One-pot synthesis of imidazopyridine derivatives

Article abstract of DOI:10.1055/s-2007-1000936

Two highly efficient and general one-pot annulation reactions are described for the synthesis of imidazopyridine derivatives (IPs). The two procedures are complementary to each other: Whereas the first one allows the production of simpler IPs, the second

Full text of DOI:10.1055/s-2007-1000936

PRACTICAL SYNTHETIC PROCEDURES
1479
One-Pot Synthesis of Imidazopyridine Derivatives
S
A
ynthesis of Imida
l
zopyrid
e
ine
D
eriva
x
tives is D. C. Parenty,* Leroy Cronin*
WestCHEM, University of Glasgow, Chemistry Department, Glasgow, G12 8QQ, UK
Fax +44(141)3304888; E-mail: L.Cronin@chem.gla.ac.uk; E-mail: Alexisp@chem.gla.ac.uk
Received 1 October 2007; revised 15 October 2007
PSP
No123
Abstract: Two highly efficient and general one-pot annulation reactions are described for the synthesis of imidazopyridine derivatives
(IPs). The two procedures are complementary to each other: Whereas the first one allows the production of simpler IPs, the second leads to
IPs with functionalized imidazole moiety. Both methodologies consist of an activation step, which raises the electrophilicity of the
N-heterocyclic starting material (i.e., quaternarization of the N-heterocycle), followed by a cascade reaction involving nucleophilic addi-
tion, substitution, rearrangement, and oxidation steps. These methodologies can be used in the synthesis of a library of drug-like molecules.
Key words: annulation reaction, one-pot reaction, cascade reaction, N-heterocycles, imidazole derivatives
Scheme 1 The ‘one-pot’ reaction methodologies leading to nonfunctionalized (Procedure 1) and functionalized (Procedure 2) imidazo-
pyridine derivatives (IPs)
SYNTHESIS 2008, No. 9, pp 1479–1485
x
x
.
x
x
.2
0
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Advanced online publication: 10.01.2008
DOI: 10.1055/s-2007-1000936; Art ID: Z23307SS
Georg Thieme Verlag Stuttgart · New York
©

1
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A. D. C. Parenty, L. Cronin
PRACTICAL SYNTHETIC PROCEDURES
Table 1 Examples of IP Molecules Obtained Using Procedures 1
and 2
Introduction
Heterocycles are present as fundamental components in
the skeleton of more than half of the biologically active
compounds produced by nature. As a consequence, the
Starting material
Product
Yield
%)
(
1
ongoing interest for developing new versatile and effi-
cient syntheses of heterocycles has always been a thread
in the synthetic community. Recently, however, it has be- 1a
come not only a question of what can be synthesized, but
how the synthesis can be achieved in the most atom effi-
cient manner. Critical objectives in modern organic chem-
istry are the improvement of efficiency, avoidance of
toxic reagents, reduction of waste, and the responsible
Br
Br
5a
quant.
N
N
N
2
,3
Br
treatment of resources. Multi-step one-pot reactions, 1b
also called cascade reactions, address many of these ob-
jectives. As they do not require workup and isolation of
intermediates, cascade reactions are indeed cleaner,
quicker as well as more efficient than traditional ‘step by
5b
65
N
N
N
Br
Br
Br
4
,5
step methodologies’. Therefore, the concept of increas-
ing the molecular complexity while decreasing the num-
ber of synthetic steps is becoming more and more
attractive.
1
1
1
1
c
d
e
f
5c
5d
5e
quant.
quant.
92
N
N
N
Recently, we have exploited the reactivity of two dielec-
trophiles, 2-bromoethylphenanthridinium and 2-acetyl-
phenanthridinium derivatives, in two annulation
reactions, producing a number of imidazo-based hetero-
Br
N
N
6
,7
cyclic frameworks. Also, it was discovered that some of
the resulting heterocycles had interesting photochromic
N
Br
7
Br
properties.
N
N
N
N
The dielectrophilic starting materials 1 and 6 (Scheme 1
and Scheme 2, A and B) are easily prepared by reacting
the corresponding N-heterocycles with an excess of 1,2-
dibromoethane or 2-bromoacetyl derivatives respectively
N
Br
(
see experimental). Various spectroscopic evidences were
O
Br
5f
O
98
gathered to allow us to propose the following reaction
6
–9
N
N
mechanism for the two annulation reactions.
