Synthesis of fused imidazoles and benzothiazoles from (hetero)aromatic ortho-diamines or ortho-aminothiophenol and aldehydes promoted by chlorotrimethylsilane

Article abstract of DOI:10.1055/s-2006-950289

New convenient conditions for benzimidazole and benzothiazole syntheses are described. A set of benzimidazoles, 3H-imidazo[4,5-b]pyridines, purines, xanthines and benzothiazoles was readily prepared from (hetero)aromatic ortho-diamines or ortho-aminothiop

Full text of DOI:10.1055/s-2006-950289

PAPER
3715
Synthesis of Fused Imidazoles and Benzothiazoles from (Hetero)Aromatic
ortho-Diamines or ortho-Aminothiophenol and Aldehydes Promoted by
Chlorotrimethylsilane
Synthesis of
a
F
e
used Imida
r
g
Benzothia
z
e
Enamine Ltd., 23 A. Matrosova st., 01103 Kiev, Ukraine
b
c
National Taras Shevchenko University, 62 Volodymyrska st., Kyiv-33, 01033 Kiev, Ukraine
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Murmanska 5, Kyiv-94, 02094 Kiev, Ukraine
Fax +380(44)5373253; E-mail: D.Volochnyuk@enamine.net
Received 12 June 2006
benzimidazole 5 and diimine 6 in the ratio ~2:1
(Scheme 1). As N-monosubstituted phenylendiamines
cannot form diimines, we then chose to optimize the reac-
tion of N-alkylphenylenediamine 1b (R = Bn, R¢ = Cl)
Abstract: New convenient conditions for benzimidazole and ben-
zothiazole syntheses are described. A set of benzimidazoles, 3H-
imidazo[4,5-b]pyridines, purines, xanthines and benzothiazoles
was readily prepared from (hetero)aromatic ortho-diamines or
ortho-aminothiophenol and aldehydes using chlorotrimethylsilane with aldehyde 2b. Under various conditions, in the pres-
in DMF as a promoter and water-acceptor agent, followed by oxi-
ence of TMSCl, the reaction gave a mixture of benzimida-
dation with air oxygen.
zoline 4 and benzimidazole 5. The reaction was carried
Key words: benzimidazoles, benzothiazoles, aldehydes, chlorotri-
methylsilane, parallel synthesis
out in a sealed tube in order to keep both the volatile TM-
SCl and the HCl formed, in the reaction mixture. After
heating the mixture was to completion, benzimidazoline 4
was oxidized to benzimidazole 5 by ultrasonic irradiation
Benzimidazoles have found commercial applications as in air for 1–3 hours.
anti-ulcer, anti-hypertensive, antiviral, antifungal, anti-tu-
mor, and antihistaminic agents as well as antihelmintic
H
N
R'
NH2
R'
N
R"
R'
R"CHO
agents in veterinarian medicine.1 The search for effective
methods for the synthesis of benzimidazole libraries for
high-throughput screening therefore remains a high prior-
ity.2 The most popular synthetic approaches to the librar-
ies are based on the cyclocondensation of
arylidenediamines with carboxylic acid derivatives or on
the condensation with aldehydes followed by oxidation.
Taking into account the wide structural diversity of com-
mercially available aldehydes, the second approach has
recently become very popular.3 Nitrobenzene, DMF or
DMSO at elevated temperatures,2d,4 as well as metal ions,5
organic oxidants such as quinones,6,2a,c tetracyanoethyl-
ene,7 benzofuroxan,8 cumarins,9 PhI(OAc)2,3b inorganic
sulfites,2b,e,10 oxone®,3a air oxygen in the presence of a
Lewis acid3d or activated carbon darco® KB11 have all
been used as oxidants in the reaction.
R"
NH
R
NH
R
N
2
R
1
3
4
O2
R = H
R"CHO
R'
N
R"
R"
R'
N
N
R"
N
R
6
5
Scheme 1
To optimize the reaction conditions, solvent, time, and the
amount of TMSCl were varied. As seen from Tables 1
and 2, the optimal reaction conditions were found to be
heating in DMF solution for two hours in the presence of
two equivalents of TMSCl. The reaction mixtures were
subsequently diluted with one to two volumes of water
and the amorphous precipitate formed was triturated in an
ultrasonic bath for several hours, providing the target
product in high yield. The crude products 5, isolated by
Examples of using aldehydes for a range of condensations
in the presence of trimethylsilyl halides as promoting and
dehydrating reagents have been recently reported.12 Con-
tinuing our research on such reactions,12a,b we investigated
the cyclocondensation of arylidenediamines with alde-
hydes in the presence of chlorotrimethylsilane (TMSCl).
It was found that heating (90 °C) equimolar amounts of simple filtration (except 5dk, which was isolated by ex-
the unsubstituted phenylendiamine 1a (R = R¢ = H) and traction with ethyl acetate), had from ~60% (in the case of
the aldehyde 2b (R = p-MeOC6H4-) in DMF, in the pres- diamine 1a and 1f) to >90% homogeneity, determined by
ence of two equivalents of TMSCl leads to a mixture of RP-HPLC, so that washing the precipitates on the filter
with methanol or acetonitrile was sufficient to obtain pure
products.
SYNTHESIS 2006, No. 21, pp 3715–3726
x
x.
x
x
.
2
0
0
6
Advanced online publication: 09.10.2006
DOI: 10.1055/s-2006-950289; Art ID: P07306SS
© Georg Thieme Verlag Stuttgart · New York

3716
S. V. Ryabukhin et al.
PAPER
substituent onto the nucleophilic carbon of the furan nu-
cleus (aldehydes 2e and 2f) or an acceptor function onto
the pyrrole nucleus (aldehyde 2g) increased their stability
so that they could tolerate the reaction conditions and suc-
cessfully gave the target products (Table 4). a,b-Unsatur-
ated aldehydes, as in the case of Oxone®,3a give complex
reaction mixtures and using aromatic and heteroaromatic
aldehydes having a formyl function shielded by two
ortho-substituents was also problematic (Table 3, Entry
6). In the latter case, as with diamines with bulky substit-
uents on the nitrogen, the reaction stopped at the stage of
a mixture of imine 3 and benzimidazole 5, and isolation of
the target products required chromatographic separation.
Nevertheless, aldehydes 2g, 2h and 2i, bearing only one
ortho-substituent, reacted readily.
