Preparation of substituted 1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-ones

Article abstract of DOI:10.1002/jhet.5570400405

A new synthetic route to 6-substituted-imidazo[4,5-c]pyridin-2-ons from 4-aminopyridine has been investigated. 4-Aminopyridine protected as alkyl carbamates were nitrated with dinitrogen pentoxide to the corresponding methyl, i-propyl and t-butyl 3-nitropyridin-4-yl carbamates (5a-c) in 51-63% yields. Attempts to substitute these in the 6-position by the ONSH and the VNS techniques succeeded with butylamine and the t-butyl carbamate 9. From the methyl or t-butyl 3-nitropyridin-4-yl carbamates 5a, 5c 1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (1) was formed in 73 and 39% yields, respectively. t-Butyl 6-N-butylamin-3-aminopyridin-4-yl carbamate (6) gave 6-butylamino-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (7) in 53% yield.

Full text of DOI:10.1002/jhet.5570400405

Preparation of Substituted 1,3-Dihydro-
585
Jul-Aug 2003
2H-imidazo[4,5-c]pyridin-2-ones
*
Jan M. Bakke , Hanna S. H. Gautun and Harald Svensen
Department of Chemistry, The Norwegian University of Science and Technology,
Sem Sælands vei 8, NO-7491 Trondheim, Norway
E-mail: jan.bakke@nt.ntnu.no
Received March 4, 2003
A new synthetic route to 6-substituted-imidazo[4,5-c]pyridin-2-ons from 4-aminopyridine has been
investigated. 4-Aminopyridine protected as alkyl carbamates were nitrated with dinitrogen pentoxide to the
corresponding methyl, i-propyl and t-butyl 3-nitropyridin-4-yl carbamates (5a-c) in 51-63 % yields.
Attempts to substitute these in the 6-position by the ONSH and the VNS techniques succeeded with butyl-
amine and the t-butyl carbamate 9. From the methyl or t-butyl 3-nitropyridin-4-yl carbamates 5a, 5c
1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (1) was formed in 73 and 39 % yields, respectively. t-Butyl 6-
N-butylamin-3-aminopyridin-4-yl carbamate (6) gave 6-butylamino-1,3-dihydro-2H-imidazo[4,5-c]-
pyridin-2-one (7) in 53 % yield.
J. Heterocyclic Chem., 40, 585(2003).
Introduction.
mono- and di-N-substituted 3,4-diaminopyridines (2),
which are converted to cyclic ureas by treatment with
appropriate carbonylating agents [10a,b,e,f,i,j]. Only a few
examples of imidazo[4,5-c]pyridin-2-ones with
substituents on the pyridine ring are given in the literature.
Imidazo[4,5-c]pyridin-2-ones in which the pyridine moiety
is part of a larger polycyclic skeleton such as quinolines
and a -carbolines have been reported [11,12]. Variously
substituted 4-hydroxy-3-nitropyridin-2-ones originating
from cyclo additions of nitromalonesters and a ketimine
have been used as substrates for preparation of
imidazo[4,5-c]pyridin-2-ones [13,14]. Bantick and co-
workers have also prepared a 4,6-substituted imidazo-
[4,5-c]pyridin-2-one using a 4-hydroxy-3-nitropyridin-2-
one as an intermediate. However, they incorporated the
nitro group by nitration of 2,4-dihydroxy-6-propylpyridine
[15].
To our knowledge, no general method for preparation of
imidazo[4,5-c]pyridin-2-ones with various types of
substituents in the 6-position (7) has been reported.
Assuming that the cyclic urea moiety can be introduced in
the final step, one is faced with the challenge of preparing
the corresponding 4-amino-3-nitro-6-substituted pyridines
as indicated in Scheme 1.
Some time ago we reported a high yield method for the
nitration of pyridine compounds in the 3-position [1]. One
of the compounds prepared was 4-amino-3-nitropyridine.
From this, 3,4-diaminopyridine (2, R = R’ = H) was made
with a 62 % over all yield from 4-aminopyridine, making it
readily available [2]. In addition to being of biological
interest itself, it might also serve as a substrate for the
synthesis of the imidazo[4,5-c]pyridine ring system. This
ring structure is incorporated into a number of biologically
active compounds [3,4]. We therefore made 2-methyl- and
2-phenyl-1H-imidazo[4,5-c]pyridine from 3,4-diamino-
pyridine [2]. We now wish to report an extension of this to
the preparation of the imidazo[4,5-c]pyridin-2-one ring
system. This is part of several pharmaceutical prepara-
tions, for instance a retroviral protease inhibitor for
HIV/Aids treatment [5] and various cephalosporin deriva-
tives [6]. Due to this, there have been reported many
synthetic routes to these compounds. 1,3-Dihydro-2H-
imidazo[4,5-c]pyridin-2-one (1) has been prepared from
3,4-diaminopyridine (2, R = R’ = H) by various reagents
such as urea [6,7], carbonyldiimidazole [5] and selenium
assisted carbon monoxide incorporation [8]. Another
reported approach utilised 3-amino-4-pyridincarbonyl
azide (prepared from 3-amino isonicotinic acid) which was
transformed into 1 [9].
