A facile and rapid one-step synthesis of 8-substituted xanthine derivatives via tandem ring closure at room temperature

Article abstract of DOI:10.1016/j.tet.2012.03.050

N-Bromo succinimide (NBS) was found to be an efficient and regioselective reagent in combination with AIBN for an unprecedented, facile and rapid one-step synthesis of 8-substituted xanthine derivatives at room temperature. The inexpensive, nontoxic and readily available NBS efficiently promoted the condensation of several aryl/cycloaryl/heteroaryl aldehydes with 5,6-diamino-1,3-dimethyluracils in presence of catalytic amount of AIBN in a single step via radical chain reaction. The notable advantages of this protocol were short reaction time, milder reaction conditions, simple work-up procedure, no requirement for chromatographic separation, use of non-hazardous reagent/solvent and applicable to a variety of substrates.

Full text of DOI:10.1016/j.tet.2012.03.050

Supplementary Material
A facile and rapid one-step synthesis of 8-substituted xanthine
derivatives via tandem ring closure at room temperature
Prabal Bandyopadhyay,a Sumit K. Agrawal,a Manisha Sathe,a Pratibha Sharma b
and M.P. Kaushik a,*
a Process Technology Development Division, Defence R & D Establishment, Jhansi Road, Gwalior 474 002
(M.P.), India.
bSchool of Chemical Sciences, Devi Ahilya University, Khandwa Road, Indore 452 001 (M.P.), India.
*E-mail: mpkaushik@rediffmail.com; Tel.: +91-751-2343972; Fax: +91-751-2340042
Contents:
Characterization of compounds
S2-S8
Copy of HPLC Chromatogram (Evidence of purity)
Copy of 1H-NMR spectra (Evidence of purity)
S9-S18
S19-S28
S1

All the synthesized 8-substituted xanthine derivatives are fully characterized by five
1
independent characterization techniques (Melting point, FT-IR, H-NMR, HPLC
and ESI-MS) as follows:
6a
8-(4-ethoxyphenyl)-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione (6a) 1
◦
Light brown solid; Yield: 0.615 g, 82%; m.p. >300 C; FT-IR (KBr, cm-1): 3170, 1691,
1652, 1613, 1249; 1H NMR (400 MHz, DMSO-d6): δ (ppm) 1.35 (t, J = 6.8 Hz, 3H,
CH3), 3.26 (s, 3H, CH3), 3.49 (s, 3H, CH3), 4.09 (q, J = 6.8 Hz, 2H, CH2), 7.02-7.04 (m,
2H), 8.05-8.07 (m, 2H), 13.59 (s, br, 1H, NH); HPLC RT (min) 3.325; ESI-MS: m/z 301
[M+H]+.
6b
8-(2-hydroxyphenyl)-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione (6b) 1
◦
Light brown solid; Yield: 0.470 g, 69%; m.p. >300 C; FT-IR (KBr, cm-1): 3460, 3149,
1
1703, 1661; H NMR (400 MHz, DMSO-d6): δ (ppm) 3.27 (s, 3H, CH3), 3.49 (s, 3H,
CH3), 6.94-6.98 (m, 1H), 6.99-7.01 (m, 1H), 7.34-7.38 (m, 1H), 8.07-8.09 (m, 1H), 11.62
(s, br, 1H, OH), 13.77 (s, br, 1H, NH); HPLC RT (min) 3.302; ESI-MS: m/z 273 [M+H]+.
6c
8-(4-hydroxyphenyl)-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione (6c) 1
◦
Light yellow solid; Yield: 0.537 g, 79%; m.p. >300 C; FT-IR (KBr, cm-1): 3343, 3187,
1
1687, 1645, 1618; H NMR (400 MHz, DMSO-d6): δ (ppm) 3.26 (s, 3H, CH3), 3.48 (s,
3H, CH3), 6.85-6.87 (m, 2H), 7.96-7.98 (m, 2H), 10.02 (s, br, 1H, OH), 13.50 (s, br, 1H,
NH); HPLC RT (min) 2.948; ESI-MS: m/z 273 [M+H]+.
S2

