Preparation of 2-aminopyridoimidazoles and 2-aminobenzimidazoles via phosphorus oxychloride-mediated cyclization of aminoureas

Article abstract of DOI:10.1021/jo500360k

The novel preparation of 2-aminopyridoimidazoles and 2-aminobenzimidazoles via the cyclization of (2-aminopyridin-3-yl)urea and (2-aminophenyl)urea substrates in the presence of phosphorus oxychloride is described. This methodology is demonstrated for a range of urea substrates with aminoimidazole products obtained in good yields and with excellent levels of purity.

Full text of DOI:10.1021/jo500360k

Note
pubs.acs.org/joc
Preparation of 2‑Aminopyridoimidazoles and
2‑Aminobenzimidazoles via Phosphorus Oxychloride-Mediated
Cyclization of Aminoureas
Rebecca E. Deasy,† Catherine N. Slattery,† and Anita R. Maguire*,‡
†Department of Chemistry, Analytical and Biological Chemistry Research Facility, University College Cork, Cork, Ireland
‡Department of Chemistry, School of Pharmacy, Synthesis and Solid State Pharmaceutical Centre, Analytical and Biological
Chemistry Research Facility, University College Cork, Cork, Ireland
Douglas P. Kjell, Mai Khanh N. Hawk, Jung Min Joo,§ and Rui Lin Gu
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, United States
Humphrey Moynihan
Eli Lilly SA, Dunderrow, Kinsale, Cork, Ireland
S
* Supporting Information
ABSTRACT: The novel preparation of 2-aminopyridoimida-
zoles and 2-aminobenzimidazoles via the cyclization of (2-
aminopyridin-3-yl)urea and (2-aminophenyl)urea substrates in
the presence of phosphorus oxychloride is described. This
methodology is demonstrated for a range of urea substrates
with aminoimidazole products obtained in good yields and
with excellent levels of purity.
Scheme 1. Alternative Synthetic Strategy for the Synthesis of
2-Aminoimidazole 1
he 2-aminoimidazole moiety is an important pharmaco-
phore in medicinal chemistry. This ring structure is found
T
in a variety of pharmacologically active compounds and in
several classes of marine natural products,1 many of which
exhibit a broad range of biological functions including
serotonergic and histaminergic receptor anatagonism2 in
addition to antiviral, antibacterial, and anticancer activities.3
As a result of their interesting biological properties, several
strategies for the synthesis of 2-aminoimidazoles have been
reported in the literature. Predominant among these is the
condensation of α-aminocarbonyls with cyanamide4 or α-
haloketones with N-acetylguanidine;5 however, these reactions
are typically pH-sensitive, require unstable precursors, and are
limited to the preparation of minimally substituted 2-amino-
imidazole motifs. A second common approach involves the
modification of an existing imidazole scaffold,6 although this
method can be hampered by the requirement for several
protection/deprotection steps.
As part of our studies toward the synthesis of LY2228820
dimesylate (see Scheme 1), a selective inhibitor of p38
mitogen-activated protein kinase that is currently under clinical
investigation for the treatment of human malignancies,7 we
wished to access the 2-aminoimidazole 1. Preparation of 1 was
initially conducted by cyclization of diamine 2 in the presence
of cyanogen bromide (Scheme 2), following literature
procedures.8,9 Using this method, the hydrobromide salt of 1
was obtained as a white solid in good yield (76%) following
crystallization in methanol/methyl tert-butyl ether (MTBE).
We wished to circumvent the use of cyanogen bromide for
the synthesis of 1, and therefore, an alternative more
environmentally benign process was sought. It was postulated
that conversion of 2 to the corresponding urea 3 and treatment
Received: February 14, 2014
Published: March 18, 2014
© 2014 American Chemical Society
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Note
toluene as a solvent allowed the use of as little as 1.5 equiv of
phosphoryl oxychloride. For ease of isolation, the solvent was
switched to acetonitrile. Isopropyl acetate, n-butyl acetate, and
anisole have also been demonstrated to be competent solvents.
Thionyl chloride and oxalyl chloride produced complicated
mixtures of products in limited experimentation.
Scheme 2. Synthesis of 2-Aminoimidazole 1 with Cyanogen
Bromide
A significant side product was observed during early
optimization studies by HPLC analysis of reaction mixtures.
The level of this side product was found to increase if reaction
time was prolonged. We tentatively assigned the side product as
the phosphoramidic acid 5 (Figure 1) based on LC-MS
analysis. After reaction completion, the addition of water at 80
°C, followed by a 1 h of stirring at this temperature, was found
to revert this side product to release 2-aminoimidazole 1.
We next wished to extend this novel methodology to include
the cyclization of a range of urea substrates featuring
modifications of the amine substituent (R), the electronic
properties of the pyridine ring (X), and the nature of the
aromatic structure (Y). For this purpose, nine novel ureas (6−
14) were targeted comprising five amine variants [R = ethyl
(6), n-butyl (7), iso-butyl (8), iso-pentyl (9), and 1,2-
dimethylpropyl (10)], one disubstituted pyridine (11), two 5-
substituted halide compounds (12 and 13), and a benzylurea
substrate (14). These compounds were prepared as previously
described for the synthesis of our original urea substrate 3
(Scheme 3), starting from commercially available 2,6-dichloro-
3-nitropyridine (synthesis of 6−10), N-neopentyl-3-nitro-
pyridin-2-amine (synthesis of 11), 5-chloro- and 5-bromo-2-
chloro-3-nitropyridine (synthesis of 12 and 13, respectively),
and 2,4-dichloro-1-nitrobenzene (synthesis of 14).
Conversion of each of 24−32 to the novel urea substrates 6−
14, respectively, was achieved as previously described for the
synthesis of 3 (potassium cyanate and hydrochloric acid in
ethanol/water at room temperature). While highly efficient
reactions were observed using this methodology for the
synthesis of the amine varied compounds (6−10) and
benzylurea 14, the formation of several side products was
noted by 1H NMR analysis for reactions of the substrates (11−
13) in which the electronic properties of the aromatic ring had
been altered relative to our original urea substrate 3. These side
of this compound with phosphoryl oxychloride may induce
cyclization to provide the desired aminoimidazole 1 as a
hydrochloride salt (Scheme 1).
To test this proposed synthetic approach, access to
compound 3 was first required. Synthesis of 3 was achieved
as shown in Scheme 3, beginning from commercially available
2,6-dichloro-3-nitropyridine (X = 6-Cl, Y = N) that was
converted to 6-chloro-N-neopentyl-3-nitropyridin-2-amine 4 by
treatment with neopentylamine [R = CH2C(CH3)3] and
triethylamine in MTBE. Nitropyridine 4 was then hydro-
genated to provide diamine 2, which was immediately carried
forward to the next synthetic step to avoid the formation of
potential oxidation side products. Conversion of 2 to the novel
urea 3 was accomplished using previously described chem-
istry10 involving reaction with potassium cyanate and hydro-
chloric acid in ethanol/water at room temperature to provide
the targeted urea 3 in good yield (69%) and without the need
for further purification.
With the required urea 3 now in hand, our strategy for the
synthesis of 2-aminoimidazole 1 was explored. Thus,
phosphoryl oxychloride (1.2 equiv) was added dropwise to a
solution of 3 in acetonitrile at room temperature. The resultant
solution was heated to 80 °C for 2 h, water was added, and the
reaction mixture cooled to give a slurry that was filtered to
isolate an off-white solid. Subsequent analysis determined that
the isolated solid was the desired 2-aminoimidazole 1, obtained
in high yield (79%) and excellent purity (99.9%) (Table 1,
entry 1).
