New Approach to the Synthesis of N7-Arylguanines and N 7-Aryladenlnes

Article abstract of DOI:10.1002/ejoc.200801002

The copper-mediated arylation of 7-methylpyrimido[1, 2-α]- purin-10(3H)-one (1) in dichloromethane or of N⁷- (climethylaminojmethyleneguanine (2) in methanol in the presence of TMEDA as a base/ligand led to the preferential formation of l-aryl-

Full text of DOI:10.1002/ejoc.200801002

FULL PAPER
DOI: 10.1002/ejoc.200801002
New Approach to the Synthesis of N7-Arylguanines and N7-Aryladenines
[a]
[b]
[a]
ˇ
ˇ
Roman Keder, Hana Dvoráková, and Dalimil Dvorák*
Keywords: Nucleobases / Nitrogen heterocycles / Copper / Boron
The copper-mediated arylation of 7-methylpyrimido[1,2-a]-
purin-10(3H)-one (1) in dichloromethane or of N2-(dimeth-
ylamino)methyleneguanine (2) in methanol in the presence
of TMEDA as a base/ligand led to the preferential formation
of 1-aryl-7-methylpyrimido[1,2-a]purin-10(3H)-ones (4) and
responding 7-arylguanines. Similar arylation of N6-(dimeth-
ylamino)methyleneadenine (15) in the presence of o-phen-
anthroline instead of TMEDA afforded mainly 7-aryladenines
after hydrolysis.
7-aryl-N2-(dimethylamino)methyleneguanines (7), respec- (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
tively. These compounds can be easily hydrolysed to the cor- Germany, 2009)
methylthiopurine,[9] 6-mercaptopurine[9] (with partial S-
Introduction
arylation), 6-(2-thienyl)purine,[9] 2-amino-6-chloropurine[9]
Substituted purines, including N-arylpurines, have re-
and 2,6-dichloropurine[9,10] has been published. Also, the
cently attracted much interest as therapeutics, molecular
microwave-assisted N9-arylation of 2-substituted amino-6-
tools and probes for investigating biological systems.[1] N9-
chloropurines has been recently reported.[11] Direct aryl-
Arylpurines have been reported to serve as agonists or ant-
ation of adenine was not possible under these conditions,
agonists for adenosine receptors,[2a–2c] corticotropin-releas-
probably due to the low solubility of adenine. This problem
ing hormone receptors[2d–2f] and folic acid receptors[2g] as
was overcome by using CH3OH/H2O as the solvent[12] or
inhibitors of enzymes like phosphatidylinositol 4-kinase,[2h]
by the arylation of N6,N6-bis-BOC-adenine, which was then
adenosine[2i] and guanine[2j] deaminase and xanthine ox-
deprotected.[13] Similarly, the direct arylation of guanine,
idase.[2k–2n] Also N9-arylpurines have been reported to exhi-
due to its insolubility in most solvents, has not been re-
bit antimicrobial activity.[2g,2o] Arylguanines may be formed
ported. However, the arylguanines may be prepared indi-
in vivo by the interaction of arene oxides formed by the
rectly by the arylation of N2,N2-bis-BOC-6-chloropurine
metabolic activation of mutagenic and carcinogenic arenes
followed by acid hydrolysis.[13] TBS-protected inosine and
such as benzene[3] or PAH with cellular DNA followed by
guanosine (in which the N9 position is occupied),[14] as well
cleavage of the modified nucleobases from the DNA.[4] N7-
as unprotected guanosine and inosine,[15] have been re-
Arylpurines have been, probably due to their poor availabil-
ported to arylate selectively at the N1 position. Adeno-
ity, much less studied. 7-Phenylguanine itself has been sug-
sine[15] and 2-amino-9-benzyl-6-chloropurine[16] may be ar-
gested as a potential biological marker of exposure to ben-
ylated at the NH2 group to give N6- or N2-aryl derivatives,
zene[5] and is therefore needed (and possibly other N7-aryl-
respectively. So far copper-mediated arylation of purine
guanines) as an analytical standard for biological monitor-
bases with arylboronic acids is highly regioselective, giving
ing studies.
exclusively N9-arylated products. Only Schultz and co-
Whereas N-alkylpurines are available by the direct N-
workers have reported the formation of small amounts
alkylation of purines,[6] the synthesis of N-arylpurines relied
(Ͻ10%) of the N7-arylated isomer in the arylation of 2,6-
until recently on the cyclization of suitable pyrimidine pre-
dichloropurine.[10] Therefore heterocyclization remains the
cursors.[7] Recently, the direct N-arylation of purine deriva-
only method for the preparation of N7-arylpurines. To the
tives with arylboronic acids in the presence of cupric acetate
best of our knowledge, the only described N7-arylpurines
and a base under anhydrous conditions was reported. Thus,
are N7-phenylguanine and several N7-arylhypoxanthines
the successful N9-arylation of purine,[8] 6-chloropurine,[9] 6-
prepared by cyclization of 4-amino-1-aryl-5-imidazolecarb-
oxylates with cyanamide,[17] which is laborious and inef-
ficient.
[a] Department of Organic Chemistry, Institute of Chemical Tech-
nology, Prague,
Technická 5, 2166 28 Prague 6, Czech Republic
Fax: +420-224-354-288
Recently we observed that under specific reaction condi-
tions and with the choice of an appropriate substrate, N7-
arylated purines are the main products of the arylation with
arylboronic acids in the presence of cupric acetate. Herein
we describe the application of this methodology to the
[b] Institute of Chemical Technology, Prague,
Technická 5, 2166 28 Prague 6, Czech Republic
Fax: + 420-224-354-288
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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Eur. J. Org. Chem. 2009, 1522–1531

Synthesis of N7-Arylguanines and N7-Aryladenines
preparation of N7-arylguanine and -adenine derivatives, in which the undesired regioisomer 5a prevailed (Table 1,
respectively. To overcome the low solubility of guanine, its entries 1 and 2), was obtained in a moderate yield. When
derivatives, 7-methylpyrimido[1,2-a]purin-10(3H)-one (1)[18] TMEDA was used as the base/ligand (Table 1, entry 3), 4a
and N2-(dimethylamino)methyleneguanine (2),[19] which and 5 were obtained in a 1:1 ratio in high yield (79%). The
can easily be converted to unprotected guanine derivatives, same ratio of 4a and 5a, but in a somewhat higher overall
were used as the starting compounds (Figure 1).
yield, was observed when 1,2-dichloroethane was used as
the solvent at room temperature. Increasing the reaction
temperature resulted in a substantial lowering of the yield
in this case (entries 4 and 5). A 1:1 ratio of regioisomers
was also obtained in THF at room temperature (entry 6).
In polar solvents like CH3OH, CH3CN and DMF, the
yields of the N-arylated products were generally low, al-
though the desired N1-arylated isomer 4a becomes the main
product. In the case of DMF the reaction was also ac-
complished at 80 °C, but led to a lowering of the yield (en-
tries 7–10). Therefore, for preparative purposes, it is prefera-
ble to use dichloromethane or 1,2-dichloroethane as the sol-
vent as it gives a higher overall yield of the desired re-
gioisomer 4. Low yields of the reaction at higher tempera-
tures (entries 5 and 10) are presumably due to a low sta-
bility of the substrate at elevated temperatures under the
reaction conditions.
Figure 1. The starting purine derivatives and their numbering.
Results and Discussion
N-Arylation of 7-Methylpyrimido[1,2-a]purin-10(3H)-one
(1)
First, phenylboronic acid (3a) was used. The reaction
was carried out in the presence of 3 equiv. of 3a, a stoichio-
metric amount of copper(II) acetate and 2 equiv. of a base/
ligand. In contrast to the results reported for the N-aryl-
ation of other purine derivatives, a mixture of both regioiso-
mers 4a (corresponding to the desired N7 isomer of unpro-
tected guanine) and 5a (corresponding to the N9 isomer of
unprotected guanine) were obtained (Scheme 1, R = H).
The mixture of 4a and 5a was easily separated by column
chromatography.
Table 1. Optimization of the reaction conditions for the N-arylation
of 1 with phenylboronic acid (3a; Scheme 1, R = H).[a]
Entry Base/ligand
Solvent
Temp.
Ratio
%
4a/5a[b] Yield[c]
1
2
3
4
5
6
7
8
9
10
2,2Ј-bipyridine
o-phenanthroline CH2Cl2
CH2Cl2
room temp.
room temp.
room temp.
1:2
1:2
1:1
1:1
1:1
1:1
3:1
2:1
1:1
2:1
46
66
79
85
36
71
44
37
35
15
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
CH2Cl2
Cl(CH2)2Cl room temp.
Cl(CH2)2Cl 70 °C
THF
CH3OH
CH3CN
DMF
room temp.
room temp.
room temp.
room temp.
80 °C
DMF
[a] Reaction conditions: PhB(OH)2 (3 equiv.), Cu(OAc)2 (1 equiv.),
base (2 equiv.). [b] Established by 1H NMR spectroscopy. [c] Iso-
lated yield of the mixture of regioisomers 4a and 5a.
