1,3-Dihydro-2H-imidazo[4,5-c]pyridin-2-one

Article abstract of DOI:10.1002/jhet.5570430341

A facile acid catalysed cyclisation method for the preparation of the cyclic urea 2H-imidazo[4,5-c]pyridin-2-one (2) in > 95% yield is reported. The biologically active compound 2 can be obtained by heating (3-amino-4-pyridinyl)-carbamic acid methyl, ethyl or tert-butyl esters (1a-c) in sulfuric acid (0.1%) or in aqueous HBF₄ (3.5 equivalents) for 10 min. - 3 hrs at 90 °C. The corresponding microwave-promoted (MW) reactions afforded the pure product 2 within few minutes. The 6-butylamino-substituted analogue (2a) was correspondingly obtained by MW irradiation in 99% yield by cyclisation of 2-(butylamino)-5-amino-4-pyridylcarbamic acid isopropyl ester (1d). Quantitative precipitation of product 2 was obtained by pH adjustment. The process represents a solvent-free, "green" method for the preparation of 2.

Full text of DOI:10.1002/jhet.5570430341

May-Jun 2006
787
1,3-Dihydro-2H-imidazo[4,5-c]pyridin-2-one
Jarle Holt, Jan M. Bakke and Anne Fiksdahl(*)
Department of Chemistry, Sem Sælands v. 8, Norwegian University of Science and Technology, NTNU,
NO-7491 Trondheim, NORWAY.
e-mail: Anne.Fiksdahl@chem.ntnu.no
Received June 26, 2005
O
O
C-OR
HN
HN
1a-c R = Me, Et, t Bu R' = H
NH
NH2
0.1 % H2SO4 or HBF4
MW (2-6 min.)
1d
R = i Pr
R' = NH-n Bu
2, 2a
R' = H, NH-n Bu
R'
N
R'
N
2, 2a
1a-d
A facile acid catalysed cyclisation method for the preparation of the cyclic urea 2H-imidazo[4,5-
c]pyridin-2-one (2) in > 95 % yield is reported. The biologically active compound 2 can be obtained by
heating (3-amino-4-pyridinyl)-carbamic acid methyl, ethyl or tert-butyl esters (1a-c) in sulfuric acid (0.1
%) or in aqueous HBF4 (3.5 equivalents) for 10 min. - 3 hrs at 90 °C. The corresponding microwave-
promoted (MW) reactions afforded the pure product 2 within few minutes. The 6-butylamino-
substituted analogue (2a) was correspondingly obtained by MW irradiation in 99 % yield by cyclisation
of 2-(butylamino)-5-amino-4-pyridylcarbamic acid isopropyl ester (1d). Quantitative precipitation of
product 2 was obtained by pH adjustment. The process represents a solvent-free, “green” method for the
preparation of 2.
J. Heterocyclic Chem., 43, 787 (2006).
Introduction.
Methyl and ethyl carbamates 3a have also been prepared
by nitration of methyl/ethyl 4-pyridylcarboxylate
followed by hydrazide formation, diazotization and
Curtius rearrangement of the acyl azide in methanol/
ethanol [10]. The 3-aminopyridyl carbamates (1a-d)
were obtained by selective reduction of the nitro group
in quantitative yield by catalytic hydrogenation. 3,4-
Diaminopyridine [11], which also may be a suitable
substrate for the preparation of (2) [12], has readily been
prepared based on the improved nitration method,
affording higher yields [6] compared to previous
methods [13].
The cyclic urea compound, imidazo[4,5-c]pyridin-2-
one (2, see Scheme 2), has been patented for its antiviral
and antibacterial activity [1-3] and has previously been
prepared by reaction of 3,4-diaminopyridine with CO and
a stoichiometric or excess amount of Se in the presence of
N-methylpyrrolidine [4]. Recently this biologically active
cyclic urea was also prepared from 3-amino-4-pyridyl
methyl and tert-butyl carbamates 1a and 1c [5]. However,
the cyclisation reactions proved to be difficult and
respectively 74 and 56 % yield were eventually obtained
by heating at 150 °C in diglyme for 24 hours. The 6-
butylamino-substituted analogue (2a) was made by the
same procedure in 55 % yield from 2-(butylamino)-5-
Scheme 1
amino-4-pyridylcarbamic
acid
tert-butyl
ester.
CO2R
CO2R
NH2
N
Imidazolopyridines have correspondingly been prepared
from 4-acetamido- and 4-benzamido-3-aminopyridine [6].
We hereby report a more convenient method for the
quantitative preparation of imidazolopyridinones (2,2a)
by less vigorous reaction conditions. The key substrates
for our syntheses are 4-amino-3-nitropyridines, which
have now been readily available through an improved
nitration method [7,8]. Our results are discussed below.
HN
N
HN
N
NO2
NH2
H2/Pd/C
>99 %
R'
R'
3a-d
1a-d
1a, 3a R = Me, R' = H
1b, 3b R = Et R' = H
1c, 3c R = t Bu R' = H
1d, 3d R = i Pr R' = NH-n Bu
Results and Discussion.
3-Amino-4-pyridyl carbamates (1a-c) afforded the
imidazolopyridine product (2) by harsh conditions heating
in 2 % sulfuric acid. However, we experienced that the
direct cyclisation of the 3-amino-4-carbamates (1a-c) to
give 2 was also successful at lower concentrations of
The 3-amino-4-pyridyl carbamate substrates (1a-d)
were prepared as shown in Scheme 1. The nitration of 4-
aminopyridine was carried out after protection of the 4-
amino group by alkoxycarbonyl to give 3a-d [5,6].