The procedure described above was the result of a limited
optimization study. Initial success was seen in neat phosphoryl
oxychloride (3 mL/g of substrate) at 100 °C. Employment of
a
Scheme 3. Preparation of Urea Substrates 3, 6−14 for 2-Aminoimidazole Synthesis
a
2, 3, 4: R = CH2C(CH3)3, X = 6-Cl, Y = N; 6, 15, 24: R = CH2CH3, X = 6-Cl, Y = N; 7, 16, 25: CH2CH2CH2CH3, X = 6-Cl, Y = N; 8, 17, 26: R =
CH2CH(CH3)2, X = 6-Cl, Y = N; 9, 18, 27: R = CH2CH2CH(CH3)2, X = 6-Cl, Y = N; 10, 19, 28: R = CH(CH3)CH(CH3)2, X = 6-Cl, Y = N; 11,
20, 29: R = CH2C(CH3)3, X = H, Y = N; 12, 21, 30: R = CH2C(CH3)3, X = 5-Cl, Y = N; 13, 22, 31: R = CH2C(CH3)3, X = 5-Br, Y = N; 14, 23, 32:
R = CH2C(CH3)3, X = 6-Cl, Y = C.
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Note
Table 1. Synthesis of 2-Aminoimidazoles
a
b
entry
urea
R
X
Y
aminoimidazole
yield (%)
purity (%)
1
2
3
6
CH2C(CH3)3
6-Cl
6-Cl
6-Cl
6-Cl
6-Cl
6-Cl
H
N
1
33
34
35
36
37
38
39
40
41
79
69
74
67
64
70
99.9
99.2
98.2
99.7
99.6
99.2
82.2
95.7
99.1
98.1
CH2CH3
N
N
N
N
N
N
N
N
3
7
CH2CH2CH2CH3
CH2CH(CH3)2
CH2CH2CH(CH3)2
CH(CH3)CH(CH3)2
CH2C(CH3)3
4
8
5
9
6
10
11
12
13
14
c
7
14
8
CH2C(CH3)3
5-Cl
5-Br
6-Cl
57
56
9
CH2C(CH3)3
10
CH2C(CH3)3
CH
76
a
b
c
Percentage isolated by filtration of reaction mixture upon reaction completion. As determined by HPLC analysis. An additional 43% of 38 (purity
= 81.9%) was isolated from mother liquor by extraction with ethyl acetate/water.
Figure 1. Phosphoramidic acid side product 5. HPLC conditions: Zorbax SB-C8 (4.6 mm ID × 75 mm, 3.5 μm) column under the following
conditions: mobile phase A, 0.1% H3PO4 in H2O; mobile phase B, 0.1% H3PO4 in acetonitrile; flow rate 1.5 mL/min; gradient 0.0 min (5% B), 15.0
min (90% B), 15.1 min (90% B), 16.1 min (5% B), 18.0 min (5% B); wavelength 225 nm; 40 °C.
products were successfully removed by chromatographic
purification, providing the required urea derivatives in high
purity for subsequent synthesis of the corresponding 2-
aminoimidazoles.
Cyclization of the novel ureas 6−14 in the presence of
phosphorus oxychloride was next conducted using the
optimized reaction conditions identified in our earlier studies
for the synthesis of 2-aminoimidazole 1. This novel method-
ology was found to be efficient for a range of straight-chain and
branched amine variants (Table 1, entries 2−6), with the
aminoimidazole products 33−37 obtained in good yields and
with excellent levels of purity (>98% by HPLC analysis).
Successful cyclization was also recorded for reaction of the urea
precursors 12 and 13 (Table 1, entries 8 and 9), in which the
halide substituent (X = Cl, Br) is present at the 5-position of
the pyridine ring, albeit with slightly reduced yields observed
relative to reactions of our 6-chloro-substituted ureas 3 and 6−
10. Significantly, this novel methodology was also found to be
applicable to the synthesis of benzimidazoles; thus, benzylurea
14 underwent efficient phosphorus oxychloride-mediated
cyclization to provide the novel product 41 in excellent yield
and purity (Table 1, entry 10).
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Note
δC(125.8 MHz, DMSO-d6) 27.2 (3 × CH3), 32.1 (C), 51.5 (CH2),
111.6 (aromatic CH), 126.6 (aromatic C), 138.7 (aromatic CH), 152.2
(aromatic C), 155.2 (aromatic C); HRMS (ESI+): Exact mass
calculated for C10H15ClN3O2 (M + H)+ 244.0853. Found 244.0844.
6-Chloro-N-ethyl-3-nitropyridin-2-amine (15). Starting from 2,6-
dichloro-3-nitropyridine (1.00 g, 5.18 mmol), triethylamine (0.84 mL,
6.01 mmol), and ethanamine (0.45 mL, 5.44 mmol). Yellow solid
(1.03 g, 99.0%), Found: C, 41.61; H, 3.96; N, 21.19; C7H8ClN3O2
requires C, 41.70; H, 4.00; N, 20.84%; mp 76−80 °C; νmax(KBr)/cm−1
3383.3, 2970.2, 1608.1, 1569.2, 1234.7; δH(400 MHz) 1.32 (3H, t, J
7.3, CH3), 3.66 (2H, dq, J 7.3/5.5, CH2), 6.60 (1H, d, J 8.6, aromatic
H), 8.32 (1H, bs, NH), 8.35 (1H, d, J 8.6, aromatic H); δC(75.5 MHz)
14.6 (CH3), 36.5 (CH2), 111.7 (aromatic CH), 126.7 (aromatic C),
137.7 (aromatic CH), 152.2 (aromatic C), 156.9 (aromatic C).
6-Chloro-N-butyl-3-nitropyridin-2-amine (16). Starting from 2,6-
dichloro-3-nitropyridine (2.00 g, 10.36 mmol), triethylamine (1.68
mL, 12.02 mmol), and butan-1-amine (1.08 mL, 10.88 mmol).
Recrystallization from 2-propanol yielded 16 as a yellow solid (2.34 g,
98.4%), Found: C, 47.21; H, 5.30; N, 18.66; C9H12ClN3O2 requires C,
47.07; H, 5.27; N, 18.30%; mp 37−39 °C; νmax(KBr)/cm−1 3396.4,
2956.4, 1608.2, 1571.9, 1235.2; δH(400 MHz) 0.98 (3H, t, J 6.9, CH3),
1.45 (2H, sym m, J 7.5, CH2), 1.68 (2H, qu, J 7.5, CH2), 3.62 (2H,
sym m, J 5.5, CH2), 6.59 (1H, d, J 8.6, aromatic H), 8.34 (1H, d, J 8.6,
aromatic H), 8.35 (1H, bs, NH); δC(75.5 MHz) 13.8 (CH3), 20.1
(CH2), 31.3 (CH2), 41.3 (CH2), 111.7 (aromatic CH), 127.8
(aromatic C), 137.7 (aromatic CH), 152.3 (aromatic C), 156.9
(aromatic C).
In contrast to the other urea substrates (3, 6−10, 12−14)
examined in this study that underwent efficient cyclization in
the presence of phosphorus oxychloride (Table 1, entries 1−6
and 8−10), urea 11, in which no halide substituent is present
on the pyridine ring, was found to produce a mixture of
reaction products. While the previously prepared 2-amino-
imidazoles (1, 33−37, and 39−41) were readily isolated as
precipitates from their respective reaction mixtures, only a
minor amount (14%) of product 38 was obtained in this
manner for reaction of 11 (Table 1, entry 7) and a reduced
level of purity (82.2%) was recorded relative to the other 2-
aminoimidazole products synthesized. Mass recovery was
improved by extraction of the mother liquor with ethyl
acetate/water; however, while the aqueous extract was found to
contain the hydrochloride salt of 38, purity was again low
(81.9%) with significant quantities of additional side products
1
observed by H NMR analysis.
In conclusion, the phosphorus oxychloride-mediated cycliza-
tion of aminoureas provides an effective route to 2-amino-
pyridoimidazoles and 2-aminobenzimidazoles, obviating the use
of hazardous reagents such as cyanogen bromide. This
methodology has been demonstrated for a range of urea
substrates with 2-aminoimidazole products obtained in good
yields and with excellent levels of purity.