The yields obtained by using TMEDA in dichlorometh-
ane and 1,2-dichloroethane were similar and the best results
were obtained at room temperature. Therefore, the more
common dichloromethane in combination with TMEDA at
room temperature (Table 1, entry 3) was used for the aryl-
ation of 1 with all three isomers 3b–d of tolylboronic acid
and also with 4-styrylboronic acid (3e), which would lead
to possible metabolites of toluene and styrene (Table 2).
With only 2 equiv. of boronic acid the corresponding N-
arylated products were obtained in high isolated yields with
higher N1/N3 arylation ratios than that obtained with un-
Scheme 1. Arylation of 7-methylpyrimido[1,2-a]purin-10(3H)-one
(1).
The ratio of the arylated products was strongly depend- substituted phenylboronic acid. The highest N1/N3 ratio of
ent on the reaction conditions, especially on the base/ligand the arylation was obtained with o-tolylboronic acid. After
and solvent (Table 1). In dichloromethane in the presence isolation by column chromatography the desired N1 isomer
of triethylamine or pyridine only traces of the N-arylated 4 was converted into the corresponding N7-arylguanine 6
products were formed. In contrast, in the presence of 2,2Ј- by alkaline hydrolysis followed by acidification (Scheme 2,
bipyridine or o-phenanthroline, the mixture of 4a and 5a, Table 2).
Eur. J. Org. Chem. 2009, 1522–1531
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R. Keder, H. Dvorˇáková, D. Dvorˇák
FULL PAPER
Table 2. Synthesis of substituted N7-arylguanines (see Schemes 1 and subsequent acid-catalyzed hydrolysis afforded the de-
and 2).[a]
sired N7-arylated guanines in high yields (Scheme 4,
Boronic
acid
R
% Yield of Ratio[c] 4/5
4 + 5[b]
Hydrolysis product
(% yield)[d]
Table 4).
3a
3b
3c
3d
3e
H
66
69
60
63
70
1.4:1
5:1
2:1
2:1
2:1
6a (68)
6b (72)
6c (60)
6d (65)
6e (89)
2-CH3
3-CH3
4-CH3
4-CH2=CH
[a] Reaction conditions: ArB(OH)2 (3) (2 equiv.), Cu(OAc)2
(1 equiv.), TMEDA (2 equiv.), CH2Cl2, room temp. [b] Sum of the
isolated yields of the N1 and N3 isomers. [c] Established by 1H
NMR spectroscopy of the crude reaction mixture. [d] Isolated yield
of the hydrolysis of the N1 isomer.
Scheme 3. Arylation of N2-(dimethylamino)methyleneguanine (2).
Scheme 2. Hydrolysis of 1-aryl-7-methylpyrimido[1,2-a]purin-
10(3H)-ones 4.
Table 3. Optimization of the reaction conditions for the N-arylation
of 2 with phenylboronic acid (3a; Scheme 3, R = H).
N-Arylation of N2-(Dimethylamino)methyleneguanine (2)
Entry Base/Ligand
Solvent
Temp.
Ratio
%
N2-(Dimethylamino)methyleneguanine (2), which can be
easily prepared by condensation of guanine with DMF di-
neopentyl acetal, was reported to produce mainly the N7
derivative by alkylation.[20] Moreover, the (dimethylamino)-
methylene protecting group can be easily removed by hy-
drolysis. Therefore, we chose this substrate for the copper-
mediated N-arylation with arylboronic acids.
7a/8a[a] Yield[b]
1
2
3
4
5
6
7
o-phenanthroline CH2Cl2
2,2Ј-bipyridine CH2Cl2
o-phenanthroline CH3OH
TMEDA
TMEDA
TMEDA
TMEDA
room temp.
room temp.
room temp.
room temp.
room temp.
60 °C
1:1
1:1
4:1
6:1
6:1
6:1
10:1
83
56
38
11
62
38
43
CH2Cl2
CH3OH
CH3OH
CH2Cl2/CH3OH room temp.
(5:1)
Similarly to 1, a mixture of N7- and N9-arylated isomers
was formed in the arylation of 2 (Scheme 3). Generally, the
yields were somewhat lower than the reactions of 1, but the
ratio of N7/N9 isomers was substantially higher (Table 3).
The highest overall yield (83%), but with a low selectivity
(1:1), was obtained with o-phenanthroline in dichlorometh-
ane at room temperature (Table 3, entry 1). The same re-
8
TMEDA
CH3CN/CH3OH room temp.
(5:1)
10:1
48
1
[a] Established by H NMR spectroscopy. [b] Isolated yield of the
mixture of regioisomers 7a and 8a.
gioselectivity, but with a lower yield, was also obtained Table 4. Synthesis of the substituted N7-arylguanines
6 (see
Schemes 3 and 4).[a]
when 2,2Ј-bipyridine in dichloromethane was used (en-
Ratio[c]
7/8
Hydrolysis product
(% yield)[d]
try 2). The application of TMEDA in dichloromethane, the
conditions that gave the best results in the arylation of 1,
afforded high N7 selectivity (6:1), but only a very low over-
Boronic
acid
R
% Yield of
7 + 8[b]
3a
H
62
58
63
69
52
6:1
9:1
4:1
3:1
2:1
6a (80)
6b (94)
6c (86)
6d (89)
6e (95)
all yield (11%) (entry 4). The same N7/N9 selectivity and 3b
2-CH3
3-CH3
4-CH3
4-CH2=CH
3c
3d
3e
an acceptable yield (62%) was obtained with TMEDA in
methanol at room temperature (entry 5). A higher tempera-
ture resulted, similarly to the arylation of 1, in a lowering
of the yield (entry 6). In a mixture of methanol/acetonitrile
or methanol/dichloromethane the N7/N9 ratio was very
high (10:1), but the overall yield was low (entries 7 and 8).
Therefore, methanol in the presence of TMEDA was used
for the arylation of 2 with other boronic acids. The yields
of the N-arylation products were comparable, but the selec-
[a] Reaction conditions: ArB(OH)2 (3) (1.5 equiv.), Cu(OAc)2
(1 equiv.), TMEDA (2 equiv.), CH3OH, room temp. [b] Sum of the
isolated yields of the N7 and N9 isomers. [c] Established by 1H
NMR spectroscopy. [d] Isolated yield of the hydrolysis of the N7
isomer.
N2-(Dimethylamino)methyleneguanine (2) was diarylated
tivities were higher than those obtained with 1 (Scheme 3, when an excess of boronic acid and a prolonged reaction
Table 4). The N7 isomer was isolated by chromatography time were used. Thus, reaction of 2 with 3 equiv. of phen-
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Synthesis of N7-Arylguanines and N7-Aryladenines
N-Arylation of N6-(Dimethylamino)methyleneadenine (15)
Encouraged by the smooth arylation of N2-(dimeth-
ylamino)methyleneguanine (2), the N-arylation of N6-(di-
methylamino)methyleneadenine (15) was also attempted.
Scheme 4. Hydrolysis of 7-aryl-N2-(dimethylamino)methylene- This compound is easily accessible by the condensation of
adenine with DMF dineopentyl acetal,[21] and its high N7
guanines (7).
selectivity in alkylation reactions has been reported.[22]
Again, copper-mediated N-arylation with phenylboronic
ylboronic acid (3a) in methanol in the presence of TMEDA
acid (3a) gave a mixture of the N7 (16) and N9 (17) isomers
and a prolonged reaction time afforded a mixture of N1,N7-
with the former prevailing (Scheme 6). In contrast to the
(9), N1,N9- (10) and N3,N7- (11) diarylated products in a
guanine derivatives, o-phenanthroline as the base/ligand
ratio of 5:1:1. The formation of N3,N9-diarylated guanine
derivatives was not observed, probably for steric reasons
gave a better yield and higher N7 selectivity than TMEDA
(Table 5). We also observed the presence of 15% N9-phenyl-
(Scheme 5). The structures of the diarylated compounds
adenine (18) in the reaction mixture when methanol was
were verified by the arylation of pure N7-phenyl-N2-(di-
used as the solvent. The formation of N3-arylated adenine
methylamino)methyleneguanine (7a), which gave a mixture
was not detected. Acid hydrolysis of 16 smoothly afforded
of 9 and 11 (overall yield 79%), and by the arylation of
N7-phenyladenine in 78% yield.
the N9 isomer 8a, which afforded only the N1,N9-diarylated
derivative 10 in 72% yield. Acid hydrolysis of the obtained
(dimethylamino)methylene derivatives 9–11 then smoothly
afforded the unprotected N1,N7-diphenylguanine (12),
N1,N9-diphenylguanine (13) and N3,N7-diphenylguanine
(14) in 77, 73 and 64% yields, respectively.
Scheme 6. Arylation of N6-(dimethylamino)methyleneadenine (15).
Table 5. Optimization of the reaction conditions for the N-arylation
of 15 with phenylboronic acid (3a; Scheme 6).
