Mild and general one-pot reduction and cyclization of aromatic and heteroaromatic 2-nitroamines to bicyclic 2 H -imidazoles

Article abstract of DOI:10.1055/s-0030-1259007

A one-pot procedure for the conversion of aromatic and heteroaromatic 2-nitroamines into bicyclic 2H-benzimidazoles is described. The procedure employs formic acid, iron powder, and an additive such as NH₄Cl to reduce the nitro group and effect the imidazole cyclization with high-yielding conversions generally within one to two hours. The compatibility with a wide range of functionality demonstrates the general utility of this procedure.

Full text of DOI:10.1055/s-0030-1259007

LETTER
2759
Mild and General One-Pot Reduction and Cyclization of Aromatic and
Heteroaromatic 2-Nitroamines to Bicyclic 2H-Imidazoles
(H
etero)aromati
m
c
2-Nitroamine
s
to
i
Bicycli
l
c
2
H
-I
y
midazoles J. Hanan,* Bryan K. Chan, Anthony A. Estrada, Daniel G. Shore, Joseph P. Lyssikatos
Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA
Fax +1(650)7424943; E-mail: hanan.emily@gene.com
Received 23 July 2010
clic examples are present in the literature, but these typi-
cally require the presence of aqueous hydrochloric acid or
supplemental triethylorthoformate and acetic acid.7 We
wished to optimize the reaction conditions to be as mild as
Abstract: A one-pot procedure for the conversion of aromatic and
heteroaromatic 2-nitroamines into bicyclic 2H-benzimidazoles is
described. The procedure employs formic acid, iron powder, and an
additive such as NH4Cl to reduce the nitro group and effect the im-
idazole cyclization with high-yielding conversions generally within possible (avoiding the use of strong mineral acids), and to
one to two hours. The compatibility with a wide range of function-
ality demonstrates the general utility of this procedure.
explore the scope of this transformation with regard to
functional-group tolerance both on benzene and heteroar-
Key words: cyclization, heterocycles, imidazole, iron, reduction
omatic cores (Scheme 1).
Using 2-nitroaniline as a test substrate, we found that iron
and formic acid alone were not sufficient to effect reduc-
tion of the nitro group. However, we found NH4Cl, which
has broader functional-group compatibility, to be a suit-
able alternative to aqueous HCl. After exploring molar ra-
tios of both iron powder and NH4Cl, the presence and type
of co-solvent, time, and temperature of the reaction, the
optimal conditions were established. For the majority of
substrates, these were determined to be 10 equivalents
iron powder, 10 equivalents NH4Cl, and a 1:1 mixture of
formic acid–isopropanol as solvent. For conversions re-
quiring a higher reaction temperature, 1-butanol could be
substituted for isopropanol.8 Under these conditions, most
reactions completed within one to two hours at 80 °C.9
While a 10 equivalent excess of both iron powder and
NH4Cl provided optimal reaction times, 2–5 equivalents
of each are sufficient to complete the transformation al-
though reaction times extend to 24 hours. Similarly, a
lower reaction temperature (60 °C) is sufficient but ex-
tends the reaction time by several fold.
Fused bicyclic imidazoles (benzimidazoles and their aza
equivalents) are a common feature in biologically active
molecules.1 Being closely related in structure to purines,
which are recognized by an enormous variety of proteins,
benzimidazoles are an important chemotype in current
pharmaceutical research.2 2-Nitroanilines can be a useful
synthetic starting point, and converted into the corre-
sponding benzimidazoles through a two-step procedure
consisting of reduction of the nitro group followed by
Phillips cyclization of the ortho-dianiline with a methy-
lene source.3 Trialkylorthoformates, formamidine acetate,
and formic acid are among methylene sources commonly
used to culminate the production of 2H-benzimidazoles.3
In order to carry out this two-step transformation in one
pot, reductants such as palladium or tin are often com-
bined with similar methylene sources.4 However, palladi-
um and other transition metals have the disadvantage of
high cost as well as incompatibility with common func-
tionality, and tin reductants are disfavored due to their
toxicity.