Standard nucleophilic aromatic substitutions (NAS)
would require the presence of a leaving group like a halogen
or a methoxy group in the 6-position. The preparation of
4-amino-6-chloro-3-nitropyridine from 4-amino-2-
chloropyridine has been reported [16]. The synthesis
proceeds via an intermediate nitramine, which rearranges
upon heating to two isomeric nitropyridines. The overall
yield of 4-amino-6-chloro-3-nitropyridine was less than
22 %. By substitution of the chloro moiety, NH , OMe, and
2
other groups have been introduced in the 6-position [16-17].
Substitution of the chloro with a methoxy group prior to
nitration has also been reported [18]. No yield was given for
the NAS step. The rearrangement of the nitramine gave
30 % of 4-amino-2-methoxy-5-nitropyridine. Another
In addition, a number of mono- and di-N-substituted imi-
dazo[4,5-c]pyridin-2-ones (3) have been reported [6,10].
These compounds may be obtained from 1 [10g,h] or from

586
J. M. Bakke, H. S. H. Gautun and H. Svensen
Vol. 40
Scheme 1
strategy for preparation of 6-substituted 4-amino-3-nitro-
pyridines has been to introduce the 4-amino group by
aminolysis of a halogen in the final step [19].
the b-nitropyridines. The conditions are such that even acid
labile groups in the nitrated molecule may survive. Thus, the
pH of the aqueous solution is ca. 2 – 3 and the temperature ca.
20 °C. The results are given in Table 1 and one point is that
no hydrolysis of the acid labile carbamates were observed
during the nitration reaction.
We have reported an efficient method for preparation of
3-nitropyridines with various substituents in the 4-position
[1]. Also, we have shown that it is possible to substitute
the 6-position of 3-nitropyridines selectively, either by
Oxidative Nucleophilic Substitution of Hydrogen (ONSH)
using various amines in the presence of potassium
permanganate [20] or by Vicarious Nucleophilic
Substitutions (VNS) using hydroxylamine or 4-amino-
1,2,4-triazole as nucleophiles [21]. With this knowledge in
hand we envisaged a new procedure for preparation of
6-substituted imidazo[4,5-c]pyridin-2-ones starting from
4-aminopyridine as depicted in Scheme 2. The 4-amino
group needs to be protected during the nitration with
dinitrogen pentoxide. We have successfully used acetyl for
this [2]. However, by instead preparing carbamates (4),
this would not only serve as a protecting group, but also be
a precursor for the cyclic urea (7) in the final step [22].
Table 1
Substrate
Method A [a]
Method B[b]
Method C[c]
1
4, R , X
4:5 [d]
4:5 [d]
4:5 [d](yield of 5) [e]
a, Me, H
b, i-Pr, H
c, t-Bu, H
d, t-Bu, Cl
47:53
-
37:62
100 : 0
85:15
-
-
5:95
3:97
11:89
100: 0
(63)
(61)
(51)
-
Nitration.
100: 0
The nitration of pyridine compounds by N O gives the N-
2
5
-
nitropyridinium nitrate. In aqueous SO /HSO this
2
3
[a] Reaction with N O in CH Cl , followed by treatment with NaHSO
3
2
5
2
2
rearranges regiospecifically to the b-nitropyridine compound
[1]. One side reaction in the present system would be the
hydrolysis of the carbamates 5 to give the corresponding 3-
nitro-4-aminopyridines. However, with the present nitration
system, it is possible to obtain acceptable to good yields of
in methanol/water. [b] Reaction with N O in SO followed by treatment
2
5
2
with water. [c] Reaction with N O in CH NO followed by treatment
2
5
3
2
1
with NaHSO in methanol/water. [d] Determined by H nmr spect-
3
roscopy of the reaction mixtures. [e] Isolated compounds, > 99 % pure by
1
H nmr spectroscopy.
Scheme 2

Jul-Aug 2003
Preparation of Substituted 1,3-Dihydro-2H-imidazo[4,5-c]pyridin-2-ones
587
From Table 1, the nitration of methyl pyridin-4-yl carb-
amate (4a) gave a better yield than that of the t-butyl
derivative (4c), 63 vs 51%. This may have some practical
implications, as methyl chloroformate used for the forma-
tion of 4a is considerably less expensive than di-tert-butyl
dicarbonate used for the preparation of 4c. Also, the final
cyclization step gave a better yield with the methyl carb-
amate 9a then the t-butyl carbamate 9c, 74 vs 56 %. All
attempts to nitrate tert-butyl 2-chloropyridin-4-yl carbon-
ate 4d failed.