N
N
H
H
The synthesis of IP derivatives 5a–f (Procedure 1,
Br
N
N
Scheme 2A) is initiated in an NH /toluene biphasic sys-
3
tem via a nucleophilic addition of ammonia onto the imi-
nium moiety of the dielectrophile starting material 1a–f.
The resulting secondary amine 2 undergoes a five-mem-
bered ring cyclization to give the imidazolidine interme-
diate 3, which shifts to the toluene phase to undergo two
successive oxidation steps leading to 4 and IPs 5a–f.6
Cl
O
6
6
a
11a
85
N
N
,7
The synthesis of substituted IP derivatives 11a–c (Proce-
dure 2, Scheme 2B) is achieved by nucleophilic addition
of ammonium acetate onto the iminium moiety of the di-
electrophile starting materials 6a–c. The resulting second-
ary amine 7 undertakes a five-membered-ring cyclization
to form the imine 9 that rearranges to the stabilized en-
amine 10 under the slightly acidic reaction conditions.
The resulting dihydroimidazole moiety of 10 is subse-
Br
N
b
N
O
11b
88
N
O
O
quently oxidized by MnO in the reaction medium leading
2
to the substituted IPs 11a–c. In both procedures, the final
products IPs 5a–f and 11a–c are recovered in a pure form,
after removing the inorganic residue of the reactions by
filtration (Table 1).
Br
6
c
11c
quant.
N
N
N
O
Synthesis 2008, No. 9, 1479–1485 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Synthesis of Imidazopyridine Derivatives
1481
A) General Procedure 1
R3
R3
R2
R1
R4
R3
R2
R4
Br
A
N
A
N
R2
R1
R4
A
N
a
b
R1
Br
90–95%
1
a–f
Br
NH3
2
H2N
Br
Br
R3
R2
R1
R4
R3
R3
A
N
R2
R4
R2
R4
65–100%
A
N
A
N
N
R1
R1
5a–f
IPs
N
N
4
3
H
imidazopyridine
derivatives
58–95% overall
B) General Procedure 2
R3
R3
R2
R4
R3
R2
R4
X
A
N
A
R2
R4
R1
c
R5
d
A
N
R1
R5
N
R5
R1
X
90–100% 6a–c
O
NH3
R6
7
H2N
R6
R6
O
O
R3
R3
R3
R2
R1
R4
R2
R4
R2
R4
A
N
A
N
A
N
R5
R5
R1
R1
R5
H
N
H
R6
N
N
H
R6
R6
H
10
O
9
8
H
83–100%
R3
R2
R1
R4
R5
R6
A
N
N
IPs
1
1a–c
A = C or N
imidazopyridine
derivatives
75–100% overall
Scheme 2 General scheme for Procedures 1 and 2. Reagents and conditions: a) 1,2-dibromoethane, 90 °C, 5 d; b) NH /toluene, MnO ,
3
2
Na CO , 4 h, reflux; c) MeCN, reflux, overnight; d) 1,4-dioxane, NH OAc, MnO , reflux, 4 h; Na CO .
2
3
4
2
2
3
Synthesis 2008, No. 9, 1479–1485 © Thieme Stuttgart · New York

1
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A. D. C. Parenty, L. Cronin
PRACTICAL SYNTHETIC PROCEDURES
Scope and Limitations
(1) In Procedure 1 (Scheme 2A), the biphasic condition
set up between NH /toluene is crucial for the reaction to
3
To the best of our knowledge, these procedures have the be successful. In these conditions, the ammonia phase par-
following limitations:
titions the electron-deficient starting material 1 away from
the electron-rich intermediates 2 and 3 dissolved in the
R3
R3
R2
R4
Br
R2
R4
Br
monophasic solvent system
like DMF
A
N
A
N
R1
R1
H
1
H
1
2
Br
Br
R3
R3
R2
R1
R4
R2
R4
A
N
A
N
R1
H
N
N
5
3
H
H
Scheme 3 Redox side reaction when the reaction is undertaken in a monophasic system
N
O
R1
R2
NH3
N
NH2
O
R1
R2
N
NH
OH
R1 R2
N
N
NH
OH
N
R1
R2
R1
H3O+
O
O
O
O
N
N
R2
R1
R1
R2
H2N
NH
N
HO
R2
R2
NH2
R1
R1
H2N
H2N
Zincke aldehydes
Scheme 4 Pyridinium starting material cannot be used in the procedures
Synthesis 2008, No. 9, 1479–1485 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Synthesis of Imidazopyridine Derivatives
1483
R3
R3
R2
R4
R3
Procedure 2
R2
R4
A
N
A
N
R2
R4
R1
A
N
NH3
R1
R5
R5
X
R5
R1
N
R6
N
R6
R6
O
IP 11
Scheme 5 Possible extension of the methodology to the annulation of a second cycle
toluene phase, preventing a redox side reaction from oc- mother liquor stirred at 90 °C until the next filtration. The reaction
8
was complete when no more precipitate was formed. The precipi-
tates were combined and washed with acetone (3 × 20 mL) to give,
after drying, the corresponding 2-bromoethylpyridinium derivative
curring (Scheme 3).