Table 1 Yields of 4 and 5 in the Reaction of 1b and 2b in the
Presence of Two Equivalents of TMSCl in Various Solvents after
Two Hours at 90 °Ca
Solvent
Yield 4 (%)
Yield 5 (%)
1
2
3
4
5
6
7
8
DMF
49
42
34
17
29
12
70
5
47
55
26
80
7
DMF–Et3N
MeCN
MeCN–Et3N
Dioxane
Dioxane–Et3N
Pyridine
72
11
89
ortho-Aminothiophenol 8, under similar conditions for
1,2-phenylenediamines, also underwent the reaction, af-
fording the corresponding benzothiazoles 9 in high yields
(Scheme 2, Table 5). The limitations on the use of the al-
dehydes were similar to those for 1,2-phenylenediamines
(Table 3).13
Pyridine–Et3N
a According to HPLC-MS data of the reaction mixtures (APSI-MS,
Agilent 1100\DAD\MSD VL G1965a).
Table 2 Yields of 4 and 5 in the Reaction of 1b and 2b Depending
on the Quantity of TMSCl and the Reaction Time at 90 °Ca
ortho-Aminophenol 11 did not give the desired products
in the reaction.14 In this case, imine 12 was isolated in high
yield, with none of the target benzoxazole 13 observed
(Scheme 3). These observations are consistent with the
data obtained for an analogous condensation using Ox-
one® as oxidant.3a
Time (h) Yield 4 (%)Yield 5 (%)
1 equiv
TMSCl
2 equiv
TMSCl
3 equiv
TMSCl
4 equiv
TMSCl
1
2
3
4
2
5
55:38
36:46
32:59
24:67
49:47
35:58
29:60
8:78
35:56
31:56
24:56
21:56
30:56
27:56
24:56
16:60
The same chemistry could be used to close other fused im-
idazole ring systems, allowing easy assembly of substitut-
ed purines, xanthines and their analogues. 2,3-
Diaminopyridine 14, and diaminopyrimidines 16, 18 and
20 underwent the reaction, affording the corresponding
3H-imidazo[4,5-b]pyridines 15,15 2,6-diaminopurines
17,16 2-aminopurin-6-ones 19 and xanthines 21,17 respec-
tively, in high yields (Scheme 4, Tables 5 and 6). The syn-
thesis of xanthines, starting from 5,6-diaminouracils and
aldehydes, have previously been reported, however in
these studies only uracils with unsubstituted amino groups
were used. The reaction proceeded in two steps: formation
of an imine of type 25, with further oxidative cyclization
by MCPBA,17a FeCl317b or DEAD17c to 26. In some cases,
the imines 25 were separated17a (Scheme 5). To the best of
our knowledge, uracils with substituents on the C(5)-ami-
no group were not used in the oxidative cyclocondensa-
tion with aldehydes due to the impossibility of formation
of imines of type 25 and the low nucleophilicity of the
C(6)-amino group for the alternative path of cyclization.18
Under the conditions reported here however, uracil 22
smoothly underwent the reaction affording N(7)-methyl
xanthines 23 in excellent yields. The success of the reac-
tion could be rationalized by the formation of an interme-
diate of type 29 through silylation of the starting uracil
(Scheme 6). Such a process would be analogous to the
formation of arylideneaminium salts from aldehydes us-
ing the silylated amine-TMSCl system described by Jahn
and co-workers.19 The limitations of the method were
found to be similar to those of the 1,2-phenylenediamines
(Table 3).
10
15
a According to HPLC-MS data of the reaction mixtures (APSI-MS,
Agilent 1100\DAD\MSD VL G1965a).
As seen from Table 4, the reaction proceeded in high yield
with a wide range of mono N-alkylsubstituted diamines
and in moderate yields with N-unsubstituted diamines and
various aldehydes. Aromatic, heteroaromatic as well as
aliphatic aldehydes could be used. Nevertheless, some
limitations have been found, and are summarized in
Table 3. N-Aryl diamines and diamines having a bulky
substituent on the nitrogen, behaved poorly in the reac-
tion. In this case, the reaction stopped at the stage of imine
3 and the target products were only obtained in 10–25%
yields (Table 3, Entry 1). Under more drastic conditions
such as higher temperature or longer reaction times, yields
of the target products remained almost the same, but side
processes led to various by-products. In most cases, un-
successful reactions could be traced to the aldehyde com-
ponents and their incompatibility towards the reaction
conditions. Aliphatic aldehydes enter into crotonic con-
densation (Table 3, Entry 3), and some aldehydes, deriva-
tives of p-electron rich heterocycles such as 2-furyl, 2(3)-
pyrrolyl-, 3-indolylaldehydes (Table 3, Entry 4), gave
complex reaction mixtures with the target benzimidazoles
only formed in trace amounts. However, introduction of a
Synthesis 2006, No. 21, 3715–3726 © Thieme Stuttgart · New York

PAPER
Synthesis of Fused Imidazoles and Benzothiazoles
3717
Table 3 Limitations of the Methodologya
Aniline
Aldehyde
Comments
Reaction stopped at the stage of imine 3. Yield of products less than 10–25%.
1
2a, 2b
NH2
R'
NH
R
R = Ar,
2
2b, 2n
Reaction stopped at the stage of imine 12.
NH2
OH
R
3
4
1b, 8
Self-condensation of the aldehyde occurred.
R
CHO
R = Ph, Et, i-Pr
1b, 8
Aldehydes unstable; target products formed in low yields (5–10%).
CHO
N
R
R = H, CH2Ph
X
CHO
X = O, NH, NMe
R
N
OHC
R = Me, Ph
5
6
1b, 8
1b, 8
Complex reaction mixture
Ph
CHO
Reaction stopped at the stage of imine 3. Yield of products 20–50%.
R
CHO
R
R'
R = Me, Cl
OHC
N
X
X = O, NPh, NBn
a According to HPLC-MS and 1H NMR of the reaction mixtures (APSI-MS, Agilent 1100\DAD\MSD VL G1965a, Varian Mercury-400 spec-
trometer).
NH2
In summary, we have developed an efficient methodology
N
S
TMSCl, DMF
O2
for the preparation of substituted, fused imidazoles and
benzothiazoles from (hetero)aromatic ortho-diamines or
ortho-aminothiophenol and aldehydes, using TMSCl as a
promoter and water scavenger. The methodology is appli-
cable to a wide variety of aldehyde substrates (aliphatic,
aromatic and heteroaromatic) and delivers the target prod-
ucts in good yields, excellent homogeneity and often in
analytically pure form. The chemical procedure is very
simple and could be easily adapted to semi-automated, so-
lution-phase parallel synthesis of fused azole libraries.
