Facile synthesis of 3,3-dialkyl-6-phenyl-imidazopyridinones

Article abstract of DOI:10.1080/00397910701215957

A series of novel 3,3-dialkylated imidazopyridinones bearing 6-aryl groups were designed as mimetics of active progesterone antagonists, 3,3-disubstituted-5-arylindoles. The four-step synthetic route is described. The key steps are base-catalyzed cyclizat

Full text of DOI:10.1080/00397910701215957

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Facile Synthesis of
3,3‐Dialkyl‐6‐phenyl‐imidazopyridinones
Weiqin Jiang a , James J. Fiordeliso a & Zhihua Sui a
a Johnson & Johnson Pharmaceutical Research and Development L.L.C. ,
Drug Discovery , Raritan, New Jersey, USA
Published online: 12 Apr 2007.
To cite this article: Weiqin Jiang , James J. Fiordeliso & Zhihua Sui (2007) Facile Synthesis of
3,3‐Dialkyl‐6‐phenyl‐imidazopyridinones, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 37:8, 1237-1249, DOI: 10.1080/00397910701215957
To link to this article: http://dx.doi.org/10.1080/00397910701215957
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Synthetic Communicationsw, 37: 1237–1249, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701215957
Facile Synthesis of 3,3-Dialkyl-6-phenyl-
imidazopyridinones
Weiqin Jiang, James J. Fiordeliso, and Zhihua Sui
Johnson & Johnson Pharmaceutical Research and Development L.L.C.,
Drug Discovery, Raritan, New Jersey, USA
Abstract: A series of novel 3,3-dialkylated imidazopyridinones bearing 6-aryl groups
were designed as mimetics of active progesterone antagonists, 3,3-disubstituted-5-ary-
lindoles. The four-step synthetic route is described. The key steps are base-catalyzed
cyclization, base-catalyzed alkylation, and Suzuki coupling reaction.
Keywords: cyclization reaction, imidazopyridinone, Suzuki coupling reaction
INTRODUCTION
A number of novel classes of nonsteroidal antiprogestins[1] have emerged
during the past several years, aimed at improving the side-effect profile
inherent with steroidal antiprogestins and exploring therapeutic opportunities
other than abortifacients, such as the treatment of breast cancer, endometrio-
sis, uterine fibroids and, contraceptive agents.
Nonsteroidal progesterone receptor antagonists, 3,3-disubstituted-5-ary-
loxindoles 1, were reported to be active in blocking progesterone-induced
alkaline phosphatase in the human breast-cancer cell line T47D.[2] The
structure–activity study showed that small alkyl and spiroalkyl groups R
are required to achieve better progesterone receptor (PR) antagonist
activity. We now report the syntheses of a series of imidazopyridinone
analogs 2 to mimic compound 1 (Fig. 1).
Received in the USA October 2, 2006
Address correspondence to Weiqin Jiang, Johnson & Johnson Pharmaceutical
Research and Development L.L.C., Drug Discovery, 1000 Route 202, Raritan, NJ
08869. E-mail: wjiang1@prdus.jnj.com
1237

1238
W. Jiang, J. J. Fiordeliso, and Z. Sui
Figure 1. Structure of arylindoles and imidazopyridinones.
To the best of our knowledge, imidazopyridinones, bearing dialkyl groups
at 3-position and an aromatic ring at 6-position, were never synthesized
before.[3] In the course of our ongoing program related to the synthesis and
the biological evaluation of progesterone receptor modulators, an efficient
and straightforward route has been developed for the synthesis of compound 2.
CHEMISTRY
The method reported by Argade[4] was first tried, where the key cyclization
step is the SN2 reaction of pyridine nitrogen to bromide adjacent to an
amide carbonyl group. However, although it works for the secondary
bromide in Argade’s report, because of the steric hindrance in tertiary
bromide 6, the cyclization step leading to desired product 7 failed, as shown
in Scheme 1.
Because the formation of the desired product involves the tertiary
bromide 6, we adopted a reaction condition reported by Helissey et al.[5] to
take advantage of the tertiary cation as a reaction intermediate. As shown in
Scheme 2, despite of the contamination of a significant amount of 11, the
desired product 10 was isolated. According to the mechanism in Scheme 3,
the formation of the side product 11 occurred because of the use of the
solvent ethanol. By changing the solvent from ethanol to a mixture of water
and dioxane, the undesired side product 11 was eliminated and the desired
product 10 was isolated in 47% yield.
Several attempts were taken to convert alcohol 10 to ketone 7. Compound
10 was first subjected to Swern oxidation conditions [Me2S(O), (COCl)2], but
the desired oxidized product 7 was not detected. When compound 10 was
Scheme 1. (i) PBr3, Br2, 708C, 17 h, 75%; (ii) (COCl)2, then 5-bromo-pyridin-2-yla-
mine 5; 40%; and (iii) a) MeLi or b) nBuLi.

