6H), 2.73 (m, 2H),
3.18 (s, 3H), 4.19 (t, 2H, J ¼ 5.6 Hz), 6.88 (d, 1H, J ¼ 2.0 Hz), 7.28 (d, 1H,
J ¼ 2.0 Hz). LC-MS (ESIþ) m=z ¼ 348.1 [M þ H]þ.
8-(Benzo[d]thiazol-2-yl)-1,3-dipropyl-1H-purine-2,6(3H,9H)-
dione (14a)
1H NMR (DMSO-d6): d 0.87 (t, 3H, J ¼ 6.0 Hz), 0.92 (t, 3H, J ¼ 6.0 Hz), 1.57
(m, 2H), 1.75 (m, 2H), 3.86 (t, 2H, J ¼ 6.0 Hz), 4.01 (t, 2H, J ¼ 6.0 Hz), 7.54 (t, 1H,
J ¼ 6.0 Hz), 7.60 (t, 1H, J ¼ 6.0 Hz), 8.10 (d, 1H, J ¼ 6.8 Hz), 8.19 (d, 1H, J ¼ 6.8 Hz),
15.30 (s, 1H). LC-MS (ESIþ) m=z ¼ 370.2 [M þ H]þ.

SYNTHESIS OF NOVEL XANTHINE DERIVATIVES
1435
8-(Benzo[d]oxazol-2-yl)-1,3-dipropyl-1H-purine-2,6(3H,9H)-
dione (14b)
1H NMR (DMSO-d6): d 0.88 (t, 3H, J ¼ 6.0 Hz), 0.93 (t, 3H, J ¼ 6.0 Hz), 1.59
(m, 2H), 1.75 (m, 2H), 3.87 (t, 2H, J ¼ 6.0 Hz), 4.02 (t, 2H, J ¼ 6.0 Hz), 7.51 (m, 2H),
7.87 (d, 2H, J ¼ 6.0 Hz), 15.20 (s, 1H). LC-MS (ESIþ) m=z ¼ 354.2 [M þ H]þ.
8-(5-Methylthiophen-2-yl)-1,3-dipropyl-1H-purine-2,6(3H,9H)-
dione (14c)[18]
1
Mp ¼ 273–274 ꢀC; H NMR (DMSO-d6): d 0.88 (m, 6H), 1.56 (m, 2H), 1.71
(m, 2H), 2.49 (s, 3H), 3.85 (t, 2H, J ¼ 6.0 Hz), 3.95 (t, 2H, J ¼ 6.0 Hz), 6.89 (d, 1H,
J ¼ 2.8 Hz), 7.69 (d, 1H, J ¼ 2.8 Hz), 13.76 (s, 1H). LC-MS (ESIþ) m=z ¼ 332.2
[M þ H]þ.
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