788
J. Holt, J. M. Bakke and A. Fiksdahl
Vol 43
Table 1
Cyclisation of 1a-c to 2, reaction conditions.
Catalyst
H SO
Amount
Temp.
Reaction time
Conversion to 2 a
Yield b
0.1 %
90 C
10-30 min., 5 mgc
3 hrs., 100 mgd
8 hrs., 5 mgc
99%
99 %
40 %
99 %
99 %
99 %
0 %
°
2
4
> 95 %
> 95 %
°
0.1 %
3.5 eqv.
40 C
90 C
HBF
10-30 min., 5 mgc
1-3 hrs, 100 mgd
5 hrs., 5 mgc
°
4
°
0.65 eqv.
7 eqv.
90 C
40 C
8 hrs., 5 mgc
°
a Conversion is based on 1H nmr of crude product, b Yield after work-up, All substrates, 1a-c, d Substrate 1a,c
c
sulfuric acid (see Scheme 2 and Table 1). Full conversion
of the carbamates (1a-c, 5-100 mg) to the cyclic urea (2)
was obtained after 10 min.-3 hours by heating at 90 °C
even with 0.1 % sulfuric acid. The catalytic cyclisation of
tert-butyl carbamate (1c) was faster than the methyl and
ethyl carbamates (1a,b). Prolonged reaction time (3 hrs.)
was required for larger batches (100 mg). Longer reaction
time (5 mg, 8 hrs.) was also needed when the reaction was
carried out at lower temperature (40 °C). The methyl,
ethyl and tert-butyl carbamates (1a-c) did also readily
undergo complete cyclisation (5 mg, 30 min.) when
sulfuric acid was replaced with 3.5 equivalents of aqueous
HBF4. Longer reaction time (5 mg, 5 hrs.) was needed
when the number of equivalents of HBF4 was reduced
(0.65 equivalent). However, no cyclisation took place at
lower temperature (40 °C), even with longer reaction time
(8 hrs.) and increased number of equivalents of HBF4 (7
equivalents).
Scheme 2
O
O
C-OR
HN
0.1 % H2SO4
or HBF4
HN
NH
NH2
Δ or MW
R'
N
R'
N
2, 2a
1a-d
1a R = Me, R' = H
2
R' = H
1b R = Et R' = H
1c R = t Bu R' = H
1d R = i Pr R' = NH-n Bu
2a R' = NH-n Bu
Recent development in microwave-accelerated (MW)
organic syntheses has shown that the method offers the
great advantage of enhanced reaction rates. The products
are often produced in higher yields and purity by such
reactions compared to conventional methods.
We have experienced that MW promoted reactions have
been successful for a number of reactions [9]. As shown
in Table 2, complete conversion of the carbamates (1a-c,
5-100 mg) into the cyclic urea product 2 was obtained
within 2-6 minutes of MW irradiation. The tert-butyl
carbamate (1c) was the more reactive, as demonstrated by
A one-pot procedure including the previous reduction
(Pd/C, H2) and the final cyclisation steps to give 2 in 95 %
yield directly from 3a-c was also successful. This would
be the method of choice for the preparation of 2.
Table 2
Cyclisation of 1a-d to 2,2a by microwave (MW) irradiation.s
MW irradiation,
reaction time
Substrate
Catalyst
Product, conversion a
1a, R = Me
1b, R = Et
0.1 % H2SO4
4 min., 5 mg
4 min., 5 mg
2 min., 5 mg
2 min., 5 mg
6 min., 5 mg
6 min., 5 mg
2 min., 5 mg
2 min., 100 mg
2 min., 5 mg
3 min.,100 mg
8 min., 5 mg
6 min., 5 mg
2, 99 %
2, 99 %
2, 99 %
2a, 99 %
2, 99 %
2, 99 %
2, 99 %
2, 99 %b
2, 99 %
2, 99 % b
2, 40 %
2a, 99 %
1c, R = t-Bu
1d, R = iPr, R’ = NHnBu
1b, R = Me
3.5 eqv. HBF4
1c, R = Et
1c, R = t-Bu
1c, R = t-Bu
0.65 eqv. HBF4
0.2 eqv. HBF4
3.5 eqv. HBF4
1d, R = iPr, R’ = NHnBu
b
a Conversion is based on 1H nmr of crude product, > 95 % yield after work-up