3,3-Dialkyl-6-phenyl-imidazopyridinones
1239
Scheme 2. (i) Br2, NaHCO3, quantitative; (ii) 5-bromo-pyridin-2-ylamine 5, EtOH,
Et3N; (iii) 5-bromo-pyridin-2-ylamine 5, H2O, 1,4-dioxane, Et3N, 47%; and (iv)
Dess–Martin oxidation, 22%.
subjected to Dess–Martin oxidation conditions, the desired product 7 was
isolated in 22% with a significant contamination of some side products, as
shown in Scheme 2.
Finally, the third route turned out to be feasible to preparing the target
compound 2. As shown in Fig. 2, compound 15 was prepared via quaterniza-
tion of pyridine nitrogen.[6] Because of the electron-deficiency caused by the
pyridine ring and the electron-withdrawing substituent Br, N-alkylation of
aminopyridine 5 is comparatively difficult. Thus, as shown in Scheme 4,
refluxing for an extended period of time (16 h) is required to generate
compound 18 with excellent purity in large quantities. Condensations
between a keto or aldehyde group and an active amino group in many pyridi-
nium salts under basic conditions have been established,[7] but the similar par-
ticipation of an ester group instead of the keto or aldehyde group is less well-
known. Cyclization of compound 18 via intramolecular aminolysis under
basic conditions (NaOMe) generated pyridine imidazole 19. An alternate
basic condition (KOH/EtOH)[8] provided the product 19 in a lower yield.
For the structure of 16 in Fig. 2, an aromatic enol structure, such as 17, is
possible. However, the aromatic imidazopyridinol structure 20, in Fig. 2,
1
was excluded by comparison of the H NMR spectral data of 19 with those
of known 3-methylene-2,3-dihydroindolizin-2-ones and indolizin-2-ol
Scheme 3.

1240
W. Jiang, J. J. Fiordeliso, and Z. Sui
Figure 2. Structures of pyridine imidazoles and their tautomeric enol forms.
derivatives.[8] For example, the 1H NMR spectra exhibited a two-proton
singlet at d 4.52, due to an active methylene in 19. The chemical shift (d
4.52) of the unsaturated ring proton in 19 was obviously higher than those
(less than d 6.50) of indolizin-2-ol derivatives.[8]
However, the synthesis of compound 19 on a large scale results in a low
yield. This is consistent with the literature-reported yield (3%) for simple 2,3-
dihydroindolizin-2-one 16 systems.[8] It was also found that compound 19 was
unstable under basic conditions for an extended period of time because of the
deprotonation of hydrogens adjacent to the carbonyl group. This is also
consistent with the literature report that compound 16 is stable in the cold
or in ethanol but decomposes rapidly in chloroform or on standing at room
temperature. We found that the reaction time of the cyclization step is
crucial for an acceptable yield. Installation of a gem-dimethyl, cyclopentane,
or cyclohexane group was realized by treating compound 19 with NaOMe and
alkyl iodide.[2b] We developed a protocol to combine the cyclization and alky-
lation steps; thus compound 23 could be generated from compound 18 in one
pot (18 ! 23). Compared to the two-step sequences (18 ! 19 ! 23), the
yield decreased slightly, and the reaction is more difficult to monitor by
thin-layer chromatography (TLC). The instability of compound 18 under
basic conditions might also contribute to the low yield for the alkylation
step (18 ! 23). In addition, as shown in Scheme 5, it was discovered that
alkylation on a simpler system, imidazo[1,2-a]pyridin-2-one 21, proceeded
Scheme 4. Reagents and conditions: (a) a-bromo-acetic acid ethyl ester, 64%; (b)
NaOMe, 15%; (c) NaOMe, 2 eq. RI, 25–50%; (d) Pd(PPh3)4, ArB(OH)2, K2CO3.
58%–80%.