R"CHO
R"
+
SH
2
8
9
Scheme 2
R"CHO
O2
NH2
OH
N
R"
N
O
2
R"
TMSCl, DMF
OH
R" = p-Br-C6H4
11
12
13
Scheme 3
Synthesis 2006, No. 21, 3715–3726 © Thieme Stuttgart · New York

3718
S. V. Ryabukhin et al.
PAPER
Br
O
O
O
Br
NH2
NH2
N
H
N
R"
R
O
NH2
NH2
R
O
N
R"
R
O
[O]
R"CHO
N
N
N
N
H
N
R"
N
N
N
N
NH2
N
14
15
R'
R'
R'
NH2
NH2
24
25
26
NH2
N
N
N
N
Scheme 5
R"
N
H
H2N
N
O
H2N
16
N
O
NH2
R"CHO
Me3Si
Me3Si
17
O
Me
N
2
O
N
Me
N
OSiMe3
TMSCl
R"CHO
SiMe3
TMSCl, DMF
N
N
22
Me
Me
NH2
N
R"
NH2
O2
N
O
N
NH2
27
O
R"
N
H
H2N
N
28
H2N
18
N
NH2
Ph
Ph
19
+ TMSCl
– TMS2O
R'''
O
O
R'''
NH
N
HN
HN
R"
Me3Si
Me3Si
O
N
O
Me
Me
O
N
NH2
O
N
– H+
+ H+
20, 21 R''' = H
22, 23 R''' = Me
N
+
R"
N
[O]
N
N
O
Ph
Ph
R"
23
20, 22
21, 23
hydrolysis
N
H
O
N
N
NH2
Scheme 4
Ph
Ph
30
29
Scheme 6
Table 4 Preparation of Benzimidazolese
N
Starting material
R¢¢CHO 2
Product
Yielda Homo-
Crystallization Yieldc Mp (°C)d
(crude) geneityb solvent
(%)
[Lit.]
(%)
66
(crude) (%)
87
NH2
CHO
N
293–294
[292]3d
5aa
5ab
5ac
i-PrOH–H2O 55
NH2
N
H
2a
1a
1a
CHO
N
220–223
[226]3d
69
58
90
86
i-PrOH
i-PrOH
65
51
OMe
MeO
N
H
2b
CHO
N
228–229
[233]20a
1a
N
Me2N
N
H
2c
Cl
NH2
Cl
N
OMe
5bb
2b
99
93
MeCN
90
141–142
N
H
Ph
N
CH2Ph
1b
1b
Cl
Cl
N
N
Me
Me
5bd
5be
99
97
88
85
MeOH
MeOH
87
81
158–159
147–148
S
OHC
OHC
S
CH2Ph
2d
N
1b
O
N
O
2e
CH2Ph
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PAPER
Synthesis of Fused Imidazoles and Benzothiazoles
3719
Table 4 Preparation of Benzimidazolese (continued)
N
Starting material
R¢¢CHO 2
Product
Yielda Homo-
Crystallization Yieldc Mp (°C)d
(crude) geneityb solvent
(%)
[Lit.]
(%)
99
(crude) (%)
Cl
OHC
O
N
N
5bf
1b
90
DMF–MeOH 94
177–178
O
Ph
CO2Et
2f
CO2Et
CN
CN
N
Cl
N
5bg
1b
96
91
MeCN
92
182–183
Me
N
N
Me
OHC
Me
Me
Ph
2g
OMe
OMe
Cl
N
OHC
N
5bh
1b
95
88
DMF–MeOH 91
171–172
N
N
Ph
N
N
2h
2b
F3C
NH2
F3C
N
OMe
5cb
5ci
99
95
92
89
MeOH
MeCN
88
90
124–125
209–210
N
Ph
N
H
CH2Ph
1c
1c
HO
HO
F3C
N
N
OHC
Cl
2i
Cl
CH2Ph
EtO2C
O
NH2
EtO
N
5db
2b
100
92
MeOH
94
103–104
N
H
N
Et
1d
1d
OMe
EtO2C
N
CHO
5dj
5ek
96
94
85
89
–
85
81
oil
N
2j
Et
O
S
O
N
NH2
S
N
N
Me2N
O
2k
MeOH
137–138
O
N
H
N
Et
1e
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3720
S. V. Ryabukhin et al.
PAPER
Table 4 Preparation of Benzimidazolese (continued)
N
Starting material
R¢¢CHO 2
Product
Yielda Homo-
Crystallization Yieldc Mp (°C)d
(crude) geneityb solvent
(%)
[Lit.]
(%)
(crude) (%)
O
S
N
N
Me2N
5el
1e
98
93
MeOH
84
152–153
N
N
O
O
OHC
OHC
N
2l
Et
O
S
N
N
Me2N
5em
5fi
1e
95
65
90
88
MeOH
85
58
184–185
>300
N
2m
2i
Et
O
O
S
HO
H2N
S
NH2
NH2
N
H2N
i-PrOH
O
O
N
H
Cl
1f
a Yield of crude material obtained after dilution of reaction mixture with 2 volumes of aq K2CO3 (~10%) and collection of the precipitate by
filtration or extraction with EtOAc
b Reversed-phase HPLC homogeneity of the crude products.
c Yields refer to pure isolated products.
d Melting points are uncorrected.
e Satisfactory microanalysis obtained C 0.33; H 0.45; N 0.25.
Table 5 Preparation of Benzothiazoles 9 and Imidazo[4,5-b]pyridines 15 Starting from 8 and 14, Respectivelyc
R¢¢CHO Product 9
Yielda (%) Mp (°C)b [Lit.]
Product 15
Yielda (%) Mp (°C)c [lit]
2a
94
96
92
91
113–114 [114]20b
74
80
87
79
>300 [>310]20g
>300 [299–300]20h
>300
N
Br
N
S
N
H
N
9a
9b
9c
15a
Br
2b
2c
2i
124–125 [123–125]20c
170–171 [173]20d
N
S
N
OMe
OMe
N
H
N
15b
Br
N
S
N
N
N
N
H
N
15c
152–153 [149–150]20e
>300
HO
HO
Br
N
S
N
N
H
N
Cl
Cl
9i
15i
Br
2k
88
129–130 [132]20f
64
284–285
N
S
N
N
N
H
N
N
9k
15k
a Yields refer to pure isolated products.
b Melting points are uncorrected.
c Satisfactory microanalysis obtained C 0.33; H 0.45; N 0.25.
Synthesis 2006, No. 21, 3715–3726 © Thieme Stuttgart · New York

PAPER
Synthesis of Fused Imidazoles and Benzothiazoles
3721
Table 6 Preparation of N(7)-Unsubstituted Purines 17, 19 and Xanthines 21d
N
Diamine R¢¢CHO 2
Product
Yielda Mp (°C)b 1H NMR, d (ppm), J (Hz)
(%) [Lit.]