(
2) In Procedure 2, liquid ammonia could not be used as
nucleophile since the carbonyl moiety of 6 enhances the 1a–f as a beige powder.
acidity of the adjacent methylene position next to the am-
CAUTION! Products 1a–f were found to be extreme irritants and
allergenics. Appropriate safety protection and utmost care are re-
monium moiety and leads, in such basic condition, to an
ylide that undertakes cycloaddition side reactions.10 In- quired while preparing and handling these compounds.
stead, ammonium acetate was used as a mild source of
2
-Bromoethylquinolinium Bromide (1b)
Compound 1b (9.05 g, 95%) was isolated as a beige powder; mp
89–290 °C (dec.).
ammonia.
(
3) The procedures were found to be general for all the N-
2
heterocyclic derivatives tested (quinoline, isoquinoline,
phenanthridine, and phthalazine), except for the simpler
pyridine. It is believed that in our reaction conditions, the
IR (KBr): 3437 (s), 3045 (w), 2981 (m), 2947 (m), 1624 (s), 1599
m), 1585 (m), 1525 (s), 1489 (w), 1450 (m), 1400 (m), 1363 (s),
242 (s), 1126 (m), 1161 (m), 1144 (m), 1049 (w), 874 (w), 816 (m),
(
1
–
1
pyridinium salt would undertake a ring-opening side reac- 800 (m), 775 cm (s).
tion upon addition of ammonia in a similar way to the
1
H NMR (D O, 400 MHz): d = 9.24 (d, J = 8.4 Hz, 1 H), 9.12 (d,
2
1
1,12
Zincke reaction
leading to a mixture of side products J = 8.4 Hz, 1 H), 8.87 (d, J = 8.4 Hz, 1 H), 8.33 (d, J = 8.4 Hz, 1 H),
(
Scheme 4). Therefore, it seems that the N-heterocycle 8.20 (t, J = 8.4 Hz, 1 H), 7.98 (m, 2 H), 5.41 (t, J = 5.8 Hz, 2 H),
4
.05 (t, J = 5.8 Hz, 2 H).
starting materials need at least one flanking aromatic sys-
tem in order to stabilize at least one of the two double
1
3
C NMR (D O, 100 MHz): d = 149.80 (C), 149.20 (CH), 138.08
2
bonds of the N-heterocyclic moiety of intermediates 3 and (C), 136.66 (CH), 131.43 (CH), 130.68 (CH), 130.55 (CH), 121.59
(
CH), 118.08 (CH), 58.59 (CH ), 29.28 (CH ).
2 2
8
(Scheme 2).
MS (FAB): m/z (%) = 237 (M – Br, 98), 236 (100), 209.9 (2), 172
2), 156 (12), 129.1 (6), 107.2 (2), 89.5 (2), 72.7 (1), 59.9 (1).
Finally, further work is ongoing to exploit the nucleophi-
licity of the imidazole moiety of IP framework 11
(
Anal. Calcd for C H Br N: C, 41.67; H, 3.49; N, 4.42. Found: C,
(
Scheme 5) in a second spontaneous annulation reaction
11 11
2
6
41.75; H, 3.50; N, 4.51.
with an electrophilic moiety on R .
Analytical and spectral data for the other pyridinium derivatives are
7
available in the published literature.
Procedures
Acetylpyridinium Derivatives 6a–c; General Procedure
All starting materials and solvents were commercially available (re-
agent grade) and used as supplied, from Aldrich Chemical Co.,
The appropriate pyridine derivative (30 mmol) was dissolved in
MeCN (40 mL) and the 2-halogenoacetyl derivative (33 mmol) was
added to the stirred solution. The mixture was refluxed overnight
1
13
without further purification. H NMR and C NMR were recorded
using a Bruker DPX 400 spectrometer operating at 400 and 100
MHz, respectively. Chemical shifts (d) are given in ppm relative to
residual solvent peak. Coupling constants (J) are given in Hz. IR
spectral analyses were performed on a JASCO 410 spectrophotom-
eter, using a KBr disc; peaks are quoted in wave numbers (cm ).