May-Jun 2006
1,3-Dihydro-2H-imidazo[4,5-c]pyridin-2-one
789
measured by Griffin apparatus. Flash chromatography: Silica
(sds, 60 A, 40-63 μm). Microwave irradiation was performed in
a microwave oven (Elram M8017NP-CF) at “Low” power (17 %
of max 800 W output). Methyl and tert-butyl carbamates (1a,c)
were prepared according to the literature [5].
the lower reaction time compared to the methyl and ethyl
substrates (1a,b). This is in correspondence to our
observations by conventional heating. The reactions of
1a,b in sulfuric acid were more rapid than in aqueous
HBF4. In contrast to our observations of cyclisation by
conventional heating, the required reaction time for full
MW conversion of larger batches (100 mg) was
approximately the same as for small batches (5 mg).
The 6-alkylamino-substituted substrate 1d was also
included in the MW experiments. Similarly, full
conversion to the corresponding cyclic urea 2a was
obtained within 2-6 min. of MW irradiation. Due to the
low solubility of the butylamino substrate 1d in water,
these experiments were carried out in DMSO.
3-Nitro-4-pyridylcarbamic acid ethyl ester (3b).
3b was prepared from 4-aminopyridine by nitration of the
corresponding carbamate according to the literature for the
1
preparation of 3a,c [5]. All data (mp, ir, H and 13C nmr, ms)
were in accordance with our previous data for 3b prepared via
Curtius rearrangement [10].
3-Amino-4-pyridinylcarbamic acid ethyl ester (1b).
The compound was prepared by reduction of 3b according to
the literature for the preparation of 1a,c [5]. 3a (500 mg, 2.37
mmol) was dissolved in methanol (10 ml) and added Pd/C (5 %,
83 mg). The solution was stirred for 16 hrs. under H2 pressure
(10 bar). The solution was filtered and off-white crystals (430
We experienced that the pH of the aqueous solution
during the extraction work-up was particularly crucial for
the yield of the urea product. Due to the urea moiety, only
moderate yields were obtained by extraction at pH 9 - 12.
The product could however, be quantitatively extracted by
ethyl acetate from a neutral solution of pH 7. The
recrystallised product was in general obtained in > 95 %
yield. However, by adjustment of pH to 7, a spontaneous
and quantitative precipitation of product 2 (pure by m.p.
1
mg, 99 %), pure by H and 13C nmr, was obtained; mp 125 - 127
°C; ir (KBr) 3388m, 3212w, 2982w, 1727s, 1589s, 1516s,
1480m, 1252s, 1211m, 1068s, 870m, 832m, 767m cm-1; 1H nmr
(300 MHz, CDCl3): ꢀ 1.33, (t, J 7.1, 3H), 3.44 (br, 2H), 4.25 (q,
J 7.1, 2H), 7.09 (br., 1H), 7.64 (d, J 5.4, 1H, H-5), 8.10 (d, J 5.4,
1H, H-6), 8.14 (s, 1H, H-2); 13C nmr (75 MHz, CDCl3): ꢀ 14.6,
62.1, 114.6, 132.3, 134.8, 140.6, 142.9, 153.7; ms: m/z 181 (M+,
100 %), 153 (2), 135 (38), 122 (9), 108 (33), 93 (4), 81 (16);
Anal. Calcd. for C8H11N3O2: C, 53,03; H, 6,12; N, 23,19.
Found: C, 52.71; H, 6.12; N, 24.61.
1
and H nmr) was observed when 2 was prepared from 1a.
This represents an even simpler work-up method for
product 2 and completes the facile protocol for a solvent-
free, “green” method for the preparation of 2.
2-Butylamino-5-amino-4-pyridylcarbamic acid isopropyl ester
(1d).
Conclusion.
This intermediate was prepared by hydrogenation of 2-N-
butylamin-5-nitro-4-pyridylcarbamic acid isopropyl ester
according to literature [5]. The solution was filtered and a purple
solid (98 %), pure by 1H nmr, was obtained. The product
decomposed by flash chromatography and was therefore used in
the next step without further purification. ir (neat) 3411w,
3004m, 2925w, 1716s, 1420m, 1363s, 1222s, 1092m, 902w
