Copper-Catalyzed Intramolecular C-H Amination: A New Entry to Substituted Xanthine Derivatives

Article abstract of DOI:10.1055/s-0036-1588821

Catalytic synthesis of xanthines was achieved in the presence of a copper catalyst. The process involves copper-catalyzed intramolecular C-H amination of benzamidines that possess a uracil moiety and produces variously substituted xanthines generally in good to high yields. This work introduces a new, facile approach to polysubstituted xanthine compounds..

Full text of DOI:10.1055/s-0036-1588821

SYNTHESIS
0
0
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9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2017, 49, A–H
special topic
A
en
M. Shimizu et al.
Special Topic
Synthesis
Copper-Catalyzed Intramolecular C–H Amination: A New Entry to
Substituted Xanthine Derivatives
Maki Shimizu
Intramolecular C–H Amination
Noboru Hayama
O
O
R3
R1
R1
H
R3
Tetsutaro Kimachi
Kiyofumi Inamoto*
N
N
HN
N
Cu cat.
N
O
N
N
O
N
School of Pharmacy and Pharmaceutical Sciences, Mukogawa Women’s
University11-68, 9-Bancho, Koshien, Nishinomiya, Hyogo 663-8179, Ja-
pan
R2
R2
R1, R2, R3 = alkyl, aryl
xanthines
inamoto@mukogawa-u.ac.jp
• 15 examples
• up to 98% isolated yield
Published as part of the Special Topic Modern Cyclization Strategies
in Synthesis
Received: 19.03.2017
Accepted after revision: 10.04.2017
Published online: 09.05.2017
literature.6 Herein we report a novel catalytic method for
synthesizing variously substituted xanthines. The process
involves copper-catalyzed intramolecular C–H amination
reaction7 of benzamidines 1 as cyclization precursors that
possess a uracil moiety, which can be prepared readily from
commercially available materials. Using the reaction condi-
tions developed, the desired cyclized products are obtained
generally in good to high yields, providing a facile, conve-
nient, and practical route to 1,3,7,8-tetrasubstituted xan-
thines (Scheme 1).8
DOI: 10.1055/s-0036-1588821; Art ID: ss-2017-c0173-st
Abstract Catalytic synthesis of xanthines was achieved in the presence
of a copper catalyst. The process involves copper-catalyzed intramolec-
ular C–H amination of benzamidines that possess a uracil moiety and
produces variously substituted xanthines generally in good to high
yields. This work introduces a new, facile approach to polysubstituted
xanthine compounds.
Key words copper, catalysis, C–H functionalization, amination,
cyclization, xanthines
O
O
R3
R1
O
R1
O
H
R3
7
N
6
N
HN
N1
2
5
4
Cu cat.
8
3
N
Xanthine derivatives constitute a considerably import-
ant class of heterocycles, possessing well-established activi-
ties as adenosine receptor antagonists and phosphodiester-
ase inhibitors.1 The therapeutic application of xanthines in-
cludes their use as diuretics and cardiac stimulants as well
as in the treatment of bronchial asthma and vascular dis-
eases.2 Despite their importance in the medicinal area, effi-
cient and applicable synthetic methods for variously substi-
tuted xanthines remain considerably scarce. Classical meth-
ods used for the construction of the xanthine framework
usually rely on the formation of the imidazole ring in the fi-
nal steps, including Traube purine synthesis starting from
6-aminouracil derivatives.3 However, they often require
lengthy, multi-step reactions with harsh reaction condi-
tions, thus limiting their usefulness in obtaining variously
functionalized xanthines.4 Although several alternate or
improved strategies have so far been reported,5 the devel-
opment of general methods for the synthesis of xanthines,
which would realize wide substrate scope and high func-
tional group tolerance, is still essential. Moreover, catalytic
cyclization approaches using transition metals for the con-
struction of the xanthine skeleton, which would provide a
more efficient and practical route, are extremely rare in the
N9
N
N
R2
R2
1
2
(xanthines)
Scheme 1 Intramolecular C–H amination for synthesis of xanthines
On the basis of our recent fruitful results of the N-het-
erocycles synthesis via palladium-catalyzed intramolecular
C–H amination,9 the reaction of benzamidine 1a in the
presence of a palladium catalyst along with a copper salt as
a reoxidant was first examined (Table 1). The use of 20 mol
% of PdCl2(PhCN)2 and 1.5 equivalents of Cu(OAc)2 as well as
1.5 equivalents of K2CO3 base in DMF resulted in the forma-
tion of the desired cyclized product 2a in fairly good yield
(Table 1, entry 1). On the other hand, the cyclization did not
proceed efficiently without the addition of a copper salt
(entry 2). Interestingly, a further screening of reaction con-
ditions revealed that xanthine 2a did produce even in the
absence of a palladium catalyst (entry 3). Intrigued by this
apparently copper-mediated C–H amination process, exam-
ination of the effect of a copper salt was subsequently per-
formed. A survey of a variety of commercially available cop-
per(I) and copper(II) salts led to the fact that CuBr2 was the
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

B
M. Shimizu et al.
Special Topic
Synthesis
best (entries 3–10 vs. 11). Essentially, the desired cycliza-
tion did not proceed efficiently in the absence of K2CO3 (en-
try 12).
Table 2 Development of Catalytic Processa
O
O
CuBr2 (20 mol%)
Me
Me
reoxidant (1.5 equiv) Me
K2CO3 (1.5 equiv)
H
N
N
NHMe
N
As copper salts turned out to be suitable for the xan-
thine synthesis via intramolecular C–H amination, efforts
were next focused on investigation to render the process
catalytic. Indeed, the use of a reduced amount (20 mol%) of
CuBr2 led to a considerable decrease in yield (Table 2, entry
1). Thus, an effect of the reoxidant was evaluated. Although
most of the reoxidants employed were unfortunately inef-
fective (entries 2–7), we were delighted to find that xan-
thine 2a was produced in 51% yield when PhI(OAc)2 was
used (entry 8). PhI(OAc)2 itself did not mediate the C–H am-
ination (entry 9).10 From subsequent systematic solvent
screening (entries 10–17), it was found that changing the
solvent system from DMF to DMSO/pyridine (1:1) enabled
this process to be performed more efficiently, providing 2a
in high yield (entry 17).
With an optimal process in hand, the substrate scope of
this newly developed xanthine synthesis was investigated
next. The above-obtained optimized reaction conditions
were found to be applicable to the synthesis of variously
substituted benzamidines 1b–o (Table 3). A wide range of
substrates that has alkyl (Me, i-Pr), benzyl, and aryl groups
as a substituent R3 were successfully utilized for the C–H
solvent
120 °C
1 h to overnight
N
O
N
N
O
N
Me
Me
1a
2a
Entry
Reoxidant
Solvent
Yield (%)b
1
2
none
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
MeCN
9
17
19
14
3
O2
3
Ag3PO4
4
Ag3PO4, O2
CF3CO2Ag
DTBP
5
6
26
13
51
0
7
TBHP
8
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
9c
10
11
12
13
14
15
16
17
63
38
39
7
1,4-dioxane
toluene
pyridine
57
41
61
74
DMF/DMSO (1:1)
DMF/pyridine (1:1)
DMSO/pyridine (1:1)
Table 1 Initial Screening of Reaction Parametersa
a Reaction was run on a 0.10 mmol scale in solvent (2 mL).
b Isolated yield.