Mass spectra were obtained using a JEOL JMS 700 spectrometer
operating in FAB, EI, or CI mode. Microanalyses were performed
on a CE-440 elemental analyzer. Melting points were determined
on a digital IA9000 series melting point apparatus, using capillary
tubes.
and left to cool down to r.t. before adding Et O (20 mL). The result-
2
ing precipitate was recovered by filtration, washed with acetone (3
×
20 mL), and dried under vacuum to give the corresponding
acetylpyridinium derivative 6a–c as a beige powder.
–
1
CAUTION! Products 6a–c were found to be extreme irritants and
allergenics. Appropriate safety protection and utmost care are re-
quired while preparing and handling these compounds.
5
-(2-Oxopropyl)phenanthridinium Chloride (6a)
Compound 6a (7.17 g, 88%) was isolated as a brown powder; mp
39–141 °C (dec.)
1
2
-Bromoethylpyridinium Derivatives 1a–f; General Procedure
The appropriate pyridine derivative (30 mmol) was dissolved in
,2-dibromoethane (114.2 g, 50 mL, 608 mmol) and stirred at 90 °C
IR (KBr): 3465 (s), 3415 (s), 3238 (w), 3066 (m), 3019 (m), 2963
(m), 2672 (w), 1851 (w), 1735 (s), 1625 (s), 1578 (m), 1533 (m),
1
–
1
for 5 d. Any precipitate formed during the reaction was recovered
daily by filtration. After each filtration, the precipitate was rinsed
with an additional amount of 1,2-dibromoethane (5 mL) and the
1447 (s), 1347 (s), 1264 (m), 1170 (s), 1039 cm (w).
1
H NMR (D O, 400 MHz): d = 9.50 (s, 1 H), 8.50 (d, J = 8.0 Hz, 1
2
H), 8.45 (d, J = 8.0 Hz, 1 H), 8.17 (d, J = 8.0 Hz, 1 H), 8.03 (t,
Synthesis 2008, No. 9, 1479–1485 © Thieme Stuttgart · New York

1
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A. D. C. Parenty, L. Cronin
PRACTICAL SYNTHETIC PROCEDURES
J = 8.0 Hz, 1 H), 7.85 (t, J = 9.0 Hz, 1 H), 7.80 (d, J = 9.0 Hz, 1 H),
IR (KBr): 3444 (s), 3069 (s), 2743 (s), 2451 (w), 1960 (m), 1934
(m), 1725 (m), 1638 (s), 1607 (s), 1518 (s), 1449 (s), 1385 (s), 1317
(s), 1224 (s), 1141 (s), 1095 (s), 953 (s), 910 (s), 882 cm (s).
7
.74 (m, 2 H), 6.05 (s, 2 H), 2.47 (s, 3 H).
–
1
1
3
C NMR (D O, 100 MHz): d = 202.36 (C), 155.52 (CH), 138.76
2
1
(
(
(
CH), 135.03 (C), 133.20 (C), 132.68 (CH), 132.15 (CH), 130.39
CH), 130.33 (CH), 125.56 (C), 124.40 (CH), 123.03 (C), 122.56
CH), 118.67 (CH), 68.00 (CH ), 26.99 (CH ).
H NMR (CDCl , 400 MHz): d = 8.63 (d, J = 8.0 Hz, 1 H), 7.86 (d,
3
J = 7.2 Hz, 1 H), 7.65 (d, J = 8.0 Hz, 1 H), 7.59 (t, J = 8.0 Hz, 1 H),
7.55 (d, J = 1.2 Hz, 1 H), 7.54 (t, J = 8.0 Hz, 1 H), 7.51 (d, J = 1.2
Hz, 1 H), 7.02 (d, J = 7.2 Hz, 1 H).
2
3
MS (CI): m/z (%) = 236.13 (M – Cl, 20), 180.12 (40), 139.14 (5),
27.15 (10), 113.17 (15), 85.14 (70), 69.08 (100).
1
3
1
C NMR (CDCl , 100 MHz): d = 143.05 (C), 131.22 (CH), 129.46
3
(
C), 128.30 (CH), 128.25 (CH), 126.94 (CH), 123.85 (C), 123.29
Analytical and spectral data for the other acetylpyridinium deriva-
7
(CH), 123.09 (CH), 114.28 (CH), 113.27 (CH).
tives are available in the published literature.