[M + H]+c
17a 16
2a
95
>300
7.54 (5 H, m, CH + NH2), 8.09 (4 H, m, 227
NH2
[>300]16, CH + NH2)
[303]21a
N
N
N
H
H2N
N
17b 15
2b
99
283–284 3.84 (3 H, s, OCH3), 7.13 (2 H, d,
3JHH = 8.4 Hz, CH), 7.31 (2 H, br s,
NH2), 8.05 (2 H, d, 3JHH = 8.7 Hz, CH),
8.43 (2 H, br s, NH2), 14.50 (1 H, br s,
NH)
257
233
NH2
N
N
OMe
N
H
H2N
N
17n 15
97
224–225 1.23 (2 H, m, CH2), 1.37 (2 H, m,
CH2), 1.51 (2 H, m, CH2), 1.67 (2 H,
m, CH2), 1.76 (2 H, m, CH2), 2.79
(1 H, m, CH), 7.13 (2 H, br s, NH2),
8.36 (2 H, br s, NH2), 13.57 (1 H, br s,
NH)
NH2
N
N
OHC
N
H
2n
H2N
N
O
19 18
21o 20
2b
76
86
>300
3.36 (3 H, s, NCH3), 3.82 (3 H, s,
OCH3), 7.08 (2 H, d, 3JHH = 8.4 Hz,
CH), 7.28 (2 H, m, NH2), 8.03 (2 H, d,
3JHH = 8.4 Hz, CH)
272
Me
N
N
OMe
N
H
H2N
O
N
277–278 1.47 (3 H, t, 3JHH = 7.0 Hz, OCH2CH3), 363
4.26 (2 H, q, 3JHH = 7.0 Hz,
H
N
HN
OCH2CH3), 5.18 (2 H, s, NCH2), 7.02
(1 H, t, 3JHH = 8.0 Hz, CH), 7.10 (1 H,
d, 3JHH = 8.4 Hz, CH), 7.23 (1 H, t,
3JHH = 7.6 Hz, CH), 7.29 (2 H, t,
3JHH = 7.6 Hz, CH), 7.40 (1 H, t,
3JHH = 8.4 Hz, CH), 7.45 (2 H, d,
3JHH = 7.6 Hz, CH), 7.99 (1 H, d,
3JHH = 8.0 Hz, CH), 11.01 (1 H, br s,
NH), 12.42 (1 H, br s, NH)
OEt
OHC
N
O
N
2o
EtO
CH2Ph
21p 20
90
261–262 4.72 (2 H, m, OCH2), 5.16 (2 H, s,
NCH2), 5.30 (1 H, d, 3JHH = 11.2 Hz,
CH), 5.46 (1 H, d, 3JHH = 11.2 Hz,
CH), 6.05 (1 H, m, CH), 7.25 (2 H, m,
CH), 7.31 (2 H, t, 3JHH = 7.6 Hz, CH),
7.37 (2 H, m, CH), 8.07 (1 H, d,
3JHH = 8.0 Hz, CH), 8.32 (1 H, s, CH),
11.21 (1 H, br s, NH), 13.78 (1 H, br s,
NH)
454
O
N
Br
O
H
N
Br
HN
O
O
N
CH2Ph
CHO
2p
a Yields refer to pure isolated products.
b Melting points are uncorrected.
c APSI-MS, Agilent 1100\DAD\MSD VL G1965a instrument.
d Satisfactory microanalysis obtained C 0.33; H 0.45; N 0.25.
Synthesis 2006, No. 21, 3715–3726 © Thieme Stuttgart · New York

3722
S. V. Ryabukhin et al.
Table 7 Preparation of N(7) Methyl Xanthines 23 from 22d
R¢¢CHO 2 Product
PAPER
N
Yielda Mp (°C)b 1H NMR, d (ppm), J (Hz)
[M + H]+c
333
(%)
[Lit.]
23a 2a
87
263–264 3.96 (3 H, s, NCH3), 5.14 (2 H, s, NCH2), 7.26 (1 H, t,
O
Me
[–]21b
3JHH = 8.4 Hz, CH), 7.32 (2 H, t, 3JHH = 8.4 Hz, CH), 7.37
(2 H, d, 3JHH = 8.4 Hz, CH), 7.57 (3 H, m, CH), 7.78 (2 H,
m, CH), 11.28 (1 H, br s, NH)
N
HN
N
O
O
N
CH2Ph
23b 2b
23e 2e
23k 2k
91
80
85
247–248 3.84 (3 H, s, OCH3), 3.96 (3 H, s, NCH3), 5.14 (2 H, s,
NCH2), 7.09 (2 H, d, 3JHH = 8.7 Hz, CH), 7.23–7.39 (5 H,
m, CH), 7.73 (2 H, d, 3JHH = 8.7 Hz, CH), 11.17 (1 H, br s,
NH)
363
337
334
O
Me
N
HN
OMe
N
N
CH2Ph
285–286 2.39 (3 H, s, CH3), 4.08 (3 H, s, NCH3), 5.13 (2 H, s,
NCH2), 6.37 (1 H, d, 3JHH = 3.3 Hz, CH), 7.07 (1 H, d,
3JHH = 3.3 Hz, CH), 7.26 (1 H, m, CH), 7.32 (4 H, m, CH),
11.20 (1 H, br s, NH)
O
Me
N
HN
O
N
O
N
CH2Ph
>300
4.33 (3 H, s, NCH3), 5.16 (2 H, s, NCH2), 7.25 (1 H, t,
3JHH = 7.6 Hz, CH), 7.32 (2 H, t, 3JHH = 7.6 Hz, CH), 7.39
(2 H, d, 3JHH = 7.6 Hz, CH), 7.52 (1 H, m, CH), 8.00 (1 H,
td, 3JHH = 8.0 Hz, 4JHH = 1.6 Hz, CH), 8.15 (1 H, d,
3JHH = 8.0 Hz, CH), 8.72 (1 H, m, CH), 11.31 (1 H, br s,
NH)
O
Me
N
HN
O
N
N
N
CH2Ph
23l 2l
90
252–253 4.00 (3 H, s, NCH3), 5.15 (2 H, s, NCH2), 7.25 (1 H, t,
3JHH = 7.6 Hz, CH), 7.32 (2 H, t, 3JHH = 7.6 Hz, CH), 7.37
(2 H, d, 3JHH = 7.6 Hz, CH), 7.59 (1 H, m, CH), 8.20 (1 H,
dt, 3JHH = 8.0 Hz, 4JHH = 2.0 Hz, CH), 8.73 (1 H, dd,
3JHH = 8.0 Hz, 4JHH = 2.0 Hz, CH), 8.98 (1 H, d, 4JHH = 2.0
Hz, CH), 11.32 (1 H, br s, NH)
334
O
Me
N
HN
N
N
O
N
CH2Ph
23m 2m
23j 2j
23n 2n
87
83
89
>300
4.04 (3 H, s, NCH3), 5.14 (2 H, s, NCH2), 7.24 (1 H, t,
3JHH = 8.0 Hz, CH), 7.31 (2 H, t, 3JHH = 8.0 Hz, CH), 7.36
(2 H, d, 3JHH = 8.0 Hz, CH), 7.79 (2 H, d, 3JHH = 6.0 Hz,
CH), 8.76 (2 H, d, 3JHH = 6.0 Hz, CH), 11.35 (1 H, br s,
NH)
334
299
O
Me
N
HN
HN
HN
N
N
O
N
CH2Ph
218–219 1.32 [6 H, d, 3JHH = 6.9 Hz, CH(CH3)2], 3.14 [1 H, hept,
3JHH = 6.9 Hz, CH(CH3)2], 3.87 (3 H, s, NCH3), 5.09 (2 H,
s, NCH2), 7.24 (3 H, m, CH), 7.42 (2 H, dd, 3JHH = 7.8 Hz,
4JHH = 1.8 Hz, CH), 10.81 (1 H, br s, NH)
O
Me
N
N
O
N
CH2Ph
194–195 1.38 (4 H, m, 2 × CH2), 1.65 (2 H, m, CH2), 1.85 (4 H, m, 339
2 × CH2), 3.13 (1 H, m, CH), 3.86 (3 H, s, NCH3), 5.08
(2 H, s, NCH2), 7.25 (3 H, t, 3JHH = 7.8 Hz, CH), 7.41 (2 H,
d, 3JHH = 7.8 Hz, CH), 10.80 (1 H, br s, NH)
O
Me
N
N
O
N
CH2Ph
a Yields refer to pure isolated products.