Fe powder
NH4Cl
NO2
In the course of our research, we had the need to transform
heterocyclic 2-nitroamines into the corresponding fused
bicyclic 2-H-imidazoles, and an efficient one-pot trans-
formation was desired. As an inexpensive and nontoxic
metal with minimal cross-reactivity, iron is an ideal re-
ductant for this purpose. One-pot nitro reduction and
benzimidazole formation mediated by iron is well prece-
dented for benzimidazoles having a carbon substituent at
the imidazole 2-position, particularly when the amine is
already acylated.5 Iron/acetic acid is a known combination
resulting in 2-methylbenzimidazoles,6 but iron used in
conjunction with formic acid as the bicyclic imidazole C-
2 carbon source is poorly explored. Several non-heterocy-
N
N
HCO2H, i-PrOH
80 °C
R1
R1
NHR2
R2
Scheme 1 One-pot conversion: o-nitroanilines into 2H-benzimida-
zoles
Using these optimized reaction conditions, we examined
the scope of this reaction with 2-nitroanilines substituted
with varying functionality (Table 1). Most products could
be obtained at >95% purity after filtration and a simple
aqueous extraction, with no chromatography required; un-
less otherwise noted, product yields given in Tables 1– 3
are determined after aqueous workup.
The reaction proceeds equally well when the aniline is ei-
ther unsubstituted or is a secondary alkyl- or aryl-substi-
tuted aniline (substrates 1–3), although the secondary
SYNLETT 2010, No. 18, pp 2759–2764
Advanced online publication: 14.10.2010
DOI: 10.1055/s-0030-1259007; Art ID: S04310ST
x
x
.x
x
.2
0
1
0
© Georg Thieme Verlag Stuttgart · New York

2760
E. J. Hanan et al.
LETTER
Table 1 Reaction Scope with Aniline Substratesa
Substrate
Time (h)
1
Productb
Isolated yield (%)
97
NO2
N
1
1
N
H
NH2
N
NO2
2
2
2
2
3
93
94
Et
N
N
H
Et
NO2
N
3
Ph
N
N
H
Ph
N
NO2
4
1
4
5
6
7
89
98
84
99
N
H
Me2N
MeO
Me2N
MeO
NH2
NO2
N
5
6
7
1
N
NH2
H
NC
NC
NO2
N
1
N
H
NH2
NO2
N
2c
N
H
Cl
Cl
Cl
Cl
NH2
NO2
NH2
N
8
1.5
8
94
N
H
I
I
NO2
N
9
1
1
9
90
94
N
H
NH2
NO2
N
10
10
N
H
NH2
CO2Me
HO
CO2Me
HO
NO2
NH2
N
11
12
13
1
1
3
11
12
13
87
N
H
O
O
NO2
NH2
N
73d
52d
N
H
TIPSO
TIPSO
NO2
N
N
NH2
H
O
O
B
B
NO2
73d
N
14
1.5
14
O
O
N
H
NH2
a Reaction conditions: substrate (1.0 mmol), Fe powder (10.0 mmol), NH4Cl (10.0 mmol), 2-PrOH (5.0 mL), formic acid (5.0 mL), 80 °C.
b All products were characterized by LC-MS and 1H NMR.10,
c Reaction at 90 °C.
d Isolated via silica gel chromatography.