3,3-Dialkyl-6-phenyl-imidazopyridinones
1241
Scheme 5.
with higher yield (65%) to generate compound 22. This indicates that the
chemical property of bromide 19 is similar to that of vinyl bromide, which
is less stable than aromatic bromide under basic conditions.
Finally, a Suzuki coupling reaction provided the target compounds 24, 25,
and 26 (see Table 1 for yield). In the literature, there are only limited examples
of Suzuki coupling reactions involving bromoenamines.[9] It is well estab-
lished that oxidative addition is often the rate-determining step in the
catalytic cycle of a Suzuki reaction.[10] Aryl and 1-alkenyl halides activated
by the proximity of electron-withdrawing groups are more reactive to the
oxidative addition than those with electron-donating groups. The reported
enamine is connected with an electron-withdrawing CF3,[9] which should
activate the halide. Consistent with the chemical property of bromide 19,
because of the sp3 configuration of the nitrogen atom in the six-membered
ring, compound 23 is chemically eqivalent to a bromoenamine connected
with an acetamide via a carbon–carbon double bond. So, the reactivity of
23 should be similar as the reported bromoenamine.[9] As a result, both deac-
tivated boronic acids (precursors for 24c, 26c) bearing electron-donating
groups and activated boronic acids (precursors for 24a, 24b, 24d, 24e, 24f,
Table 1. Synthesis of 6-aryl 3,3-gem-dimethyl or spiral imidazopyridinones 30, 31,
and 32
Comp
R, R
Ar
Yield (%)
24a
24b
24c
24d
24e
24f
Dimethyl
Dimethyl
3-Cl-phenyl
67
73
54
72
65
75
73
60
58
58
80
71
65
67
3-CF3-phenyl
3-MeO-phenyl
3-F-phenyl
Dimethyl
Dimethyl
Dimethyl
Dimethyl
Dimethyl
2,4-di-F-phenyl
3,5-di-CF3-phenyl
3,5-di-F-phenyl
3-Cl-phenyl
24g
25a
25b
25c
25d
26a
26b
26c
Spirocyclopentane
Spirocyclopentane
Spirocyclopentane
Spirocyclopentane
Spirocyclohexane
Spirocyclohexane
Spirocyclohexane
3-F-phenyl
3, 4-di-Cl-phenyl
3,5-di-CF3-phenyl
3-Cl-phenyl
3-CF3-phenyl
3-MeO-phenyl