b Melting points are uncorrected.
c APSI-MS, Agilent 1100\DAD\MSD VL G1965a instrument.
d Satisfactory microanalysis obtained C 0.33; H 0.45; N 0.25.
Synthesis 2006, No. 21, 3715–3726 © Thieme Stuttgart · New York

PAPER
Synthesis of Fused Imidazoles and Benzothiazoles
3723
Table 8 1H NMR and APSI-MS Data of Benzimidazoles 5a
N
1H NMR, d (ppm), J (Hz)
[M + H]+
5ac
3.03 [6 H, s, N(CH3)2], 6.92 (2 H, d, 3JHH = 9.0 Hz, CH), 7.47 (2 H, td, 3JHH = 6.3 Hz, 4JHH = 3.0 Hz, CH), 7.73 (2 H, dd, 238
3JHH = 6.3 Hz, 4JHH = 3.0 Hz, CH), 8.23 (2 H, d, 3JHH = 9.0 Hz, CH)
5bb
5bd
3.89 (3 H, s, OCH3), 5.74 (2 H, s, CH2), 7.15 (4 H, d, 3JHH = 8.8 Hz, CH), 7.31 (3 H, m, CH), 7.42 (1 H, dd, 3JHH = 8.8 Hz, 349
4JHH = 1.2 Hz, CH), 7.65 (1 H, d, 3JHH = 8.8 Hz, CH), 7.85 (2 H, d, 3JHH = 8.8 Hz, CH), 7.91 (1 H, d, 4JHH = 1.2 Hz, CH)
2.55 (3 H, s, CH3), 5.71 (2 H, s, CH2), 6.82 (1 H, d, 4JHH = 3.6 Hz, CH), 7.08 (2 H, d, 3JHH = 8.8 Hz, CH), 7.20 (1 H, dd, 339
3JHH = 8.8 Hz, 4JHH = 1.2 Hz, CH), 7.30 (3 H, m, CH), 7.41 (1 H, d, 3JHH = 8.8 Hz, CH), 7.67 (1 H, d, 4JHH = 3.6 Hz, CH),
7.90 (1 H, d, 4JHH = 1.2 Hz, CH)
5be
5bf
2.38 (3 H, s, CH3), 5.73 (2 H, s, CH2), 6.20 (1 H, d, 4JHH = 3.2 Hz, CH), 6.96 (1 H, d, 4JHH = 3.2 Hz, CH), 7.11 (2 H, d,
3JHH = 8.8 Hz, CH), 7.14 (1 H, dd, 3JHH = 8.8 Hz, 4JHH = 1.2 Hz, CH), 7.24 (3 H, m, CH), 7.40 (1 H, d, 3JHH = 8.8 Hz, CH),
7.58 (1 H, d, 4JHH = 1.2 Hz, CH)
323
1.41 (3 H, t, 3JHH = 6.8 Hz, CH2CH3), 4.34 (2 H, q, 3JHH = 6.8 Hz, CH2CH3), 5.91 (2 H, s, CH2), 7.17 (2 H, d, 3JHH = 8.4 457
Hz, CH), 7.30 (4 H, m, CH), 7.43 (1 H, d, 4JHH = 3.2 Hz, CH), 7.56 (1 H, dd, 3JHH = 8.8 Hz, 4JHH = 1.2 Hz, CH), 7.67 (2 H,
d, 3JHH = 8.4 Hz, CH), 7.71 (1 H, d, 3JHH = 8.8 Hz, CH), 7.90 (1 H, d, 4JHH = 1.2 Hz, CH), 7.94 (2 H, d, 3JHH = 8.4 Hz, CH)
5bg
5bh
5cb
5ci
2.49 (3 H, s, CH3), 3.74 (3 H, s, NCH3), 5.48 (2 H, s, CH2), 6.87 (1 H, s, CH), 6.99 (2 H, d, 3JHH = 7.6 Hz, CH), 7.11 (1 H, 361
dd, 3JHH = 8.8 Hz, 4JHH = 1.6 Hz, CH), 7.29 (4 H, m, CH), 7.63 (1 H, d, 4JHH = 1.6 Hz, CH)
3.79 (3 H, s, OCH3), 5.19 (2 H, s, CH2), 6.82 (2 H, d, 3JHH = 8.0 Hz, CH), 6.90 (2 H, m, CH), 7.14 (4 H, m, CH), 7.32 (2 H, 491
m, CH), 7.47 (4 H, m, CH), 7.69 (1 H, s, CH), 7.90 (2 H, d, 3JHH = 8.0 Hz, CH), 8.71 (1 H, s, CH)
3.86 (3 H, s, OCH3), 5.57 (2 H, s, CH2), 6.99 (2 H, d, 3JHH = 8.8 Hz, CH), 7.08 (2 H, d, 3JHH = 7.6 Hz, CH), 7.29 (3 H, m, 383
CH), 7.43 (2 H, s, CH), 7.64 (2 H, d, 3JHH = 8.8 Hz, CH), 7.98 (1 H, s, CH)
5.50 (2 H, s, CH2), 7.04 (3 H, d, 3JHH = 8.4 Hz, CH), 7.25 (3 H, m, CH), 7.32 (1 H, dd, 3JHH = 8.4 Hz, 4JHH = 2.4 Hz, CH), 403
7.39 (1 H, d, 4JHH = 2.4 Hz, CH), 7.44 (1 H, d, 3JHH = 8.4 Hz, CH), 7.51 (1 H, d, 3JHH = 8.4 Hz, CH), 7.99 (1 H, s, CH),
10.82 (1 H, br s, OH)
5db
5dj
5ek
5el
1.43 (6 H, t, 3JHH = 6.8 Hz, OCH2CH3 and NCH2CH3), 3.89 (3 H, s, OCH3), 4.37 (4 H, q, 3JHH = 6.8 Hz, OCH2CH3 and
NCH2CH3),7.08 (2 H, d, 3JHH = 8.4 Hz, CH), 7.56 (1 H, d, 3JHH = 8.4 Hz, CH), 7.70 (2 H, d, 3JHH = 8.4 Hz, CH), 7.90 (1 H,