Base/ligand
Solvent
Temp.
Ratio 16/17[a] % Yield[b]
Phenanthroline
Phenanthroline
TMEDA
CH2Cl2 room temp.
CH3OH room temp.
CH2Cl2 room temp.
CH3OH room temp.
5:1
6:1
–
71
75[c]
trace
57[c]
TMEDA
3:2
1
[a] Established by H NMR spectroscopy. [b] Isolated yield of the
mixture of regioisomers 16 and 17. [c] The formation of 18 (15%)
was observed.
Scheme 5. Diarylation of N2-(dimethylamino)methyleneguanine
(2).
Eur. J. Org. Chem. 2009, 1522–1531
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R. Keder, H. Dvorˇáková, D. Dvorˇák
FULL PAPER
Identification of Products and Determination of the
Regioselectivity
Table 6. Important 1H and 13C NMR shifts of the N7- and N9-
arylated purine derivatives in CDCl3 (Figure 1).
Comp.
R
2-H/8-H
C-3a/C-4 C-10a/C-5
C-2/C-8
The products obtained were characterized by the usual
4a
5a
H
H
2-Me
2-Me
3-Me
3-Me
4-Me
4-Me
4-CH2=CH
4-CH2=CH
H
H
2-Me
2-Me
3-Me
3-Me
4-Me
8.28
8.21
8.13
8.00
8.28
8.17
8.26
8.18
8.30
8.19
7.95
7.83
7.73
7.65
7.91
7.83
7.91
7.81
7.92
7.84
7.97
7.81
7.69
159.7
149.5
159.2
110.0
118.9
146.7
141.0
147.2
1
spectral methods, for example, H and 13C NMR and IR
[a]
spectroscopy. As the products give erratic elemental analy- 4b
ses, probably due to incomplete combustion, HRMS was
–
[b]
[b]
[b]
5b
4c
5c
4d
5d
4e
5e
7a
8a
7b
–
–
–
–
–
[a]
[a]
159.6
149.5
159.4
149.6
159.5
149.5
160.7
150.0
159.7
150.9
160.5
150.0
160.5
150.1
used instead. The structures of the obtained compounds
119.0
141.2
1
were determined by NMR spectroscopy. The H, 13C and
[a]
[a]
–
–
2D NMR (HMQC and HMBC) techniques were used for
the assignment of all the protons and carbons in heterocy-
clic rings of the compounds 4, 5, 7, 8, 16 and 17.[23] The
rules formulated by Kjellberg and Johansson[24] were used
119.0
109.6
119.0
111.1
121.1
112.5
120.4
111.1
121.0
111.2
121.0
141.2
146.5
140.8
143.0
137.4
143.3
138.6
143.0
137.7
143.0
137.6
142.9
137.5
143.1
137.1
140.0
to distinguish between the N7 and N9 isomers on the basis
1
of their H and 13C NMR shifts. (It is important to note 8b
7c
8c
7d
8d
7e
8e
9
10
that these rules are valid only for spectra measured in
CDCl3; in [D6]DMSO the rules cannot be used.) The 8-H
signals of the N9 isomers were reported to be shifted upfield
4-Me
relative to the corresponding signals of the N7 isomers. The
[a]
[a]
4-CH2=CH
4-CH2=CH
1,7-DiPh
1,9-DiPh
3,7-DiPh
–
–
[a]
signals of C-5 and C-8 should be very distinctive in the 13C
–
121.2
111.3
120.8
112.5
NMR spectra: the signals of C-5 in the N9 isomers should
158.7
148.2
150.5
be deshielded relative to those of the N7 isomers, whereas
11
the 13C NMR signals of C-8 of the N9 isomers should be
shifted upfield relative to the corresponding signals of the
N7 isomers. We also noticed that the shifts of the C-4 sig-
nals could be used to distinguish between the N7 and N9
isomers. The C-4 signals of the N7 isomers are deshielded
relative to those of the N9 isomers. All these trends can be
seen in Table 6. In the case of (dimethylamino)methylene
derivatives 7 and 8 (Figure 2), in which theoretically reac-
tion on the pyrimidine ring is possible, substitution on the
imidazole part was confirmed by HMBC experiments by
the detection of a three-bond interaction between 8-H and
the ipso-carbon of the aromatic ring. As 7-phenylguanine[12]
(6a), 9-phenylguanine[11] and 9-phenyladenine[10] (18) have
been described, the above assignment was confirmed after
hydrolysis of the corresponding protected derivatives by
comparison of their spectra with published data.
As far as the diphenylated compounds are concerned, the
position of one phenyl ring was unambiguously given by
their preparation starting from the N7- or N9-phenyl deriva-
tive. The chemical shifts of C-8 and C-5 follow the pattern
of the previously discussed N7- and N9-monoarylated com-
pounds and do not significantly differ from them. The only
difference can be found at C-4; one of the compounds ob-
tained by phenylation of the N7-phenyl derivative has a sim-
ilar chemical shift at C-4 as that obtained by arylation of
[a] Not detected. [b] Due to a small amount of sample the 13C
NMR spectrum was not recorded.
Figure 2. Numbering of the ring atoms of the prepared purine de-
rivatives.
13C NMR shift at C-4 of 158.7 ppm and the 3,7-disubsti-
tuted compound 11 to that having C-4 at δ = 150.5 ppm.
Conclusions
N7-Arylated guanine and adenine derivatives can be
the N9 isomer (and as other N9-aryl derivatives; Table 6). easily prepared by Cu-mediated arylation of 7-methylpyr-
The influence of the aryl ring attached to the N9 position imido[1,2-a]purin-10(3H)-one (1) or N2-(dimethylamino)-
should be very similar to that having an aryl ring attached methyleneguanine (2) with boronic acids and subsequent
to N3. Moreover, it can be expected that the formation of hydrolysis. For guanine derivatives 1 and 2 the highest N7
the 3,9-diphenylguanine derivative would be disfavoured for selectivities were obtained in methanol by using TMEDA
steric reasons and that this compound will not be formed. as the base/ligand, whereas N6-(dimethylamino)methyl-
Therefore, the structure of the 1,9-diphenyl derivative 10 eneadenine (15) gave the best results when o-phenanthroline
[δ(C-4) = 148.2 ppm] was assigned to the compound pre- was used as the base/ligand in methanol. This methodology
pared by the arylation of 9-phenyl-N2-[(dimethylamino)- allows the preparation of N7-arylpurines that are otherwise
methylene]guanine (8a). On the other hand, the 1,7-di- hard to access and that may be used, for example, as analyt-
phenyl derivative 9 was determined as that isomer having a ical standards for biological monitoring studies.
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Synthesis of N7-Arylguanines and N7-Aryladenines
(CH3), 17.1 (CH3Ph), 119.3 (C-5), 126.6, 127.7, 129.3, 130.6, 132.5,
134.9, 135.0, 132.5 (C-8), 147.5 (C-4a), 149.2 (C-3a), 158.2 (C-10),
163.2 (C-6) ppm. 1H NMR (600 MHz, CDCl3): δ = 2.17 (s, 3 H,
CH3), 2.43 (s, 3 H, CH3), 7.32 (d, J = 9.4 Hz, 1 H, Ar-H), 7.37 (t,
J = 8.8 Hz, 1 H, Ar-H), 7.42 (d, J = 8.8 Hz, 1 H, Ar-H), 7.47 (t, J
= 9.4 Hz, 1 H, Ar-H), 8.13 (s, 1 H, 2-H), 8.87 (s, 1 H, 6-H), 8.98
(s, 1 H, 8-H) ppm. 13C NMR (600 MHz, CDCl3): δ = 15.7 (CH3),
17.9 (CH3), 119.6 (C-7), 127.2 (CH-Ar), 127.7 (CH-Ar), 130.4 (CH-
Ar), 131.5 (CH-Ar), 132.9 (C-8), 134.9 (Cq-Ar), 135.7 (Cq-Ar),
147.2 (C-2), 148.4 (C-4a), 150.0 (C-10), 159.2 (C-3a), 162.6 (C-
Experimental Section
General: Dichloromethane was dried by distillation from calcium
hydride, methanol was dried by distillation from magnesium and
stored over molecular sieves. Other chemicals of analytical or syn-
thetic grade were obtained from commercial sources and were used
as received. The starting compounds 1,[13] 2[14] and 15[16] were pre-
pared according to published procedures. 1H and 13C NMR spectra
were recorded with a Bruker Avance DRX500 (500 MHz) or Var-
ian Mercury 300 (300 MHz) spectrometer with Fourier transforma-
tion. HMQC and HMBC NMR spectra were recorded with a
Bruker Avance DRX500 (500 MHz) spectrometer. Mass spectra
were measured with a Autospec Ultima (Waters, Great Britain)
magnetic segment mass spectrometer by using the ionization by
electron impact technique. IR spectra were recorded with a Nicolet
740 FTIR spectrometer with a Bruker IFS 66 microscope by using
the ATR technique. Column chromatography was performed on
silica gel 60 obtained from Fluka: particle size 0.063–0.200 mm or,
for flash chromatography, 0.035–0.070 mm.