Cyclisation Reactions.
We have reported the facile cyclisation of 4-acetamido-
and 4-benzamido-3-aminopyridine to the corresponding
imidazo[4,5-c]pyridines in acetic acid [2]. The carbamates
5a, 5c and 6 were accordingly reduced to the corres-
ponding amines (9a, 9c and 10) in high yields, and these
were cyclised to the imidazo[4,5-c]pyridinones 1 and 7.
Scheme 4
Substitution Reactions.
We have reported the substitution of hydrogen by
ammonia itself and a range of other amines in the position
para to the nitro group in a series of 4-substituted-3-
nitropyridines by the ONSH methodology [20]. We there-
fore attempted the reaction of 5a-c with ammonia, n-butyl-
amine, diethylamine and aniline under ONSH conditions.
However, the products from all reactions were either
starting material or 4-amino-3-nitro pyridine except for the
1
reaction of n-butylamine with 5b (R = i-Pr, 29 %) and 5c
1
(R = t-Bu, 56 %).
As 4-acetamido-3-nitropyridine is both readily available
and can be easily hydrolysed to 4-amino-3-nitropyridine
we also investigated the substitution reactions with this
substance, as the products might be starting materials for 6
and by that 7:
This cyclisation reaction proved to be difficult, particu-
larly in the light of our experience with the 4-acylamido-3-
aminopyridines [2]. The results from a series of experi-
ments are given in Table 2.
Scheme 3
Table 2.
The attempted ONSH reactions with 8 did not give any
substitution in the 6-position of the pyridine ring, only
aminolysis of the acetyl group.
We have reported the successful VNS reactions on 3-
nitropyridine [21] and we tried this methodology to substi-
tuted 5a, 5c and 8 with hydroxylamine and 1-amino-1,3,4-
triazole without success.
Substrate Reaction conditions
Product (yield, %)
9c
9c
9c
MeOH, 64 °C, 18 h
MeOH, H SO (2 %), 18 h
AcOH, 114 °C, 24 h
No reaction
No reaction
3-acetamido-4-
aminopyridine
No reaction
Finally, as our earlier results indicated that the ONSH
reactions gave better results with electron withdrawing
groups in the 4-position of the pyridine ring, we tried to
oxidise the amino group of 4-amino-3-nitropyridine to a
nitro group. To our surprise, this was not possible either by
nitric acid, potassium permanganate or by sodium
hypochlorite. We were therefore left with two series of
carbamates for the cyclisation to the imidazopyrdinones 1
and 7, one with a hydrogen atom and one with n-butylamine
in the position para to the nitro group, that is, 5 and 6.
2
4
9c
9c
DMAP, Et N, 1,4-dioxane,
110 °C, 19h
NaH, 1,4-dioxane,110 °C, 43 h
3
t-butyl 4-aminopyridyl-
3-carbamate
1 (56 %)[a]
1 (74 %) [a]
7 (55 %) [b]
9c
9a
10
diglyme, 150 °C, 24 h
diglyme, 150 °C, 24 h
diglyme, 150 °C
[a] Yield after crystallisation; [b] Yield after flash chromatography.

588
J. M. Bakke, H. S. H. Gautun and H. Svensen
Vol. 40
g, 7.88 mmol) in a mixture of methanol (15 mL) and water (5 ml)
was added. The reaction was stirred at room temperature over
night. H nmr of the reaction mixture (methanol-d4) showed 4a
As can be seen from Table 2, addition of acid or base
resulted in two different reaction paths, with acetic acid,
4-amino-3-acetamidopyridine was formed and with
sodium hydride in 1,4-dioxane, trans carbamoylation took
place, forming tert-butyl 4-aminopyridin-3-yl carbamate.
However, complete conversion to the cyclic ureas was
1
and 5a in a ratio of 47:53.
Method B.
DNP (0.61 g, 5.65 mmol) was dissolved in liquid SO2 (ca. 30
mL) at –78 °C. To this solution was added 4a (0.399 g, 2.63
mmol) which was dissolved gradually as the temperature was
allowed to rise to around –20 °C. After 2 hours the mixture was
poured into ice-water (50 mL). 1H nmr of the mixture indicated a
ratio between 4a and 5a of 85:25.
1
accomplished in diglyme at 150 °C. From H nmr spec-
troscopy only one product (1 or 7) was present at the end
of the reaction. For both 1,3-dihydro-2H-imidazo[4,5-c]-
pyridin-2-one (1) and 6-butyl-1,3-dihydro-2H-imidazo-
[4,5-c]pyridin-2-one (7), acceptable yields were obtained
after crystallisation or flash chromatography. 1,3-Dihydro-
2H-imidazo[4,5-c]pyridin-2-one (1) itself could be formed
from both methyl and t-butyl 3-nitropyridin-4-yl carb-
amates (5a and 5c). As 5a was formed by a less expensive
route than 5c, this may be the best starting material for 1.