d, 3JHH = 8.4 Hz, CH), 8.27 (1 H, s, CH)
325
1.35 [6 H, d, 3JHH = 7.2 Hz, CH(CH3)2], 1.43 (6 H, t, 3JHH = 6.8 Hz, OCH2CH3 and NCH2CH3), 4.17 [1 H, hept, 3JHH = 7.2 261
Hz, CH(CH3)2], 4.37 (4 H, q, 3JHH = 6.8 Hz, OCH2CH3 and NCH2CH3), 7.61 (1 H, d, 3JHH = 8.4 Hz, CH), 7.87 (1 H, d,
3JHH = 8.4 Hz, CH), 8.18 (1 H, s, CH)
1.50 (3 H, t, 3JHH = 7.2 Hz, CH2CH3), 2.67 [6 H, s, N(CH3)2], 4.97 (2 H, q, 3JHH = 7.2 Hz, CH2CH3), 7.50 (1 H, dd,
3JHH = 8.0 Hz, 3JHH = 5.2 Hz, CH), 7.66 (1 H, d, 3JHH = 8.8 Hz, CH), 7.78 (1 H, d, 3JHH = 8.8 Hz, CH), 7.99 (1 H, t,
3JHH = 8.0 Hz, CH), 8.07 (1 H, s, CH), 8.41 (1 H, d, 3JHH = 8.0 Hz, CH), 8.73 (1 H, d, 3JHH = 5.2 Hz, CH)
331
1.47 (3 H, t, 3JHH = 7.2 Hz, CH2CH3), 2.68 [6 H, s, N(CH3)2], 4.45 (2 H, q, 3JHH = 7.2 Hz, CH2CH3), 7.57 (1 H, dd,
3JHH = 8.0 Hz, 3JHH = 5.2 Hz, CH), 7.68 (1 H, dd, 3JHH = 8.4 Hz, 4JHH = 1.6 Hz, CH), 7.82 (1 H, d, 3JHH = 8.4 Hz, CH), 8.08
(1 H, d, 4JHH = 1.6 Hz, CH), 8.19 (1 H, dt, 3JHH = 8.0 Hz, 4JHH = 1.6 Hz, CH), 8.75 (1 H, dd, 3JHH = 5.2 Hz, 4JHH = 1.6 Hz,
CH), 8.96 (1 H, d, 4JHH = 1.6 Hz, CH)
331
5em
5fi
1.47 (3 H, t, 3JHH = 7.2 Hz, CH2CH3), 2.67 [6 H, s, N(CH3)2], 4.51 (2 H, q, 3JHH = 7.2 Hz, CH2CH3), 7.70 (1 H, dd,
3JHH = 8.8 Hz, 4JHH = 1.6 Hz, CH), 7.86 (1 H, d, 3JHH = 8.8 Hz, CH), 7.89 (2 H, d, 3JHH = 5.2 Hz, CH), 8.10 (1 H, d,
4JHH = 1.6 Hz, CH), 8.86 (2 H, d, 3JHH = 5.2 Hz, CH)
331
324
7.00 (1 H, d, 3JHH = 8.8 Hz, CH), 7.15 (2 H, s, NH2), 7.30 (1 H, dd, 3JHH = 8.8 Hz, 4JHH = 1.2 Hz, CH), 7.73 (1 H, d,
3JHH = 8.8 Hz, CH), 7.78 (1 H, d, 3JHH = 8.8 Hz, CH), 8.12 (1 H, s, CH), 8.14 (1 H, d, 4JHH = 1.2 Hz, CH), 10.20 (1 H, br
s, OH)
a DMSO-d6
All commercially available starting materials were used without ad-
ditional purification. All solvents were purified by standard meth-
ods. All procedures were carried out under an open atmosphere with
no precautions taken to exclude ambient moisture. 1H and 13C (400
and 100 MHz, respectively) were recorded on a Varian Mercury-
400 spectrometer with TMS as an internal standard. HPLC APSI
MS spectra were recorded on Agilent 1100\DAD\MSD VL G1965a
instrument. A Branson 2510E-MT ultrasonic bath was used.
Commercially unavailable starting 1,2-phenylenediamines 1b–d,22
1e, 1f,23 heterocyclic diamines 18,24 20,21b 2221b and aldehydes 2f25
and 2h26 were obtained according to the literature procedures. See
Tables 6, 7 and 8 for 1H NMR data.
N1-Benzyl-4-chlorobenzene-1,2-diamine (1b)
Mp 77–78 °C.
Synthesis 2006, No. 21, 3715–3726 © Thieme Stuttgart · New York

3724
S. V. Ryabukhin et al.
PAPER
3
1H NMR (400 MHz, DMSO-d6): d = 4.27 (2 H, d, JHH = 4.4 Hz,
5bg
3
CH2), 4.93 (2 H, s, NH2), 5.25 (1 H, d, JHH = 4.4 Hz, NH), 6.26
13C NMR (125 MHz, DMSO-d6): d = 11.6, 33.4, 47.7, 103.5, 111.1,
112.6, 114.0, 118.8, 119.0, 122.8, 126.6, 126.9, 128.0, 129.3, 134.6,
137.2, 138.6, 144.0, 150.5.
(1 H, d, 3JHH = 8.4 Hz, CH), 6.38 (1 H, dd, 3JHH = 8.4 Hz, 4JHH = 2.0
Hz, CH), 6.57 (1 H, d, 4JHH = 2.0 Hz, CH), 7.23 (1 H, t, 3JHH = 8.2
Hz, CH), 7.29–7.37 (4 H, m, CH).