6d
8-(4-ethylphenyl)-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione (6d) 1
◦
Milky white solid; Yield: 0.540 g, 76%; m.p. >300 C; FT-IR (KBr, cm-1): 3173, 1705,
1667; 1H NMR (400 MHz, DMSO-d6): δ (ppm) 1.21 (t, J = 7.6 Hz, 3H, CH3), 2.66 (q, J
= 7.6 Hz, 2H, CH2), 3.27 (s, 3H, CH3), 3.50 (s, 3H, CH3), 7.34-7.36 (m, 2H), 8.04-8.06
(m, 2H), 13.75 (s, br, 1H, NH); HPLC RT (min) 3.503; ESI-MS: m/z 285 [M+H]+.
6e
8-(4-(dimethylamino)phenyl)-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione (6e) 1
◦
Light brown solid; Yield: 0.508 g, 68%; m.p >300 C; FT-IR (KBr, cm-1): 3174, 1699,
1
1652, 1609; H NMR (400 MHz, DMSO-d6): δ (ppm) 2.99 (s, 6H, 2CH3), 3.26 (s, 3H,
CH3), 3.49 (s, 3H, CH3), 6.77-6.79 (m, 2H), 7.96-7.98 (m, 2H), 13.33 (s, br, 1H, NH);
HPLC RT (min) 3.354; ESI-MS: m/z 300 [M+H]+.
6f
8-(4-tert-butylphenyl)-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione (6f) 2
◦
Off white solid; Yield: 0.515 g, 66%; m.p. >300 C; FT-IR (KBr, cm-1): 3154, 1701,
1
1650; H NMR (400 MHz, DMSO-d6): δ (ppm) 1.31 (s, 9H, 3CH3), 3.27 (s, 3H, CH3),
3.50 (s, 3H, CH3), 7.52-7.54 (m, 2H), 8.06-8.08 (m, 2H), 13.75 (s, br, 1H, NH); HPLC
RT (min) 3.675; ESI-MS: m/z 313 [M+H]+.
6g
8-(4-ethoxy-3-methoxyphenyl)-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione (6g) 3
◦
Off white solid; Yield: 0.619 g, 75%; m.p. >300 C; FT-IR (KBr, cm-1): 3182, 1703,
1
1646, 1594, 1274; H NMR (400 MHz, DMSO-d6): δ (ppm) 1.35 (t, J = 6.8 Hz, 3H,
S3

CH3), 3.26 (s, 3H, CH3), 3.49 (s, 3H, CH3), 3.84 (s, 3H, OCH3), 4.07 (q, J = 6.8 Hz, 2H,
CH2), 7.04-7.06 (m, 1H), 7.69-7.71 (m, 1H), 7.73 (s, 1H), 13.59 (s, br, 1H, NH); HPLC
RT (min) 3.232; ESI-MS: m/z 331 [M+H]+.
6h
8-(3,4,5-trimethoxyphenyl)-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione (6h) 4
◦
Light brown solid; Yield: 0.623 g, 72%; m.p. >300 C; FTIR (KBr): 3156, 1708, 1665,
1
1226 cm-1; H NMR (400 MHz, DMSO-d6): δ (ppm) 3.27 (s, 3H, CH3), 3.51 (s, 3H,
CH3), 3.72 (s, 3H, OCH3), 3.87 (s, 6H, 2OCH3), 7.48 (s, 2H), 13.74 (s, br, 1H, NH);
HPLC RT (min) 3.112; ESI-MS: m/z 347 [M+H]+.
6i
8-(5-bromo-2-hydroxyphenyl)-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione (6i) 3
◦
Light brown solid; Yield: 0.650 g, 74%; m.p. >300 C; FT-IR (KBr, cm-1): 3453, 3183,
1
1705, 1645, 1605, 1257, 728; H NMR (400 MHz, DMSO-d6): δ (ppm) 3.26 (s, 3H,
CH3), 3.47 (s, 3H, CH3), 6.94-6.96 (m, 1H), 7.46-7.48 (m, 1H), 8.26 (s, 1H), 11.67 (s, br,
1H, OH), 13.80 (s, br, 1H, NH); HPLC RT (min) 3.658; ESI-MS: m/z 352 [M+H]+.
6j
8-(5-bromo-2-methoxyphenyl)-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione (6j) 3
◦
Light brown solid; Yield: 0.712 g, 78%; m.p. >300 C; FT-IR (KBr, cm-1): 3166, 1693,
1
1657, 1277, 760; H NMR (400 MHz, DMSO-d6): δ (ppm) 3.26 (s, 3H, CH3), 3.50 (s,
3H, CH3), 3.93 (s, 3H, OCH3), 7.17-7.19 (m, 1H), 7.63-7.65 (m, 1H), 8.10 (s, 1H), 13.01
(s, br, 1H, NH); HPLC RT (min) 4.031; ESI-MS: m/z 366 [M+H]+.
S4