Synlett 2010, No. 18, 2759–2764 © Thieme Stuttgart · New York

LETTER
(Hetero)aromatic 2-Nitroamines to Bicyclic 2H-Imidazoles
2761
anilines require a slightly longer reaction time. The phe- We next turned our attention to heterocyclic substrates,
nyl ring may be substituted with either electron-donating which are of great interest in our medicinal chemistry pro-
(substrates 4 and 5) or electron-withdrawing substituents grams (Table 2). We found that the one-pot transforma-
(substrates 6–10) while still resulting in excellent yields. tion was highly efficient for a variety of heterocyclic
Halogens in various positions are well tolerated under substrates, although some limitations were observed. The
these conditions (substrates 7–9), which is particularly quinoline substrate proceeded uneventfully, with no
useful since halogen-containing substrates are often in- change in reaction conditions required to provide the
compatible with palladium-catalyzed nitro group reduc- product in excellent yield (substrate 15). The more com-
tions. Both the phenol and allyloxy-containing substrates plex benzimidazole-containing pyridyl substrate 16 re-
also resulted in good conversion into product (substrates quired a reaction time of 2.5 hours, but provided the
11 and 12). Surprisingly, a TIPS-protected phenol provid- cyclized product in excellent yield. Pyridine substrate 17
ed the corresponding TIPS-containing product (substrate required an even longer 22 hours at 80 °C to complete the
13), albeit in moderate yield. This substrate required a cyclization, and while the conversion was good (79% by
slightly longer reaction time of three hours to go to com- crude HPLC), the exceedingly poor solubility of the prod-
pletion, by which point some desilylated phenol was ob- uct in any combination of dichloromethane and methanol
served. Even a boronate pinacol ester was compatible or isopropanol reduced the isolated yield significantly. In-
with these reaction conditions, providing the cyclized terestingly, the pyridine regioisomers 18 and 19, 5-nitro-
product in good yield (substrate 14).
pyridin-4-amines, required
a
substantially higher
Table 2 Reaction Scope with Heterocyclic Substrates
Substrate
Conditionsa Time (h)
Productb
Isolated yield (%)
95
NH2
N
NH
NO2
15
A
B
A
1
15
N
N
N
NO2
NH
N
N
N
16
17
2.5
22
16
98c
N
N
HN
HN
Br
Br
NO2
N
17
36c (79d)
N
N
N
NH2
NO2
H
N
N
N
N
18
19
C
C
120
24
18
74
N
Ph
Ph
NH2
NO2
H
N
N
19
23e
N
Cl
Cl
N
NH2
H
H
N
O
NO2
20
21
A
A
1
2
20
21
100d
N
H
NH
N
N
N
H
Ph
Me
Me
Ph
NO2
N
0
N
N
O
N
H
O
NH2
a Reaction conditions: Fe powder (10 equiv), NH4Cl (10 equiv) with (A) substrate (1.0 mmol), 2-PrOH (5.0 mL), formic acid (5.0 mL), 80 °C;
(B) substrate (0.32 mmol), 2-PrOH (4.0 mL), formic acid (4.0 mL), 80 °C; (C) substrate (1.0 mmol), 1-BuOH (5.0 mL), formic acid (5.0 mL),
120 °C.
b All products were characterized by LC-MS and 1H NMR.10
c Isolated via silica gel chromatography.
d Crude yield as determined by HPLC.
e Isolated via reversed-phase HPLC.
Synlett 2010, No. 18, 2759–2764 © Thieme Stuttgart · New York

2762
E. J. Hanan et al.
LETTER
temperature and longer reaction time than the 3-nitropyri-
din-2-amines 16 and 17. Substrate 18 proved to be ex-
traordinarily recalcitrant to cyclization: reduction and
monoformylation was observed after 24 hours at 120 °C,
with complete cyclization to the product occurring after 5
days. However, despite extended heating at high temper-
ature, no side products were observed, and the product
was isolated in good yield. 2-Halo-pyridine substrates
such as 19 exposed some limitations to this method, with
the extended heating at high temperatures resulting in the
formation of degradation side products and comparatively
poor product yields (23% yield for compound 19 after
nontrivial preparatory HPLC separation).
Table 3 Comparison of Additives in the Conversion of 2-Nitro-N-
phenylaniline into 1-Phenyl-1H-benzo[d]imidazolea
Additive
NH4Cl
LiCl
Isolated yield (%)
94
97
96
88
33
NaCl
NaI
none
a Reaction conditions: 2-nitro-N-phenylaniline (1.0 mmol), Fe pow-
der (10.0 mmol), additive (10.0 mmol), 2-PrOH (5.0 mL), formic acid
(5.0 mL), 80 °C, 2 h.