6) ppm. IR: ν = 3411, 3111, 2924, 1706, 1537, 1512, 1495, 1470,
˜
1375, 1330, 1248, 1299.1070, 957, 779 cm–1. HRMS (EI): calcd. for
C16H13N5O 291.1120; found 291.1124.
7-Methyl-3-(2-methylphenyl)pyrimido[1,2-a]purin-10(3H)-one (5b):
1
Yellow powder; yield 7 mg (11%). H NMR (500 MHz, CDCl3): δ
= 2.43 (s, 3 H, CH3) 2.46 (s, 3 H, CH3Ar), 7.34–7.42 (m, 4 H, Ar-
H), 8.00 (s, 1 H, 2-H), 8.82 (s, 1 H, 6-H), 9.29 (s, 1 H, 8-H) ppm.
7-Methyl-1-(3-methylphenyl)pyrimido[1,2-a]purin-10(3H)-one (4c):
Yellow powder; yield 38 mg (39%); m.p. 252–258 °C. 1H NMR
(500 MHz, [D6]DMSO): δ = 2.39 (s, 3 H, CH3), 2.41 (s, 3 H,
CH3Ar), 7.31–7.32 (m, 1 H, Ar-H), 7.45–7.50 (m, 3 H, Ar-H), 8.79
(br. s, 1 H, 2-H), 8.97 (s, 1 H, 6-H), 9.08 (s, 1 H, 8-H) ppm. 13C
NMR (500 MHz, [D6]DMSO): δ = 14.6 (CH3), 20.9 (CH3Ar),
119.4 (C-10a), 122.2 (C-7), 125.6, 128.7, 132.8, 135.1, 138.5 (C-8),
147.5 (C-4a), 149.2 (C-3a), 158.9 (C-10), 163.3 (C-6) ppm. 1H
NMR (600 MHz, CDCl3): δ = 2.45 (s, 3 H, CH3), 2.48 (s, 3 H,
CH3), 7.31–7.36 (m, 3 H, Ar-H), 7.45 (t, J = 9.4 Hz, 1 H, Ar-H),
8.28 (s, 1 H, 2-H), 8.88 (s, 1 H, 6-H), 9.07 (s, 1 H, 8-H) ppm. 13C
NMR (600 MHz, CDCl3): δ = 15.6 (CH3), 21.6 (CH3), 119.5 (C-
7), 122.4 (CH-Ar), 125.8 (CH-Ar), 129.3 (CH-Ar), 129.9 (CH-Ar),
132.8 (C-8), 135.2 (Cq-Ar), 139.7 (Cq-Ar), 148.1 (C-4a), 149.7 (C-
General Procedure for the N-Arylation of Purine Derivatives 1 and
2: A mixture of purine derivative (0.33 mmol), arylboronic acid
(0.66 mmol, for diarylation 1.00 mmol), base/ligand (0.66 mmol)
(TMEDA for 1 and 2, o-phenanthroline for 15), anhydrous cop-
per(II) acetate (0.33 mmol) and dried (4-Å molecular sieves,
250 mg) in dry solvent (CH2Cl2 for 1, CH3OH for 2 and 15; 5 mL)
in a 50 mL round-bottomed flask connected to a reflux condenser
and with an anhydrous calcium chloride tube was stirred at ambi-
ent temperature for 24 h (compounds 9–11 for 48 h). Then meth-
anol (15 mL) was added and the resulting mixture was filtered
through Celite, evaporated and purified by flash chromatography
on silica gel. Acetone/ethyl acetate (1:1) was used for the separation
of 4 and 5 (N3 isomers 5 eluted first), for the separation of (dimeth-
ylamino)methylene derivatives 7 and 8 a mixture of chloroform/
methanol (10:1) was used (N7 isomer 7 eluted first). The diphenyl
derivatives 9–11 were prepared on a 0.1 mmol scale and separated
by using chloroform/methanol (20:1). The order of elution was 9,
10 and 11.
10), 159.6 (C-3a), 162.8 (C-6) ppm. IR: ν = 3106, 3043, 2921, 2852,
˜
1712, 1512, 1465, 1375, 1325, 1263, 1221, 780, 691 cm–1. HRMS
(EI): calcd. for C16H13N5O 291.1120; found 291.1115.
7-Methyl-3-(3-methylphenyl)pyrimido[1,2-a]purin-10(3H)-one (5c):
Yellow powder; yield 20 mg (21%); m.p. 219–224 °C. 1H NMR
(500 MHz, CDCl3): δ = 2.47 (s, 3 H, CH3), 2.48 (s, 3 H, CH3Ar),
7.29–7.55 (m, 4 H, Ar), 8.17 (s, 1 H, 2-H), 8.86 (s, 1 H, 6-H), 9.29
(s, 1 H, 8-H) ppm. 13C NMR (500 MHz, CDCl3): δ = 15.3 (CH3),
21.5 (CH3Ar), 119.0 (C-10a), 119.7 (C-7), 121.3, 125.6, 129.3,
129.7, 134.2, 134.2 (C-8), 141.2 (C-2), 148.5 (C-4a), 149.5 (C-3a),
7-Methyl-1-phenylpyrimido[1,2-a]purin-10(3H)-one (4a): Yellow
powder; yield 36 mg (39%); m.p. 211–214 °C. 1H NMR (600 MHz,
CDCl3): δ = 2.43 (s, 3 H, CH3), 7.45–7.70 (m, 5 H, Ph-H), 8.28 (s,
1 H, 2-H), 8.87 (s, 1 H, 6-H), 9.03 (s, 1 H, 8-H) ppm. 13C NMR
(600 MHz, CDCl3): δ = 15.7 (CH3), 110.0 (C-10a), 119.8 (C-7),
125.4 (CH-Ph), 129.2 (CH-Ph), 129.7 (CH-Ph), 135.4 (Cq-Ph),
133.0 (C-8), 146.7 (C-2), 148.3 (C-4a), 149.9 (C-10), 159.7 (C-3a),
152.7 (C-10), 163.1 (C-6) ppm. IR: ν = 3129, 3099, 2918, 1719,
˜
1708, 1526, 1480, 1369, 1321, 1206, 1108, 910, 779 cm–1. HRMS
(EI): calcd. for C16H13N5O 291.1120; found 291.1115.
163.1 (C-6) ppm. IR: ν = 3102, 2924, 1710, 1554, 1534, 1511, 1495,
˜
7-Methyl-1-(4-methylphenyl)pyrimido[1,2-a]purin-10(3H)-one (4d):
Yellow powder; yield 40 mg (42%); m.p. 281–284 °C. 1H NMR
(500 MHz, [D6]DMSO): δ = 2.46 (s, 6 H, CH3, CH3Ar), 7.35–7.44
(m, 4 H, Ar-H), 8.31 (br. s, 1 H, 2-H), 8.90 (s, 1 H, 6-H), 9.05 (s,
1 H, 8-H) ppm. 13C NMR (500 MHz, [D6]DMSO): δ = 14.6 (CH3),
20.6 (CH3Ar), 119.3 (C-10a), 124.9, 129.3, 132.7, 132.8 (C-8), 137.7
(C-2), 147.4 (C-4a), 149.1 (C-3a), 158.9 (C-10), 163.2 (C-6) ppm.
1H NMR (600 MHz, CDCl3): δ = 2.45 and 2.46 (2 s, 6 H, 2CH3),
7.36 (d, J = 9.9 Hz, 2 H, Ar-H), 7.43 (d, J = 9.9 Hz, 2 H, Ar-H),
8.26 (s, 1 H, 2-H), 8.87 (s, 1 H, 6-H), 9.04 (s, 1 H, 8-H) ppm. 13C
NMR (600 MHz, CDCl3): δ = 15.4 (CH3), 21.2 (CH3), 119.4 (C-
7), 125.0 (CH-Ar), 130.0 (CH-Ar), 132.7 (C-8), 139.2 (Cq-Ar),
1470, 1457, 1377, 1340, 1214, 955, 779 cm–1. HRMS (EI): calcd.
for C15H11N5O 277.0964; found 277.0977.
7-Methyl-3-phenylpyrimido[1,2-a]purin-10(3H)-one (5a): Yellow
powder; yield 24 mg (27%); m.p. 179–184 °C. 1H NMR (500 MHz,
CDCl3): δ = 2.47 (s, 3 H, CH3), 7.47–7.76 (m, 5 H, Ph-H), 8.21 (s,
1 H, 2-H), 8.85 (s, 1 H, 6-H), 9.28 (s, 1 H, 8-H) ppm. 13C NMR
(500 MHz, CDCl3): δ = 15.3 (CH3), 118.9 (C-10a), 119.8 (C-7),
124.0, 128.5, 129.9, 132.4, 134.2 (C-8), 141.0 (C-2), 148.5 (C-4a),
149.5 (C-3a), 152.6 (C-10), 163.2 (C-6) ppm. IR: ν = 3384, 3128,
˜
3097, 2921, 1722, 1530, 1481, 1378, 1313, 1209, 1112, 908,
779 cm–1. HRMS (EI): calcd. for C15H11N5O 277.0964; found
277.0962.