6k
8-(3-(trifluoromethoxy)phenyl)-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione (6k) 3
◦
Off white solid; Yield: 0.672 g, 79%; m.p. >300 C; FT-IR (KBr, cm-1): 3170, 1699,
1668, 1596, 1295, 984; 1H NMR (400 MHz, DMSO-d6): δ (ppm) 3.27 (s, 3H, CH3), 3.50
(s, 3H, CH3), 7.48-7.50 (m, 1H), 7.64-7.68 (m, 1H), 8.10 (s, 1H), 8.16-8.18 (m, 1H),
14.09 (s, br, 1H, NH); HPLC RT (min) 3.322; ESI-MS: m/z 341 [M+H]+.
6l
4-(1,3-dimethyl-2,6-dioxo-1H-purin-8-yl)benzaldehyde (6l) 5
◦
Yellow solid; Yield: 0.511 g, 72%; m.p. >300 C; FT-IR (KBr, cm-1): 3157, 1699, 1648,
1
1603, 1530, 1212; H NMR (400 MHz, DMSO-d6): δ (ppm) 3.27 (s, 3H, CH3), 3.51 (s,
3H, CH3), 8.01-8.03 (m, 2H), 8.32-8.34 (m, 2H), 10.05 (s, 1H, CHO), 14.15 (s, br, 1H,
NH); HPLC RT (min) 3.153; ESI-MS: m/z 285 [M+H]+.
6m
8-(4-(trifluoromethylphenyl)-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione (6m) 6
◦
Off white solid; Yield: 0.656 g, 81%; m.p. >300 C; FT-IR (KBr, cm-1): 3143, 1714,
1
1647, 1602, 1119; H NMR (400 MHz, DMSO-d6): δ (ppm) 3.27 (s, 3H, CH3), 3.51 (s,
3H, CH3), 7.88-7.90 (m, 2H), 8.33-8.35 (m, 2H), 14.17 (s, br, 1H, NH); HPLC RT (min)
3.336; ESI-MS: m/z 325 [M+H]+.
O
H
N
N
6n
N
HO
O
N
O
2-(1,3-dimethyl-2,6-dioxo-1H-purin-8-yl)benzoic acid (6n) 1
◦
Light brown solid; Yield: 0.480 g, 64%; m.p. >300 C; FT-IR (KBr, cm-1): 3463, 3185,
1
1696, 1660, 1605; H NMR (400 MHz, DMSO-d6): δ (ppm) 3.27 (s, 3H, CH3), 3.46 (s,
S5