Pd catalyst (20 mol%)
copper salt (1.5 equiv)
K2CO3 (1.5 equiv)
O
O
Me
Me
Me
c In the absence of CuBr2.
H
N
N
NHMe
N
DMF
100–120 °C
1 h to overnight
N
O
N
N
O
N
cyclization, affording the corresponding xanthines general-
ly in good to high yields. Halogen atoms such as F, Cl, and Br
were all compatible with this transformation (Table 3, en-
tries 5–7 and 12). In addition to 1,3-dialkylxanthines 2a–n,
1,3-diphenylxanthine 2o could also be prepared in good
yield, indicating the wide substrate scope of the catalytic
system (entry 15).11
In conclusion, we have developed a copper-based cata-
lytic system that successfully effects intramolecular C–H
amination of benzamidines possessing a uracil moiety,
leading to a novel method for the construction of xanthine
scaffolds. Variously substituted benzamidines, which can
be readily prepared from commercially available materials,
were smoothly reacted in the presence of a CuBr2 catalyst
along with PhI(OAc)2 as the reoxidant. Studies to improve
the catalytic efficiency of the process as well as to further
broaden the substrate scope are currently under way.
Me
Me
1a
2a
Entry
Pd catalyst
Copper salt
Yield (%)b
1
2
PdCl2(PhCN)2
PdCl2(PhCN)2
none
Cu(OAc)2
none
52
trace
65
0
3
Cu(OAc)2
CuO
4
none
5
none
CuCl
0
6
none
CuI
0
7
none
CuTCc
Cu(acac)2
CuF2
37
14
trace
11
70
2
8
none
9
none
10
11
12d
none
CuCl2
none
CuBr2
CuBr2
none
a Reaction was run on a 0.10 mmol scale in DMF (2 mL).
b Isolated yield.
c CuTC: Copper(I) thiophene-2-carboxylate.
d In the absence of K2CO3.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

C
M. Shimizu et al.
Special Topic
Synthesis
Table 3 Substrate Scopea
was removed under a reduced pressure and the crude N-substituted
benzamidine obtained was used for the next reaction without further
purification.
O
CuBr2 (20 mol%)
PhI(OAc)2 (1.5 equiv)
K2CO3 (1.5 equiv)
O
R3
R1
O
R1
O
H
R3
N
A solution of the above crude N-substituted benzamidine (10.0
mmol) in DMF (5 mL) was added dropwise at 0 °C to a solution of NaH
(20.0 mmol) in DMF (5 mL) and stirred for 30 min. A solution of 1,3-
dimethyl-6-chlorouracil (5.0 mmol) in DMF (5 mL) was added drop-
wise at 0 °C and the reaction mixture was stirred at 80 °C overnight.
Sat. aq NH4Cl (20 mL) was added at 0 °C and the mixture was extract-
ed with EtOAc (5 × 10 mL). The combined organic phases were
washed with H2O (2 × 10 mL) and brine (1 × 10 mL), and dried
(MgSO4). The solvent was removed under reduced pressure and the
crude material was purified by silica gel column chromatography to
give 1a–e,h,k–o.
N
HN
N
DMSO/pyridine (1:1)
100–120 °C, 1–27 h
N
N
N
N
R2
R2
1a–o
2a–o
Entry
2
R1
Me
R2
Me
R3
Me
Yield (%)b
1
2
2a
2b
2c
2d
2e
2f
74
42
51
78
77
98
89
78
80
89
96
98
61
58
77
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Pr
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Pr
i-Pr
3
Bn
4
Ph
Benzamidines 1f,g,i,j; General Procedure B
5
4-FC6H4
A mixture of benzamidine hydrochloride (5.0 mmol), aryl iodide (7.5
mmol), CuI (1.0 mmol), and Cs2CO3 (15.0 mmol) in DMF (10 mL) was
stirred at 90 °C overnight. H2O (10 mL) was added and the mixture
was extracted with EtOAc (3 × 10 mL). The combined organic phases
were washed with H2O (3 × 10 mL) and brine (1 × 10 mL), and dried
(Na2SO4). The solvent was removed under a reduced pressure and the
crude material was purified by silica gel column chromatography to
give the intermediate N-substituted benzamidine.
6
4-ClC6H4
7
2g
2h
2i
4-BrC6H4
8
4-MeOC6H4
2-MeOC6H4
3-MeC6H4
9
10
11
12
13
14
15
2j
2k
2l
3,4,5-(MeO)3C6H2
A solution of the above N-substituted benzamidine (1.0 mmol) in
DMF (5 mL) was added dropwise at 0 °C to a solution of NaH (4.0
mmol) in DMF (5 mL) and stirred for 30 min. A solution of 1,3-di-
methyl-6-chlorouracil (2.0 mmol) in DMF (5 mL) was added dropwise
at 0 °C and the reaction mixture was stirred at 80 °C overnight. Sat. aq
NH4Cl (10 mL) was added at 0 °C and the mixture was extracted with
EtOAc (5 × 10 mL). The combined organic phases were washed with
H2O (2 × 10 mL) and brine (1 × 10 mL), and dried (MgSO4). The solvent
was removed under a reduced pressure and the crude material was
purified by silica gel column chromatography to give 1f,g,i,j.
3-Cl-4-MeOC6H3
2m
2n
2o
Me
Me
Me
Hex
Ph
Hex
Ph
a Reaction was run on a 0.10 mmol scale in solvent (2 mL).
b Isolated yield.
N-(1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-6-yl)-N′-
methylbenzamidine (1a)
All reactions were carried out under an argon atmosphere unless oth-
erwise noted. Anhydrous solvents, including DMSO and pyridine,
were purchased from Sigma-Aldrich. All other commercially available
materials were purchased from Sigma-Aldrich, Tokyo Chemical Indus-
try Co., and Wako Pure Chemical Industries, and were used as re-
ceived. Melting points were measured with a Yanaco micro melting
point apparatus and are uncorrected. IR spectra were recorded on a
Shimadzu IRAffinity-1 spectrophotometer. 1H NMR spectra were re-
corded on a Jeol JNM-ECP400 (400 MHz) spectrometer. Chemical
shifts (δ) are given from TMS (0 ppm) in CDCl3 and coupling constants
are expressed in hertz (Hz). Standard abbreviations are used to de-
note signal multiplicities. 13C NMR spectra were recorded on a Jeol
JNM-ECP400 (100 MHz) spectrometer. Chemical shifts (δ) are given
from 13CDCl3 (77.0 ppm). Mass spectra and high-resolution mass
spectra were recorded on a Jeol JMS-700 instrument.
According to General Procedure A, starting from MeNH2; mp 234.5–
238.9 °C; colorless needles (hexane/EtOAc).
IR (film): 3252, 1686, 1653, 1630, 1587, 1560, 1474, 1431, 1410,
1277, 1240, 1211 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.42 (1 H, t, J = 7.6 Hz), 7.35 (2 H, t, J =
7.6 Hz), 7.20 (2 H, d, J = 7.6 Hz), 5.72 (1 H, br), 4.43 (1 H, s), 3.49 (3 H,
s), 3.20 (3 H, s), 3.06 (3 H, d, J = 4.8 Hz).