6-Chloro-N-isobutyl-3-nitropyridin-2-amine (17). Starting from
2,6-dichloro-3-nitropyridine (2.50 g, 12.95 mmol), triethylamine (2.09
mL, 15.03 mmol), and 2-methylpropan-1-amine (1.35 mL, 13.60
mmol). Recrystallization from 2-propanol yielded 17 as a yellow solid
(2.49 g, 83.5%), mp 63−65 °C; νmax(KBr)/cm−1 3376.4, 2959.6,
1607.8, 1572.1, 1211.2; δH(400 MHz) 1.02 (6H, d, J 6.8, 2 × CH3),
1.92−2.05 (1H, sym m, CH), 3.45−3.48 (2H, m, CH2), 6.59 (1H, d, J
8.6, aromatic H), 8.35 (1H, d, J 8.6, aromatic H), 8.45 (1H, bs, NH);
δC(75.5 MHz) 20.2 (2 × CH3), 28.2 (CH), 48.8 (CH2), 111.6
(aromatic CH), 126.5 (aromatic C), 137.7 (aromatic CH), 152.5
(aromatic C), 156.8 (aromatic C); HRMS (ES+): Exact mass
calculated for C9H13ClN3O2 (M + H)+ 230.0696. Found: 230.0683.
6-Chloro-N-isopentyl-3-nitropyridin-2-amine (18). Starting from
2,6-dichloro-3-nitropyridine (2.50 g, 12.95 mmol), triethylamine (2.09
mL, 15.03 mmol), and 3-methylbutan-1-amine (1.58 mL, 13.60
mmol). Yellow oil (2.97 g, 94.2%), Found: C, 49.60; H, 5.86; N, 17.49;
C10H14ClN3O2 requires C, 49.29; H, 5.79; N, 17.24%; νmax(film)/cm−1
3383.7, 2957.8, 1606.3, 1570.9, 1235.2; δH(400 MHz) 0.98 (6H, d, J
6.5, 2 × CH3), 1.54−1.62 (2H, m, CH2), 1.71 (1H, sym m, J 6.6, CH),
3.63 (2H, sym m, J 5.5/1.8, CH2), 6.60 (1H, d, J 8.6, aromatic H), 8.33
(1H, bs, NH), 8.35 (1H, d, J 8.6, aromatic H); δC(75.5 MHz) 22.5 (2
× CH3), 25.9 (CH), 38.1 (CH2), 39.9 (CH2), 111.6 (aromatic CH),
126.5 (aromatic C), 137.7 (aromatic CH), 152.3 (aromatic C), 156.9
(aromatic C).
6-Chloro-N-(3-methylbutan-2-yl)-3-nitropyridin-2-amine (19).
Starting from 2,6-dichloro-3-nitropyridine (1.00 g, 5.18 mmol),
triethylamine (0.84 mL, 6.01 mmol), and 3-methylbutan-2-amine
(0.63 mL, 5.44 mmol). Purification by column chromatography
(eluent = 100% hexane) yielded 19 as a yellow oil (1.00 g, 79.0%),
νmax(film)/cm−1 3372.4, 2964.3, 1603.2, 1570.7, 1492.9, 1261.5;
δH(400 MHz) 0.98 (3H, d, J 10.8, CH3), 1.00 (3H, d, J 10.8, CH3),
1.23 (3H, d, J 6.4, CH3), 1.83−1.95 (1H, sym m, CH), 4.27−4.36
(1H, sym m, CH), 6.57 (1H, d, J 8.6, aromatic H), 8.34 (1H, d, J 8.6,
aromatic H), 8.38 (1H, bs, NH); δC(75.5 MHz) 17.4, 18.48, 18.54 (3
× CH3), 32.9, 52.0 (2 × CH), 111.5 (aromatic CH), 126.2 (aromatic
C), 137.8 (aromatic CH), 152.0 (aromatic C), 156.9 (aromatic C);
HRMS (ES+): Exact mass calculated for C10H15ClN3O2 (M + H)+
244.0853. Found: 244.0844.
EXPERIMENTAL SECTION
■
All reactions were carried out under an inert atmosphere. NMR
spectra were recorded on a 300, 400, or 500 MHz NMR spectrometer.
All spectra were recorded at room temperature (∼20 °C) in
deuterated chloroform (CDCl3), unless otherwise stated, using
tetramethylsilane (TMS) as an internal standard. COSY and
HETCOR correlations were used to confirm the NMR peak
assignments of all novel compounds. Infrared (IR) spectra were
obtained as films on NaCl plates or as KBr disks, and wavelengths are
reported in cm−1. High-resolution mass spectrometry (HRMS) was
performed on a TOF instrument in electrospray ionization (ESI)
mode; samples were made up in acetonitrile or acetonitrile/water.
Elemental analysis was performed using a PerkinElmer 240 and Exeter
Analytical CE440 elemental analysers. Flash column chromatography
was carried out using Kieselgel 60, 0.040−0.063 mm. Thin-layer
chromatography (TLC) was carried out on precoated silica gel plates
(60 PF254). HPLC analysis of aminoimidazole products was carried
out using a Zorbax RX-C8 (4.6 mm ID × 250 mm, 5 μm) column
under the following conditions: mobile phase A, 0.1% H3PO4 in H2O;
mobile phase B, 0.1% H3PO4 in acetonitrile; flow rate 1.5 mL/min;
gradient 0.0 min (5% B), 15.0 min (90% B), 15.5 min (90% B), 16.5
min (5% B), 20.0 min (5% B); wavelength 254 nm; 40 °C.
General Procedure for Synthesis of Nitropyridin-2-amines 4,
15−19, 21, and 22. Amine (5.20 mmol) was added dropwise to a
solution of nitropyridine substrate (5.18 mmol) and triethylamine
(0.84 mL, 6.01 mmol) in methyl tert-butyl ether (12 mL) at −5 °C.
The reaction mixture was stirred overnight at room temperature and
then washed with water (20 mL) and brine (20 mL × 3). The organic
phase was dried with magnesium sulfate, filtered, and concentrated
under reduced pressure to give the crude nitropyridin-2-amines 4, 15−
19, 21, and 22. The nitropyridin-2-amines 15, 18, 21, and 22 were
utilized without further purification; 19 was purified by column
chromatography on silica gel using hexane as eluent, while 4, 16, 17,
were recrystallized from 2-propanol.
6-Chloro-N-neopentyl-3-nitropyridin-2-amine (4). Starting from
2,6-dichloro-3-nitropyridine (1.00 g, 5.18 mmol), triethylamine (0.84
mL, 6.01 mmol), and 2,2-dimethylpropan-1-amine (0.61 mL, 5.20
mmol). Recrystallization from 2-propanol yielded 4 as a yellow solid
(1.13 g, 89.5%); νmax(KBr)/cm−1 3378.3, 2958.4, 1609.2, 1571.4,
1519.5, 1595.8, 1235.6; δH(500 MHz, DMSO-d6) 0.95 (9H, s, 3 ×
CH3), 3.41 (2H, d, J 6.2, CH2), 6.79−6.76 (1H, m, aromatic H),
8.45−8.41 (1H, m, aromatic H), 8.53 (1H, t, J 5.7, aromatic H);
5-Chloro-N-neopentyl-3-nitropyridin-2-amine (21). Starting from
2,5-dichloro-3-nitropyridine (2.00 g, 10.36 mmol), triethylamine (1.68
mL, 12.02 mmol), and 2,2-dimethylpropan-1-amine (1.22 mL, 10.36
mmol). Orange solid (2.27 g, 89.5%), mp 72−74 °C; νmax(KBr)/cm−1
3394.2, 2958.9, 1610.3, 1567.3, 1204.6; δH(300 MHz) 1.01 (9H, s, 3 ×
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Note
CH3), 3.49 (2H, d, J 5.7, CH2), 8.34 (1H, d, J 2.4, aromatic H), 8.41
(1H, d, J 2.4, aromatic H), 8.39 (1H, bs, NH); δC(75.5 MHz) 27.4 (3
× CH3), 31.9 (C), 52.4 (CH2), 117.5 (aromatic C), 127.1 (aromatic
C), 134.1 (aromatic CH), 151.6 (aromatic C), 154.5 (aromatic CH);