1242
W. Jiang, J. J. Fiordeliso, and Z. Sui
24g, etc.) bearing electron-withdrawing groups gave good yields of coupling
products in the Suzuki reaction within a similar amount of reaction time. It is
known that a very wide range of palladium(0) catalysts, such as PdCl2(PPh3)2
and Pd(OAc)2/PPh3, can be used for Suzuki reactions. Pd(PPh3)4 is chosen
because of its stability to air and ease of handling. Inorganic bases, such as
K2CO3, K3PO4, KOH, or NaOtBu, are necessary for the Suzuki reaction, in
order to accelerate the transmetalation of aryl group from boron to
palladium by quaternizing the boron with negatively charged anion from
bases. The most commonly used base, K2CO3, was employed here. In
Table 1, the yields for the Suzuki coupling reaction are slightly lower than
what was reported by the literature [89–96%, Pd(PPh3)4, NaOH/benzene].[9]
In summary, a novel series of dialkylated imidazopyridinone compounds
were prepared by cyclization reaction under basic conditions, followed by
anionic alkylation to provide the C3 substitution, and then by Suzuki
coupling reaction to install the C6 aromatic ring. These compounds only
showed weak activities as progesterone receptor antagonists. Future work to
utilize this methodology to access other substituted imidazopyridinones,
aiming at improving the biological activities, is in progress.
EXPERIMENTAL
General Information for Chemistry
NMR spectra were obtained at 400 MHz and 300 MHz on Brucker Avance
300 and Avance 400 spectrometers. Chemical shifts are reported in ppm
downfield from TMS as an internal standard. Thin-layer chromatography
(TLC) was carried out using 2.5 ꢀ 7.5-cm silica gel 60 (250-mM-layer)
plates with UV detection. Magnesium sulfate was employed to dry organic
extracts prior to concentration by rotary evaporation. Flash chromatography
was done using EM science silical gel 60 (230–400 mesh). Standard
solvents from J. T. Baker were used as received. Anhydrous solvents from
J. T. Baker or Aldrich and all other commercially available reagents were
used without further purification. Mass spectra were obtained on a Hewlett-
Packard 5989A quadrupole mass spectrometer. Silica gel (E. Merck, 230–
400 mesh) was used for all flash chromatography. TLC was performed on
Analtech silica-gel GF prescored plates (250 mm). High pressure liquid chro-
matograph (HPLC) analysis was carried out on Agilent 1100 Series LC/MSD
equipment.
2-Amino-5-bromo-1-ethoxycarbonylmethyl-pyridinium Bromide (18)
2-Amino-5-bromopyridine (10.88 g, 62.9 mmol) was dissolved in acetone
(65 mL). Ethyl bromoacetate (7.7 mL, 69.2 mmol) to this solution was
added. The solution was heated to reflux overnight under nitrogen. The

3,3-Dialkyl-6-phenyl-imidazopyridinones
1243
reaction mixture was cooled, and an off-white solid was obtained by filtration.
The solid was washed with acetone, then dried to provide the title compound
as an off-white solid (13.74 g, 64%). 1H NMR (DMSO-d6) d 8.91 (s, 2H), 8.42
(d, J ¼ 2.2 Hz, 1H), 8.09 (dd, J ¼ 2.2 and 9.5 Hz, 1H), 7.10 (d, J ¼ 9.5 Hz,
1H), 5.11 (s, 2H), 4.21 (q, J ¼ 7.1 and 14.2, 2H), 1.26 (t, J ¼ 7.1, 3H); MS
(m/e): 259 (MHþ).
6-Bromo-imidazo[1,2-a]pyridin-2-one (19)
To a solution of 2-amino-5-bromo-1-ethoxycarbonylmethyl-pyridinium
bromide 18 (0.11 g, 0.323 mmol) in methanol (2 mL), sodium methoxide
(25 wt%, 0.090 g, 0.417 mmol) was added. The reaction mixture was stirred
at room temperature under nitrogen. The process was closely monitored by
HPLC-MS. As soon as HPLC showed no more product was formed, the
reaction mixture was immediately quenched with water and then extracted
three times with ethyl acetate. The organic extracts were washed with brine,
dried, filtered, and evaporated to yield a tan solid. The crude material was
purified by column chromatography, eluting with 3–10% methanol/dichloro-
1
methane, to afford the product as a brown solid (12 mg, 15%). H NMR
(CDCl3) d 7.85 (s, 1H), 7.67 (dd, J ¼ 1.6, 9.5 Hz, 1H), 7.07 (d, J ¼ 9.5 Hz,
1H), 4.52 (s, 2H); MS (m/e): 215 (MHþ); HRMS: calcd. MHþ for
C7H5BrN2O 212.9672; found 212.9664.
6-Bromo-3,3-dimethyl-imidazo[1,2-a]pyridin-2-one (23a)
A solution of 2-amino-5-bromo-1-ethoxycarbonylmethyl-pyridinium bromide
18 (6.11 g, 17.97 mmol) in 100 mL of ethanol was prepared, followed by the
addition of sodium ethoxide (21 wt%, 20.5 mL, 54.9 mmol). After 1 h, iodo-
methane was added (2.3 mL, 37.7 mmol), and the reaction was stirred at room
temperature overnight. The solvent was evaporated, and the residue was taken
up in dichloromethane. The mixture was filtered, and the filtrate was concen-
trated and purified by column chromatography, eluting with 5% methanol/
1
dichloromethane. The product was obtained as a tan solid (1.07 g, 25%). H
NMR (CDCl3) d 7.73 (s, 1H), 7.67 (dd, J ¼ 1.8 and 9.4 Hz, 1H), 7.13
(d, J ¼ 9.4 Hz, 1H), 1.59 (s, 6H); MS (m/e): 241 (MHþ); HRMS: calcd.
MHþ for C9H9BrN2O 240.9976; found 240.9979.
6-Bromo-3,3-spiro[cyclopentane]-imidazo[1,2-a]pyridin-2-one (23b)
6-Bromo-imidazo[1,2-a]pyridin-2-one 19 (0.211 g, 1.0 mmol), NaOMe (25%
in MeOH, 0.26 g, 1.2 mmol), was stirred in MeOH (5.0 mL). 1,4-Diiodobu-
tane (0.310 g, 1.0 mmol) was added slowly. This was stirred at ambient