13C NMR (100 MHz, CDCl3): δ = 163.2, 161.3, 158.2, 152.7, 132.7,
131.0, 129.1, 127.2, 88.2, 30.4, 29.1, 27.6.
MS (EI): m/z (%) = 272 (83) [M+], 271 (100).
HRMS: m/z calcd for C14H16N4O2: 272.1273; found: 272.1274.
N-Isopropyl-N′-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrim-
Benzamidines 1a–e,h,k–o; General Procedure A
idin-6-yl)benzamidine (1b)
The required amine (20.0 mmol) was added dropwise at 0 °C to a
solution of ethyl benzimidate hydrochloride (10.0 mmol) in EtOH (15
mL) and the reaction mixture was stirred at r.t. to reflux overnight.
EtOH was removed under a reduced pressure and 1 M aq NaOH (15
mL) was added. The mixture was extracted with CHCl3 (3 × 10 mL)
and the combined organic phases were dried (MgSO4): The solvent
According to General Procedure A, starting from i-PrNH2; mp 216.6–
219.1 °C; colorless needles (hexane/EtOAc).
IR (film): 3265, 1690, 1630, 1605, 1585, 1541, 1528, 1431, 1375,
1277, 1236, 1167, 1101 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.43 (1 H, t, J = 7.6 Hz), 7.36 (2 H, t, J =
7.3 Hz), 7.20 (2 H, d, J = 7.3 Hz), 5.21 (1 H, br), 4.43 (1 H, s), 4.29–4.21
(1 H, m), 3.49 (3 H, s), 3.23 (3 H, s), 1.31 (6 H, d, J = 6.4 Hz).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

D
M. Shimizu et al.
Special Topic
Synthesis
13C NMR (100 MHz, CDCl3): δ = 163.2, 159.8, 158.1, 152.8, 133.0,
131.0, 129.1, 127.2, 88.2, 44.1, 30.5, 27.6, 22.4.
MS (EI): m/z (%) = 300 (100) [M+].
1H NMR (400 MHz, CDCl3): δ = 7.56–7.54 (3 H, m), 7.47 (1 H, t, J = 7.4
Hz), 7.41–7.37 (2 H, m), 7.33–7.26 (4 H, m), 4.53 (1 H, s), 3.44 (3 H, s),
3.16 (3 H, s).
13C NMR (100 MHz, CDCl3): δ = 163.1, 157.6, 157.5, 152.5, 137.0,
132.6, 131.5, 130.1, 129.3, 129.1, 127.3, 122.1, 88.6, 30.8, 27.6.
HRMS: m/z calcd for C16H20N4O2: 300.1586; found: 300.1586.
MS (EI): m/z (%) = 368 (86) [M+], 367 (100).
HRMS: m/z calcd for C19H1735ClN4O2: 368.1040; found: 368.1041.
N-Benzyl-N′-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimi-
din-6-yl)benzamidine (1c)
According to General Procedure A, starting from benzylamine; mp
227.5–229.0 °C; colorless needles (hexane/EtOAc).
N-(4-Bromophenyl)-N′-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetra-
hydropyrimidin-6-yl)benzamidine (1g)
IR (film): 3275, 1686, 1630, 1609, 1589, 1541, 1528, 1431, 1329,
1279, 1209, 1163, 1128 cm–1
.
According to General Procedure B, starting from 1-bromo-4-iodo-
benzene; mp 264.3–268.1 °C; pale yellow scales (hexane/EtOAc).
1H NMR (400 MHz, CDCl3): δ = 7.46–7.32 (8 H, m), 7.24 (2 H, d, J = 8.0
Hz), 5.66 (1 H, br), 4.68 (2 H, d, J = 5.6 Hz), 4.49 (1 H, s), 3.39 (3 H, s),
3.23 (3 H, s).
IR (film): 3275, 1701, 1630, 1582, 1528, 1489, 1429, 1395, 1375,
1340, 1277, 1202, 1094, 1072, 1007 cm–1
.
13C NMR (100 MHz, CDCl3): δ = 163.2, 160.2, 157.9, 152.7, 137.4,
132.5, 131.3, 129.3, 129.0, 127.9, 127.7, 127.2, 88.5, 46.4, 30.4, 27.6.
MS (EI): m/z (%) = 348 (100) [M+].
1H NMR (400 MHz, CDCl3): δ = 7.50–7.46 (5 H, m), 7.40 (2 H, t, J = 7.6
Hz), 7.34 (1 H, br), 7.29 (2 H, d, J = 7.6 Hz), 4.56 (1 H, s), 3.45 (3 H, s),
3.19 (3 H, s).
13C NMR (100 MHz, CDCl3): δ = 163.0, 157.5, 157.4, 152.5, 137.5,
132.6, 132.1, 131.5, 129.4, 127.3, 122.4, 117.8, 88.7, 30.8, 27.7.
HRMS: m/z calcd for C20H20N4O2: 348.1586; found: 348.1583.
MS (EI): m/z (%) = 413 (100), 412 (78) [M+].
HRMS: m/z calcd for C19H1779BrN4O2: 412.0535; found: 412.0461.
N-(1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-6-yl)-N′-
phenylbenzamidine (1d)
According to General Procedure A, starting from aniline; mp 107.7–
110.2 °C; colorless needles (hexane/EtOAc).
N-(4-Methoxyphenyl)-N′-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetra-
hydropyrimidin-6-yl)benzamidine (1h)
IR (film): 3275, 1695, 1628, 1585, 1541, 1528, 1508, 1499, 1491,
1474, 1466, 1458, 1431, 1375, 1340, 1204, 1094 cm–1
.
According to General Procedure A, starting from 4-methoxyaniline;
mp 180.6–182.4 °C; pale yellow needles (hexane/EtOAc).
1H NMR (400 MHz, CDCl3): δ = 7.59 (2 H, d, J = 7.7 Hz), 7.52 (1 H, br),
7.45 (1 H, d, J = 7.7 Hz), 7.40–7.34 (4 H, m), 7.29 (2 H, d, J = 7.7 Hz),
7.18 (1 H, t, J = 7.7 Hz), 4.54 (1 H, s), 3.45 (3 H, s), 3.16 (3 H, s).
IR (film): 3280, 1692, 1632, 1589, 1541, 1535, 1510, 1437, 1414,
1375, 1344,1292, 1248, 1204, 1093, 10332, 1001 cm–1
.
13C NMR (100 MHz, CDCl3): δ = 163.1, 157.6 (2 C), 152.5, 138.5, 132.9,
131.3, 129.2, 129.0, 127.4, 125.0, 120.9, 88.5, 30.7, 27.6.
MS (EI): m/z (%) = 334 (93) [M+], 333 (100).
1H NMR (400 MHz, CDCl3): δ = 7.48–7.38 (5 H, m), 7.32 (2 H, d, J = 7.2
Hz), 7.10 (1 H, br), 6.89 (2 H, d, J = 8.8 Hz), 4.58 (1 H, s), 3.82 (3 H, s),
3.45 (3 H, s), 3.22 (3 H, s).