+
MS (EI): m/z (%) = 168.1 (M , 100), 141 (12), 114 (30), 113 (5),
Procedure 1: Imidazopyridines 5a–f
70.5 (10), 63 (5), 49 (3).
Under stirring, liquid ammonia (40 mL) was added to an open
round-bottomed flask containing toluene (40 mL). To the resulting
cold biphasic solution was added under stirring the corresponding
+
HRMS: m/z calcd for C H N : 168.0687 (M ); found: 168.0689.
1
1
8
2
5
-Methylimidazo[1,2-a]quinoline (5d)
2
-bromoethylpyridinium bromide derivative 1a–f (4 mmol), fol-
Yield: 730 mg (quant); brown oil; R = 0.2 (EtOAc).
f
lowed by addition of MnO (3.5 g, 40 mmol, 10 equiv) and Na CO
2
2
3
IR (KBr): 3407 (s), 2912 (w), 1621 (s), 1455 (s), 1420 (s), 1325 (s),
(
2.12 g, 20 mmol, 5 equiv). The mixture was left stirring until com-
–
1
1
198 (s), 1148 (m), 865 cm (m).
plete evaporation of the ammonia phase (i.e., 1 to 2 h, until the mix-
ture reached r.t.) and the toluene was maintained at reflux for 4 h.
The mixture was then filtered on glass frit (no. 4) and the residue
was rinsed extensively with acetone. Finally, the mother liquor was
concentrated to dryness to afford analytically pure imidazopy-
ridines 5a–f, without further purification.
1
H NMR (CDCl , 400 MHz): d = 7.90 (s, 1 H), 7.83 (d, J = 7.8 Hz,
H), 7.81 (d, J = 7.8 Hz, 1 H), 7.55 (t, J = 7.8 Hz, 1 H), 7.50 (d,
J = 1.2 Hz, 1 H), 7.41 (t, J = 7.8 Hz, 1 H), 7.32 (d, J = 1.2 Hz, 1 H),
3
1
2
.53 (s, 3 H).
1
3
C NMR (CDCl , 100 MHz): d = 133.04 (C), 128.62 (CH), 128.28
C), 125.81 (CH), 124.59 (CH), 123.88 (C), 121.87 (CH), 116.51
CH), 115.36 (CH), 110.58 (CH), 19.29 (CH3).
3
(
(
Imidazo[1,2-f]phenanthridine (5a)
Yield: 870 mg (quant); yellow powder; mp 77–78 °C; R = 0.3
f
+
(EtOAc).
MS (EI): m/z (%) = 182.1 (M , 100), 181.1 (98), 154.1 (20), 127
(
29), 91 (19), 77 (12), 63 (11), 51 (10).
IR (KBr): 3432 (s), 1629 (m), 1532 (m), 1495 (w), 1463 (m), 1439
–
1
+
(
m), 1316 (m), 1262 (s), 1104 (s), 803 (m), 719 cm (s).
HRMS (EI): m/z calcd for C12H N : 182.0844 (M ); found:
10 2
1
182.0840.
H NMR (CDCl , 400 MHz): d = 8.79 (m, 1 H), 8.51 (dd, J = 8.0,
3
1
.0 Hz, 1 H), 8.42 (m, 1 H), 8.05 (d, J = 1.2 Hz, 1 H), 7.93 (dd,
Imidazo[2,1-a]phthalazine (5e)
Yield: 620 mg (92%); yellow powder; mp 74–75 °C; R = 0.3
J = 8.0, 1.0 Hz, 1 H), 7.7 (m, 3 H), 7.68 (d, J = 1.2 Hz, 1 H), 7.58
(
f
td, J = 8.0, 1.0 Hz, 1 H).
(EtOAc).
1
3
C NMR (CDCl , 100 MHz): d = 142.08 (C), 131.49 (C), 130.45
3
IR (KBr): 3110 (s), 2382 (m), 1984 (m), 1964 (m), 1855 (m), 1721
(
(
(
C), 129.19 (CH), 129.06 (CH), 128.86 (CH), 127.68 (C), 125.53
CH), 124.59 (CH), 124.29 (CH), 122.42 (CH), 121.91 (C), 115.94
CH), 112.15 (CH).
(
(
1
m), 1656 (s), 1557 (s), 1523 (s), 1449 (s), 1337 (s), 1240 (s), 1141
s), 1068 (s), 904 (s) 862 cm (s).