5ci
N1-Benzyl-4-(trifluoromethyl)benzene-1,2-diamine (1c)
Mp 87–88 °C.
13C NMR (125 MHz, DMSO-d6): d = 48.3, 112.6, 117.1, 118.5,
118.9, 119.8, 123.2, 123.3 (1JCF = 270 Hz), 123.5 (2JCF = 31 Hz),
127.2, 128.1, 129.1, 131.2, 132.0, 136.7, 137.9, 142.6, 153.6, 155.2.
1H NMR (400 MHz, DMSO-d6): d = 4.35 (2 H, s, CH2), 4.58 (2 H,
br s, NH2), 5.48 (1 H, br s, NH), 6.33 (1 H, d, 3JHH = 8.4 Hz, CH),
5db
3
4
6.68 (1 H, dd, JHH = 8.4 Hz, JHH = 1.8 Hz, CH), 6.81 (1 H, d,
4JHH = 1.8 Hz, CH), 7.20 (1 H, t, 3JHH = 8.4 Hz, CH), 7.30 (2 H, t,
3JHH = 8.4 Hz, CH), 7.34 (2 H, t, 3JHH = 8.4 Hz, CH).
13C NMR (125 MHz, DMSO-d6): d = 14.7, 15.4, 48.2, 55.8, 61.0,
111.2, 114.8, 121.0, 122.5, 123.7, 124.2, 131.1, 139.2, 142.7, 155.3,
161.1, 166.8.
Ethyl 3-Amino-4-(ethylamino)benzoate (1d)
Mp 94–95 °C.
5dj
13C NMR (125 MHz, DMSO-d6): d = 14.2, 15.2, 21.7, 25.7, 37.9,
3
1H NMR (400 MHz, DMSO-d6): d = 1.38 (3 H, t, JHH = 7.1 Hz,
60.4, 110.0, 120.2, 122.7, 123.1, 138.0, 142.0, 161.6, 166.3.
OCH2CH3), 4.25 (2 H, q, 3JHH = 7.1 Hz, OCH2CH3), 4.75 (2 H, br s,
NH2), 5.06 (1 H, br s, NH), 6.50 (1 H, d, JHH = 8.4 Hz, CH), 6.91
3
5em
(1 H, d, 3JHH = 8.4 Hz, CH), 6.98 (1 H, s, CH).
13C NMR (125 MHz, DMSO-d6): d = 15.5, 34.5, 38.2, 112.8, 120.2,
123.0, 125.0, 129.6, 138.8, 140.2, 142.2, 148.2, 152.3.
3-Amino-4-(ethylamino)-N,N-dimethylbenzenesulfonamide
(1e)
Preparation of Benzothiazoles 9; General Procedure
Mp 155–156 °C.
1H NMR (400 MHz, DMSO-d6): d = 1.29 (3 H, t, JHH = 7.0 Hz,
NCH2CH3), 2.57 [6 H, s, N(CH3)2], 3.24 (2 H, q, JHH = 7.0 Hz,
Compounds 9 were prepared from 8 and 2 using the above proce-
dure for 5. Compounds 9a–c and 9k were recrystallized from i-
PrOH–H2O, 9i from neat i-PrOH. Spectral data of all compounds
were in agreement with those previously reported.20b–f
3
3
NCH2CH3), 4.70 (2 H, br s, NH2), 5.01 (1 H, br s, NH), 6.44 (1 H,
d, 3JHH = 8.4 Hz, CH), 6.88 (2 H, d + s, 3JHH = 8.4 Hz, CH).
2-{[(4-Bromophenyl)methylene]amino}-4-methylphenol (12)
o-Aminophenole 11 (4 mmol) and p-bromobenzaldehyde 2 (4
mmol) were placed in a 15 mL pressure tube and dissolved in DMF
(10 mL). TMSCl (10 mmol) was added dropwise to the solution and
the tube was thoroughly sealed and heated on a water-bath for 2–4
h. After cooling, the flask was opened (Caution! Excess pressure in-
side), Et3N was added dropwise and the reaction mixture was al-
lowed to stand at r.t. in an ultrasonic bath for 1 h. The reaction
mixture was then poured into H2O (20 mL) and allowed to stand at
r.t. in an ultrasonic bath for 1 h. The precipitate formed was filtered
and washed with a small amount of i-PrOH and then with MeOH.
4-Formyl-1,5-dimethylpyrrole-2-carbonitrile (2g)
To a stirring solution of 1,5-dimethyl-1H-pyrrole-2-carbonitrile (5
g, 0.042 mol) in DMF (20 mL) was added, dropwise, POCl3 (6.37
g, 0.042 mol). The reaction mixture was maintained at r.t. for 3 h
then H2O (30 mL) was added in one portion and the resulting mix-
ture was diluted with aq NaOH (40%, 20 mL) at 0 °C. The precipi-
tate formed was filtered, dried and washed with Et2O (50 mL)
affording 2g.
Yield: 4.6 g, (75%); mp 116–117 °C.
1H NMR (400 MHz, DMSO-d6): d = 2.57 (3 H, s, CH3), 3.71 (3 H,
s, NCH3), 7.19 (1 H, s, CH), 9.75 (1 H, s, CHO).
Yield: 70%; mp 123–124 °C (Lit.27 83–84 °C).
1H NMR (400 MHz, CDCl3): d = 2.29 (3 H, s, OCH3), 6.60 (1 H, d,
3JHH = 8.7 Hz, CH), 6.69 (1 H, s, CH), 7.12 (1 H, d, 3JHH = 8.7 Hz,
CH), 7.60 (2 H, d, 3JHH = 8.7 Hz, CH), 7.94 (2 H, d, 3JHH = 8.7 Hz,
CH), 8.68 (1 H, s, CH), 11.10 (1 H, br s, OH).
13C NMR (125 MHz, CDCl3): d = 21.5, 115.3, 115.6, 120.9, 125.8,
129.9, 132.1, 132.4, 134.8, 139.8, 152.3, 154.1.
Preparation of Benzimidazoles; General Procedure
Aniline 1 (4 mmol) and an appropriate aldehyde 2 (4 mmol) were
placed in a 15 mL pressure tube and dissolved in DMF (10 mL).
TMSCl (10 mmol) was added dropwise to the solution and the tube
was thoroughly sealed and heated on a water-bath for 2–4 h. After
cooling, the flask was opened (Caution! Excess pressure inside) and
the reaction mixture was poured into H2O (20 mL) and allowed to
stand at r.t. in an ultrasonic bath for 1 h. The precipitate formed was
filtered and washed with a small amount of i-PrOH and then with
MeOH. Recrystallization from an appropriate solvent yielded the
targeted compound (see Table 4).