13C NMR (100 MHz, CDCl3): δ = 163.1, 157.7, 157.1, 152.6, 133.0,
131.3, 129.3, 127.4, 122.9, 114.3, 88.5, 55.5, 30.7, 27.6.
HRMS: m/z calcd for C19H18N4O2: 334.1430; found: 334.1428.
MS (EI): m/z (%) = 364 (100) [M+].
N-(4-Fluorophenyl)-N′-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetra-
hydropyrimidin-6-yl)benzamidine (1e)
HRMS: m/z calcd for C20H20N4O3: 364.1535; found: 364.1533.
According to General Procedure A, starting from 4-fluoroaniline; mp
225.9–226.8 °C; colorless scales (hexane/EtOAc).
N-(2-Methoxyphenyl)-N′-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetra-
hydropyrimidin-6-yl)benzamidine (1i)
IR (film): 3283, 1695, 1630, 1609, 1593, 1541, 1528, 1508, 1437,
1408, 1375, 1340, 1277, 1200, 1092, 1001 cm–1
.
According to General Procedure B, starting from 2-iodoanisole; mp
221.5–222.7 °C; pale yellow prisms (hexane/EtOAc).
1H NMR (400 MHz, CDCl3): δ = 7.54–7.47 (3 H, m), 7.43 (2 H, t, J = 7.3
Hz), 7.32 (2 H, d, J = 7.3 Hz), 7.09–7.04 (3 H, m), 4.61 (1 H, s), 3.46 (3 H,
s), 3.23 (3H, s).
IR (film): 3390, 1695, 1641, 1628, 1618, 1587, 1533, 1458, 1429,
1371, 1288, 1250, 1202, 1115, 1026 cm–1
.
13C NMR (100 MHz, CDCl3): δ = 163.1, 159.9 (J = 244.0 Hz), 157.7,
157.4, 152.6, 134.3 (J = 3.2 Hz), 132.7, 131.6, 129.5, 127.3, 122.9 (J =
8.0 Hz), 115.9 (J = 22.2 Hz), 88.8, 30.8, 27.7.
1H NMR (400 MHz, CDCl3): δ = 8.38 (1 H, d, J = 7.9 Hz), 7.60 (1 H, br),
7.51–7.42 (3 H, m), 7.35 (2 H, d, J = 7.6 Hz), 7.12 (1 H, t, J = 7.9 Hz),
7.00 (1 H, t, J = 7.9 Hz), 6.94 (1 H, d, J = 7.9 Hz), 4.62 (1 H, s), 3.90 (3 H,
s), 3.51 (3 H, s), 3.27 (3 H, s).
13C NMR (100 MHz, CDCl3): δ = 163.1, 157.6, 157.1, 152.7, 148.7,
133.4, 131.4, 129.4, 128.1, 127.4, 124.6, 121.0, 120.3, 110.2, 88.7, 55.9,
30.8, 27.7.
MS (EI): m/z (%) = 352 (88) [M+], 351 (100).
HRMS: m/z calcd for C19H17FN4O2: 352.1336; found: 352.1336.
N-(4-Chlorophenyl)-N′-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetra-
hydropyrimidin-6-yl)benzamidine (1f)
MS (EI): m/z (%) = 364 (42) [M+], 333 (100).
HRMS: m/z calcd for C20H20N4O3: 364.1535; found: 364.1537.
According to General Procedure B, starting from 1-chloro-4-iodo-
benzene; mp 253.6–256.2 °C; yellow scales (hexane/EtOAc).
N-(1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-6-yl)-N′-
(3-methylphenyl)benzamidine (1j)
IR (film): 3279, 1695, 1632, 1584, 1533, 1491, 1437, 1400, 1375,
1341, 1277, 1204, 1088, 1013, 1001 cm–1
.
According to General Procedure B, starting from 3-iodotoluene; mp
215.1–217.2 °C; colorless needles (hexane/EtOAc).
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M. Shimizu et al.
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Synthesis
IR (film): 3273, 1692, 1630, 1609, 1585, 1545, 1533, 1489, 1429,
1375, 1339, 1277, 1261, 1225, 1209, 1169, 1098, 1026 cm–1
N-(1,3-Dihexyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-6-yl)-N′-
methylbenzamidine (1n)
.
1H NMR (400 MHz, CDCl3): δ = 7.47–7.22 (9 H, m), 6.99 (1 H, d, J = 7.2
Hz), 4.57 (1 H, s), 3.45 (3 H, s), 3.19 (3 H, s), 2.36 (3 H, s).
13C NMR (100 MHz, CDCl3): δ = 163.1, 157.6 (2 C), 152.6, 139.0, 138.3,
133.0, 131.3, 129.2, 128.9, 127.3, 125.9, 121.5, 118.0, 88.5, 30.7, 27.6,
21.5.
According to General Procedure A using 1,3-dihexyl-6-chlorouracil in-
stead of 1,3-dimethyl-6-chlorouracil, and starting from MeNH2; mp
98.5–102.6 °C; brown scales (hexane/EtOAc).
IR (film): 3273, 1692, 1636, 1587, 1553, 1437, 1420, 1400, 1368,
1315, 1263, 1155, 1123, 1067, 1032 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.42 (1 H, t, J = 7.3 Hz), 7.35 (2 H, t, J =
7.3 Hz), 7.24 (2 H, d, J = 7.3 Hz), 5.58 (1 H, br), 4.35 (1 H, s), 4.02 (2 H,
t, J = 7.3 Hz), 3.80 (2 H, t, J = 7.3 Hz), 3.04 (3 H, s), 1.77 (2 H, quint, J =
7.3 Hz), 1.56–1.53 (2 H, m), 1.42–1.27 (12 H, m), 0.90 (3 H, t, J = 7.3
Hz), 0.86 (3 H, t, J = 7.3 Hz).
13C NMR (100 MHz, CDCl3): δ = 163.0, 161.1, 157.6, 152.2, 132.6,
131.0, 129.1, 127.2, 88.4, 43.8, 41.0, 31.53, 31.50, 29.1, 28.6, 27.7,
26.61, 26.58, 22.6, 22.5, 14.0.
MS (EI): m/z (%) = 348 (100) [M+].
HRMS: m/z calcd for C20H20N4O2: 348.1586; found: 348.1588.
N-(3,4,5-Trimethoxyphenyl)-N′-(1,3-dimethyl-2,4-dioxo-1,2,3,4-
tetrahydropyrimidin-6-yl)benzamidine (1k)
According to General Procedure A, starting from 3,4,5-trimethoxy-
aniline; mp 220.8–222.2 °C; white scales (hexane/EtOAc).
IR (film): 3289, 1701, 1630, 1589, 1541, 1505, 1431, 1412, 1375,
MS (EI): m/z (%) = 412 (99) [M+], 395 (100)
1323, 1229, 1126, 1098, 1003 cm–1
.
HRMS: m/z calcd for C24H36N4O2: 412.2838; found: 412.2840.
1H NMR (400 MHz, CDCl3): δ = 7.48 (1 H, t, J = 7.3 Hz), 7.42 (2 H, t, J =
7.3 Hz), 7.32 (2 H, d, J = 7.3 Hz), 7.11 (1 H, br), 6.89 (2 H, s), 4.60 (1 H,
s), 3.84 (3 H, s), 3.82 (6 H, s), 3.51 (3 H, s), 3.23 (3 H, s).