Five-membered heterocyclic rings proved to be challeng-
ing substrates. Under standard reaction conditions, pyra-
zole substrate 20 was rapidly converted into the reduced
and monoformylated intermediate product 20 as shown in
Table 2, but this intermediate did not cyclize to yield the
desired 5,5-bicyclic system even after prolonged heating
at 120 °C. This is perhaps unsurprising, since the only lit-
erature reports for cyclizing acylated 4,5-diaminopyra-
zoles require either phosphoryl trichloride or thionyl
chloride to first form the highly activated imidoyl chlo-
ride.11 3-Methyl-4-nitroisoxazol-5-amine 21 was also
subjected to the standard reaction conditions, but only de-
composition of the starting material was observed.12
into solution and renewing the available source of Fe(0).
It is remarkable that while LiCl works quite well, the in-
expensive and easier-to-handle NH4Cl and NaCl salts per-
form equally well.
In conclusion, we have optimized a simple one-pot con-
version of aromatic ortho-nitroamines into cyclized C2–H
bicyclic imidazoles using inexpensive and easily handled
reagents. This reaction is tolerant of a wide range of func-
tionality and may be applied to heterocyclic substrates.
We are optimistic that the flexibility in choice of co-sol-
vent and additive will allow this method to be useful in a
wide range of organic syntheses.
In an attempt to determine the role played by the NH4Cl
additive, we examined the performance of other salts as
additives in the conversion of 2-nitro-N-phenylaniline
into 1-phenyl-1H-benzo[d]imidazole (Table 3). NH4Cl
could be replaced by LiCl or NaCl with no decrease in
yield. NaI resulted in a slower reduction, with 88% prod-
uct isolated after two hours with the mass balance identi-
fied as the unreduced nitro starting material. When no
additive is used, the nitro reduction is exceedingly slug-
gish, with only 33% conversion after two hours (the re-
maining material was identified as unreacted 2-nitro-N-
phenylaniline). Considering that iron powder is oxidized
to FeCl2 and FeCl3 in the presence of hydrochloric acid,
Representative Experimental Procedure
1H-Benzo[d]imidazole15 (1)
A 40 mL glass vial was charged with o-nitroaniline (0.138 g, 1.00
mmol), iron powder 325 mesh (0.558 g, 10.0 mmol), NH4Cl (0.535
g, 10.0 mmol), and a magnetic stir bar. 2-PrOH (5.0 mL) and formic
acid (5.0 mL) were added, and the reaction vial was sealed with a
Teflon-lined cap. The reaction mixture was stirred at 80 °C for 1 h
at which time LC-MS analysis indicated that conversion into the
product was complete. The reaction mixture was diluted with 2-
PrOH (10 mL) and filtered to remove insoluble materials. The fil-
trate was concentrated to dryness, and the resulting residue parti-
we wanted to determine if the halide (X) salt additives are tioned between CH2Cl2 (20 mL) and (5 mL) sat. aq NaHCO3. The
aqueous layer was extracted with additional CH2Cl2 (5 × 20 mL).
The combined organic extracts were dried over MgSO4, filtered,
and concentrated to yield the pure product as a light yellow solid
merely promoting the formation of FeX2 in the reaction
mixture, with FeX2 as the active reductant. However,
when the reaction was attempted using FeCl2 instead of
iron powder with no additional salt additives, absolutely
no reduction was observed, suggesting that Fe(0) is the ac-
tive reducing agent.
1
(0.114 g, 97%). ESI-MS: m/z = 119.4 [M + H]+. H NMR (400
MHz, DMSO): d = 12.42 (s, 1 H), 8.20 (s, 1 H), 7.58 (m, 2 H), 7.18
(dd, J = 6.0, 3.1 Hz, 2 H).