The biologically active cyclic urea, pyridoimidazolone
(2) was prepared in > 95 % yield by acid catalysed
cyclisation from (3-amino-4-pyridinyl)-carbamic acid
methyl, ethyl or tert-butyl ester (1a-c) by heating (90 °C /
10 min.-3 hrs) in sulfuric acid (0.1 %) or in aqueous HBF4
(3.5 equivalents). Correspondingly, the microwave-
promoted (MW) reactions afforded the pure product 2
quantitatively within few minutes. The 6-butylamino-
substituted analogue (2a) was also prepared by MW
irradiation (99 %) by cyclisation of the precursor 1d.
Quantitative precipitation of product 2 was obtained by
pH adjustment of the reaction mixture. Our conditions
were thus excellent for the simple preparation of the five-
membered cyclic urea product (2), which was obtained by
less vigorous reaction conditions and in higher yield than
previous methods. The facile protocol represents a
solvent-free, “green” method for the preparation of 2.
1
cm-1; H nmr (300 MHz, CDCl3): ꢀ 0.96, (t, J 5.4, 3H, CH3),
1.31 (d, J 4.5, 6H, 2 CH3), 1.41 (dt, J 5.4, 2H, CH2), 1.58 (m,
2H, CH2), 2.71 (br, NH2), 3.21 (br, s, 2H, NH-CH2), 4.34 (br, s,
NH), 5.02 (hept, J 4.5, CH), 7.14 (s, 1H, H-3), 7.63 (br, NH),
7.70 (s, 1H, H-6); 13C nmr (100 MHz, CDCl3): ꢀ 13.8, 20.1,
21.0, 31.6, 42.4, 69.0, 94.1, 119.6, 141.5, 141.7, 152.8, 156.9;
ms: m/z 266 (M+, 37 %), 224 (12), 205 (27), 191 (43), 177 (57),
163 (34), 151 (52), 137 (88), 84 (57), 66 (100).
1,3-Dihydro-2H-imidazo[4,5-c]pyridin-2-one (2).
General procedure using i) sulfuric acid or ii) HBF4.
The alkyl carbamate (1a-c, approx. 5 mg, 0.025 mmol, 1 eqv.)
was dissolved in i) 0.1 % sulfuric acid (0.5 ml) or ii) a solution
of water (0.5 ml) and aqueous HBF4 (50 %, 0.09 mmol, 3.5 eqv.)
and heated. By both methods 1H nmr of the crude product
showed complete conversion of the carbamates (1a-c) to the
cyclic urea product 2 after heating of the solution (90 °C) for 10
min.(1c)/30 min. (1a,b). See Table 1 for other reaction
conditions. Three hours reaction time was needed for 100 mg
batches in 5 ml solution. Alternatively, corresponding batches of
1a-c (5-100 mg in 0.5-5 ml solutions) were irradiated in a
EXPERIMENTAL
1
Solvents: pro analysi quality. H / 13C nmr: Bruker Avance
DPX 300 and 400 MHz spectrometers, chemical shifts are
reported in ppm downfield from TMS. J values are given in Hz.
ms: Finnigan MAT 95 XL (EI / 70 eV). ir: Nicolet 20SXC FT-
IR spectrophotometer. All melting points are uncorrected,

790
J. Holt, J. M. Bakke and A. Fiksdahl
Vol 43
REFERENCES
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When prepared from the methyl carbamate (1a, 100 mg),
spontaneous quantitative precipitation of product 2, (pure by
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1
m.p., H and 13C nmr), was obtained directly by pH adjustment.
The recrystallised product 2 was obtained in > 95 % yield.
Alternatively, 2 could be prepared directly in 95 % isolated yield
directly from 3a-c in a one-pot procedure by reduction (Pd/C-
H2) via 1a-c and cyclisation by heating or MW. This would be
the method of choice for the preparation of 2. All data (mp, ir,
1H and 13C nmr, ms) were in accordance with literature [5].
6-(Butylamino)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one
(2a).
The product was prepared in 99 % yield by MW irradiation
from 1d as described for the preparation of 2, i) or ii) above, see
Table 2. Water was however replaced by DMSO. Spectroscopic
data were in accordance with literature [5].
Acknowledgements.
Financial support from the Research Council of Norway is
gratefully acknowledged.