13C NMR (100 MHz, CDCl3): δ = 163.0, 157.6, 157.3, 153.4, 152.6,
135.6, 134.3, 133.0, 131.4, 129.4, 127.3, 98.8, 88.8, 61.0, 56.2, 30.7,
27.7.
N-(1,3-Diphenyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-6-yl)-N′-
methylbenzamidine (1o)
According to General Procedure A using 1,3-diphenyl-6-chlorouracil
instead of 1,3-dimethyl-6-chlorouracil, and starting from MeNH2; mp
259.7–262.8 °C; yellow scales (hexane/EtOAc).
MS (EI): m/z (%) = 424 (100) [M+].
IR (film): 3302, 1707, 1647, 1630, 1585, 1560, 1545, 1533, 1491,
HRMS: m/z calcd for C22H24N4O5: 424.1747; found: 424.1743.
1381, 1333, 1285, 1217, 1155, 1111, 1072, 1011 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.49–7.20 (15 H, m), 5.23 (1 H, br), 4.72
(1 H, s), 2.64 (3 H, d, J = 4.8 Hz).
13C NMR (100 MHz, CDCl3): δ = 163.2, 160.0, 158.2, 152.3, 136.9,
135.6, 132.5, 131.1, 129.2, 129.1, 128.9, 128.7, 128.6, 128.2, 128.1,
127.2, 88.6, 28.9.
N-(3-Chloro-4-methoxyphenyl)-N′-(1,3-dimethyl-2,4-dioxo-
1,2,3,4-tetrahydropyrimidin-6-yl)benzamidine (1l)
According to General Procedure A, starting from 3-chloro-4-methoxy-
aniline; mp 244.9–246.9 °C; colorless needles (hexane/EtOAc).
IR (film): 3267, 1701, 1628, 1611, 1585, 1501, 1429, 1400, 1375,
MS (EI): m/z (%) = 396 (61) [M+], 276 (100).
1279, 1261, 1202, 1096, 1063, 1022, 1001 cm–1
.
HRMS: m/z calcd for C24H20N4O2: 396.1586; found: 396.1585.
1H NMR (400 MHz, CDCl3): δ = 7.66 (1 H, d, J = 2.0 Hz), 7.49–7.38 (4 H,
m), 7.29 (2 H, d, J = 8.0 Hz), 7.23 (1 H, br), 6.92 (1 H, d, J = 8.8 Hz), 4.55
(1 H, s), 3.91 (3 H, s), 3.45 (3 H, s), 3.20 (3 H, s).
13C NMR (100 MHz, CDCl3): δ = 163.1, 157.6, 157.5, 152.6, 132.7,
131.8, 131.5, 129.3, 127.3, 123.6, 122.7, 120.7, 112.2, 88.7, 56.4, 30.8,
27.7.
Cu-Catalyzed Xanthine Synthesis; 1,3,7-Trimethyl-8-phenylxan-
thine (2a); Typical Procedure (Table 2, Entry 17)
A mixture of 1a (27.2 mg, 0.10 mmol), CuBr2 (4.5 mg, 0.020 mmol),
PhI(OAc)2 (48.3 mg, 0.15 mmol), and K2CO3 (20.7 mg, 0.15 mmol) in
DMSO (1 mL) and pyridine (1 mL) was stirred at 120 °C for 4 h. Sat. aq
NH4Cl (5 mL) was added and the mixture was filtered through a pad
of Celite. The filtrate was extracted with CHCl3 (3 × 10 mL) and the
combined organic phases were washed with H2O (2 × 10 mL) and
brine (1 × 10 mL), and dried (Na2SO4). The solvent was removed under
reduced pressure and the crude material was purified by silica gel col-
umn chromatography using hexane/EtOAc (1:1) as an eluent to give
xanthine 2a; yield: 20.0 mg (74%); colorless solid.
MS (EI): m/z (%) = 398 (100) [M+].
HRMS: m/z calcd for C20H1935ClN4O3: 398.1146; found: 398.1140.
N-Methyl-N′-(1,3-Dipropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimi-
din-6-yl)benzamidine (1m)
According to General Procedure A using 1,3-dipropyl-6-chlorouracil
instead of 1,3-dimethyl-6-chlorouracil, and starting from MeNH2; mp
189.1–191.2 °C; pale yellow needles (hexane/EtOAc).
IR (film): 1701, 1655, 1630, 1605, 1541, 1458, 1427, 1377, 1341,
1290, 1233, 1080, 1036 cm–1
.
IR (film): 3237, 1686, 1630, 1584, 1545, 1533, 1437, 1420, 1398,
1H NMR (400 MHz, CDCl3): δ = 7.71–7.68 (2 H, m), 7.55–7.51 (3 H, m),
1379, 1364, 1341, 1323, 1279, 1260, 1153, 1051 cm–1
.
4.06 (3 H, s), 3.63 (3 H, s), 3.44 (3 H, s).
13C NMR (100 MHz, CDCl3): δ = 155.6, 152.1, 151.7, 148.3, 130.3,
129.2, 128.9, 128.5, 108.6, 33.8, 29.7, 27.9.
MS (EI): m/z (%) = 270 (100) [M+].
1H NMR (400 MHz, CDCl3): δ = 7.43 (1 H, t, J = 7.2 Hz), 7.36 (2 H, t, J =
7.2 Hz), 7.24 (2 H, d, J = 7.2 Hz), 5.57 (1 H, br), 4.35 (1 H, s), 3.99 (2 H,
t, J = 7.4 Hz), 3.78 (2 H, t, J = 7.4 Hz), 3.04 (3 H, d, J = 4.8 Hz), 1.80 (2 H,
sext, J = 7.4 Hz), 1.58 (2 H, sext, J = 7.4 Hz), 1.00 (3 H, t, J = 7.4 Hz), 0.87
(3 H, t, J = 7.4 Hz).
HRMS: m/z calcd for C14H14N4O2: 270.1117; found: 270.1119.
13C NMR (100 MHz, CDCl3): δ = 163.1, 161.1, 157.6, 152.3, 132.6,
131.0, 129.1, 127.2, 88.3, 45.2, 42.4, 29.2, 22.0, 21.0, 11.3, 11.2.
MS (EI): m/z (%) = 328 (100) [M+].
7-Isopropyl-1,3-dimethyl-8-phenylxanthine (2b)
Reaction conditions: 120 °C, 27 h; colorless solid; yield: 12.4 mg
(42%).
HRMS: m/z calcd for C18H24N4O2: 328.1899; found: 328.1893.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

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M. Shimizu et al.
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Synthesis
IR (film): 1701, 1663, 1543, 1518, 1452, 1395, 1225, 1211, 1036, 1022
cm–1
13C NMR (100 MHz, CDCl3): δ = 154.4, 151.6, 151.3, 148.8, 135.5,
134.1, 130.2, 129.4, 129.2, 129.0, 128.6, 128.0, 109.0, 29.9, 28.0.
.