3H, CH3), 7.58-7.62 (m, 1H), 7.64-7.67 (m, 1H), 7.70-7.72 (m, 1H), 7.82-7.84 (m, 1H),
12.98 (s, br, 1H, COOH), 13.75 (s, br, 1H, NH); HPLC RT (min) 3.958; ESI-MS: m/z
301 [M+H]+.
6o
8-(furan-2-yl)-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione (6o) 7
◦
Dark brown solid; Yield: 0.382 g, 62%; m.p. >300 C; FT-IR (KBr, cm-1): 3126, 1707,
1
1648, 1601, 1253; H NMR (400 MHz, DMSO-d6): δ (ppm) 3.25 (s, 3H, CH3), 3.46 (s,
3H, CH3), 6.81-6.82 (m, 1H), 7.22-7.23 (m, 1H), 7.89-7.90 (m, 1H), 13.98 (s, br, 1H,
NH); HPLC RT (min) 3.196; ESI-MS: m/z 247 [M+H]+.
6p
8-(pyridin-3-yl)-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione (6p) 8
◦
Light brown solid; Yield: 0.502 g, 78%; m.p. >300 C; FT-IR (KBr, cm-1): 3146, 1695,
1
1645, 1607; H NMR (400 MHz, DMSO-d6): δ (ppm) 3.27 (s, 3H, CH3), 3.50 (s, 3H,
CH3), 7.53-7.56 (m, 1H), 8.42-8.45 (m, 1H), 7.65-7.66 (m, 1H), 9.27 (s, 1H), 14.09 (s, br,
1H, NH); HPLC RT (min) 3.047; ESI-MS: m/z 258 [M+H]+.
6q
8-(1H-indol-3-yl)-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione (6q) 9
◦
Green solid; Yield: 0.546 g, 74%; m.p. >300 C; FT-IR (KBr, cm-1): 3294, 1688, 1648,
1
1586; H NMR (400 MHz, DMSO-d6): δ (ppm) 3.27 (s, 3H, CH3), 3.57 (s, 3H, CH3),
7.17-7.21 (m, 2H), 7.46-7.48 (m, 1H), 8.22 (s, 1H), 8.40-8.42 (m, 1H), 11.70 (s, br, 1H,
NH of indole), 13.27 (s, br, 1H, NH); HPLC RT (min) 3.399; ESI-MS: m/z 296 [M+H]+.
S6

6r
8-(4-methoxynaphthalen-1-yl)-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione (6r) 3
◦
Dark green solid; Yield: 0.546 g, 65%; m.p. >300 C; FT-IR (KBr, cm-1): 3202, 1697,
1
1648, 1252; H NMR (400 MHz, DMSO-d6): δ (ppm) 3.25 (s, 3H, CH3), 3.55 (s, 3H,
CH3), 4.06 (s, 3H, OCH3), 7.11-7.13 (m, 1H), 7.57-7.61 (m, 1H), 7.63-7.65 (m, 1H),
7.92-7.94 (m, 1H), 8.25-8.27 (m, 1H), 8.88-8.90 (m, 1H), 13.71 (s, br, 1H, NH); HPLC
RT (min) 3.303; ESI-MS: m/z 337 [M+H]+.
6s
8-styryl-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione (6s) 10
◦
Pale yellow solid; Yield: 0.536 g, 76%; m.p. >300 C; FT-IR (KBr, cm-1): 3152, 1694,
1
1645, 1601; H NMR (400 MHz, DMSO-d6): δ (ppm) 3.25 (s, 3H, CH3), 3.48 (s, 3H,
CH3), 7.01-7.05 (m, 1H), 7.36-7.38 (m, 2H), 7.41-7.44 (m, 1H), 7.61-7.63 (m, 2H), 7.67
(s, 1H), 13.59 (s, br, 1H, NH); HPLC RT (min) 3.303; ESI-MS: m/z 283 [M+H]+.
References
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Appl. 2009, WO 2009118759 A2 20091001.
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Chem. 2006, 14, 3512.
1
HPLC Chromatogram and H-NMR spectra for all the synthesized 8-substituted
xanthine derivatives are given below as evidence of purity:
S8

HPLC Chromatogram of 8-(4-ethoxyphenyl)-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione (6a)
HPLC Chromatogram of 8-(2-hydroxyphenyl)-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione (6b)
S9

HPLC Chromatogram of 8-(4-hydroxyphenyl)-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione (6c)
HPLC Chromatogram of 8-(4-ethylphenyl)-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione (6d)
S10

HPLC Chromatogram of 8-(4-(dimethylamino)phenyl)-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione (6e)
HPLC Chromatogram of 8-(4-tert-butylphenyl)-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione (6f)
S11