The ability of chloride salts to promote metal-based reac-
tions has been observed by others. Notably, the work of
Knochel et. al. provides the observation that LiCl allows
the direct insertion of zinc into aryl-iodide bonds, pro-
vides a ‘spectacular rate increase’ for Br–Mg exchange,
and forms a solubilized iron(II) base for the ferration of
arenes.13 Knochel and co-workers propose that LiCl solu-
bilizes organometallic complexes, thereby constantly
cleaning the metal surface and allowing further reactions
to take place.14 We suggest that the halide salts are serving
a similar function here, accelerating the transfer of iron
References and Notes
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Synlett 2010, No. 18, 2759–2764 © Thieme Stuttgart · New York

LETTER
(Hetero)aromatic 2-Nitroamines to Bicyclic 2H-Imidazoles
(10) Analytical Data for Compounds 2–19
2763
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1-Ethyl-1H-benzo[d]imidazole16 (2)
ESI-MS: m/z = 147.4 [M + H]+. 1H NMR (400 MHz,
DMSO): d = 8.23 (s, 1 H), 7.62 (dd, J = 18.0, 7.9 Hz, 2 H),
7.22 (dt, J = 15.0, 7.2 Hz, 2 H), 4.28 (q, J = 7.3 Hz, 2 H),
1.41 (t, J = 7.3 Hz, 3 H).
1-Phenyl-1H-benzo[d]imidazole17 (3)
ESI-MS: m/z = 195.4 [M + H]+. 1H NMR (400 MHz,
DMSO): d = 8.56 (s, 1 H), 7.78 (dd, J = 6.5, 2.3 Hz, 1 H),
7.69 (dd, J = 8.4, 1.1 Hz, 2 H), 7.67–7.60 (m, 3 H), 7.51 (t,
J = 7.2 Hz, 1 H), 7.38–7.28 (m, 2 H).
N,N-Dimethyl-1H-benzo[d]imidazol-6-amine (4)
ESI-MS: m/z = 162.4 [M + H]+. 1H NMR (400 MHz,
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6.78 (d, J = 7.9 Hz, 2 H), 2.88 (s, 6 H).
5-Ethoxy-1H-benzo[d]imidazole18 (5)
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(8) The role of the alcohol co-solvent in this reaction is to
increase solubilization of the substrate and may be omitted
for substrates with good solubility in neat formic acid
(unpublished observation).
ESI-MS: m/z = 163.0 [M + H]+. 1H NMR (400 MHz,
DMSO, reported as a mixture of tautomers): d = 12.25 (br s,
0.4 H), 12.20 (br s, 0.6 H), 8.10 (br s, 0.4 H), 8.04 (br s, 0.6
H), 7.49 (br d, J = 8.8 Hz, 0.6 H), 7.38 (br d, J = 8.2 Hz, 0.4
H), 7.14 (br s, 0.4 H), 6.98 (br s, 0.6 H), 6.83–6.77 (m, 1 H),
4.03 (q, J = 6.9 Hz, 2 H), 1.34 (t, J = 6.9 Hz, 3 H).
1H-Benzo[d]imidazole-5-carbonitrile19 (6)
ESI-MS: m/z = 144.4 [M + H]+. 1H NMR (400 MHz,
DMSO): d = 12.96 (s, 1 H), 8.47 (s, 1 H), 8.16 (s, 1 H), 7.76
(d, J = 8.0 Hz, 1 H), 7.59 (d, J = 8.1 Hz, 1 H).
5-Chloro-1H-benzo[d]imidazole20 (7)
ESI-MS: m/z = 152.9 [M + H]+. 1H NMR (400 MHz,
DMSO): d = 12.60 (s, 1 H), 8.27 (s, 1 H), 7.62 (m, 2 H), 7.22
(d, J = 7.7 Hz, 1 H).
4-Chloro-1H-benzo[d]imidazole21 (8)
ESI-MS: m/z = 153.4 [M + H]+. 1H NMR (400 MHz,
DMSO): d = 8.31 (s, 1 H), 7.55 (d, J = 7.9 Hz, 1 H), 7.30–
7.05 (m, 2 H).