1H NMR (400 MHz, CDCl3): δ = 7.58–7.52 (5 H, m), 4.69 (1 H, sept, J =
6.9 Hz), 3.63 (3 H, s) 3.47 (3 H, s), 1.65 (6 H, d, J = 6.8 Hz).
13C NMR (100 MHz, CDCl3): δ = 154.6, 152.1, 151.7, 149.7, 130.3,
MS (EI): m/z (%) = 366 (100) [M+].
HRMS: m/z calcd for C19H1535ClN4O2: 366.0884; found: 366.0873.
129.7, 129.4, 128.9, 107.6, 50.9, 29.9, 28.6, 21.8.
MS (EI): m/z (%) = 298 (60) [M+], 256 (100).
7-(4-Bromophenyl)-1,3-dimethyl-8-phenylxanthine (2g)
Reaction conditions: 120 °C, 1 h; colorless solid; yield: 36.4 mg (89%).
HRMS: m/z calcd for C16H18N4O2: 298.1430; found: 298.1434.
IR (film): 1701, 1663, 1605, 1528, 1491, 1445, 1395, 1331, 1225,
1132, 1065, 1047 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.57 (2 H, d, J = 8.4 Hz), 7.44 (2 H, d, J =
7.5 Hz), 7.39 (1 H, t, J = 7.5 Hz), 7.32 (2 H, t, J = 7.5 Hz), 7.20 (2 H, d, J =
8.4 Hz), 3.70 (3 H, s), 3.37 (3 H, s).
7-Benzyl-1,3-dimethyl-8-phenylxanthine (2c)
Reaction conditions: 120 °C, 23 h; colorless solid; yield: 17.5 mg
(51%).
IR (film): 1701, 1660, 1605, 1541, 1514, 1497, 1452, 1433, 1389,
13C NMR (100 MHz, CDCl3): δ = 154.5, 151.6, 151.3, 148.8, 134.7,
132.4, 130.3, 129.3, 129.2, 128.6, 128.1, 123.5, 109.0, 29.9, 28.0.
1346, 1288, 1227, 1219, 1125, 1076, 1038, 1001 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.58 (2 H, d, J = 7.8 Hz), 7.50–7.43 (3 H,
m), 7.30–7.25 (3 H, m), 7.04 (2 H, d, J = 7.8 Hz), 5.64 (2 H, s), 3.65 (3 H,
s), 3.41 (3 H, s).
MS (EI): m/z (%) = 410 (100) [M+].
HRMS: m/z calcd for C19H1579BrN4O2: 410.0378; found: 410.0375.
13C NMR (100 MHz, CDCl3): δ = 155.2, 152.6, 151.7, 148.6, 136.6,
130.5, 129.2, 128.94, 128.86, 128.6, 127.9, 126.5, 108.0, 49.4, 29.8,
28.0.
7-(4-Methoxyphenyl)-1,3-dimethyl-8-phenylxanthine (2h)
Reaction conditions: 120 °C, 4 h; colorless solid; yield: 28.2 mg (78%).
IR (film): 1734, 1701, 1663, 1609, 1533, 1508, 1458, 1298, 1250,
MS (EI): m/z (%) = 346 (100) [M+].
1173, 1049, 1030 cm–1
.
HRMS: m/z calcd for C20H18N4O2: 346.1430; found: 346.1424.
1H NMR (400 MHz, CDCl3): δ = 7.48 (2 H, d, J = 6.8 Hz), 7.37–7.22 (5 H,
m), 6.95 (2 H, d, J = 8.8 Hz), 3.85 (3 H, s), 3.70 (3 H, s), 3.37 (3 H, s).
13C NMR (100 MHz, CDCl3): δ = 160.1, 154.5, 151.7, 151.3, 148.6,
1,3-Dimethyl-7,8-diphenylxanthine (2d)
Reaction conditions: 120 °C, 1 h; colorless solid; yield: 26.0 mg (78%).
129.9, 129.2, 128.7, 128.5, 128.4, 114.4, 109.4, 55.5, 29.8, 28.0.
IR (film): 1701, 1663, 1655, 1533, 1508, 1497, 1491, 1458, 1437, 1225
MS (EI): m/z (%) = 362 (100) [M+].
cm–1
.
HRMS: m/z calcd for C20H18N4O3: 362.1379; found: 362.1381.
1H NMR (400 MHz, CDCl3): δ = 7.49–7.44 (5 H, m), 7.37–7.25 (5 H, m),
3.71 (3 H, s), 3.37 (3 H, s).
13C NMR (100 MHz, CDCl3): δ = 154.5, 151.7, 151.2, 148.7, 135.8,
130.0, 129.4, 129.2, 128.4, 127.7, 109.2, 29.9, 28.0.
MS (EI): m/z (%) = 332 (100) [M+].
7-(2-Methoxyphenyl)-1,3-dimethyl-8-phenylxanthine (2i)
Reaction conditions: 120 °C, 1 h; yellow solid; yield: 29.1 mg (80%).
IR (film): 1705, 1665, 1535, 1504, 1452, 1445, 1396, 1283, 1265,
1242, 1223, 1184, 1161, 1125, 1090, 1043, 1024 cm–1
.
HRMS: m/z calcd for C19H16N4O2: 332.1273; found: 332.1274.
1H NMR (400 MHz, CDCl3): δ = 7.50–7.43 (3 H, m), 7.33 (1 H, t, J = 7.4
Hz), 7.29–7.25 (3 H, m), 7.05–6.98 (2 H, m), 3.71 (3 H, s), 3.63 (3 H, s),
3.36 (3 H, s).
7-(4-Fluorophenyl)-1,3-dimethyl-8-phenylxanthine (2e)
Reaction conditions: 120 °C, 2 h; colorless solid; yield: 26.8 mg (77%).
13C NMR (100 MHz, CDCl3): δ = 154.8, 154.4, 151.8, 151.7, 148.6,
131.1, 129.9, 129.1, 128.9, 128.5, 128.3, 125.0, 120.8, 112.2, 109.3,
55.7, 29.8, 27.9.
IR (film): 1701, 1663, 1647, 1605, 1570, 1558, 1533, 1508, 1449,
1368, 1329, 1252, 1221, 1047 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.45 (2 H, d, J = 7.7 Hz), 7.38 (1 H, t, J =
7.7 Hz), 7.32–7.29 (4 H, m), 7.14 (2 H, t, J = 7.7 Hz), 3.78 (3 H, s), 3.71
(3 H, s).
MS (EI): m/z (%) = 362 (100) [M+].
HRMS: m/z calcd for C20H18N4O3: 362.1379; found: 362.1382.
13C NMR (100 MHz, CDCl3): δ = 162.8 (d, J = 249.5 Hz), 154.5, 151.6,
151.4, 148.7, 131.8 (d, J = 3.2 Hz), 130.2, 129.5 (d, J = 8.7 Hz), 129.2,
128.6, 128.2, 116.3 (d, J = 23.0 Hz), 109.2, 29.9, 28.0.
7-(3-Methylphenyl)-1,3-dimethyl-8-phenylxanthine (2j)
Reaction conditions: 120 °C, 1 h; colorless solid; yield: 30.9 mg (89%).