147.9 (C-4a), 149.6 (C-3a), 159.4 (C-10), 162.7 (C-6) ppm. IR: ν =
˜
3100, 2924, 2863, 1706, 1652, 1533, 1516, 1376, 1330, 1214, 954,
779 cm–1. HRMS (EI): calcd. for C16H13N5O 291.1120; found
291.1126.
7-Methyl-1-(2-methylphenyl)pyrimido[1,2-a]purin-10(3H)-one (4b):
Yellow powder; yield 60 mg (58%); m.p. 276–282 °C. 1H NMR
(500 MHz, [D6]DMSO): δ = 2.10 (s, 3 H, CH3Ar), 2.37 (s, 3 H,
CH3), 7.37–7.49 (m, 4 H, Ar-H), 8.64 (br. s, 1 H, 2-H), 8.90 (s, 2
H, 6-H and 8-H) ppm. 13C NMR (500 MHz, [D6]DMSO): δ = 14.6
7-Methyl-3-(4-methylphenyl)pyrimido[1,2-a]purin-10(3H)-one (5d):
Yellow powder; yield 20 mg (21%); m.p. 225–230 °C. 1H NMR
Eur. J. Org. Chem. 2009, 1522–1531
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1527

R. Keder, H. Dvorˇáková, D. Dvorˇák
FULL PAPER
(500 MHz, CDCl3): δ = 2.45 (s, 3 H, CH3), 2.48 (s, 3 H, CH3Ar), (500 MHz, CDCl3): δ = 2.16 (s, 3 H, CH3Ar), 3.02 and 3.12 (2 s,
7.35–7.37 (m, 2 H, Ar-H), 7.61–7.63 (m, 2 H, Ar-H), 8.18 (s, 1 H, 2- 6 H, 2 CH3), 7.26–7.36 (m, 4 H, Ar-H), 7.73 (s, 1 H, 8-H), 8.79 (s,
H), 8.85 (s, 1 H, 6-H), 9.28 (s, 1 H, 8-H) ppm. 13C NMR (500 MHz,
1 H, 11-H), 9.80 (br. s, 1 H, 1-H) ppm. 13C NMR (500 MHz,
CDCl3): δ = 15.3 (CH3), 21.1 (CH3Ar), 119.0 (C-10a), 119.6 (C-7), CDCl3): δ = 17.5 (CH3Ar), 34.9 and 41.1 (2 CH3), 112.5 (C-5),
123.9, 130.4, 132.7, 138.6, 134.2 (C-8), 141.2 (C-2), 148.5 (C-4a), 126.5, 127.2, 129.2, 130.9, 135.1, 135.2, 143.3 (C-8), 155.0 (C-6),
149.6 (C-10), 152.7 (C-3a), 163.1 (C-6) ppm. IR: ν = 3088, 2924, 156.5 (C-2), 158.1 (C-11), 159.7 (C-4) ppm. IR: ν = 3102, 2923,
˜
2526, 1729, 1532, 1487, 1379, 1328, 1310, 1221, 1111, 985, 911,
779 cm–1. HRMS (EI): calcd. for C16H13N5O 291.1120; found
291.1129.
˜
2852, 1686, 1635, 1557, 1516, 1430, 1348, 1321, 1206, 1107, 979,
783, 765 cm–1. HRMS (EI): calcd. for C15H16N6O 296.1386; found
296.1372.
N2-[(Dimethylamino)methylene]-9-(2-methylphenyl)guanine
(8b):
1-(4-Ethenylphenyl)-7-methylpyrimido[1,2-a]purin-10(3H)-one (4e):
Yellow powder; yield 44 mg (44%); m.p. 275–280 °C. 1H NMR
(300 MHz, [D6]DMSO): δ = 2.39 (s, 3 H, CH3), 5.37 (d, J =
11.0 Hz, 1 H, CH=CH2), 5.97 (d, J = 17.5 Hz, 1 H, CH=CH2),
6.84 (dd, J = 11.0, J = 17.5 Hz, 1 H), 7.65–7.67 (m, 4 H, Ar-H),
8.80 (s, 1 H, 2-H), 8.98 (s, 1 H, 6-H), 9.07 (s, 1 H, 8-H) ppm. 13C
NMR (500 MHz, [D6]DMSO): δ = 14.6 (CH3), 115.6 (CH2=CH),
119.5 (C-10a), 125.2, 126.6, 134.5, 137.0, 132.7 (C-8), 135.6
(CH2=CH), 147.6 (C-4a), 149.2 (C-3a), 158.9 (C-10), 163.4 (C-
1
Amorphous solid; yield 6 mg (6%). H NMR (500 MHz, CDCl3):
δ = 2.18 (s, 3 H, CH3Ar), 3.06 and 3.10 (2 s, 6 H, 2 CH3), 7.27–
7.44 (m, 4 H, Ar-H), 7.65 (s, 1 H, 8-H), 8.43 (s, 1 H, 11-H), 9.01
(br. s, 1 H, 1-H) ppm. 13C NMR (500 MHz, CDCl3): δ = 18.7
(CH3Ar), 35.1 and 41.3 (2 CH3), 120.4 (C-5), 126.9, 127.7, 129.3,
131.3, 133.7, 135.5, 138.6 (C-8), 150.9 (C-4), 156.8 (C-2), 157.9 (C-
11) ppm.
N2-[(Dimethylamino)methylene]-7-(3-methylphenyl)guanine
(7c):
1
6) ppm. H NMR (600 MHz, CDCl3): δ = 2.46 (s, 3 H, CH3), 5.39
White powder; yield 49 mg (50%); m.p. 243–247 °C. 1H NMR
(500 MHz, CDCl3): δ = 2.41 (s, 3 H, CH3Ar), 3.06 and 3.14 (2 s,
6 H, 2 CH3), 7.19–7.21 (m, 1 H, Ar-H), 7.32–7.35 (m, 3 H, Ar-H),
7.91 (s, 1 H, 8-H), 8.82 (s, 1 H, 11-H), 9.59 (br. s, 1 H, 1-H) ppm.
13C NMR (500 MHz, CDCl3): δ = 21.3 (CH3Ar), 34.9 and 41.2 (2
CH3), 111.1 (C-5), 121.9, 125.1, 128.8, 128.9, 135.6, 139.1, 143.0
(C-8), 154.8 (C-6), 156.5 (C-2), 158.3 (C-11), 160.5 (C-4) ppm. IR:
(d, J = 10.9 Hz, 1 H, cis CH=CH2), 5.85 (d, J = 17.6 Hz, 1 H,
trans CH=CH2), 6.80 (dd, J = 10.9, 17.6 Hz, 1 H, CH=CH2), 7.52
(d, J = 8.5 Hz, Ar-H), 7.60 (d, J = 8.4 Hz, Ar-H), 8.30 (s, 1 H, 2-
H), 8.89 (s, 1 H, 6-H), 9.06 (s, 1 H, 8-H) ppm. 13C NMR (600 MHz,
CDCl3): δ = 15.5 (CH3), 109.6 (10a), 115.8 (=CH2), 119.5 (C-7),
125.2 (CH-Ar), 127.1 (CH-Ar), 132.7 (C-8), 134.3 (Cq-Ar), 135.5
(CH=), 138.3 (Cq-Ar), 146.5 (C-2), 148.0 (C-4a), 149.6 (C-10),
ν = 3098, 2966, 2920, 2815, 1671, 1627, 1550, 1513, 1427, 1380,
˜
159.5 (C-3a), 162.9 (C-6) ppm. IR: ν = 3099, 2919, 1715, 1556,
˜
1344, 1321, 1271, 1241, 1140, 1101, 781, 684 cm–1. HRMS (EI):
calcd. for C15H16N6O 296.1386; found 296.1374.
1534, 1517, 1470, 1379, 1332, 1254, 1214, 955, 779 cm–1. HRMS
(EI): calcd. for C17H13N5O 303.1120; found 303.1119.