HRMS (ES+): Exact mass calculated for C10H15ClN3O2 (M + H)+
244.0853. Found: 244.0841.
5-Bromo-N-neopentyl-3-nitropyridin-2-amine (22). Starting from
5-bromo-2-chloro-3-nitropyridine (2.00 g, 8.42 mmol), triethylamine
(1.36 mL, 9.77 mmol), and 2,2-dimethylpropan-1-amine (0.99 mL,
8.42 mmol). Orange solid (2.20 g, 90.7%), mp 66−68 °C; νmax(KBr)/
cm−1 3394.3, 2959.4, 1603.5, 1565.9, 1203.6; δH(300 MHz) 1.01 (9H,
s, 3 × CH3), 3.48 (2H, d, J 6.0, CH2), 8.38 (1H, bs, NH), 8.41 (1H, d,
J 2.4, aromatic H), 8.54 (1H, d, J 2.1, aromatic H); δC(75.5 MHz) 27.4
(3 × CH3), 32.0 (C), 52.4 (CH2), 104.0 (aromatic C), 127.8
(aromatic C), 136.8 (aromatic CH), 151.8 (aromatic C), 156.4
(aromatic CH); HRMS (ES+): Exact mass calculated for C10H15-
BrN3O2 (M + H)+ 288.0348. Found: 288.0345.
General Procedure for Synthesis of Nitropyridin-2-amine 20
and 2-Aminonitrobenzene 23. Amine (30.30 mmol) was added
dropwise to a suspension of nitropyridine or nitrobenzene substrate
(20.18 mmol) and sodium carbonate (3.74 g, 35.31 mmol) in EtOH
(35 mL) at room temperature and stirred overnight. The resultant
slurry was concentrated, diluted with water, and slowly neutralized
with concentrated hydrochloric acid to pH = 7. The suspension was
cooled to 0 °C for 1 h, and the observed solid was collected by vacuum
filtration and washed with ice-cold water. If no solid was observed, the
reaction mixture was instead extracted with ethyl acetate to obtain the
desired amine product.
N-Neopentyl-3-nitropyridin-2-amine (20). Starting from 2-chloro-
3-nitropyridine (3.20 g, 20.18 mmol), 2,2-dimethylpropan-1-amine
(3.57 mL, 30.30 mmol), and sodium carbonate (3.74 g, 35.31 mmol).
Yellow oil (4.14 g, 98.1%). Found: C, 57.43; H, 7.25; N, 19.91;
C10H15N3O2 requires C, 57.40; H, 7.23; N, 20.08%; νmax(film)/cm−1
3393.2. 2959.5, 1611.6, 1574.4, 1510.8, 1503.7, 1234.2; δH(300 MHz)
1.03 (9H, s, 3 × CH3), 3.50 (2H, d, J 5.7, CH2), 6.60 (1H, dd, J 8.3/
4.6, aromatic CH), 8.38−8.45 (2H, m, aromatic H), 8.44 (1H, bs,
NH); δC(75.5 MHz) 27.5 (3 × CH3), 31.9 (C), 52.3 (CH2), 111.4
(aromatic CH), 127.8 (aromatic C), 135.4 (aromatic CH), 153.3
(aromatic C), 155.9 (aromatic CH).
5-Chloro-N-neopentyl-2-nitroaniline (23). Starting from 2,4-
dichloro-1-nitrobenzene (5.00 g, 26.01 mmol), 2,2-dimethylpropan-
1-amine (4.60 mL, 39.10 mmol), and sodium carbonate (4.83 g, 45.63
mmol). Recrystallization from hexane yielded 23 as a bright yellow
solid (5.16 g, 81.7%), mp 92−94 °C; νmax(KBr)/cm−1 3375.2, 2960.6,
1614.5, 1566.7, 1492.7, 1243.1; δH(400 MHz) 1.07 (9H, s, 3 × CH3),
3.05 (2H, d, J 5.2, CH2), 6.58 (1H, dd, J 9.1/2.1, aromatic H), 6.85
(1H, d, J 2.1, aromatic H), 8.12 (1H, d, J 9.1, aromatic H), 8.27 (1H,
bs, NH); δC(75.5 MHz) 27.6 (3 × CH3), 31.7 (C), 54.9 (CH2), 113.3
(aromatic CH), 115.6 (aromatic CH), 128.3 (aromatic CH), 131.1
(aromatic C), 142.9 (aromatic C), 146.4 (aromatic C); HRMS (ES+):
exact mass calculated for C11H16ClN2O2 (M + H)+ 243.0882. Found:
243.0889.
General Procedure for Hydrogenations. A mixture of platinum
on activated carbon (0.76 g, 3.90 mmol, 5% w/w, 5% on carbon),
water (2.5 mL), and hypophosphorous acid (0.21 mL, 1.89 mmol) was
added to a solution of nitro 4, 15−23 (20.52 mmol) in toluene (50
mL). The reaction mixture was hydrogenated at 50 psi overnight at
room temperature. The crude reaction mixture was filtered over Celite
with absolute ethanol as eluent. The mother liquor was evaporated
under reduced pressure to provide 2, 24−32.
6-Chloro-N2-neopentylpyridine-2,3-diamine (2). Starting from 4
(5.00 g, 20.52 mmol), Pt/C (0.76 g, 3.90 mmol), and hypophos-
phorous acid (0.21 mL, 1.89 mmol). Dark brown solid (4.21 g,
96.2%); δH(300 MHz) 0.99 (9H, s, 3 × CH3), 3.10 (2H, bs, 2 × NH),
3.26 (2H, s, CH2), 4.37 (1H, bs, NH), 6.46 (1H, d, J 7.7, aromatic H),
6.80 (1H, d, J 7.7, aromatic H).
6-Chloro-N2-ethylpyridine-2,3-diamine (24). Starting from 15
(3.00 g, 14.88 mmol), Pt/C (0.55 g, 2.83 mmol, 5%), and
hypophosphorous acid (0.15 mL, 1.37 mmol). Dark blue solid (2.53
g, 99.5%); δH(400 MHz) 1.26 (3H, t, J 7.2, CH3), 2.35 (3H, 3 × NH),
3.46 (2H, q, J 7.2, CH2), 6.48 (1H, d, J 7.7, aromatic H), 6.79 (1H, d, J
7.7, aromatic H).
6-Chloro-N2-butylpyridine-2,3-diamine (25). Starting from 16
(1.50 g, 6.53 mmol), Pt/C (0.24 g, 1.24 mmol, 5%), and
hypophosphorous acid (0.066 mL, 0.60 mmol). Dark blue oily solid
(1.22 g, 93.7%); δH(400 MHz) 0.96 (3H, t, J 7.3, CH3), 1.43 (2H, sym
m, J 7.3, CH2), 1.61 (2H, qu, J 7.4, CH2), 2.85 (3H, 3 × NH), 3.42
(2H, t, J 7.2, CH2), 6.47 (1H, d, J 7.7, aromatic H), 6.79 (1H, d, J 7.7,
aromatic H).
6-Chloro-N2-isobutylpyridine-2,3-diamine (26). Starting from 17
(1.50 g, 6.53 mmol), Pt/C (0.24 g, 1.24 mmol, 5%), and
hypophosphorous acid (0.066 mL, 0.60 mmol). Dark blue solid
(1.27 g, 97.6%); δH(400 MHz) 0.99 (6H, d, J 6.7, 2 × CH3), 1.82−
1.99 (1H, m, CH), 3.04 (2H, bs, NH2), 3.26 (2H, d, J 6.9, CH2), 4.31
(1H, bs, NH), 6.46 (1H, d, J 7.7, aromatic H), 6.78 (1H, d, J 7.7,
aromatic H).