IR (film): 1705, 1665, 1605, 1533, 1491, 1452, 1395, 1364, 1331,
MS (EI): m/z (%) = 350 (25) [M+], 256 (100).
1225, 1132, 1055 cm–1
.
HRMS: m/z calcd for C19H15FN4O2: 350.1179; found: 350.1180.
1H NMR (400 MHz, CDCl3): δ = 7.48–7.45 (2 H, m), 7.37–7.32 (2 H, m),
7.30–7.28 (3 H, m), 7.13–7.11 (2 H, m), 3.71 (3 H, s), 3.38 (3 H, s), 2.37
(3 H, s).
7-(4-Chlorophenyl)-1,3-dimethyl-8-phenylxanthine (2f)
Reaction conditions: 120 °C, 1 h; colorless solid; yield: 35.9 mg (98%).
13C NMR (100 MHz, CDCl3): δ = 154.4, 151.7, 151.1, 148.6, 139.3,
135.7, 130.2, 130.0, 129.1, 129.0, 128.5, 128.4, 128.1, 124.7, 109.3,
29.8, 28.0, 21.3.
IR (film): 1707, 1665, 1647, 1607, 1533, 1508, 1495, 1452, 1398,
1368, 1329, 1225, 1090, 1049 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.45–7.24 (9 H, m), 3.70 (3 H, s), 3.37
MS (EI): m/z (%) = 346 (100) [M+].
(3 H, s).
HRMS: m/z calcd for C20H18N4O2: 346.1430; found: 346.1433.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

G
M. Shimizu et al.
Special Topic
Synthesis
7-(3,4,5-Trimethoxyphenyl)-1,3-dimethyl-8-phenylxanthine (2k)
Reaction conditions: 120 °C, 1 h; colorless solid; yield: 40.6 mg (96%).
IR (film): 1705, 1663, 1601, 1533, 1506, 1452, 1420, 1339, 1312,
7-Methyl-1,3,8-triphenylxanthine (2o)
Reaction conditions: 100 °C, 21 h; colorless solid; yield: 14.7 mg
(77%).
1283, 1237, 1236, 1128, 1040, 1007 cm–1
.
IR (film): 1713, 1674, 1589, 1526, 1514, 1491, 1450, 1425, 1389,
1375, 1331, 1296, 1146, 1115, 1072 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.50 (2 H, d, J = 8.0 Hz), 7.39–7.28 (3 H,
m), 6.54 (2 H, s), 3.90, (3 H, s), 3.74 (6 H, s), 3.70 (3 H, s), 3.39 (3 H, s).
1H NMR (400 MHz, CDCl3): δ = 7.64–7.62 (2 H, m), 7.54–7.38 (11 H,
m), 7.35–7.33 (2 H, m), 4.07 (3 H, s).
13C NMR (100 MHz, CDCl3): δ = 154.3, 153.3, 151.6, 151.2, 148.6,
138.8, 131.0, 130.1, 129.0, 128.5, 109.2, 105.5, 61.0, 56.3, 29.8, 28.0.
MS (EI): m/z (%) = 422 (100) [M+].
13C NMR (100 MHz, CDCl3): δ = 155.6, 152.5, 151.2, 148.8, 135.5,
134.8, 130.3, 129.33, 129.25, 129.1, 128.83, 128.78, 128.60, 128.58,
128.3, 109.1, 33.9.
HRMS: m/z calcd for C22H22N4O5: 422.1590; found: 422.1589.
MS (EI): m/z (%) = 394 (100) [M+].
HRMS: m/z calcd for C24H18N4O2: 394.1430; found: 394.1429.
7-(3-Chloro-4-methoxyphenyl)-1,3-dimethyl-8-phenylxanthine
(2l)
Reaction conditions: 120 °C, 1 h; yellow solid; yield: 38.9 mg (98%).
Funding Information
IR (film): 1705, 1665, 1603, 1535, 1503, 1452, 1294, 1265, 1223,
1184, 1150, 1134, 1098, 1065, 1022, 1007 cm–1
.
We gratefully acknowledge financial support by a Grant-in-Aid for
Scientific Research (C) (No. 16K08187) from the Japan Society for the
1H NMR (400 MHz, CDCl3): δ = 7.48 (2 H, d, J = 7.2 Hz), 7.40–7.29 (4 H,
m), 7.23 (1 H, dd, J = 8.5, 2.6 Hz), 6.97 (1 H, d, J = 8.5 Hz), 3.95 (3 H, s),
3.69 (3 H, s), 3.37 (3 H, s).
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13C NMR (100 MHz, CDCl3): δ = 155.8, 154.4, 151.6, 151.3, 148.6,
130.2, 129.4, 129.1, 128.6, 128.5, 128.1, 127.1, 122.9, 111.7, 109.2,
56.3, 29.8, 28.0.
MS (EI): m/z (%) = 396 (100) [M+].
HRMS: m/z calcd for C20H1735ClN4O3: 396.0989; found: 396.0988.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1588821.
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References
7-Methyl-1,3-dipropyl-8-phenylxanthine (2m)
Reaction conditions: 100 °C, 22 h; colorless solid; yield: 20.0 mg
(61%).
(1) (a) Daly, J. W. J. Med. Chem. 1982, 25, 197. (b) Stevanovich, V.
Drug News Perspect 1989, 2, 82. (c) Jacobson, K. A.; van Galen, P.
J. M.; Williams, M. J. Med. Chem. 1992, 35, 407.
IR (film): 1701, 1659, 1601, 1539, 1518, 1452, 1429, 1379, 1335,
1263, 1186, 1074, 1061 cm–1
.
(2) For selected recent examples, see: (a) Strappaghetti, G.;
Corsano, S.; Barbaro, R.; Giannaccini, G.; Betti, L. Bioorg. Med.
Chem. 2001, 9, 575. (b) Hayallah, A. M.; Sandoval-Ramírez, J.;
Reith, U.; Schobert, U.; Preiss, B.; Schumacher, B.; Daly, J. W.;
Müller, C. E. J. Med. Chem. 2002, 45, 1500. (c) Wang, Y.;
Chackalamannil, S.; Hu, Z.; Boyle, C. D.; Lankin, C. M.; Xia, Y.; Xu,
R.; Asberom, T.; Pissarnitski, D.; Stamford, A. W.; Greenlee, W.
J.; Skell, J.; Kurowski, S.; Vemulapalli, S.; Palamanda, J.; Chintala,
M.; Wu, P.; Myers, J.; Wang, P. Bioorg. Med. Chem. Lett. 2002, 12,
3149. (d) Suzuki, H.; Yamamoto, M.; Shimura, S.; Miyamoto, K.;
Yamamoto, K.; Sawanishi, H. Chem. Pharm. Bull. 2002, 50, 1163.
(e) Baraldi, P. G.; Tabrizi, M. A.; Preti, D.; Bovero, A.; Romagnoli,
R.; Fruttarolo, F.; Zaid, N. A.; Moorman, A. R.; Varani, K.; Gessi,
S.; Merighi, S.; Borea, P. A. J. Med. Chem. 2004, 47, 1434.