N2-[(Dimethylamino)methylene]-9-(3-methylphenyl)guanine
(8c):
3-(4-Ethenylphenyl)-7-methylpyrimido[1,2-a]purin-10(3H)-one (5e):
Yellow powder; yield 26 mg (26%); m.p. 186–191 °C. 1H NMR
(500 MHz, CDCl3): δ = 2.46 (s, 3 H, CH3), 5.34 (d, J = 10.9 Hz, 1
H, CH=CH2), 5.81 (d, J = 17.6 Hz, 1 H, CH=CH2), 6.76 (dd, J =
10.9, J = 17.6 Hz, 1 H), 7.56–7.58 (m, 2 H, Ar-H), 7.70–7.72 (m,
2 H, Ar-H), 8.19 (br. s, 1 H, 2-H), 8.84 (s, 1 H, 6-H), 9.26 (br. s, 1
H, 8-H) ppm. 13C NMR (500 MHz, CDCl3): δ = 15.3 (CH3), 115.4
(CH2=CH), 119.0 (C-10a), 119.8 (C-7), 123.9, 127.5, 133.5, 134.6
(C-8), 135.4 (CH2=CH), 137.7, 140.8 (C-2), 148.4 (C-4a), 149.5 (C-
Amorphous solid; yield 12 mg (13%). 1H NMR (500 MHz,
CDCl3): δ = 2.45 (s, 3 H, CH3Ar), 3.10 and 3.15 (2 s, 6 H, 2 CH3),
7.23–7.26 (m, 1 H, Ar-H), 7.39–7.42 (m, 3 H, Ar-H), 7.83 (s, 1 H,
8-H), 8.54 (s, 1 H, 11-H), 9.00 (br. s, 1 H, 1-H) ppm. 13C NMR
(500 MHz, CDCl3): δ = 18.7 (CH3Ar), 35.2 and 41.4 (2 CH3), 121.0
(C-5), 121.2, 124.5, 128.7, 129.3, 134.9, 139.7, 137.7 (C-8), 150.0
(C-4), 156.8 (C-2), 157.8 (C-6), 158.0 (C-11) ppm. IR: ν = 3102,
˜
2955, 2925, 2856, 1684, 1628, 1519, 1426, 1344, 1112 cm–1. HRMS
(EI): calcd. for C15H16N6O 296.1386; found 296.1402.
3a), 152.6 (C-10), 163.2 (C-6) ppm. IR: ν = 3378, 3101, 2926, 1731,
˜
1532, 1488, 1377, 1331, 1221, 1110, 987, 912, 781 cm–1. HRMS
(EI): calcd. for C17H13N5O 303.1120; found 303.1118.
N2-[(Dimethylamino)methylene]-7-(4-methylphenyl)guanine
(7d):
1
White powder; yield 52 mg (53%); m.p. Ͼ300 °C (dec.). H NMR
(500 MHz, CDCl3): δ = 2.40 (s, 3 H, CH3Ar), 3.08 and 3.16 (2 s,
6 H, 2 CH3), 7.26–7.28 (m, 2 H, Ar-H), 7.41–7.43 (m, 2 H, Ar-H),
7.91 (s, 1 H, 8-H), 8.83 (s, 1 H, 11-H), 9.20 (br. s, 1 H, 1-H) ppm.
13C NMR (500 MHz, CDCl3): δ = 21.1 (CH3Ph), 34.9 and 41.2 (2
CH3), 111.2 (C-5), 124.5, 129.7, 133.2, 138.2, 143.0 (C-8), 154.7 (C-
N2-[(Dimethylamino)methylene]-7-phenylguanine (7a): White pow-
der; yield 50 mg (53%); m.p. 278–284 °C. 1H NMR (500 MHz,
CDCl3): δ = 3.08 and 3.16 (2 s, 6 H, 2 CH3), 7.40–7.57 (m, 5 H,
Ar-H), 7.95 (s, 1 H, 8-H), 8.84 (s, 1 H, 11-H), 9.60 (br. s, 1 H, 1-
H) ppm. 13C NMR (500 MHz, CDCl3): δ = 35.0 and 41.2 (2 CH3),
111.1 (C-5), 124.6, 128.1, 129.1, 135.7, 143.0 (C-8), 155.0 (C-6),
6), 156.4 (C-2), 158.3 (C-11), 160.5 (C-4) ppm. IR: ν = 3109, 3031,
˜
2921, 1679, 1639, 1553, 1529, 1389, 1384, 1332, 1266, 1237, 1147,
1109, 848, 820, 782 cm–1. HRMS (EI): calcd. for C15H16N6O
296.1386; found 296.1394.
156.5 (C-2), 158.3 (C-11), 160.7 (C-4) ppm. IR: ν = 3122, 3076,
˜
3032, 2921, 1669, 1635, 1555, 1520, 1433, 1385, 1341, 1267, 1240,
1147, 1112, 759 cm–1. HRMS (EI): calcd. for C14H14N6O 282.1229;
found 282.1225.
N2-[(Dimethylamino)methylene]-9-(4-methylphenyl)guanine
(8d):
Amorphous solid; yield 15 mg (16%). 1H NMR (500 MHz,
CDCl3): δ = 2.44 (s, 3 H, CH3Ar), 3.11 and 3.16 (2 s, 6 H, 2 CH3),
7.32–7.34 (m, 2 H, Ar-H), 7.48–7.49 (m, 2 H, Ar-H), 7.81 (s, 1 H,
8-H), 8.55 (s, 1 H, 11-H), 9.26 (br. s, 1 H, 1-H) ppm. 13C NMR
(500 MHz, CDCl3): δ = 21.1 (CH3Ph), 35.2 and 41.4 (2 CH3), 121.0
(C-5), 123.8, 130.1, 132.5, 137.9, 137.6 (C-8), 150.1 (C-4), 156.8 (C-
N2-[(Dimethylamino)methylene]-9-phenylguanine (8a): Amorphous
solid; yield 8 mg (9%). 1H NMR (500 MHz, CDCl3): δ = 3.11 and
3.16 (2 s, 6 H, 2 CH3), 7.41–7.62 (m, 5 H, Ph-H), 7.83 (s, 1 H, 8-
H), 8.55 (s, 1 H, 11-H), 9.63 (br. s, 1 H, 1-H) ppm. 13C NMR
(500 MHz, CDCl3): δ = 35.2 and 41.4 (2 CH3), 121.1 (C-5), 123.8,
127.8, 129.5, 135.1, 137.4 (C-8), 150.0 (C-4), 156.9 (C-2), 158.0 (C-
2), 157.9 (C-11), 158.0 (C-6) ppm. IR: ν = 3092, 3029, 2927, 2861,
˜
11), 158.2 (C-6) ppm. IR: ν = 3093, 2925, 2850, 1691, 1637, 1545,
˜
1678, 1641, 1552, 1436, 1371, 1274, 1171, 1121, 996, 824, 784 cm–1.
HRMS (EI): calcd. for C15H16N6O 296.1386; found 296.1371.
1430, 1356, 1154, 1116, 962, 765, 691 cm–1. HRMS (EI): calcd. for
C14H14N6O 282.1229; found 282.1226.
N2-[(Dimethylamino)methylene]-7-(2-methylphenyl)guanine
(7b): N2-[(Dimethylamino)methylene]-7-(4-ethenylphenyl)guanine
(7e):
White powder; yield 51 mg (52%); m.p. 254–257 °C. 1H NMR
White powder; yield 35 mg (35%); m.p. 266–272 °C. 1H NMR
1528
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Eur. J. Org. Chem. 2009, 1522–1531

Synthesis of N7-Arylguanines and N7-Aryladenines
(500 MHz, CDCl3): δ = 3.05 and 3.15 (2 s, 6 H, 2 CH3), 5.29 (d, J
7-Phenylguanine (6a):[12] White powder; yield 15 mg (68%,
= 11.1 Hz, 1 H, CH=CH2), 5.77 (d, J = 17.1 Hz, 1 H, CH=CH2), Method A), 18 mg (80%, Method B); m.p. Ͼ 300 °C. 1H NMR
6.68 (dd, J = 10.8, J = 17.6 Hz, 1 H) 7.45–7.52 (m, 4 H, Ar-H), (300 MHz, DMSO): δ = 6.22 (br. s, 2 H, NH2), 7.41–7.60 (m, 5 H,
7.92 (br. s, 1 H, 8-H), 8.76 (s, 1 H, 11-H), 9.61 (br. s, 1 H, 1- Ph-H), 8.23 (s, 1 H, 8-H), 10.83 (br. s, 1 H, NH) ppm. 13C NMR
H) ppm. 13C NMR (500 MHz, CDCl3): δ = 35.0 and 41.3 (2 CH3),
115.2 (CH2=CH), 124.6, 126.9, 134.9, 137.6, 135.7 (CH2=CH),
(500 MHz, DMSO): δ = 107.6 (CH3), 124.4, 127.5, 128.8, 135.7,
143.3 (C-5), 153.1 (C-2), 153.8 (C-6), 161.2 (C-4) ppm. IR: ν =
˜
142.9 (C-8), 154.5 (C-6), 156.4 (C-2), 158.3 (C-11) ppm. HRMS 3311, 3162, 2922, 2852, 2767, 1670, 1558, 1496, 1471, 1390, 1334,
(EI): calcd. for C17H13N5O 308.1386; found 308.1369.
1240, 1141, 1110, 981, 761, 690 cm–1. HRMS (EI): calcd. for
C11H9N5O 227.0807; found 227.0810.