The present method compares well with the reported
processes for the synthesis of 1 [5-9]. For 6-butyl-1,3-
dihydro-2H-imidazo[4,5-c]pyridin-2-one (7) the present
method appears to be the only one reported.
Method C.
DNP (0.71 g, 6.57 mmol) was dissolved in freshly distilled.
nitromethane (12 mL) in an ice-water bath. To this solution was
added 4a (0.500 g, 3.29 mmol). After stirring for 10 minutes on
the ice-water bath a solution of sodium bisulfite (1.03 g, 9.90
mmol) in a 3:1 mixture of methanol and water (20 mL) was
added. The reaction was stirred at room temperature over night.
1H nmr of the reaction mixture (methanol-d4) showed 4a and 5a
in a ratio of 5:95.
The solvents were evaporated and the residue dissolved in
ethyl acetate (30 mL) and water (20 mL). The pH was adjusted to
>7 by addition of aqueous sodium hydroxide (1 M). The layers
were separated and the aqueous layer extracted with ethyl acetate
(4 x 20 mL). The combined organic layers were dried (MgSO4)
and the solvent evaporated to give 0.408 g of a yellow solid
(96 % pure by 1H nmr, 63 % yield). This product was used with-
out further purification in the following studies. An analytically
pure sample was obtained by flash chromatography (3 % acetone
in dichloromethane). This gave a light yellow solid with
Conclusion.
We have investigated a new synthetic route to 6-
substituted-imidazo[4,5-c]pyridin-2-ones from readily
available 4-amino-3-nitropyridine via the corresponding 4-
alkyl carbamates (5a- c). Substitutions of these compounds
in the 6-position by the ONSH and the VNS techniques
were attempted. This worked well for substitution with
butylamine but not with ammonia or other amines. From
the methyl or t-butyl 3-nitro-4-pyridinyl carbamates 5a, 5c
and 7, 1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-on (1) and
6-butylamino-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-
1
mp 141.5 -143.0 °C (lit 140 – 142 °C [28]) H nmr (deuteri-
ochloroform): d 3.88 (s, 3H, CH3), 8.55 (d, 1H, H-5, J = 5.9 Hz),
8.66 (d, 1H, H-6, J = 5.9 Hz), 9.37 (s, 1H, H-2), 10.03 (br s, 1H,
NH) ppm; 13C nmr (deuteriochloroform): d 53.4 (OCH3), 113.3,
131.3 (C-NO2), 141.9, 148.0, 152.78 (C=O), 155.2 ppm; ir:
(potassium bromide): 3280 (m), 1730 (s), 1710 (m), 1595 (s),
1570 (m), 1560 (m), 1490 (m), 1450 (m), 1400 (m), 1340 (s),
1250 (m), 1235 (m), 1200 (m), 1170 (m), 1050 (m), 940 (m); ms:
( 250 °C, 70 eV) m/z 198 (M+1, 3), 197 (M+, 28), 165 (5), 152
(8), 151 (100), 136 (18), 122 (8), 119 (8), 94 (13), 93 (13), 92
(10), 91 (14), 80 (11), 79 (47), 78 (15), 66 (16), 65 (23), 64 (37),
63 (5), 59 (63), 54 (5), 53 (25), 52 (41), 51 (11), 50 (8); hrms:
observed: M+ 197.0438. Calculated for C7H7N3O4 : 197.0437.
2
3
one (7, R = H, R = Bu) were formed in good yields.
EXPERIMENTAL
The nmr spectra were recorded on a Bruker Avance DPX 300
MHz instrument, using the solvents for calibration of the chemi-
cal shifts. The ir spectra were recorded on a Nicolet 20SxC FT-IR
spectrometer. The ms and hrms were recorded on a MAT 95 XL
spectrometer. Dinitrogen pentoxide was prepared from dintrogen
tetroxide and ozone [23]. The solvents were dried according to
standard procedures [24].Literature procedures were used for the
preparation of 4-amino-2-chloropyridine [25], methyl pyridin-4-
yl carbamate (4a) [22c], i-propyl pyridin-4-yl carbamate (4b)
[22c] and t-butyl pyridin-4-yl carbamate (4c) [26]. Compound 4d
was prepared according to Pauls et al. [27] using sodium hydride
as base instead of sodium bistrimethylsilyl amide.
Isopropyl 3-Nitropyridin-4-yl Carbamate (5b).