–
1
H NMR (CDCl , 400 MHz): d = 8.59 (s, 1 H), 8.56 (d, J = 8.0 Hz,
H), 7.85 (d, J = 1.6 Hz, 2 H), 7.83 (m, 2 H), 7.65 (t, J = 8.0 Hz, 1
3
MS (FAB): m/z (%) = 219.4 (M + 1, 100), 178.7 (3), 164.9 (2), 98.8
5), 71.2 (7), 57.4 (10).
1
(
H), 7.58 (d, J = 1.6 Hz, 1 H).
Anal. Calcd for C H N : C, 82.55; H, 4.62; N, 12.84. Found: C,
8
15
10
2
13
C NMR (CDCl , 100 MHz): d = 145.78 (CH), 133.31 (CH),
3
2.40; H, 4.65; N, 12.90.
1
1
31.88 (C), 129.73 (CH), 129.11 (CH), 127.65 (CH), 125.45 (C),
22.86 (C), 122.49 (CH), 117.54 (CH).
Imidazo[1,2-a]quinoline (5b)
Yield: 440 mg (65%); brown oil; R = 0.2 (EtOAc).
MS (CI+): m/z (%) = 170.12 (M + H, 100), 169.12 (25), 147.11 (20),
31.12 (12), 115.10 (3).
f
1
IR (KBr): 3367 (s), 1613 (s), 1557 (s), 1536 (s), 1487 (m), 1446 (s),
–
1
+
1
419 (s), 1317 (s), 1279 (m), 1217 (s), 1088 (s), 870 cm (m).
HRMS (EI): m/z calcd for C10H N : 169.0640 (M ); found:
7 3
1
169.0637.
H NMR (CDCl , 400 MHz): d = 7.98 (d, J = 1.6 Hz, 1 H), 7.84 (d,
3
J = 8.0 Hz, 1 H), 7.74 (d, J = 8.0 Hz, 1 H), 7.58 (d, J = 1.6 Hz, 1 H),
N-Imidazo[1,2-a]quinolin-4-ylacetamide (5f)
Yield: 880 mg (98%); pale yellow powder; mp 153–154 °C;
Rf = 0.2 (EtOAc).
7
.57 (t, J = 8.0 Hz, 1 H), 7.50 (d, J = 9.6 Hz, 1 H), 7.43 (d, J = 9.6
Hz, 1 H), 7.39 (t, J = 8.0 Hz, 1 H).
1
3
C NMR (CDCl , 100 MHz): d = 143.98 (C), 132.73 (C), 132.52
3
IR (KBr): 3446 (w), 3147 (m), 2924 (m), 2770 (w), 1681 (s), 1557
(CH), 129.15 (CH), 128.78 (CH), 126.06 (CH), 124.76 (CH),
(
(
1
s), 1520 (s), 1458 (m), 1421 (s), 1369 (m), 1331 (s), 1310 (m), 1260
s), 1142 (m), 1003 (w) 872 (m), 846 cm (m).
1
23.43 (C), 117.33 (CH), 115.16 (CH), 111.05 (CH).
–
1
+
MS (EI): m/z (%) = 168.1 (M , 100), 140 (12), 128 (28), 114 (20),
8
H NMR (CDCl , 400 MHz): d = 9.2 (s, 1 H), 8.61 (s, 1 H), 8.04 (d,
3
4 (11), 63 (8), 51 (5).
J = 1.6 Hz, 1 H), 7.81 (t, J = 7.8 Hz, 2 H), 7.58 (d, J = 1.6 Hz, 1 H),
7.54 (t, J = 7.8 Hz, 1 H), 7.45 (t, J = 7.8 Hz, 1 H), 2.31 (s, 3 H).
+
HRMS (EI): m/z calcd for C H N : 168.0687 (M ); found:
1
1
1
8
2
68.0689.
1
3
C NMR (CDCl , 100 MHz): d = 130.13 (CH), 129.79 (CH),
3
1
28.42 (CH), 121.50 (CH), 119.56 (CH), 114.68 (CH), 75 (CH ).
3
Imidazo[2,1-a]isoquinoline (5c)
Yield: 670 mg (quant); brown powder; mp 69–70 °C; R = 0.25
+
MS (EI): m/z (%) = 225.1 (M , 35), 183.1 (100), 155.1 (20), 128 (5),
f
(EtOAc).
101 (5), 82.9 (5), 49 (3).