N2-[(Dimethylamino)methylene]-9-(4-ethenylphenyl)guanine
(8e):
Amorphous solid; yield 17 mg (17%). 1H NMR (500 MHz,
CDCl3): δ = 3.11 and 3.16 (2 s, 6 H, 2 CH3), 5.35 (d, J = 11.1 Hz,
1 H, CH=CH2), 5.81 (d, J = 17.6 Hz, 1 H, CH=CH2), 6.76 (dd, J
= 10.8, J = 17.3 Hz, 1 H, CH=CH2), 7.55–7.56 (m, 4 H, Ar-H),
7.84 (br. s, 1 H, 8-H), 8.55 (s, 1 H, 11-H), 9.36 (br. s, 1 H, 1-
H) ppm. 13C NMR (500 MHz, CDCl3): δ = 35.2 and 41.4 (2 CH3),
115.2 (CH2=CH), 121.2 (C-5), 123.9, 127.2, 134.4, 137.3, 135.6
(CH2=CH), 137.5 (C-8), 156.8 (C-2), 157.9 (C-6), 158.0 (C-
7-(2-Methylphenyl)guanine (6b): White powder; yield 17 mg (72%,
Method A), 23 mg (94%, Method B); m.p. Ͼ300 °C. 1H NMR
(300 MHz, DMSO): δ = 2.08 (s, 3 H, CH3), 6.21 (br. s, 2 H, NH2),
7.30–7.40 (m, 4 H, Ar-H), 7.99 (s, 1 H, 8-H), 11.32 (br. s, 1 H,
NH) ppm. 13C NMR (500 MHz, DMSO): δ = 17.1 (CH3), 109.3
(C-5), 126.5, 127.3, 128.8, 130.5, 134.7, 135.5, 143.5 (C-8), 153.1
(C-2), 153.8 (C-6), 160.1 (C-4) ppm. IR: ν = 3319, 3142, 3049, 2811,
˜
1690, 1639, 1556, 1496, 1463, 1403, 1322, 1238, 1146, 1107, 981,
762, 694 cm–1. HRMS (EI): calcd. for C12H11N5O 241.0964; found
241.0969.
11) ppm. IR: ν = 3473, 3091, 2922, 2852, 1668, 1658, 1625, 1522,
˜
1427, 1343, 1167, 1118, 966, 849, 785 cm–1. HRMS (EI): calcd. for
C17H13N5O 308.1386; found 303.1396.
7-(3-Methylphenyl)guanine (6c): White powder; yield 15 mg (60%,
Method A), 20 mg (86%, Method B); m.p. Ͼ300 °C. 1H NMR
(300 MHz, DMSO): δ = 2.37 (s, 3 H, CH3), 6.22 (br. s, 2 H, NH2),
7.23–7.40 (m, 4 H, Ar-H), 8.20 (s, 1 H, 8-H), 10.81 (br. s, 1 H,
NH) ppm. 13C NMR (600 MHz, DMSO): δ = 20.9 (CH3), 107.7
(C-5), 121.6, 124.8, 128.1, 128.6, 135.7, 138.4, 143.3 (C-8), 153.1
N2-[(Dimethylamino)methylene]-1,7-diphenylguanine (9): White
powder; yield 23 mg (63%); m.p. 255–260 °C. 1H NMR (500 MHz,
CDCl3): δ = 3.08 and 3.16 (2 s, 6 H, 2 CH3), 7.18–7.55 (m, 10 H,
2 Ph-H), 7.97 (s, 1 H, 8-H), 8.66 (s, 1 H, 11-H) ppm. 13C NMR
(500 MHz, CDCl3): δ = 34.5 and 40.8 (2 CH3), 111.3 (C-5), 124.9,
127.5, 128.0, 128.5, 128.7, 129.0, 135.6, 138.0, 143.1 (C-8), 155.4
(C-2), 153.8 (C-6), 161.1 (C-4) ppm. IR: ν = 3297, 3116, 2928, 2859,
˜
2784, 2721, 1689, 1601, 1554, 1496, 1478, 1389, 1323, 1271, 1250,
1199, 1116, 912, 857, 772, 684 cm–1. HRMS (EI): calcd. for
C12H11N5O 241.0964; found 241.0957.
(C-6), 156.8 (C-11), 157.0 (C-2), 158.7 (C-4) ppm. IR: ν = 3081,
˜
3060, 2926, 1693, 1624, 1532, 1490, 1424, 1384, 1337, 1261, 1119,
779 cm–1. HRMS (EI): calcd. for C20H18N6O 358.1542; found
358.1545.
7-(4-Methylphenyl)guanine (6d): White powder; yield 16 mg (65%,
Method A), 21 mg (89%, Method B); m.p. Ͼ300 °C. 1H NMR
(600 MHz, DMSO): δ = 2.37 (s, 3 H, CH3), 6.26 (br. s, 2 H, NH2),
7.30–7.46 (m, 4 H, Ar-H), 8.22 (s, 1 H, 8-H), 10.88 (br. s, 1 H,
NH) ppm. 13C NMR (500 MHz, DMSO): δ = 20.6 (CH3), 107.7
(C-5), 124.3, 129.2, 133.2, 137.1, 143.2 (C-8), 153.0 (C-2), 153.7 (C-
N2-[(Dimethylamino)methylene]-1,9-diphenylguanine (10): White
powder; yield 21 mg (59%); m.p. 214–218 °C. 1H NMR (500 MHz,
CDCl3): δ = 2.63 and 3.03 (2 s, 6 H, 2 CH3), 7.18–7.64 (m, 10 H,
2 Ph-H), 7.81 (s, 1 H, 8-H), 8.35 (s, 1 H, 11-H) ppm. 13C NMR
(500 MHz, CDCl3): δ = 34.6 and 40.9 (2 CH3), 120.8 (C-5), 123.6,
127.4, 127.7, 128.5, 128.7, 129.5, 135.1, 138.2, 137.1 (C-8), 148.2
6), 162.3 (C-4) ppm. IR: ν = 3321, 3156, 2894, 2762, 1681, 1659,
˜
1610, 1550, 1512, 1473, 1393, 1328, 1243, 1147, 1110, 983, 884,
855, 818, 774, 691 cm–1. HRMS (EI): calcd. for C12H11N5O
241.0964; found 241.0969.
(C-4), 156.4 (C-11), 157.2 (C-2), 158.3 (C-6) ppm. IR: ν = 2924,
˜
2853, 1694, 1624, 1503, 1484, 1371, 1343, 1122, 726 cm–1. HRMS
(EI): calcd. for C20H18N6O 358.1542; found 358.1561.
7-(4-Ethenylphenyl)guanine (6e): White powder; yield 22 mg (89%,
Method A), 24 mg (95%, Method B); m.p. Ͼ300 °C. 1H NMR
(300 MHz, DMSO): δ = 5.31 (d, J = 10.8 Hz, 1 H, CH=CH2), 5.89
(d, J = 17.6 Hz, 1 H, CH=CH2), 6.20 (br. s, 2 H, NH2), 6.78 (dd,
J = 10.8, J = 17.9 Hz, 1 H), 7.40–7.56 (m, 4 H, Ar-H), 8.18 (br. s,
1 H, 8-H), 10.85 (br. s, 1 H, NH) ppm. 13C NMR (500 MHz,
CDCl3): δ = 114.5 (C-5), 115.1 (CH2=CH), 124.4, 127.6, 135.1,
136.3, 135.6 (CH2=CH), 143.2 (C-8), 153.3 (C-2), 153.9 (C-6),
N2-[(Dimethylamino)methylene]-3,7-diphenylguanine (11): White
powder; yield 5 mg (16%); m.p. 158–162 °C. H NMR (500 MHz,
CDCl3): δ = 2.78 and 3.09 (2 s, 6 H, 2 CH3), 7.39–7.60 (m, 10 H,
2 Ph-H), 7.69 (s, 1 H, 8-H), 8.80 (s, 1 H, 11-H) ppm. 13C NMR
(500 MHz, CDCl3): δ = 34.8 and 41.0 (2 CH3), 112.5 (C-5), 124.9,
128.3, 128.4, 128.0, 128.5, 128.7, 129.0, 135.6, 138.0, 140.0 (C-8),
1
150.5 (C-4), 156.2 (C-2), 158.8 (C-11), 161.7 (C-6) ppm. IR: ν =
˜
3105, 3060, 2921, 2851, 1651, 1640, 1600, 1494, 1467, 1432, 1420,
1369, 1350, 1151, 1122, 1042, 780, 764 cm–1. HRMS (EI): calcd.
for C20H18N6O 358.1542; found 358.1559.
161.2 (C-4) ppm. IR: ν = 3489, 3324, 3107, 1701, 1631, 1544, 1508,
˜
1495, 1389, 1331, 1111, 756, 694 cm–1. HRMS (EI): calcd. for
C13H11N5O 253.0964; found 253.1000.