Isopropyl pyridin-4-yl carbamate (4b) (3.00 g, 16.30 mmol)
was nitrated using Method C as described for 4a above. 1H nmr
(methanol-d4) of the reaction mixture showed 4b and 5b in a
ratio of 3:97. Work up gave 2.26 g of a light brown sold (>99 %
1
pure by H nmr, 61 % yield). This product was used without
further purification in the subsequent studies. A sample was puri-
fied for analysis by flash chromatography (5 % acetone in
dichloromethane). This gave an off-white solid with mp.
Methyl 3-Nitropyridin-4-yl Carbamate (5a).
Method A.
1
97.0–99.0 °C. H nmr (deuteriochloroform): d 1.36 (d, 6H, 2 x
CH3, J = 6.2 Hz), 5.08 (hp,1H, CH, J = 6.2 Hz), 8.56 (d, 1H, H-5,
J = 6.0 Hz), 8.64 (d, 1H, H-6, J = 6.0 Hz), 9.36 (s, 1H, H-2), 9.93
(br s, 1H, NH) ppm; 13C nmr (deuteriochloroform): d 21.9, 70.9,
113.3, 131.4, 142.1, 148.0, 151.9, 155.1 ppm; ir: (potassium
bromide): 3360 (m), 1730 (s), 1605 (s), 1570 (s), 1520 (m), 1500
Dinitrogen pentoxide (DNP) (0.57 g, 5.28 mmol) was
dissolved in CH2Cl2 (10 mL) which was precooled on an ice-
water bath. To this solution was added methyl pyridin-4-yl carb-
amate (4a) (0.402 g, 2.63 mmol). The reaction was stirred for 10
minutes on the ice-water bath before a solution of NaHSO3 (0.82

Jul-Aug 2003
Preparation of Substituted 1,3-Dihydro-2H-imidazo[4,5-c]pyridin-2-ones
589
(s), 1490 (m), 1430 (br, m), 1345 (s), 1255 (m), 1230 (s), 1210
(m), 1175 (m), 1100 (s), 1045 (m), 915 (m), 880 (m), 850 (s), 800
(m), 760 (s) cm-1; ms: (250 °C, 70 eV) m/z 226 (M+1, 5), 225
(M+, 41), 166 (28), 140 (13), 139 (96), 122 (13), 121 (5), 119
(10), 94 (5), 93 (22), 91(8), 79 (10), 66 (7), 64 (15), 52 (6); hrms:
observed: M+ 225.07489. Calculated for C9H11N3O4:
225.07496.
(67), 166 (18), 163 (15), 122 (5), 121 (48), 120 (11), 119 (5),
106 (7), 94 (5), 93 (7), 92 (5), 67 (7), 45 (11), 43 (28) ppm;
hrms: observed: M+ 296.1478. Calculated for C13H20N4O4
296.1485.
:
t-Butyl 2-N-Butylamin-5-nitropyridin-4-yl Carbamate (6c)
A solution of 5c (0.513, 2.15 mmol) was treated in the same
manner as described for 5b. This gave a crude product, which
was crystallised from methanol/water to give 0.373 g
(56 % yield) of a yellow crystalline material. mp 154-155 °C.
1H nmr (deuteriochloroform): d 0.97 (tr, 3H, CH3, J = 7.3 Hz),
1.37–1.49 (m, 2H, CH2), 1.54 (s, 9H, 3 x CH3), 1.59–1.68 (m,
2H, CH2), 3.36 (br s, 2H, CH2), 5.30 (br s, 1H, NH), 7.44 (s, 1H,
H-3), 9.02 (s, 1H, H-6), 10.09 (br s, 1H, NH) ppm; 13C nmr
(dimethyl sulfoxide-d6): d 15.1, 19.6, 27.7, 31.0, 83.1, 93.4,
124.8, 140.9, 150.5, 151.2, 161.9 ppm; one signal which was
covered by dimethylsufoxide was observed at 42.5 ppm for a run
in deuteriochloroform; ir: (potassium bromide) 3315 (m),
3210 (m), 1760 (s), 1610 (s), 1570 (s), 1550 (s), 1510 (s),
1510 (m), 1490 (m), 1450 (w), 1410 (m), 1385 (m), 1300 (m),
1270 (s), 1240 (s), 1195 (m), 1150 (s), 1130 (m), 870 (m),
840 (m), 760 (m) cm-1; ms: (250 °C, 70 eV) m/z 311 (M+1, 3),
310 (M+, 18), 293 (26), 254 (10), 238 (6), 237 (30), 225 (46), 212
(35), 211 (81), 210 (16), 208 (5), 198 (39), 194 (6), 193 (22), 192
(6), 182 (5), 181 (49), 168 (31), 167 (100), 163 (8), 154 (34), 152
(5), 151 (6), 150 (5), 149 (21), 147 (7), 139 (6), 137 (11), 135
(13), 124 (9), 122 (5), 121 (60), 120 (16), 119 (5), 106 (6), 94 (5),
93 (8), 81 (5), 67 (6), 57 (53), 56 (8), 55 (8), 52 (5); hrms:
observed: M+ 310.1638, Calculated for C14H22N4O4: 310.1641.