Synthesis 2008, No. 9, 1479–1485 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Synthesis of Imidazopyridine Derivatives
1485
Anal. Calcd for C H N O: C, 69.32; H, 4.92; N, 18.66. Found: C,
2,3-Dimethylimidazo[1,2-f]phenanthridine (11c)
13
11
3
6
9.12; H, 4.83; N, 18.45.
Yield: 985 mg (~100%); beige powder; mp 135–136 °C; R = 0.4
f
(
EtOAc).
Procedure 2: Imidazopyridines 11a–c
IR (KBr): 3383 (m), 3054 (m), 2975 (m), 2919 (m), 2858 (m), 1945
To a stirred suspension of the appropriate acetylpyridinium deriva-
tive 6a–c (4 mmol) in 1,4-dioxane (40 mL) at r.t. was added
NH OAc (1.23 g, 16 mmol, 4 equiv), followed by MnO (3.5 g, 40
(
(
1
m), 1664 (m), 1595 (s), 1573 (s), 1531 (s), 1542 (s), 1398 (s), 1372
s), 1040 (m), 945 (m), 817 cm (m).
–1
4
2
H NMR (CDCl , 400 MHz): d = 8.61 (d, J = 8.0 Hz, 1 H), 8.37 (d,
mmol, 10 equiv). The mixture was refluxed for 4 h before adding
Na CO (4.24 g, 40 mmol, 10 equiv). The suspension was then
3
J = 8.0 Hz, 1 H), 7.47 (t, J = 8.0 Hz,1 H), 7.39 (t, J = 8.0 Hz, 1 H),
.75 (s, 3 H), 2.39 (s, 3 H).
2
3
2
cooled down to r.t. and Et O (10 mL) was added to precipitate any
2
inorganic side products. The mixture was filtered on glass frit (no.
13
C NMR (CDCl , 100 MHz): d = 140.90 (C), 136.97 (C), 133.80
3
4
) and the residue was rinsed extensively with acetone. Finally, the
(
(
(
C), 128.58 (CH), 128.44 (CH), 128.22 (CH), 127.13 (C), 124.56
CH), 124.18 (CH), 124.13 (CH), 122.49 (C), 122.05 (C), 120.88
C), 116.29 (CH), 14.30 (CH ), 12.92 (CH ).
mother liquor was concentrated to dryness to afford analytically
pure IPs 11a–c, without further purification.
3
3
+
MS (EI): m/z (%) = 246.1 (M , 100), 245.1 (50), 231.1 (10), 204.1
2
-Methylimidazo[1,2-f]phenanthridine (11a)
(10), 178.1 (10), 177.1 (10), 123.1 (9), 122.1 (3), 84 (4), 82.9 (4), 49
Yield: 790 mg (85%); brown powder; mp 130–131 °C; R = 0.4
f
(
4).
(
EtOAc).
+
HRMS (EI): m/z calcd for C H N : 246.1157 (M ); found:
1
7
14
2
IR (KBr): 3372 (w), 3146 (m), 3067 (w), 2915 (m), 1607 (m), 1591
2
46.1158.
(
(
1
s), 1550 (s), 1591 (s), 1550 (s), 1530 (s), 1460 (s), 1433 (s), 1392
–
1
s), 1349 (m), 1313 (s) 1233 (w), 1109 (m), 1036 cm (w).
H NMR (CDCl , 400 MHz): d = 8.46 (d, J = 8.0 Hz, 1 H), 8.14 (d, Acknowledgment
3
J = 8.0 Hz, 1 H), 8.10 (d, J = 8.0 Hz, 1 H), 7.48 (t, J = 8.0 Hz, 1 H),
7
2
We thank the EPSRC, Scottish Enterprise, and the University of
Glasgow for their financial support.
.44 (m, 3 H), 7.34 (t, J = 8.0 Hz, 1 H), 7.22 (t, J = 8.0 Hz, 1 H),
.38 (s, 3 H).
1
3
C NMR CDCl , 100 MHz): d = 141.73 (C), 140.86 (C), 131.39
3
(
(
(
C), 128.55 (CH), 128.23 (CH), 127.21 (C), 124.51 (CH), 123.89 References
CH), 123.86 (CH), 123.22 (C), 122.44 (CH), 122.20 (CH), 121.26
(
1) Comprehensive Heterocyclic Chemistry, Vol. 4; Katritzky,
A. R.; Rees, C. W., Eds.; Pergamon Press: New York, 1984,
–38.