Preparation of the Arylguanines
1,7-Diphenylguanine (12): White powder; yield 23 mg (77%,
Method B); m.p. 289–292 °C. 1H NMR (500 MHz, DMSO): δ =
6.14 (br. s, 2 H, NH2), 7.31–7.56 (m, 10 H, Ph-H), 8.30 (s, 1 H, 8-
H) ppm. 13C NMR (500 MHz, DMSO): δ = 107.5 (C-5), 124.6,
127.6, 128.6, 129.1, 129.9, 135.6, 143.9 (C-8), 153.1 (C-2), 153.7 (C-
Method A. Hydrolysis of the Arylated Pyrimidopurines: The pyrimi-
dopurine derivative (0.1 mmol) was heated at reflux in 0.1  NaOH
(5 mL) for 4–6 h. After neutralization with 1  hydrochloric acid,
the white precipitate was collected by filtration. An analytical sam-
ple was crystallized from DMF and washed with water.
6), 159.6 (C-4) ppm. IR: ν = 3489, 3108, 1700, 1614, 1544, 1506,
˜
1454, 1434, 1389, 1336, 1269, 1114, 756, 695 cm–1. HRMS (EI):
calcd. for C17H13N5O 303.1120; found 303.1125.
Method B. Hydrolysis of the Arylated (Dimethylamino)methylenepu-
rine Derivatives: The (dimethylamino)methylenepurine derivative
(0.1 mmol) was heated at reflux in 1.0  HCl (5 mL) for 1–2 h.
After neutralization with ammonia (24% aqueous solution), the
white precipitate was collected by filtration.
1,9-Diphenylguanine (13): White powder; yield 22 mg (73%,
Method B); m.p. 295–298 °C. 1H NMR (500 MHz, DMSO): δ =
6.13 (br. s, 2 H, NH2), 7.31–7.56 (m, 10 H, Ph-H), 8.30 (s, 1 H, 8-
Eur. J. Org. Chem. 2009, 1522–1531
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1529

R. Keder, H. Dvorˇáková, D. Dvorˇák
FULL PAPER
H) ppm. 13C NMR (500 MHz, DMSO): δ = 107.4 (C-5), 124.5,
127.5, 128.6, 129.0, 129.8, 135.5, 143.8 (C-8), 153.0 (C-2), 153.6 (C-
Supporting Information (see also the footnote on the first page of
1
this article): H and 13C NMR spectra of compounds 6a–e, 12–14,
6), 159.5 (C-4) ppm. IR: ν = 3484, 3290, 3107, 3061, 1705, 1618,
18 and 19.
˜
1547, 1508, 1391, 1337, 1230, 1114, 757, 693 cm–1. HRMS (EI):
calcd. for C17H13N5O 303.1120; found 303.1120.
Acknowledgments
3,7-Diphenylguanine (14): White powder; yield 19 mg (64%,
Method B); m.p. 285–290 °C. 1H NMR (500 MHz, DMSO): δ =
6.40 (br. s, 2 H, NH2), 7.30–7.32 (m, 2 H, Ph-H), 7.45–7.58 (m, 6
H, Ph-H), 7.77–7.79 (m, 2 H, Ph-H), 8.11 (s, 1 H, 8-H) ppm. 13C
NMR (500 MHz, DMSO): δ = 116.7 (C-5), 123.8, 127.7, 129.0,
129.1, 129.4, 130.0, 135.1, 135.7, 136.7 (C-8), 149.6 (C-4), 153.9 (C-
2), 156.9 (C-6) ppm. HRMS (EI): calcd. for C17H13N5O 303.1120;
found 303.1120.
This project was supported by the Research Center “The Structure
and Synthetic Applications of Transition Metal Complexes
– LC06070” of the Ministry of Education, Youth and Sports of the
Czech Republic, by the MSM6046137301 research project of the
same Ministry, and by the Grant Agency of the Czech Republic
(grant No. 203/06/0888).
Arylation of N6-(Dimethylamino)methyleneadenine (15): A mixture
of 15 (0.33 mmol), phenylboronic acid (0.66 mmol), o-phenan-
throline (0.66 mmol), anhydrous copper(II) acetate (0.33 mmol)
and dried 4 Å molecular sieves (250 mg) in dry CH3OH (5 mL) in
a 50 mL round-bottomed flask connected to a reflux condenser
and with an anhydrous calcium chloride tube was stirred at ambi-
ent temperature for 24 h. Then methanol (15 mL) was added and
resulting mixture was filtered through Celite, evaporated and puri-
fied by flash chromatography on silica gel. Besides the arylated
(dimethylamino)methylene derivatives 16 and 17, the formation of
deprotected 9-phenyladenine (18; 15%) was also observed. Al-
though the separation of 18 was without problems using chloro-
form/methanol (10:1), chromatographic separation of 16 and 17
(first eluted) turned out to be difficult and laborious. Acid hydroly-
sis (Method B) of a mixture of 16 and 17 (0.1 mmol), which was
obtained in 71% yield, followed by chromatographic separation of
18 and 19 using chloroform/methanol (5:1) was much more effec-
tive.
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N6-[(Dimethylamino)methylene]-7-phenyladenine (16): White pow-
der; yield 52 mg (59%); m.p. 145–149 °C. 1H NMR (300 MHz,
CDCl3): δ = 2.68 and 3.06 (2 s, 6 H, 2 CH3), 7.41–7.47 (m, 5 H,
Ph-H), 8.13 (s, 1 H, 2-H), 8.64 (s, 1 H, 8-H), 8.67 (s, 1 H, 11-
H) ppm. 13C NMR (500 MHz, CDCl3): δ = 34.7 and 40.8 (2 CH3),
117.6, 126.7, 128.1, 128.3, 136.5, 145.6, 153.0, 154.8, 155.6,
161.5 ppm. IR: ν = 3107, 3050, 2923, 1631, 1573, 1540, 1499, 1453,
˜
1422, 1394, 1355, 1331, 1313, 1211, 1059, 878 cm–1. HRMS (EI):
calcd. for C14H14N6 266.1280; found 266.1300.
N6-[(Dimethylamino)methylene]-9-phenyladenine (17): Amorphous
solid; yield 11 mg (12%). 1H NMR (500 MHz, CDCl3): δ = 3.25
and 3.30 (2 s, 6 H, 2 CH3), 7.41–7.48 (m, 1 H, Ph-H), 7.55–7.61
(m, 2 H, Ph-H), 7.70–7.73 (m, 2 H, Ph-H), 8.20 (s, 1 H, 2-H), 8.64
(s, 1 H, 8-H), 9.11 (s, 1 H, 11-H) ppm.
9-Phenyladenine (18):[10] White powder; overall yield 17 mg (25%);
m.p. 245–246 °C (ethanol) [lit.:[25] 245–246 °C (ethanol)]. 1H NMR
(500 MHz, DMSO): δ = 7.40–7.47 (m, 3 H, Ph-H, NH2), 7.58–7.61
(m, 2 H, Ph-H), 7.90–7.92 (m, 2 H, Ph-H), 8.23 (s, 1 H, 2-H), 8.61
(s, 1 H, 8-H) ppm. 13C NMR (500 MHz, DMSO): δ = 119.3 (C-5),
122.9, 127.4, 129.5, 135.1, 139.7 (C-8), 149.1 (C-2), 153.0 (C-6),
[3]
[4]
[5]
[6]
156.3 (C-4) ppm. IR: ν = 3287, 3148, 3040, 1676, 1601, 1510, 1447,
˜
1417, 1374, 1333, 1310, 1300, 1187, 964, 758, 715 cm–1. HRMS
(EI): calcd. for C11H9N5 211.0858; found 211.0853.
7-Phenyladenine (19): Light-yellow powder; yield 17 mg (78%,
Method B); m.p. 264–267 °C. 1H NMR (500 MHz, DMSO): δ =
6.15 (br. s, 2 H, NH2), 7.57–7.66 (m, 5 H, Ph-H), 8.33 (s, 1 H, 2-
H), 8.53 (s, 1 H, 8-H) ppm. 13C NMR (500 MHz, DMSO): δ =
107.6 (C-5), 124.4, 127.5, 128.8, 135.7, 143.3 (C-8), 153.1 (C-2),
[7]
153.8 (C-6), 161.2 (C-4) ppm. IR: ν = 3467, 3288, 3120, 3092, 1641,
˜
1599, 1553, 1495, 1476, 1405, 1343, 1305, 1233, 1177, 777 cm–1.
HRMS (EI): calcd. for C11H9N5 211.0858; found 211.0855.
1530
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 1522–1531

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[10]
[11]
[12]
[23] In several cases (5a, 5c, 4c–e, 7e, 8e, 12 and 13) some base
signals in 13C NMR were missing due to broadening. This was
also evident in the 1H NMR spectra in which the signals of the
base protons were broadened. Such phenomena are usually the
result of some dynamic process. However, in the case of com-
pounds 4 and 5 this is not the case. We found that the broaden-
ing of the base signals is due to the coordination of trace
amounts of paramagnetic Cu2+ ion. The broadening disap-
peared after treatment of the dichloromethane solutions of the
compounds 4 and 5 with Divergan® HM (BASF), an insoluble
vinylimidazole/vinylpyrrolidone copolymer, which efficiently
removes traces of metal ions.
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Received: October 15, 2008
Published Online: February 19, 2009
Eur. J. Org. Chem. 2009, 1522–1531
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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