t-Butyl 3-Nitropyridin-4-yl Carbamate (5c).
t-Butyl pyridin-4-yl carbamate (4c) (1.001 g, 5.15 mmol) was
nitrated using Method C as described for 4a above. 1H nmr
(methanol-d4) of the reaction mixture showed4c and 5c in a ratio
of 11:89. Work up gave 0.855 g orange solid. Purification by
flash chromatography (3 % acetone in dichloromethane) gave
0.631 g off-white solid (>99 % pure by 1H nmr, 51 % yield) with
mp 113.0–115.0 °C. 1H nmr (deuteriochloroform): d 1.56 (s, 9H,
3 x CH3), 8.54 (d, 1H, H-5, J = 6.0 Hz), 8.61 (d, 1H, H-6, J =
6.0 Hz), 9.34 (s, 1H, H-2), 9.82 (br s, 1H, NH) ppm; 13C nmr
(deuteriochloroform): d 28.5, 83.7, 113.6, 132.2, 142.8, 148.3,
151.6, 155.2 ppm; ir: (potassium bromide) 3360 (m), 1730 (s),
1600 (s), 1565 (s), 1520 (s), 1500 (s), 1435 (br, s), 1405 (m),
1365 (m), 1345 (s), 1320 (m), 1250 (br, s), 1230 (br, s), 1140 (br,
s), 1120 (s), 1050 (m), 1040 (m), 860 (m), 850 (m), 840 (m),
825 (m), 760 (m), 750 (s) cm-1; ms: (250 °C, 70 eV) m/z 240
(M+1, 1.5) 239 (M+, 7), 166 (12), 140 (10), 139 (15), 135 (7),
121 (6), 119 (8), 93 (8), 91 (7), 79 (6), 66 (7), 64 (11), 59 (31), 58
(8), 57 (100), 56 (9), 55 (5), 52 (6); hrms: observed: M+ 239.0907
Calculated for C10H13N3O4 : 239.0906.
Isopropyl 2-N-Butylamin-5-nitropyridin-4-yl Carbamate (6b).
Methyl 3-Aminopyridin-4-yl Carbamate (9a).
To a solution of 5b (0.503 g, 2.24 mmol) in n-butylamine
(12 mL) was added potassium permanganate (1.32 g,
8.38 mmol) and the mixture stirred vigorously at room temper-
ature. Additional portions of potassium permanganate (0.79 g)
was added with 1 hour intervals. After 3 hours dimethyl
sulfoxide (5 mL) was added. After a total reaction time of
To a solution of 5a (0.119 g, 0.60 mmol) in ethyl acetate
(10 mL) was added 5% palladium on carbon (0.021 g) and the
mixture stirred under hydrogen (10 bar) for 24 hours. The reac-
tion mixture was filtered through celite and the solvent evapo-
rated under reduced pressure. This gave 0.098 g of an orange oil
(>98 % pure by GC, 98 % yield). A sample was crystallised
from chloroform to give orange crystals with mp 124.0-
126.0 °C. 1H nmr (dimethyl sulfoxide-d6): d 3.69 (s, 1H, CH3),
5.14 (br s, 2H, NH2), 7.51 (d, 1H, H-5, J = 5.3 Hz), 7.71 (d, 1H,
H-6, J = 5.3 Hz), 7.95 (s, 1H, H-2), 8.94 (br s, 1H, NH) ppm;
13C nmr (methanol-d4): d 53.1, 116.6, 134.1, 136.7, 138.6,
139.9, 156.3 ppm; ir: (potassium bromide) 4310 (w), 3355 (w),
3243 (w), 1747 (m), 1728 (s), 1590 (s), 1525 (s), 1505 (m),
1431 (m), 1316 (m), 1248 (m), 1222 (s), 1192 (m), 1066 (m)
cm-1; ms: (250 °C, 70 eV) m/z 167 (M+, 97), 136 (29), 135
(100), 109 (5), 108 (36), 107 (25), 81 (48), 80 (28), 79 (5), 59
(8), 54 (22), 53 (22), 52 (21); hrms: observed: M+ 167.06956.
Calculated for C7H9N3O2: 167.06948.
1
6 hours H nmr of the reaction mixture indicated that the reac-
tion had stopped. The reaction was poured into water (100 mL)
and the resulting mixture filtered. The filtrate was extracted
with dichloromethane (3 x 100 mL). The combined organic
layers were washed with brine (80 mL), dried (magnesium
sulfate) and the solvent evaporated under reduced pressure.