1244
W. Jiang, J. J. Fiordeliso, and Z. Sui
temperature for 16 h. The reaction mixture was diluted with water and then
extracted three times with ethyl acetate. The organic extracts were washed
with brine, dried, filtered, and evaporated to yield a tan solid. The crude
material was purified by column chromatography, eluting with 5%
methanol/dichloromethane, to afford a white solid (20 mg, 20%). Several
runs with different scales were carried out, and the best yield was 50%. Mp
192.0–193.08C (decomp.); 1H NMR (CDCl3) d 7.68 (s, 1H), 7.62
(d, J ¼ 12.0 Hz, 1H), 7.04 (d, J ¼ 12.0 Hz, 1H), 2.52–1.83 (m, 8H); MS
(m/e): 267(MHþ); HRMS: calcd. MHþ for C11H11BrN2O 267.0133; found
267.0125.
6-Bromo-3,3-spiro[cyclohexane]-imidazo[1,2-a]pyridin-2-one (23c)
A solution of 2-amino-5-bromo-1-ethoxycarbonylmethyl-pyridinium bromide
18 (4.66 g, 13.70 mmol) in 80 mL of ethanol was prepared followed by
sodium ethoxide (21 wt%, 15.4 mL, 41.11 mmol). After 1 h, 1,5-diiodopen-
tane was added (2.2 mL, 15.07 mmol), and the reaction was allowed to
proceed overnight. The reaction mixture was diluted with water and then
extracted three times with ethyl acetate. The organic extracts were washed
with brine, dried, filtered, and evaporated to yield a tan solid. The
crude material was purified by column chromatography, eluting with
5% methanol/dichloromethane, to afford an orange solid (1.15 g, 30%).
1H NMR (CDCl3) d 7.73 (d, J ¼ 1.8 Hz, 1H), 7.63 (dd, J ¼ 2.2 and
9.4 Hz, 1H), 7.07 (d, J ¼ 9.0 Hz, 1H), 2.35–2.24 (m, 2H), 2.01–1.96
(m, 2H), 1.88–1.81 (m, 1H), 1.75–1.64 (m, 4H), 1.46–1.37 (s, 1H);
MS (m/e): 281(MHþ); HRMS: calcd. MHþ for C12H13BrN2O 281.0289;
found 281.0292.
6-(3-Chloro-phenyl)-3,3-dimethyl-imidazo[1,2-a]pyridin-2-one (24a)
To a round-bottom flask, 6-bromo-3,3-dimethyl-imidazo[1,2-a]pyridin-2-one
23a (60 mg, 0.25 mmol), 3-chlorophenylboronic acid (39 mg, 0.25 mmol),
potassium carbonate (69 mg, 0.25 mmol), Pd(PPh3)4 (29 mg, 0.025 mmol),
dioxane (5 mL), and water (1 mL) were added. The mixture was heated at
reflux until the starting material was consumed. The solution was cooled,
and water was added. The reaction mixture was extracted twice with ethyl
acetate, and the combined organic layers were dried, filtered, and concen-
trated. The residue was purified by column chromatography, eluting with
5% methanol/dichloromethane, to provide the desired product as an off-
white solid (43 mg, 63%). Mp 191.0–192.08C; 1H NMR (CDCl3) d7.84
(dd, J ¼ 1.8 and 9.1 Hz, 1H), 7.74 (s, 1H), 7.46–7.27 (m, 5H), 1.64 (s, 6H);
MS (m/e): 273 (MHþ); HRMS: calcd. MHþ for C15H13ClN2O 273.0794;
found 273.0800.