Preparation of Imidazo[4,5-b]pyridines 15; General Procedure
Compounds 15 were prepared from 14 and 2 using the above proce-
dure for 5. Compounds 15a–c and 15i were recrystallized from
MeCN, 15k from MeOH.
15a and 15b
5dj
Spectral data of compounds were in agreement with those previous-
ly reported.20g,h
Obtained following the above general procedure, but the mixture
obtained after dilution with H2O was extracted with EtOAc (2 × 10
mL). The organic layer was dried (MgSO4), the solvent was evapo-
rated under reduced pressure and the crude product was purified by
flash silica gel column chromatography (neat EtOAc).
15c
1H NMR (400 MHz, DMSO-d6): d = 3.01 [3 H, s, N(CH3)2], 6.79
(2 H, d, 3JHH = 8.4 Hz, CH), 8.00 (1 H, d, 4JHH = 1.6 Hz, CH), 8.10
(2 H, d, 3JHH = 8.4 Hz, CH), 8.24 (1 H, d, 4JHH = 1.6 Hz, CH).
5aa and 5ab
13C NMR (125 MHz, DMSO-d6): d = 34.6, 112.2, 113.6, 113.9,
124.7, 129.2, 144.1, 149.8, 152.9, 153.6, 155.0.
APSI-MS: m/z [M + 1]+ = 317.
Spectral data of compounds were in agreement with those previous-
ly reported.3d
Synthesis 2006, No. 21, 3715–3726 © Thieme Stuttgart · New York

PAPER
15i
Synthesis of Fused Imidazoles and Benzothiazoles
3725
23e
1H NMR (400 MHz, DMSO-d6): d = 7.09 (1 H, d, JHH = 8.8 Hz,
CH), 7.45 (1 H, dd, 3JHH = 8.8 Hz, 4JHH = 1.6 Hz, CH), 8.21 (1 H, d,
4JHH = 2.0 Hz, CH), 8.36 (1 H, s, CH), 8.49 (1 H, d, 4JHH = 2.0 Hz,
CH), 12.90 (1 H, br s, OH).
13C NMR (125 MHz, DMSO-d6): d = 13.9, 33.8, 45.1, 107.9, 109.1,
115.3, 127.7, 128.9, 137.4, 142.1, 143.1, 149.4, 151.0, 155.3,
155.35.
3
23k
13C NMR (125 MHz, DMSO-d6): d = 113.6, 113.7, 119.0, 119.2,
123.1, 126.5, 132.3, 145.1, 149.1, 151.8, 153.0, 156.9.
13C NMR (125 MHz, DMSO-d6): d = 35.6, 45.3, 109.8, 124.8,
124.9, 127.8, 128.1, 128.9, 137.5, 138.1, 147.9. 148.9, 149.0, 149.5,
151.1, 155.7.
APSI-MS: m/z [M + H]+ = 325.
15k
23m
1H NMR (400 MHz, DMSO-d6): d = 7.50 (1 H, dd, 3JHH = 8.0 Hz,
13C NMR (125 MHz, DMSO-d6): d = 34.3, 45.3, 109.7, 123.4,
127.9, 128.1, 128.9, 136.1, 137.4, 148.7, 149.2, 150.6, 151.0, 155.6.
3JHH = 5.2 Hz, CH), 7.97 (1 H, td, JHH = 8.0 Hz, JHH = 0.8 Hz,
CH), 8.06 (1 H, d, 4JHH = 1.6 Hz, CH), 8.36 (1 H, d, 4JHH = 2.0 Hz,
CH), 8.41 (1 H, d, 3JHH = 8.0 Hz, CH), 8.74 (1 H, d, 3JHH = 5.2 Hz,
CH).
3
4
23j
13C NMR (125 MHz, DMSO-d6): d = 21.2, 25.6, 31.6, 45.1, 107.2,
APSI-MS: m/z [M + 1]+ = 276.
127.8, 128.3, 128.8, 137.6, 149.1, 151.1, 155.3, 159.0.
Preparation of 2,6-Diaminopurines 17; General Procedure
2,4,5,6-Tetraaminopyrimidine sulphate 16 (3 mmol) and an appro-
priate aldehyde 2 (3.5 mmol) were placed in a 15 mL pressure tube
and dissolved in DMF (10 mL). TMSCl (12 mmol) was added drop-
wise to the solution and the tube was thoroughly sealed and heated
on a water-bath for 8 h. After cooling, the flask was opened (Cau-
tion! Excess pressure inside) and the reaction mixture was poured
into H2O (20 mL) and allowed to stand at r.t. in an ultrasonic bath
for 1 h. The precipitate formed was filtered and washed with a small
amount of i-PrOH and then with MeCN. Compounds 17a and 17b
were recrystallized from DMF–MeOH, 17n was recrystallized from
DMF–i-PrOH.
References
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17b
13C NMR (125 MHz, DMSO-d6): d = 55.5, 113.8, 114.7, 120.8,
128.0, 151.1, 152.6, 153.7, 153.9, 161.3.
2-Amino-8-(4-methoxyphenyl)-1-methyl-1,7-dihydro-6H-pu-
rin-6-one (19)
Prepared from 18 and 2b using the above procedure for 17 and re-
crystallized from DMF–i-PrOH.
13C NMR (125 MHz, DMSO-d6): d = 28.8, 55.9, 97.1, 114.1, 115.0,
120.4, 128.6, 137.6, 154.7, 161.6, 162.8.
Preparation of Xanthines 21 and 23; General Procedure
Uracil 20 or 22 (3 mmol) and an appropriate aldehyde 2 (4 mmol)
were placed in a 15 mL pressure tube and dissolved in DMF (10
mL). TMSCl (10 mmol) was added dropwise to the solution and the
tube was thoroughly sealed and heated on a water-bath for 8–12 h.
After cooling, the flask was opened (Caution! Excess pressure in-
side) and the reaction mixture was poured into H2O (20 mL) and al-
lowed to stand at r.t. in an ultrasonic bath for 1 h. The precipitate
formed was filtered and washed with a small amount of i-PrOH and
then with MeCN. Solvent for crystallization: 21o, 21p, 23j, 23 k–
m, 23q: DMF–i-PrOH; 23a, 23b, 23e: DMF–MeOH.
21o
13C NMR (125 MHz, DMSO-d6): d = 14.8, 45.5, 64.2, 108.0, 113.1,
117.9, 121.0, 127.8, 128.1, 128.9, 130.8, 132.2, 137.7, 148.4, 149.8,
151.3, 154.8, 156.4.
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Synthesis 2006, No. 21, 3715–3726 © Thieme Stuttgart · New York

3726
S. V. Ryabukhin et al.
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Synthesis 2006, No. 21, 3715–3726 © Thieme Stuttgart · New York