This gave 0.633 g of an oil, which was purified by flash chro-
matography (2 % acetone in dichloromethane) to give 0.189 g
(>98 % pure by 1H nmr, 29 % yield) of a purple, crystalline
product. mp 124.0–125.0 °C. 1H nmr (deuteriochloroform): d
0.97 (tr, 3H, CH3, J = 7.3 Hz), 1.33 (d, 6H, 2 x CH3), J = 6.3
Hz), 1.37-1.49 (m, 2H, CH2), 1.50–1.69 (m, 2H, CH2), 3.36 (br
s, 2H, CH2), 4.97–5.10 (m, 1H, CH), 5.30 (br s, 1H, NH), 7.46
(s, 1H, H-3), 9.02 (s, 1H, H-6), 10.20 (br s, 1H, NH) ppm; 13C
nmr (dimethyl sulfoxide-d6): d 13.9, 19.8, 21.8, 31.1, 69.7,
94.2, 125.2, 141.0, 150.6, 152.0, 162.1 ppm; one signal which
was covered by dimethylsufoxide signals was observed at 42.2
ppm for a run in deuteriochloroform; ir: (potassium bromide)
3341 (m), 3230 (br m), 2982 (m), 2958 (m), 2935 (m), 2867
(m), 1737 (s), 1620 (s), 1577 (s), 1557 (s), 1514 (s), 1496 (s),
1455 (m), 1421 (s), 1374 (m), 1341 (m), 1303 (s), 1277 (s),
1246 (s), 1190 (s), 1136 (m), 1105 (s), 1041 (m), 998 (m), 847
(m), 759 (m) cm-1; ms: (250 °C, 70 eV) m/z 297 (M+1, 3), 296
M+ (31), 280 (17), 279 (71), 268 (6), 267 (49), 254 (27), 253
(68), 240 (44), 237 (18), 225 (38), 212 (18), 211 (100), 208
(10), 206 (5), 198 (18), 193 (6), 192 (5), 181 (19), 168 (11), 167
t-Butyl 3-Aminopyridin-4-yl Carbamate (9c).
A solution of 5c (0.657 g, 2.75 mmol) in methanol (20 mL)
was treated in the same manner as described for reduction of 5a.
This gave 0.546 g (> 99 % pure by GC, 95 % yield) of a white
crystalline material. mp 118.0–19.0 °C. 1H nmr (deuterio-
chloroform): d 1.53 (s, 9H, 3 x CH3), 3.49 (br.s, 2H, NH2 ), 6.96
(br s, 1H, NH), 7.62 (d, 1H, H-5, J = 5.4 Hz,), 8.07 (d, 1H, H-6, J
= 5.4 Hz), 8.11 (s, H-2, 1H) ppm; 13C nmr (deuteriochloroform):
d 28.3, 81.5, 114.2, 131.8, 134.9, 140.7, 143.1, 152.5 ppm; ir:
(potassium bromide): 3378 (m), 3227 (m), 2982 (m), 1736 (s),
1716 (s), 1589 (s), 1520 (s), 1434 (s), 1369 (m), 1334 (m), 1315

590
J. M. Bakke, H. S. H. Gautun and H. Svensen
Vol. 40
REFERENCES AND NOTES
(m), 1270 (s), 1253 (s), 1224 (m), 1156 (s), 865 (m), 825 (m)
cm-1; ms: (250 °C, 70 eV) m/z 209 (M+, 3), 154 (6), 153 (90),
136 (21), 135 (56), 110 (5), 109 (84), 108 (5), 107 (7), 97 (7), 95
(5), 85 (7), 83 (7), 82 (8), 81 (11), 80 (11), 71 (11), 69 (11), 67 (6),
59 (56), 57 (100), 56 (14), 55 (20), 54 (8), 53 (13), 52 (8); hrms:
observed: M + 209.11604. Calculated for C 10H15N3O2:
209.11643.
[1] J. M. Bakke, E. Ranes, J. Riha and H. Svensen, Acta Chem.
Scand., 53, 141 (1999).
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D. H. Steinman, J. A. Trautmann, D. H. Albert, T. J. Magoc, P. Tapang,
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D.W.Vine, J. Chem. Res (S),196 (1997).
t-Butyl 6-N-Butylamin-3-aminopyridin-4-yl Carbamate (10).