3,3-Dialkyl-6-phenyl-imidazopyridinones
1245
3,3-Dimethyl-6-(3-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridin-
2-one (24b)
The title product was prepared in 73% yield as an off-white solid according to
the procedure described for compound 24a, using 6-bromo-3,3-dimethyl-
imidazo[1,2-a]pyridin-2-one 23a and 3-trifluoromethylphenyl boronic acid
1
as starting material. H NMR (CDCl3) d 7.86 (dd, J ¼ 2.1 and 9.2 Hz, 1H),
7.76 (s, J ¼ 1.5 Hz, 1H), 7.70–7.61 (m, 4H), 7.30 (d, J ¼ 9.2, 1H), 1.65
(s, 6H); MS (m/e): 307 (MHþ); HRMS: calcd. MHþ for C16H13F3N2O
307.1058; found 307.1052.
6-(3-Methoxy-phenyl)-3,3-dimethyl-imidazo[1,2-a]pyridin-2-one (24c)
The title compound was prepared in 54% yield according to the
procedure described for compound 24a, starting from 23a and 3-meth-
oxyphenyl boronic acid. 1H NMR (CDCl3) d 7.86 (dd, J ¼ 2.1 and
9.2 Hz, 1H), 7.73 (d, J ¼ 1.5 Hz, 1H), 7.43–7.39 (m, 1H), 7.28–7.25
(m, 1H), 7.05 (m, 1H), 6.97–6.94 (m, 2H), 3.88 (s, 3H), 1.63 (s, 6H);
MS (m/e): 269 (MHþ); HRMS: calcd. MHþ for C16H16N2O2 269.1290;
found 269.1296.
6-(3-Fluoro-phenyl)-3,3-dimethyl-imidazo[1,2-a]pyridin-2-one (24d)
The title compound was prepared in 72% yield according to the procedure
described for compound 24a, starting from 23a and 3-fluorophenyl boronic
1
acid. Mp 183.0–184.08C; H NMR (CDCl3) d 7.84 (dd, J ¼ 2.1 and 9.2 Hz,
1H), 7.75 (d, J ¼ 1.6 Hz, 1H), 7.49–7.43 (m, 1H), 7.29–7.24 (m, 2H),
7.19–7.10 (m, 2H), 1.64 (m, 6H); MS (m/e): 257 (MHþ); HRMS: calcd.
MHþ for C15H13FN2O 257.1090; found 257.1084.
6-(2,4-Difluoro-phenyl)-3,3-dimethyl-imidazo[1,2-a]pyridin-2-one (24e)
The title product was prepared in 65% yield as a white solid according to the
procedure described for compound 24a, using 23a and 2,4-di-fluorophenyl
1
boronic acid as starting material. Mp 200.0–201.08C; H NMR (CDCl3) d
7.78–7.74 (m, 2H), 7.37 (m, 1H), 7.28–7.26 (m, 1H), 7.05–6.95 (m, 2H),
1.62 (s, 6H); MS (m/e): 275 (MHþ); HRMS: calcd. MHþ for C15H12FN2O
275.0996; found 275.1008.