6-Chloro-N2-isopentylpyridine-2,3-diamine (27). Starting from 18
(1.50 g, 6.16 mmol), Pt/C (0.23 g, 1.17 mmol, 5%), and
hypophosphorous acid (0.062 mL, 0.57 mmol). Dark blue oily solid
(1.30 g, 98.6%); δH(400 MHz) 0.96 (6H, d, J 7.1, 2 × CH3), 1.52 (2H,
q, J 7.1, CH2), 1.72 (1H, sym m, J 6.7, CH), 3.17 (3H, bs, 3 × NH),
3.43 (2H, t, J 7.4, CH2), 6.47 (1H, d, J 7.7, aromatic H), 6.78 (1H, d, J
7.7, aromatic H).
6-Chloro-N2-(3-methylbutan-2-yl)pyridine-2,3-diamine (28).
Starting from 19 (1.50 g, 6.16 mmol), Pt/C (0.23 g, 1.17 mmol,
5%), and hypophosphorous acid (0.062 mL, 0.57 mmol). Dark blue oil
(1.31 g, 99.5%); δH(400 MHz) 0.93 (3H, d, J 6.8, CH3), 0.96 (3H, d, J
6.8, CH3), 1.14 (3H, d, J 6.8, CH3), 1.75−1.91 (1H, m, CH), 3.37
(3H, bs, 3 × NH), 4.01−4.10 (1H, m, CH), 6.43 (1H, d, J 8.0,
aromatic H), 6.79 (1H, d, J 8.0, aromatic H).
N2-Neopentylpyridine-2,3-diamine (29). Starting from 20 (1.50 g,
7.17 mmol), Pt/C (0.27 g, 1.36 mmol, 5%), and hypophosphorous
acid (0.072 mL, 0.66 mmol). Dark blue solid (1.19 g, 92.3%); δH(400
MHz) 1.01 (9H, s, 3 × CH3), 3.28 (2H, s, CH2), 4.49 (1H, bs, NH),
6.48 (1H, dd, J 7.7/5.2, aromatic CH), 6.83 (1H, dd, J 7.4/1.5,
aromatic H), 7.71 (1H, dd, J 5.2/1.3, aromatic H).
5-Chloro-N2-neopentylpyridine-2,3-diamine (30). Starting from
21 (1.50 g, 6.16 mmol), Pt/C (0.23 g, 1.17 mmol, 5%), and
hypophosphorous acid (0.062 mL, 0.57 mmol). Dark black solid (1.31
g, 99.5%); δH(400 MHz) 0.99 (9H, s, 3 × CH3), 3.25 (2H, s, CH2),
6.83 (1H, d, J 2.0, aromatic H), 7.65 (1H, d, J 2.4, aromatic H).
5-Bromo-N2-neopentylpyridine-2,3-diamine (31). Starting from
22 (1.50 g, 5.21 mmol), Pt/C (0.19 g, 0.99 mmol, 5%), and
hypophosphorous acid (0.052 mL, 0.48 mmol). Dark black solid (1.34
g, 99.5%); δH(400 MHz) 0.99 (9H, s, 3 × CH3), 3.25 (2H, s, CH2),
6.95 (1H, d, J 2.4, aromatic H), 7.73 (1H, d, J 2.0, aromatic H).
5-Chloro-N1-neopentylbenzene-1,2-diamine (32). Starting from
23 (1.50 g, 6.18 mmol), Pt/C (0.23 g, 1.17 mmol, 5%), and
hypophosphorous acid (0.062 mL, 0.57 mmol). Dark blue oily solid
(1.29 g, 98.4%); δH(400 MHz) 1.03 (9H, s, 3 × CH3), 2.84 (2H, s,
CH2), 3.01 (3H, bs, 3 × NH), 6.57−6.65 (3H, m, 3 × aromatic H).
General Procedure for Synthesis of Ureas. A solution of
potassium cyanate (2.09 g, 25.30 mmol) in water (5 mL) and aqueous
hydrochloric acid (7.16 mL, 35.82 mmol, 5 N) were added dropwise
separately over 1 h to diamine 2, 24−32 (21.06 mmol) in ethanol (15
mL) at room temperature. A staggered addition was employed where
an excess of aqueous hydrochloric acid was maintained in the reaction
mixture throughout the addition process. The reaction mixture was
stirred for 30 min, after which water (15 mL) was added, and the
resultant mixture was stirred for a further 2 h. The reaction slurry was
filtered, and the cake was washed with toluene and dried under
vacuum overnight to give the crude urea products 3, 6−14.11 The
ureas 3, 6−10, and 14 were utilized without further purification, while
11−13 were purified by column chromatography on silica gel using
10% ethyl acetate in hexane as eluent.
1-[6-Chloro-2-(neopentylamino)pyridin-3-yl]urea (3). Starting
from 2 (4.50 g, 21.06 mmol), potassium cyanate (2.09 g, 25.30
mmol), and hydrochloric acid (7.16 mL, 35.82 mmol, 5 N). Gray solid
(3.74 g, 69.0%); νmax(KBr)/cm−1 3267.9, 2960.2, 1662.4, 1613.6,
1538.9, 1514.4, 1432.8; δH(500 MHz, DMSO-d6) 0.94−0.90 (9H, m, 3
3692
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Note
× CH3), 3.16 (2H d, J 5.8, CH2), 5.96 (1H, d, J 5.8, NH), 5.98 (2H,
bs, NH2), 6.50 (1H, d, J 7.9, aromatic CH), 7.44 (1H, d, J 7.9, aromatic
CH), 7.85 (1H, bs, NH); δC(125.8 MHz, DMSO-d6) 27.41 (3 ×
CH3), 32.01 (C), 51.81 (CH2), 109.9 (aromatic CH), 119.4 (aromatic
C), 132.7 (aromatic CH), 142.1 (aromatic C), 152.6 (aromatic C),
156.6 (CO); HRMS (ESI+): exact mass calculated for C11H18ClN4O
(M + H)+ 257.1164. Found: 257.1157.
1-[6-Chloro-2-(ethylamino)pyridin-3-yl]urea (6). Starting from 24
(2.60 g, 15.15 mmol), potassium cyanate (1.51 g, 18.18 mmol), and
hydrochloric acid (5.15 mL, 25.8 mmol, 5 N). Gray solid (2.59 g,
80.0%), mp 163−165 °C; νmax(KBr)/cm−1 3442.8, 1654.2, 1601.9,
1543.3, 1495.9; δH(400 MHz, DMSO-d6) 1.16 (3H, t, J 7.2, CH3),
3.30 (2H, q, J 7.2, CH2), 6.03 (2H, bs, 2 × NH), 6.37 (1H, bs, NH),
6.49 (1H, d, J 8.0, aromatic H), 7.69 (1H, d, J 8.0, aromatic H), 8.29
(1H, bs, NH); δC(75.5 MHz) 14.5 (CH3), 35.7 (CH2), 109.6
(aromatic CH), 120.1 (aromatic C), 130.0 (aromatic CH), 141.0
(aromatic C), 150.9 (aromatic C), 156.4 (CO); HRMS (ES+): exact
mass calculated for C8H12ClN4O (M + H)+ 215.0700. Found:
215.0696.
1-[6-Chloro-2-(butylamino)pyridin-3-yl]urea (7). Starting from 25
(1.20 g, 6.01 mmol), potassium cyanate (0.60 g, 7.21 mmol), and
hydrochloric acid (2.04 mL, 10.22 mmol, 5 N). Light gray solid (1.41
g, 96.3%), mp 145−148 °C; νmax(KBr)/cm−1 3407.3, 3277.2, 1666.4,
1608.5, 1550.0, 1501.5, 1437.8; δH(400 MHz) 0.91 (3H, t, J 7.3, CH3),
1.36 (2H, sym m, J 7.4, CH2), 1.54 (2H, qu, J 7.4, CH2), 3.23−3.30
(2H, m, CH2), 5.98 (2H, bs, 2 × NH), 6.20 (1H, bt, J 5.0, NH), 6.50
(1H, d, J 7.9, aromatic H), 7.57 (1H, d, J 7.9, aromatic H), 7.92 (1H,
bs, NH); δC(75.5 MHz) 13.8 (CH3), 19.7 (CH2), 30.9 (CH2), 40.6
(CH2), 109.7 (aromatic CH), 119.7 (aromatic C), 131.3 (aromatic
CH), 141.7 (aromatic C), 151.6 (aromatic C), 156.5 (CO); HRMS
(ES+): exact mass calculated for C10H16ClN4O (M + H)+ 243.0997.