A solution of 6c (0.615 g, 1.98 mmol) in ethyl acetate (30 mL)
was treated in the same manner as 5a. Evaporation of the solvent
1
gave 0.385 g of a light purple oil (> 98% pure by H nmr, 69%
yield) which deteriorated quickly after isolation. The crude prod-
uct was used immediately in the next step without full character-
isation. 1H nmr (deuteriochloroform): d 0.95 (tr, 3H, CH3, J = 7.3
Hz), 1.35–1.63 (m, 6H, 2 x CH2), 2.72 (br s, 2H, NH2), 3.22 (tr,
2H, CH2, J = 7.00 Hz), 4.47 (br s, 1H, NH), 7.12 (s, 1H, H-3),
7.68 (br s, 1H, NH), 7.70 (s, 1H, H-6) ppm; 13C nmr (methanol-
d4): d 11.8, 20.7, 28.9, 32.3, 42.1, 80.4, 98.5, 125.5, 136.7, 136.8,
153.3, 154.6 ppm;
[5] G. V. Delluca, US 5763469 (1998); Chem. Abstr., 129, 67775
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ˇ
[9a] M. Debeljak-Susˇtar, B. Stanovnik, M. Tisˇler and Z. Zrimsˇek,
1,3-Dihydro-2H-imidazo[4,5-c]pyridin-2-one (1).
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A solution of 9a (0.308 g, 1.84 mmol) in diglyme (10 mL) was
heated in an oil bath at 150 °C for 24 hours. The reaction was
cooled to room temperature and most of the solvent evaporated
under reduced pressure. The oily residue was crystallised from
water to give 0.185 g of light brown crystals (74 % yield) with
mp 305.0–306.0 °C (lit 304-305 °C [7], 315 °C [9a]. 1H nmr
(dimethyl sulfoxide-d6): d 6.97 (d, 1H, H-7, J = 5.2 Hz), 8.09 (d,
1H, H-6, J = 5.2 Hz), 8.13 (s, 1H, H-4), 10.99 (br s, 1H, NH),
11.06 (br s, 1H, NH) ppm; 13C nmr (dimethyl sulfoxide-d6): d
104.3, 127.4, 129.1, 135.2, 142.0, 154.8 ppm; ir: (potassium bro-
mide) 3481 (br m), 3300-2100 (br m), 1729 (s), 1626 (s)m 1609
(s), 1487 (s), 1217 (m), 1203 (m), 1188 (m), 1157(m), 1935 (m),
999 (m), 883 (m), 808 (m), 720 (s), 632 (s) cm-1; ms: (250 °C,70
eV) m/z 136 (M+1, 9), 135 (M+, 100), 107 (15), 80 (23), 53 (22),
52 (12), 44 (9); hrms: observed: M+ 135.04334. Calculated for
C6H5N3O : 135.04326.
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Chem., 18,1537 (1981).
Treatment of 9c (0.506 g, 2.42 mmol) according to the proce-
dure given for cyclisation of 9a gave, after crystallisation 0.184
g of light brown crystals (56 % yield) with mp 308-310 °C.
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[13a] A. Dornow and H. v. Plessen, Chem. Ber. 99, 244 (1966);
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6-N-Butylamino-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (7).
[14a] C. Coburn, C. WO 9927930 (1999); Chem. Abstr., 131, 31937
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A solution of t-butyl 6-N-butylamino-3-aminopyridin-4-yl car-
bamate (10) (0.384 g, 1.37 mmol) was treated in the same manner
as described for cyclisation of 9a. Flash chromatography (ethyl
acetate:methanol:aqueous ammonia= 95:4:1) of the crude oily
product gave 0.155 g of a light brown powder (55 %) with 229 °C
1
(decomposed). H nmr (dimethyl sulfoxide-d6): d 0.89 (tr, 3H,
[15] J. R.Bantick, H. G. Beaton, S. L. Cooper, S. Hill, S. C. Hirst,
T. McInally, J. Spencer, A. C. Tinker and P. A. Willis, Bioorg. Med.
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CH3, J = 7.2 Hz), 1.23–1.56 (m, 4H, 2 x CH2), 3.13 (br m, 2H,
CH2), 5.85 (tr, 1H, NH, J = 5.5 Hz,), 6.03 (s, 1H, H-7), 7.52 (s,
1H, H-4), 10.20 (br s, 1H, NH), 10.53 (br s, 1H, NH) ppm; 13
C
·
[16a] Z. Talik and E. Plazek, Chem. Abstr., 51, 12089 (1957);
nmr (dimethyl sulfoxide-d6): d 13.9, 19.9, 31.39, 41.8, 87.00,
120.1, 125.6, 138.5, 154.7, 155.3 ppm; ir (potassium bromide)
3600 – 2600 (broad signal with the following peaks: 3329, 3194,
2957, 2928), 1710 (s), 1648 (s), 1502 (m), 1475 (m) cm-1; ms:
(250 °C,70 eV) m/z 207 (M+1, 3), 206 (M+, 21), 190 (6), 177
(24), 164 (15), 163 (100), 150 (36), 136 (7), 135 (10), 134 (20);
hrms: observed: M+ 206.1166. Calculated for C10H14N4O:
206.1168.
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Jul-Aug 2003
Preparation of Substituted 1,3-Dihydro-2H-imidazo[4,5-c]pyridin-2-ones
591
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