1246
W. Jiang, J. J. Fiordeliso, and Z. Sui
6-(3,5-Bis-trifluoromethyl-phenyl)-3,3-dimethyl-imidazo[1,2-
a]pyridin-2-one (24f)
The title compound was prepared in 75% yield according to the procedure
described for compound 24a, starting from 23a and 3,5-di-trifluoromethylphe-
nyl boronic acid. Mp 229.0–230.08C; 1H NMR (CDCl3) d 7.93–7.91 (m, 3H),
7.88–7.86 (m, 2H), 7.33 (dd, J ¼ 1.8 and 8.4 Hz, 1H), 1.67 (s, 6H); MS (m/
e): 375 (MHþ); HRMS: calcd. MHþ for C17H12F6N2O 375.0932; found
375.0933.
6-(3,5-Difluoro-phenyl)-3,3-dimethyl-imidazo[1,2-a]pyridin-2-one (24g)
The title product was prepared in 73% yield as a yellow solid according to the
procedure described for compound 24a, using 23a and 3,5-difluorophenyl
1
boronic acid as starting material. Mp 182.0–183.08C; H NMR (CDCl3) d
7.81 (dd, J ¼ 2.1 and 9.2 Hz, 1H), 7.77 (d, J ¼ 1.4 Hz, 1H), 7.29 (d, J ¼
0.6 Hz, 1H), 7.02–6.98 (m, 2H), 6.90–6.84 (m, 1H), 1.64 (s, 6H); MS (m/e):
275(MHþ); HRMS: calcd. MHþ for C15H12FN2O 275.0996; found 275.1009.
6-(3-Chloro-phenyl)-3,3-spiro[pentane]-imidazo[1,2-a]pyridin-2-
one (25a)
The title compound was prepared in 60% yield according to the procedure
described for compound 24a, starting from 6-bromo-3,3-spiro[cyclopenane]-
imidazo[1,2-a]pyridin-2-one 23b and 3-chlorophenyl boronic acid. Mp
1
201.0–202.08C; H NMR (CDCl3) d 7.80 (dd, J ¼ 2.1 and 9.2 Hz, 1H),
7.73 (d, J ¼ 1.6 Hz, 1H), 7.45–7.39 (m, 3H), 7.34–7.31 (m, 1H), 7.25–
7.23 (m, 1H), 2.53–2.48 (m, 2H), 2.20–2.16 (m, 2H), 2.05–1.94 (m, 4H);
MS (m/e): 299 (MHþ); HRMS: calcd. MHþ for C17H15ClN2O 299.0951;
found 299.0945.
6-(3-Fluoro-phenyl)-3,3-spiro[pentane]-imidazo[1,2-a]pyridin-2-
one (25b)
The title compound was prepared in 58% yield according to the procedure
described for compound 24a, starting from 23b and 3-fluorophenyl boronic
1
acid. Mp 193.0–194.08C; H NMR (CDCl3) d 7.81 (dd, J ¼ 2.0 and 9.1 Hz,
1H), 7.74 (d, J ¼ 1.8 Hz, 1H), 7.49–7.43 (m, 1H), 7.27–7.22 (m, 2H),
7.17–7.10 (m, 2H), 2.54–2.48 (m, 2H), 2.21–2.14 (m, 2H), 2.08–1.94
(m, 4H); MS (m/e): 283 (MHþ); HRMS: calcd. MHþ for C17H15FN2O
283.1246; found 283.1242.