Found: 243.1001.
1-[6-Chloro-2-(isobutylamino)pyridin-3-yl]urea (8). Starting from
26 (1.99 g, 9.99 mmol), potassium cyanate (0.99 g, 11.99 mmol), and
hydrochloric acid (3.40 mL, 16.98 mmol, 5 N). Gray solid (2.08 g,
85.6%), mp 165−167 °C; νmax(KBr)/cm−1 3455.9, 3265.7, 2954.0,
1663.0, 1595.2; δH(300 MHz, DMSO-d6) 0.91 (6H, d, J 6.7, 2 × CH3),
1.81−1.98 (1H, m, CH), 3.07−3.12 (2H, m, CH2), 6.03 (2H, bs,
NH2), 6.29 (1H, bt, J 5.2, NH), 6.49 (1H, d, J 7.9, aromatic H), 7.58
(1H, d, J 7.9, aromatic H), 8.08 (1H, bs, NH); δC(75.5 MHz, DMSO-
d6) 20.8 (CH3), 27.9 (CH), 49.1 (CH2), 110.1 (aromatic CH), 120.2
(aromatic C), 131.8 (aromatic CH), 142.1 (aromatic C), 152.2
(aromatic C), 157.0 (CO); HRMS (ES+): Exact mass calculated for
C10H16ClN4O (M + H)+ 243.1013. Found: 243.1006.
1-[6-Chloro-2-(isopentylamino)pyridin-3-yl]urea (9). Starting
from 27 (2.60 g, 12.17 mmol), potassium cyanate (1.21 g, 14.60
mmol), and hydrochloric acid (4.14 mL, 20.68 mmol, 5 N). Light gray
solid (2.57 g, 82.5%), mp 167−169 °C; νmax(KBr)/cm−1 3447.9
3200.5, 1666.9, 1610.1, 1538.3, 1420.2, 1358.3; δH(400 MHz, DMSO-
d6) 0.92 (6H, d, J 6.6, 2 × CH3), 1.45 (2H, q, J 7.1, CH2), 1.65 (1H,
sym m, J 6.6, CH), 3.44 (2H, t, J 7.4, CH2), 5.93 (2H, bs, 2 × NH),
6.08 (1H, bs, NH), 6.51 (1H, d, J 7.9, aromatic H), 7.53 (1H, d, J 7.9,
aromatic H), 7.73 (1H, bs, NH); δC(75.5 MHz) 22.1 (CH3), 22.5
(CH), 37.9 (CH2), 39.0 (CH2), 109.7 (aromatic CH), 119.7 (aromatic
C), 131.6 (aromatic CH), 141.8 (aromatic C), 151.8 (aromatic C),
156.5 (CO); HRMS (ES+): exact mass calculated for C11H18ClN4O
(M + H)+ 257.1169. Found: 257.1166.
1-[6-Chloro-2-{(3-methylbutan-2-yl)amino}pyridin-3-yl]urea (10).
Starting from 28 (2.07 g, 9.68 mmol), potassium cyanate (0.96 g,
11.61 mmol), and hydrochloric acid (3.29 mL, 16.45 mmol, 5 N).
Dark gray solid (2.09 g, 84.1%), mp 134−136 °C; νmax(KBr)/cm−1
3381.0, 2963.9, 1662.6, 1609.0, 1498.6; δH(300 MHz, DMSO-d6) 0.90
(6H, t, J 6.8, 2 × CH3), 1.08 (3H, d, J 6.6, CH3), 1.73−1.86 (1H, sym
m, CH), 3.97−3.82 (1H, sym m, CH), 5.73 (1H, bd, J 7.9, NH), 5.94
(2H, bs, NH2), 6.49 (1H, d, J 7.9, aromatic H), 7.50 (1H, d, J 7.9,
aromatic H), 7.77 (1H, s, NH); δC(75.5 MHz) 17.4, 18.3, 18.9 (3 ×
CH3), 32.9, 51.3 (2 × CH), 110.8 (aromatic CH), 115.2 (aromatic C),
137.7 (aromatic CH), 148.9 (aromatic C), 154.9 (aromatic C), 157.8
(CO); HRMS (ES+): Exact mass calculated for C11H18ClN4O (M +
H)+ 257.1169. Found: 257.1160.
1-[2-(Neopentylamino)pyridin-3-yl]urea (11). Starting from 29
(3.50 g, 19.52 mmol), potassium cyanate (1.94 g, 23.43 mmol), and
hydrochloric acid (6.64 mL, 33.20 mmol, 5 N). Purification by column
chromatography (eluent = 10% ethyl acetate in hexane) gave 11 as a
gray solid (0.74 g, 16.9%), mp 163−165 °C; νmax(KBr)/cm−1 3412.7,
3257.5, 2957.6, 1743.6, 1661.6, 1610.8, 1538.6, 1465.3, 1369.6; δH(400
MHz, DMSO-d6) 0.92 (9H, s, 3 × CH3), 3.22 (2H, d, J 5.9, CH2),
5.60 (1H, bt, J 5.3, NH), 5.92 (2H, bs, NH2), 6.49 (1H, dd, J 7.5/5.0,
aromatic CH), 7.41 (1H, d, J 7.5, aromatic CH), 7.76 (1H, d, J 7.5,
aromatic CH), 7.81 (1H, bs, NH); δC(75.5 MHz) 27.9 (3 × CH3),
32.4 (C), 52.2 (CH2), 111.9 (aromatic CH), 120.9 (aromatic C),
130.6 (aromatic CH), 142.7 (aromatic CH), 153.3 (aromatic C) 157.3
(CO); HRMS (ES+): exact mass calculated for C11H19N4O (M + H)+
223.1559. Found: 223.1556.
1-[5-Chloro-2-(neopentylamino)pyridin-3-yl]urea (12). Starting
from 30 (2.19 g, 10.26 mmol), potassium cyanate (1.02 g, 12.31
mmol), and hydrochloric acid (3.49 mL, 17.44 mmol, 5 N).
Purification by column chromatography (eluent = 10% ethyl acetate
in hexane) gave 12 as a gray solid (0.51 g, 19.3%), mp 159−160 °C;
νmax(KBr)/cm−1 3462.5, 3239.3, 2954.6, 1664.1, 1590.4, 1529.3,
1425.1, 1359.2; δH(300 MHz, DMSO-d6) 0.92 (9H, s, 3 × CH3),
3.23 (2H, d, J 6.0, CH2), 5.74 (1H, bt, J 5.9, NH), 6.06 (2H, bs, NH2),
7.66 (1H, d, J 2.4, aromatic CH), 7.73 (1H, d, J 2.4, aromatic CH),
7.95 (1H, bs, NH); δC(75.5 MHz, DMSO-d6) 27.9 (3 × CH3), 32.5
(C), 52.2 (CH2), 117.2 (aromatic C), 122.2 (aromatic C), 128.2
(aromatic CH), 139.2 (aromatic CH), 150.9 (aromatic C) 156.8
(CO); HRMS (ES+): exact mass calculated for C11H18N4OCl (M +
H)+ 257.1169. Found: 257.1160.
1-[5-Bromo-2-(neopentylamino)pyridin-3-yl]urea (13). Starting
from 31 (2.10 g, 8.13 mmol), potassium cyanate (0.81 g, 9.76
mmol), and hydrochloric acid (2.77 mL, 13.83 mmol, 5 N).