HPLC Chromatogram of 8-(4-ethoxy-3-methoxyphenyl)-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione (6g)
HPLC Chromatogram of 8-(3,4,5-trimethoxyphenyl)-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione (6h)
S12

HPLC Chromatogram of 8-(5-bromo-2-hydroxyphenyl)-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione (6i)
HPLC Chromatogram of 8-(5-bromo-2-methoxyphenyl)-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione (6j)
S13

HPLC Chromatogram of 8-(3-(trifluoromethoxy)phenyl)-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione (6k)
HPLC Chromatogram of 4-(1,3-dimethyl-2,6-dioxo-1H-purin-8-yl)benzaldehyde (6l)
S14

HPLC Chromatogram of 8-(4-(trifluoromethylphenyl)-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione (6m)
HPLC Chromatogram of 2-(1,3-dimethyl-2,6-dioxo-1H-purin-8-yl)benzoic acid (6n)
S15

HPLC Chromatogram of 8-(furan-2-yl)-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione (6o)
HPLC Chromatogram of 8-(pyridin-3-yl)-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione (6p)
S16

HPLC Chromatogram of 8-(1H-indol-3-yl)-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione (6q)
HPLC Chromatogram of 8-(4-methoxynaphthalen-1-yl)-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione (6r)
S17

HPLC Chromatogram of 8-styryl-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione (6s)
1H-NMR spectra of 1,3-dimethyl-8-(4-ethylphenyl)-1H-purine-2,6-dione (d) (DMSO-d6)
S18

1H-NMR spectrum of 8-(4-ethoxyphenyl)-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione (6a) (DMSO-d6)
1H-NMR spectrum of 8-(2-hydroxyphenyl)-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione (6b) (DMSO-d6)
S19

1H-NMR spectrum of 8-(4-hydroxyphenyl)-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione (6c) (DMSO-d6)
1H-NMR spectrum of 8-(4-ethylphenyl)-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione (6d) (DMSO-d6)
S20

1H-NMR spectrum of 8-(4-(dimethylamino)phenyl)-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione (6e) (DMSO-d6)
1H-NMR spectrum of 8-(4-tert-butylphenyl)-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione (6f) (DMSO-d6)
S21

1H-NMR spectrum of 8-(4-ethoxy-3-methoxyphenyl)-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione (6g) (DMSO-d6)
O
O
H
N
N
O
N
O
N
1H-NMR spectrum of 8-(3,4,5-trimethoxyphenyl)-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione (6h) (DMSO-d6)
S22

1H-NMR spectrum of 8-(5-bromo-2-hydroxyphenyl)-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione (6i) (DMSO-d6)
1H-NMR spectrum of 8-(5-bromo-2-methoxyphenyl)-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione (6j) (DMSO-d6)
S23

1H-NMR spectrum of 8-(3-(trifluoromethoxy)phenyl)-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione (6k) (DMSO-d6)
1H-NMR spectrum of 4-(1,3-dimethyl-2,6-dioxo-1H-purin-8-yl)benzaldehyde (6l) (DMSO-d6)
S24

1H-NMR spectrum of 8-(4-(trifluoromethylphenyl)-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione (6m) (DMSO-d6)
1H-NMR spectrum of 2-(1,3-dimethyl-2,6-dioxo-1H-purin-8-yl)benzoic acid (6n) (DMSO-d6)
S25

1H-NMR spectrum of 8-(furan-2-yl)-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione (6o) (DMSO-d6)
1H-NMR spectrum of 8-(pyridin-3-yl)-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione (6p) (DMSO-d6)
S26

1H-NMR spectrum of 8-(1H-indol-3-yl)-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione (6q) (DMSO-d6)
1H-NMR spectrum of 8-(4-methoxynaphthalen-1-yl)-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione (6r) (DMSO-d6)
S27

1H-NMR spectrum of 8-styryl-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione (6s) (DMSO-d6)
S28