(f) Zablocki, J.; Kalla, R.; Perry, T.; Palle, V.; Varkhedkar, V.; Xiao,
D.; Piscopio, A.; Maa, T.; Gimbel, A.; Hao, J.; Chu, N.; Leung, K.;
Zeng, D. Bioorg. Med. Chem. Lett. 2005, 15, 609. (g) Kalla, R. V.;
Elzein, E.; Perry, T.; Li, X.; Palle, V.; Varkhedkar, V.; Gimble, A.;
Maa, T.; Zeng, D.; Zablocki, J. J. Med. Chem. 2006, 49, 3682.
(h) Yadav, R.; Bansal, R.; Kachler, S.; Klotz, K. N. Eur. J. Med.
Chem. 2014, 75, 327.
1H NMR (400 MHz, CDCl3): δ = 7.69–7.67 (2 H, m), 7.54–7.51 (3 H, m),
4.12 (2 H, t, J = 7.4 Hz), 4.05 (3 H, s), 4.01 (2 H, t, J = 7.4 Hz), 1.84 (2 H,
sext, J = 7.4 Hz), 1.71 (2 H, sext, J = 7.4 Hz), 1.01–0.96 (6 H, m).
13C NMR (100 MHz, CDCl3): δ = 155.6, 152.0, 151.2, 148.2, 130.2,
129.2, 128.8, 128.6, 108.6, 44.8, 42.8, 33.8, 21.38, 21.36, 11.3, 11.1.
MS (EI): m/z (%) = 326 (100) [M+].
HRMS: m/z calcd for C18H22N4O2: 326.1743; found: 326.1741.
1,3-Dihexyl-7-methyl-8-phenylxanthine (2n)
Reaction conditions: 100 °C, 21 h; colorless solid; yield: 23.7 mg
(58%).
IR (film): 1701, 1658, 1601, 1537, 1518, 1452, 1429, 1402, 1377,
1337, 1314, 1269, 1240, 1219, 1167, 1080, 1028 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.69–7.67 (2 H, m), 7.53–7.51 (3 H, m),
4.14 (2 H, t, J = 8.0 Hz), 4.05 (3 H, s), 4.03 (2 H, t, J = 8.0 Hz), 1.80 (2 H,
quint, J = 7.4 Hz), 1.67 (2 H, quint, J = 7.4 Hz), 1.41–1.26 (12 H, m),
0.91–0.86 (6 H, m).
13C NMR (100 MHz, CDCl3): δ = 155.6, 152.0, 151.1, 148.2, 130.2,
129.2, 128.8, 128.6, 108.7, 43.4, 41.4, 33.8, 31.54, 31.46, 29.7, 28.1,
26.7, 26.4, 22.6, 22.5, 14.00, 13.96.
(3) (a) Traube, W. Ber. Dtsch. Chem. Ges. 1900, 33, 3035. (b) Lister, J.
H. The Purines, Supplement 1, In The Chemistry of Heterocyclic
Compounds;
5
4Vo.
l
Taylor, E. C.; Weissberger, A., Eds.; Wiley: New
MS (EI): m/z (%) = 410 (100) [M+].
York, 1996.
(4) (a) Garst, J. E.; Kramer, G. L.; Wu, Y. J.; Wells, J. N. J. Med. Chem.
1976, 19, 499. (b) Müller, C. E. Synthesis 1993, 125. (c) Müller, C.
E.; Sandoval-Ramírez, J. Synthesis 1995, 1295. (d) Weyler, S.;
HRMS: m/z calcd for C24H34N4O2: 410.2682; found: 410.2684.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

H
M. Shimizu et al.
Special Topic
Synthesis
Hayallah, A. M.; Müller, C. E. Tetrahedron 2003, 59, 47. (e) Zajac,
M. A.; Zakrzewski, A. G.; Kowal, M. G.; Narayan, S. Synth.
Commun. 2003, 33, 3291.
Rev. 2015, 115, 1622. (c) Zhang, Q.; Chen, K.; Shi, B.-F. Synlett
2014, 25, 1941. (d) Gephart, R. T. III.; Warren, T. H. Organometal-
lics 2012, 31, 7728. (e) Armstrong, A.; Collins, J. C. Angew. Chem.
Int. Ed. 2010, 49, 2282.
(5) (a) Bridson, P. K.; Wang, X. Synthesis 1995, 855. (b) Herr, R. J.;
Vogt, P. F.; Meckler, H.; Trova, M. P. J. Org. Chem. 2002, 67, 188.
(c) Hergueta, A. R.; Figueira, M. J.; López, C.; Caamaño, O.;
Fernández, F.; Rodríguez-Borges, J. E. Chem. Pharm. Bull. 2002,
50, 1379. (d) Zavialov, I. A.; Dahanukar, V. H.; Nguyen, H.; Orr,
C.; Andrews, D. R. Org. Lett. 2004, 6, 2237. (e) He, R.; Lam, Y.
J. Comb. Chem. 2005, 7, 916. (f) He, R.; Ching, S. M.; Lam, Y.
J. Comb. Chem. 2006, 8, 923. (g) LaBeaume, P.; Dong, M.;
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E.; Jones, G. B. Org. Biomol. Chem. 2010, 8, 4155.
(6) There is one report that involves copper-catalyzed intramolecu-
lar C–Br amination for the synthesis of several heterocycles
including xanthines. However, only few examples were shown
and it is unknown whether the approach is general and applica-
ble for the xanthine synthesis: Szczepankiewicz, B. G.; Rohde, J.
J.; Kurukulasuriya, R. Org. Lett. 2005, 7, 1833.
(8) During the course of preparation of this manuscript, similar
xanthine synthesis based on intramolecular copper-catalyzed
C–H amination was reported, see: Morel, B.; Franck, P.; Bidange,
J.; Sergeyev, S.; Smith, D. A.; Moseley, J. D.; Maes, B. U. W. Chem-
SusChem 2017, 10, 467.
(9) (a) Inamoto, K.; Saito, T.; Katsuno, M.; Sakamoto, T.; Hiroya, K.
Org. Lett. 2007, 9, 2931. (b) Inamoto, K.; Saito, T.; Hiroya, K.; Doi,
T. Synlett 2008, 3157. (c) Inamoto, K.; Saito, T.; Hiroya, K.; Doi, T.
J. Org. Chem. 2010, 75, 3900. (d) Inamoto, K.; Kawasaki, J.;
Hiroya, K.; Kondo, Y.; Doi, T. Chem. Commun. 2012, 48, 4332.
(e) Inamoto, K. Chem. Pharm. Bull. 2013, 61, 987.
(10) For a metal-free C–H amination utilizing hypervalent iodine(III)
reagents such as PhI(OAc)2, see: Manna, S.; Serebrennikova, P.
O.; Utepova, I. A.; Antonchick, A. P. Org. Lett. 2015, 17, 4588and
references cited therein.
(7) For reviews on Cu-catalyzed C–H amination, see:
(a) Subramanian, P.; Rudolf, G. C.; Kaliappan, K. P. Chem. Asian J.
2016, 11, 168. (b) Guo, X.-X.; Gu, D.-W.; Wu, Z.; Zhang, W. Chem.
(11) Unfortunately, the precise reaction mechanism of the process is
unclear at present. For some reaction mechanisms of Cu-cata-
lyzed C–H functionalization, see refs. 7a and 7b.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H