5-Iodo-1H-benzo[d]imidazole22 (9)
ESI-MS: m/z = 244.9 [M + H]+. 1H NMR (400 MHz,
DMSO): d = 12.52 (br s, 1 H), 8.19 (s, 1 H), 7.95 (s, 1 H),
7.47 (dd, J = 8.4, 1.4 Hz, 1 H), 7.43 (d, J = 8.4 Hz, 1 H).
Methyl 1H-Benzo[d]imidazole-7-carboxylate23 (10)
ESI-MS: m/z = 177.3 [M + H]+. 1H NMR (400 MHz,
DMSO): d = 12.56 (s, 1 H), 8.31 (s, 1 H), 7.97 (d, J = 8.0 Hz,
1 H), 7.86 (d, J = 7.6 Hz, 1 H), 7.32 (t, J = 7.8 Hz, 1 H), 3.95
(s, 3 H).
1H-Benzo[d]imidazol-5-ol24 (11)
ESI-MS: m/z = 135.4 [M + H]+. 1H NMR (400 MHz,
DMSO): d = 12.21 (br s, 1 H), 9.08 (s, 1 H), 8.03 (s, 1 H),
7.37 (d, J = 8.6 Hz, 1 H), 6.87 (s, 1 H), 6.68 (d, J = 8.5 Hz,
1 H).
5-(Allyloxy)-1H-benzo[d]imidazole (12)
ESI-MS: m/z = 175.4 [M + H]+. 1H NMR (400 MHz,
DMSO): d = 12.25 (s, 1 H), 8.08 (s, 1 H), 7.45 (s, 1 H), 7.08
(s, 1 H), 6.83 (dd, J = 8.7, 2.0 Hz, 1 H), 6.07 (ddt, J = 17.2,
10.5, 5.2 Hz, 1 H), 5.41 (ddd, J = 17.3, 3.4, 1.6 Hz, 1 H), 5.26
(dd, J = 10.5, 1.5 Hz, 1 H), 4.61–4.54 (m, 2 H).
5-(Triisopropylsilyloxy)-1H-benzo[d]imidazole (13)
ESI-MS: m/z = 291.4 [M + H]+. 1H NMR (400 MHz,
DMSO): d = 12.17 (s, 1 H), 8.09 (s, 1 H), 7.43 (s, 1 H), 6.99
(s, 1 H), 6.76 (d, J = 8.9 Hz, 1 H), 1.25 (dd, J = 14.9, 7.2 Hz,
3 H), 1.07 (d, J = 7.4 Hz, 18 H).
5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-
benzo[d]imidazole (14)
ESI-MS: m/z = 245.4 [M + H]+. 1H NMR (400 MHz,
DMSO): d = 12.48 (s, 1 H), 8.24 (s, 1 H), 7.90 (s, 1 H), 7.57
(s, 1 H), 7.50 (d, 1 H), 1.31 (s, 12 H).
(9) If the reaction is followed by LC-MS at shorter time
intervals, the progression from starting material to bisaniline
to N-formylated aniline to cyclized product can typically be
observed.
3H-Imidazo[4,5-f]quinoline25 (15)
ESI-MS: m/z = 169.9 [M + H]+. 1H NMR (400 MHz,
DMSO): d = 13.51 (br s, 0.5 H), 12.94 (br s, 0.5 H), 8.86–
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E. J. Hanan et al.
LETTER
isomerization and hydrolysis: Pinho e Melo, T. M. V. D.
8.85 (m, 1 H), 8.78 (br s, 1 H), 8.38 (br s, 1 H), 7.97 (br d,
J = 7.8 Hz, 1 H), 7.81 (d, J = 8.9 Hz, 1 H), 7.61 (dd, J = 8.3,
4.3 Hz, 1 H).
Curr. Org. Chem. 2005, 9, 925.
(13) (a) Krasovskiy, A.; Malakhov, V.; Gavryushin, A.; Knochel,
P. Angew. Chem. Int. Ed. 2006, 45, 6040. (b) Krasovskiy,
A.; Knochel, P. Angew. Chem. Int. Ed. 2004, 43, 3333.
(c) Wunderlich, S. H.; Knochel, P. Angew. Chem. Int. Ed.
2009, 48, 9717.