2) Tietze, L. F. Chem. Rev. 1996, 96, 115.
CH), 115.49 (CH), 108.86 (CH), 14.31 (CH3).
+
MS (EI): m/z (%) = 232.1 (M , 100), 204.1 (10), 178.1 (11), 177.1
(
1
10), 116 (15), 82.9 (12), 76 (5), 49 (5).
(
+
HRMS (EI): m/z calcd for C H N : 232.1000 (M ); found:
2
(3) Pellisier, H. Tetrahedron 2006, 62, 1619.
(4) Enders, D.; Grondal, C.; Hüttl, M. R. M. Angew. Chem. Int.
Ed. 2007, 46, 1570.
1
6
12
2
32.0998.
2
-(4-Methoxyphenyl)imidazo[1,2-f]phenanthridine (11b)
(5) Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G. Angew.
Chem. Int. Ed. 2006, 45, 7134.
(6) Parenty, A. D. C.; Guthrie, K. M.; Song, Y.-F.; Smith, L. V.;
Yield: 1.14 g (88%); beige powder; mp 160–161 °C; R = 0.7
f
(
EtOAc).
Burkholder, E.; Cronin, L. Chem. Commun. 2006, 1194.
7) Parenty, A. D. C.; Song, Y.-F.; Richmond, C. J.; Cronin, L.
Org. Lett. 2007, 9, 2253.
IR (KBr): 3442 (s), 3143 (w), 2939 (w), 2837 (w), 2898 (m), 1561
(
(
(
(
1
m), 1462 (s), 1436 (s), 1399 (m), 1295 (w), 1245 (s), 1033 (s), 943
w), 828 cm–1 (s).
8) Parenty, A. D. C.; Smith, L. V.; Pickering, A. L.; Long, D.
H NMR (CDCl , 400 MHz): d = 8.69 (d, J = 7.2 Hz, 1 H), 8.40 (d,
L.; Cronin, L. J. Org. Chem. 2004, 69, 5934.
3
J = 8.0 Hz, 1 H), 8.32 (d, J = 7.2 Hz, 1 H), 8.09 (s, 1 H), 7.91 (d,
J = 8.8 Hz, 2 H), 7.83 (d, J = 8.0 Hz, 1 H), 7.57 (m, 3 H), 7.44 (t,
J = 7.2 Hz, 1 H), 6.94 (d, J = 8.8 Hz, 2 H), 3.80 (s, 3 H).
(9) Parenty, A. D. C.; Smith, L. V.; Cronin, L. Tetrahedron
2005, 61, 8410.
(10) (a) Tóth, J.; Nedves, A.; Dancsó, A.; Blaskó, G.; Tke, L.;
Nyerges, M. Synthesis 2007, 1003. (b) Krauze, A.; Vitolina,
R.; Garaliene, V.; Sile, L.; Klusa, V.; Duburs, G. Eur. J.
Med. Chem. 2005, 40, 1163. (c) Fang, X.; Wu, Y. M.; Deng,
J.; Wang, S. W. Tetrahedron 2004, 60, 5487.
1
3
C NMR (CDCl , 100 MHz): d = 159.35 (C), 144.03 (C), 142.61
3
(C), 131.70 (C), 128.84 (CH), 128.58 (CH), 128.51 (CH), 127.52
(C), 127.05 (CH), 126.75 (C), 124.94 (CH), 124.45 (CH), 124.21
(C), 123.59 (C), 123.59 (C), 122.35 (CH), 121.76 (C), 115.80 (CH),
(
11) (a) Zincke, T. Justus Liebigs Ann. Chem. 1903, 330, 361.
1
14.18 (CH), 106.69 (CH), 55.36 (CH3).
(
b) Zincke, T. Justus Liebigs Ann. Chem. 1904, 333, 296.
+
MS (EI): m/z = 324.1 (M , 100), 309.1 (22), 281.1 (20), 246.1 (25),
(
c) Zincke, T.; Wurker, W. Justus Liebigs Ann. Chem. 1905,
2
4
45.1 (18), 179.1 (20), 178.1 (15), 162.1 (11), 140.1 (10), 69 (10),
4 (50).
338, 107.
(
12) Kearney, A. M.; Vanderwal, C. D. Angew. Chem. Int. Ed.
2006, 45, 7803.
+
HRMS (EI): m/z calcd for C H ON : 324.1263 (M ); found:
2
2
16
2
3
24.1264.
Synthesis 2008, No. 9, 1479–1485 © Thieme Stuttgart · New York