Purification by column chromatography (eluent = 10% ethyl acetate
in hexane) gave 13 as a gray solid (0.72 g, 29.5%), mp 165−167 °C;
νmax(KBr)/cm−1 3469.3, 3234.5, 2954.2, 1666.5, 1586.3, 1537.7,
1497.1, 1424.7; δH(400 MHz, DMSO-d6) 0.86 (9H, s, 3 × CH3),
3.16 (2H, d, J 5.8, CH2), 5.93 (1H, bt, J 5.7, NH), 6.12 (2H, bs, NH2),
7.69 (1H, d, J 2.0, aromatic CH), 7.79 (1H, d, J 2.0, aromatic CH),
8.36 (1H, bs, NH); δC(75.5 MHz, DMSO-d6) 28.1 (3 × CH3), 32.6
(C), 52.4 (CH2), 104.7 (aromatic C), 123.1 (aromatic C), 128.3
(aromatic CH), 140.2 (aromatic CH), 150.0 (aromatic C) 157.0
(CO); HRMS (ES+) exact mass calculated for C11H18N4OBr (M +
H)+ 301.0664. Found: 301.0668.
1-[4-Chloro-2-(neopentylamino)phenyl]urea (14). Starting from
32 (1.80 g, 8.46 mmol), potassium cyanate (0.84 g, 10.15 mmol), and
hydrochloric acid (2.88 mL, 14.39 mmol, 5 N). Dark red solid (2.12 g,
98.0%), mp 105−107 °C; νmax(KBr)/cm−1 3304.2, 1959.6, 1656.7,
1604.7, 1531.1, 1476.9; δH(400 MHz) 1.00 (9H, s, 3 × CH3), 2.89
(2H, s, CH2), 4.65 (2H, bs, 2 × NH), 5.95 (1H, bs, NH), 6.62 (1H,
dd, J 8.2/2.3, aromatic H), 6.69 (1H, d, J 2.3, aromatic H), 7.04 (1H,
d, J 8.2, aromatic H); δC(75.5 MHz) 27.9 (3 × CH3), 32.2 (C), 56.5
(CH2), 110.7 (aromatic CH), 115.5 (aromatic CH), 124.6 (aromatic
C), 126.3 (aromatic CH), 129.8 (aromatic C), 144.8 (aromatic C),
157.5 (CO); HRMS (ES+): exact mass calculated for C12H19ClN3O
(M + H)+ 256.1217. Found: 256.1215.
General Procedure for Synthesis of 2-Aminoimidazoles.
Phosphoryl oxychloride (1.61 mL, 17.29 mmol) was added dropwise
to a solution of urea 3, 6−14 (14.41 mmol) in acetonitrile (29 mL) at
room temperature. The resultant solution was heated under reflux at
80 °C for 2 h. Water (15 mL) was added to the reaction mixture, and
the mixture was heated at 80 °C for a further 1 h. The resulting
mixture was cooled to room temperature, and the slurry was filtered.
The cake was washed with water and dried under vacuum overnight to
give 2-aminoimidazoles 1, 33−41.
5-Chloro-3-neopentyl-3H-imidazo[4,5-b]pyridin-2-amine hydro-
chloride (1). Starting from 3 (3.70 g, 14.41 mmol) and phosphoryl
oxychloride (1.61 mL, 17.29 mmol). Off-white solid (3.14 g, 78.9%,
99.9% pure by HPLC analysis); νmax(KBr)/cm−1 2962.9, 1680.2,
1599.1, 1512.2, 1473.3, 1458.0, 1420.2; δH(500 MHz, DMSO-d6) 0.98
(9H, s, 3 × CH3), 3.96 (2H, s, CH2), 7.34 (1H, d, J 8.3, aromatic CH),
7.78 (1H, d, J 8.3, aromatic CH), 9.11 (2H, bs, NH2); δC(125.8 MHz,
3693
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Note
DMSO-d6) 27.5 (3 × CH3), 34.3 (C), 51.5 (CH2), 118.8 (aromatic
CH), 121.9 (aromatic CH), 122.8 (aromatic C), 142.1 (aromatic C),
144.2 (aromatic C), 152.2 (aromatic C); HRMS (ESI+): exact mass
calculated for C11H16ClN4 (M + H)+ 239.1058. Found: 239.1053.
5-Chloro-3-ethyl-3H-imidazo[4,5-b]pyridin-2-amine hydrochlor-
ide (33). Starting from 6 (1.26 g, 5.87 mmol) and phosphoryl
oxychloride (0.66 mL, 7.04 mmol). Light gray solid (0.94 g, 68.7%,
99.2% pure by HPLC analysis), mp 237−239 °C; νmax(KBr)/cm−1
3020.5, 1677.9, 1603.9, 1518.0, 1422.7; δH(400 MHz, DMSO-d6) 1.30
(3H, t, J 7.2, CH3), 4.17 (2H, q, J 7.2, CH2), 7.38 (1H, d, J 8.2,
aromatic H), 7.81 (1H, d, J 8.2, aromatic H), 9.26 (2H, bs, NH2);
δC(75.5 MHz, DMSO-d6) 13.4 (CH3), 36.9 (CH2), 119.3 (aromatic
CH), 122.5 (aromatic CH), 122.9 (aromatic C), 143.1 (aromatic C),
143.5 (aromatic C), 151.2 (aromatic C); HRMS (ES+): exact mass
calculated for C8H10ClN4 (M + H)+ 197.0594. Found: 197.0589.
5-Chloro-3-butyl-3H-imidazo[4,5-b]pyridin-2-amine hydrochlor-
ide (34). Starting from 7 (1.20 g, 4.94 mmol) and phosphoryl
oxychloride (0.55 mL, 5.93 mmol). Brown solid (0.96 g, 74.2%, 98.2%
pure by HPLC analysis), mp 179−181 °C; νmax(KBr)/cm−1 2959.2,
1681.6, 1523.7, 1428.8; δH(400 MHz, DMSO-d6) 0.77 (3H, t, J 7.4,
CH3), 1.19 (2H, sym m, J 7.6, CH2), 1.55 (2H, qu, J 7.6, CH2), 3.95
(2H, t, J 7.4, CH2), 7.21 (1H, d, J 8.2, aromatic H), 7.63 (1H, d, J 8.2,
aromatic H), 8.84 (2H, bs, NH2); δC(75.5 MHz, DMSO-d6) 14.0 (3 ×
CH3), 19.6 (CH2), 19.9 (CH2), 41.5 (CH2), 119.3 (aromatic CH),
122.6 (aromatic CH), 123.2 (aromatic C), 142.9 (aromatic C), 143.9
(aromatic C), 151.6 (C); HRMS (ES+): exact mass calculated for
C10H14ClN4 (M + H)+ 225.0907. Found: 225.0905.
5-Chloro-3-isobutyl-3H-imidazo[4,5-b]pyridin-2-amine (35).
Starting from 8 (1.00 g, 4.12 mmol) and phosphoryl oxychloride
(0.46 mL, 4.94 mmol). Light brown solid (0.72 g, 67.3%, 99.7% pure
by HPLC analysis), mp 236−238 °C; νmax(KBr)/cm−1 2964.2, 1679.7,
1601.9, 1420.4; δH(400 MHz, DMSO-d6) 0.91 (6H, d, J 6.8, 2 × CH3),
2.13−2.27 (1H, sym m, CH), 3.95 (2H, d, J 7.6 CH2), 7.35 (1H, d, J
8.4, aromatic H), 7.80 (1H, d, J 8.4, aromatic H), 9.17 (2H, bs, NH2);
δC(150 MHz, DMSO-d6) 19.3 (2 × CH3), 26.9 (CH), 47.9 (CH2),
118.9 (aromatic CH), 122.1 (aromatic CH), 122.4 (aromatic C), 142.4
(aromatic C), 143.6 (aromatic C), 151.2 (C); HRMS (ES+): Exact
mass calculated for C10H14ClN4 (M + H)+ 225.0907. Found:
225.0905.
5-Chloro-3-isopentyl-3H-imidazo[4,5-b]pyridin-2-amine (36).