(14) Piller, F. M.; Appukkuttan, P.; Gavryushin, A.; Helm, M.;
Knochel, P. Angew. Chem. Int. Ed. 2008, 47, 6802.
(15) Wundt, E. Ber. Dtsch. Chem. Ges. 1878, 11, 826.
(16) v. Auwers, K.; Maws, W. Ber. Dtsch. Chem. Ges. 1928, 61,
2415.
(17) Fischer, O.; Rigaud, M. Ber. Dtsch. Chem. Ges. 1901, 34,
4204.
(18) Sekikawa, I. Bull. Chem. Soc. Jpn. 1958, 31, 252.
(19) Van Vliet, D. S.; Gillespie, P.; Scicinski, J. J. Tetrahedron
Lett. 2005, 46, 6741.
(20) Fischer, O. Ber. Dtsch. Chem. Ges. 1904, 37, 557.
(21) Rabiger, D. J.; Joullie, M. M. J. Chem. Soc. 1964, 915.
(22) Rabiger, D. J.; Joullie, M. M. J. Org. Chem. 1961, 26, 1649.
(23) Howell, J. R.; Rasmussen, M. Austr. J. Chem. 1993, 46,
1177.
(24) Robinson, F. M.; Miller, I. M.; McPherson, J. F.; Folkers, K.
J. Am. Chem. Soc. 1955, 77, 5192.
3-{1H-Benzo[d]imidazol-5-yl}-3H-imidazo[4,5-
b]pyridine (16)
ESI-MS: m/z = 250.2 [M + H]+. 1H NMR (400 MHz,
DMSO): d = 12.72 (s, 1 H), 8.83 (s, 1 H), 8.36 (s, 1 H), 8.28
(s, 1 H), 8.13 (s, 1 H), 8.02 (s, 1 H), 7.85–7.60 (m, 2 H), 2.46
(s, 3 H).
6-Bromo-7-methyl-3H-imidazo[4,5-b]pyridine26 (17)
ESI-MS: m/z = 211.9 [M + H]+. 1H NMR (400 MHz,
DMSO): d = 8.42 (s, 1 H), 8.40 (s, 1 H), 2.60 (s, 3 H).
6-Phenyl-1H-imidazo[4,5-c]pyridine (18)
ESI-MS: m/z = 196.3 [M + H]+. 1H NMR (400 MHz,
DMSO): d = 9.00 (s, 1 H), 8.40 (s, 1 H), 8.16–8.06 (m, 3 H),
7.53–7.43 (m, 2 H), 7.43–7.34 (m, 1 H).
6-Chloro-1H-imidazo[4,5-c]pyridine27 (19)
ESI-MS: m/z = 153.8 [M + H]+. 1H NMR (400 MHz,
DMSO): d = 8.74 (s, 1 H), 8.45 (s, 1 H), 7.67 (s, 1 H).
(11) (a) Bongartz, J.-P.; Andre, M.; Meerpoel, L.; Boeckx, G. M.;
Van Lommen, G.; Buyck, C.; Obrecht, D.; Ermert, P.;
Luther, A. WO 2008/148840 A1, 2008. (b) Popil’nichenko,
S. V.; Brovarets, B. S.; Drach, B. S. Russ. J. Org. Chem.
2004, 40, 219.
(12) (a) FeCl2 has been reported to reductively cleave isoxazoles:
Auricchio, S.; Bini, A.; Pastormerlo, E.; Truscello, A. M.
Tetrahedron 1997, 53, 10911. (b) Nitro-isoxazoles have
been reported to undergo acid-catalyzed thermal
(25) Weidenhagen, R.; Weeden, U. Ber. Dtsch. Chem. Ges. 1938,
71, 2347.
(26) Graboyes, H.; Day, A. R. J. Am. Chem. Soc. 1957, 79, 6421.
(27) Rousseau, R. J.; Robins, R. K. J. Heterocycl. Chem. 1965, 2,
196.
Synlett 2010, No. 18, 2759–2764 © Thieme Stuttgart · New York