3,3-Dialkyl-6-phenyl-imidazopyridinones
1247
6-(3,4-Dichloro-phenyl)-3,3-spiro[pentane]-imidazo[1,2-a]pyridin-
2-one (25c)
The title compound was prepared in 58% yield according to the procedure
described for compound 24a, starting from 6-bromo-3,3- spiro[cyclope-
nane]-imidazo[1,2-a]pyridin-2-one 23b and 3, 4-dichloro-phenyl boronic
1
acid. Mp 263.0–264.08C; H NMR (CDCl3) d 7.77 (dd, J ¼ 2.1 and 9.2 Hz,
1H), 7.72 (m, 1H), 7.57–7.53 (m, 2H), 7.30–7.23 (m, 2H), 2.53–2.47
(m, 2H), 2.21–2.14 (m, 2H), 2.08–1.94 (m, 4H); MS (m/e): 331 (MH2);
HRMS: calcd. MHþ for C17H14Cl2N2O 333.0561; found 333.0569.
6-(3,5-Bis-trifluoromethyl-phenyl)-3,3-spiro[pentane]-imidazo[1,2-
a]pyridin-2-one (25d)
The title compound was prepared in 80% yield according to the procedure
described for compound 24a, starting from 23b and 3,5-bis-trifluoromethyl-
1
phenyl boronic acid. H NMR (CDCl3) d 7.93 (s, 1H), 7.88 (s, 2H), 7.84–
7.79 (m, 2H), 7.30–7.28 (m, 1H), 2.54–2.48 (m, 2H), 2.23–2.16 (m, 2H),
2.09–1.97 (m, 4H); MS (m/e): 401 (MHþ); HRMS: calcd. MHþ for
C19H14F6N2O 401.1088; found 401.1094.
6-(3-Chloro-phenyl)-3,3-spiro[cyclohexane]-imidazo[1,2-a]pyridin-
2-one (26a)
The title compound was prepared in 71% yield according to the procedure
described for compound 24a, starting from 6-bromo-3,3- spiro[cyclohepane]-
1
imidazo[1,2-a]pyridin-2-one 23c and 3-chloro-phenyl boronic acid. H NMR
(CDCl3) d 7.81 (dd, J ¼ 2.1 and 9.2 Hz, 1H), 7.76 (d, J ¼ 1.4, 1H), 7.45–
7.33 (m, 3H), 7.25–7.23 (m, 2H), 2.40–2.30 (m, 2H), 2.05–2.00 (m, 2H),
1.91–1.86 (m, 1H), 1.78–1.71 (m, 4H), 1.49–1.42 (m, 1H); MS (m/e): 313
(MHþ); HRMS: calcd. MHþ for C18H17ClN2O 313.1108; found 313.1109.
6-(3-Trifluoromethyl-phenyl)-3,3-spiro[cyclohexane]-imidazo[1,2-
a]pyridin-2-one (26b)
The title compound was prepared in 65% yield according to the
procedure described for compound 24a, starting from 23c and 3-trifluoro-
methyl–phenyl boronic acid. 1H NMR (CDCl3) d 7.84 (dd, J ¼ 2.2 and
9.2 Hz, 1H), 7.78 (d, J ¼ 1.4 Hz, 1H), 7.69–7.62 (m, 4H), 7.28–7.25
(m, 1H), 2.39–2.32 (m, 2H), 2.05–2.00 (m, 2H), 1.91–1.86 (m, 1H), 1.80–
1.71 (m, 4H), 1.47–1.43 (m, 1H); MS (m/e): 347 (MHþ); HRMS: calcd.
MHþ for C19H17F3N2O 347.1371; found 347.1365.

1248
W. Jiang, J. J. Fiordeliso, and Z. Sui
6-(3-Methoxy-phenyl)-3,3-spiro[cyclohexane]-imidazo[1,2-
a]pyridin-2-one (26c)
The title compound was prepared in 67% yield according to the procedure
described for compound 24a, starting from 23c and 3-methoxy-phenyl
1
boronic acid. Mp 187.0–188.08C; H NMR (CDCl3) d 7.83 (dd, J ¼ 2.1
and 9.2 Hz, 1H), 7.77 (d, J ¼ 1.4 Hz, 1H), 7.40–7.38 (m, 1H), 7.24–7.22
(m, 1H), 7.04–7.02 (m, 1H), 6.97–6.95 (m, 2H), 3.88 (s, 3H), 2.40–2.30
(m, 2H), 2.05–2.00 (m, 2H), 1.92–1.80 (s, 1H), 1.77–1.68 (m, 4H), 1.50–
1.38 (m, 1H); MS (m/e): 309 (MHþ); HRMS: calcd. MHþ for C19H20N2O2
309.1603; found 309.1606.
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