Starting from 9 (1.20 g, 4.67 mmol) and phosphoryl oxychloride
(0.52 mL, 5.61 mmol). Cream solid (0.82 g, 64.1%, 99.6% pure by
HPLC analysis), mp 224−226 °C; νmax(KBr)/cm−1 2961.8, 1675.6,
1600.4, 1522.3, 1420.5; δH(400 MHz, DMSO-d6) 0.96 (6H, d, J 5.7, 2
× CH3), 1.54−1.62 (3H, m, CH and CH2), 4.12 (2H, t, J 6.8, CH2),
7.36 (1H, d, J 8.2, aromatic H), 7.79 (1H, d, J 8.2, aromatic H), 9.05
(2H, bs, NH2); δC(75.5 MHz, DMSO-d6) 22.6 (2 × CH3), 25.6 (CH),
36.2 (CH2), 40.3 (CH2), 119.4 (aromatic CH), 122.5 (aromatic CH),
123.0 (aromatic C), 143.2 (aromatic C), 143.8 (aromatic C), 151.4
(C); HRMS (ES+): exact mass calculated for C11H16ClN4 (M + H)+
239.1063. Found: 239.1057.
5-Chloro-3-(3-methylbutan-2-yl)-3H-imidazo[4,5-b]pyridin-2-
amine hydrochloride (37). Starting from 10 (1.25 g, 4.86 mmol) and
phosphoryl oxychloride (0.54 mL, 5.83 mmol). Black solid (0.93 g,
69.9%, 99.2% pure by HPLC analysis), mp 89−92 °C; νmax(KBr)/
cm−1 3107.6, 2971.8, 1674.4, 1422.6; δH(400 MHz, DMSO-d6) 0.77
(3H, d, J 6.8, CH3), 1.11 (3H, d, J 6.8, CH3), 1.65 (3H, d, J 6.8, CH3),
2.58−2.68 (1H, sym m, CH), 4.34−4.45 (1H, sym m, CH), 7.43 (1H,
d, J 8.0, aromatic H), 7.87 (1H, d, J 8.4, aromatic H), 9.20 (2H, bs,
NH2); δC(150 MHz, DMSO-d6) 15.84, 19.36, 19.42 (3 × CH3), 30.7,
57.6 (2 × CH), 118.8 (aromatic CH), 122.2 (aromatic CH), 122.7
(aromatic C), 141.9 (aromatic C), 142.9 (aromatic C), 150.9 (C);
HRMS (ES+): Exact mass calculated for C11H16ClN4 (M + H)+
239.1063. Found: 239.1059.
aromatic H), 9.14 (2H, bs, NH2); δC(75.5 MHz, DMSO-d6) 27.5 (3 ×
CH3), 34.4 (C), 51.1 (CH2), 118.9 (aromatic CH), 119.1 (aromatic
CH), 124.4 (aromatic C), 141.4 (aromatic CH), 144.9 (aromatic C),
152.3 (C); HRMS (ES+): Exact mass calculated for C11H17N4 (M +
H)+ 205.1453. Found: 205.1443. Note: Mother liquor was extracted
with ethyl acetate and water; aqueous layer was isolated and
concentrated to give 38 as a red oily solid (0.34 g, 42.5%, 81.9%
pure by HPLC analysis). Evidence for the presence of a phosphorus
byproduct was observed by 1H and 31P NMR analysis for both samples
of 38 isolated (not detected by HPLC analysis).
6-Chloro-3-neopentyl-3H-imidazo[4,5-b]pyridin-2-amine (39).
Starting from 12 (0.47 g, 1.81 mmol) and phosphoryl oxychloride
(0.20 mL, 2.18 mmol). Brown solid (0.28 g, 57.0%, 95.7% pure by
HPLC analysis), mp > 240 °C; νmax(KBr)/cm−1 3079.4, 2963.5,
1687.1, 1623.8, 1513.6, 1470.2; δH(400 MHz, DMSO-d6) 0.99 (9H, s,
3 × CH3), 4.03 (2H, s, CH2), 7.89 (1H, d, J 2.1, aromatic H), 7.94
(1H, d, J 2.1, aromatic H), 9.32 (2H, bs, NH2); δC(75.5 MHz, DMSO-
d6) 28.0 (3 × CH3), 34.8 (C), 51.9 (CH2), 119.2 (aromatic CH),
124.3 (aromatic C), 126.3 (aromatic C), 140.6 (aromatic CH), 143.9
(aromatic C), 152.9 (C); HRMS (ES+): Exact mass calculated for
C11H16ClN4 (M + H)+ 239.1063. Found: 239.1057.
6-Bromo-3-neopentyl-3H-imidazo[4,5-b]pyridin-2-amine (40).
Starting from 13 (0.52 g, 1.72 mmol) and phosphoryl oxychloride
(0.19 mL, 2.07 mmol). Light brown solid (0.31 g, 56.2%, 99.1% pure
by HPLC analysis), mp > 240 °C; νmax(KBr)/cm−1 3119.2, 2961.2,
1700.2, 1617.5, 1588.9, 1476.2; δH(400 MHz, DMSO-d6) 0.94 (9H, s,
3 × CH3), 3.62 (2H, s, CH2), 7.48 (1H, d, J 1.8, aromatic H), 8.03
(1H, d, J 1.8, aromatic H); δC(75.5 MHz, DMSO-d6) 28.5 (3 × CH3),
34.2 (C), 50.8 (CH2), 111.9 (aromatic C), 117.4 (aromatic CH),
124.5 (aromatic C), 139.9 (aromatic CH), 144.6 (aromatic C), 154.7
(C); HRMS (ES+): Exact mass calculated for C11H16BrN4 (M + H)+
283.0558. Found: 283.0553.
6-Chloro-1-neopentyl-1H-benzo[d]imidazol-2-amine hydrochlor-
ide (41). Starting from 14 (1.00 g, 3.91 mmol) and phosphoryl
oxychloride (0.44 mL, 4.69 mmol). Off-white solid (0.89 g, 83.1%,
99.0% pure by HPLC analysis), 98.1% pure by HPLC analysis), mp
220−222 °C; νmax(KBr)/cm−1 3108.6, 1668.0, 1515.8, 1480.7, 1401.4;
δH(400 MHz, DMSO-d6) 0.99 (9H, s, 3 × CH3), 4.02 (2H, s, CH2),
7.27 (1H, dd, J 8.5/1.8, aromatic H), 7.38 (1H, d, J 8.5, aromatic H),
7.72 (1H, d, J 1.8, aromatic H), 8.68 (2H, bs, NH2); δC(75.5 MHz,
DMSO-d6) 27.9 (CH3), 35.4 (C), 52.7 (CH2), 112.0 (aromatic CH),
113.3 (aromatic CH), 123.6 (aromatic CH), 127.1 (aromatic C), 129.4
(aromatic C), 133.4 (aromatic C), 152.4 (C); HRMS (ES+): exact
mass calculated for C12H17ClN3 (M + H)+ 238.1111. Found:
238.1102.
ASSOCIATED CONTENT
■
S
* Supporting Information
Spectral and analytical data: copies of 1H and 13C NMR spectra
and HPLC profiles of all novel 2-aminoimidazoles (1, 33−41).
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: a.maguire@ucc.ie.
Present Address
§Department of Chemistry, Pusan National University, Busan,
609-735 Korea.
Notes
The authors declare no competing financial interest.
3-Neopentyl-3H-imidazo[4,5-b]pyridin-2-amine hydrochloride
(38). Starting from 11 (0.70 g, 3.15 mmol) and phosphoryl
oxychloride (0.35 mL, 3.78 mmol). Light brown solid (0.10 g,
13.6%, 82.2% pure by HPLC analysis), δH(400 MHz, DMSO-d6); 1.06
(9H, s, 3 × CH3), 4.11 (2H, s, CH2), 7.36 (1H, dd, J 7.9/5.0, aromatic
H), 7.84 (1H, dd, J 7.9/1.3, aromatic H), 8.28 (1H, dd, J 5.0/1.3,
ACKNOWLEDGMENTS
■
Enterprise Ireland (UP/2011/0097) and Eli Lilly are acknowl-
edged for the financial support of C.N.S. and R.E.D.
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The Journal of Organic Chemistry
Note
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