Synthesis of substituted imidazo[1,2-h][1,7]naphthyridines as H +/K+-ATPase inhibiting drug precursors via directed ortho-metalation of imidazo[1,2-a]pyridines

Article abstract of DOI:10.1055/s-2008-1067264

Selective directed ortho-metalation (DOM) of 2,3-dimethyl-8-(pivaloylamino) imidazo[1,2-a]pyridine in the 7-position was achieved with tert-butyllithium. Subsequent reaction of the lithiated derivative with tributylchlorostannane to the corresponding 7-tr

Full text of DOI:10.1055/s-2008-1067264

PAPER
3065
Synthesis of Substituted Imidazo[1,2-h][1,7]naphthyridines as
H+/K+-ATPase Inhibiting Drug Precursors via Directed ortho-Metalation
of Imidazo[1,2-a]pyridines
Synthesis
ö
of Substitute
r
d
Imidaz
g
onaphthyridines vi
S
a
D
O
M
enn-Bilfinger,* Bernhard Kohl, Georg Rainer, Wilm Buhr, Hans Christof Holst, Peter Jan Zimmermann
ALTANA Pharma AG, now Nycomed GmbH, Byk-Gulden-Str.2, 78467 Konstanz, Germany
Fax +49(7531)8492505; E-mail: joerg.senn-bilfinger@nycomed.com
Received 28 May 2008
side reactions due to the lowered nucleophilicity of the
pyridine nitrogen. Therefore, we decided to introduce the
7-substituent in 2 via DOM at a later stage in the synthe-
sis, when the imidazo[1,2-a]pyridine core had already
Abstract: Selective directed ortho-metalation (DOM) of 2,3-di-
methyl-8-(pivaloylamino)imidazo[1,2-a]pyridine in the 7-position
was achieved with tert-butyllithium. Subsequent reaction of the
lithiated derivative with tributylchlorostannane to the correspond-
ing 7-trialkylstannyl analogue and palladium-catalyzed Stille acyla- been elaborated. Since earlier reports on the metalation of
tion with 3-arylpropenoic acid chlorides in the presence of lithium
chloride gave the corresponding 7-acylated imidazopyridines in
good yields. Cyclization to the target imidazonaphthyridines, which
recting group,6 and is also assisting in the cyclization re-
are precursors in the synthesis of gastric H+/K+-ATPase inhibiting
drugs, was achieved by treatment with strong acid. For scaled-up
aminopyridines demonstrated that the pivaloylamino
(2,2-dimethylpropanoylamino) group is a useful ortho-di-
action to the imidazo[1,2-a]pyridine, we envisioned the
readily available 8-(pivaloylamino)imidazo[1,2-a]pyri-
dine 3 as a suitable starting point. The introduction of a 7-
trialkylstannyl group by DOM reaction of imidazo[1,2-
a]pyridine 3 would then allow further Stille cross-
coupling reactions with substituted cinnamoyl chlorides,
giving access to various 7-acyl-substituted imidazo[1,2-
a]pyridines 2 (Scheme 1, route b).7,8
production of 2,3-dimethyl-9-phenyl-9,10-dihydroimidazo[1,2-
h][1,7]naphthyridin-7(8H)-one, a tin-free process has been devel-
oped. Accordingly, the 7-lithiated 2,3-dimethyl-8-(pivaloyl-
amino)imidazo[1,2-a]pyridine was reacted directly with
cinnamaldehyde and the resultant alcohol oxidized with manganese
dioxide to give the unsaturated 7-acylated imidazopyridine.
Key words: cyclizations, directed ortho-metalation, H+/K+-
ATPase, lithiation, Stille reaction
N
N
R
b
Directed ortho-metalation (DOM) is one of the most pow-
erful and versatile methods for the rapid synthesis of poly-
functionalized compounds in synthetic organic
chemistry.1 In connection with palladium-catalyzed
cross-coupling reactions, this methodology has also vastly
enlarged the chemical arsenal of synthetic methods en
route to highly functionalized aromatic and heteroaromat-
ic compounds with high diversity in medicinal chemistry.2
In this account, we report on the use of the DOM reaction
and subsequent Stille cross-coupling reaction as key steps
in the synthesis of side-chain rigidized 9-arylimida-
zonaphthyridines 1.3 These derivatives were targeted as
precursors for the synthesis of H+/K+-ATPase inhibiting
compounds to be developed as gastric antisecretory drugs.
The retrosynthetic analysis depicted in Scheme 1 reveals
that the target structure 1 may be derived by cyclization of
7-(prop-2-enoyl)imidazo[1,2-a]pyridine 2, analogously to
known procedures for the preparation of quinolones.4 The
general route towards substituted imidazo[1,2-a]pyridines
comprises the condensation of appropriately substituted
2-aminopyridines with a-halocarbonyl compounds.5
However, the starting 4-acyl-2,3-diaminopyridines are
not easily accessible by conventional methods (Scheme 1,
route a). Furthermore, these are prone to a multitude of
O
O
N
N
a
NH
HN
Ar
Ar
1. DOM
1
2
2. Stille cross
coupling
b
a
N
R
O
N
N
NH2
HN
Ar
HN
3
O
Scheme 1 Retrosynthetic analysis of 1
Thus, reaction of commercially available 2-nitropyridin-
3-amine (4) with pivaloyl chloride in the presence of tri-
ethylamine provided the 3-(pivaloylamino) derivative 5,
which was hydrogenated to give the protected diaminopy-
ridine 6. Subsequent condensation with 3-chlorobutan-2-
one and basic workup of the precipitated hydrochloride
3·HCl led to 8-(pivaloylamino)imidazo[1,2-a]pyridine 3
in high overall yield (Scheme 2).
Having obtained the 8-(pivaloylamino)imidazo[1,2-a]py-
ridine 3, the sequence of DOM and subsequent reaction of
the lithiated intermediate with tributylchlorostannane was
investigated. In a first approach, the imidazo[1,2-a]pyri-
dine 3 was reacted with n-butyllithium (3 equiv) com-
SYNTHESIS 2008, No. 19, pp 3065–3070
x
x.
x
x
.
2
0
0
8
Advanced online publication: 05.09.2008
DOI: 10.1055/s-2008-1067264; Art ID: Z12608SS
© Georg Thieme Verlag Stuttgart · New York

3066
J. Senn-Bilfinger et al.
PAPER
N
N
N
O
N
NO2
O
NH2
O
N
i
ii
iii
NO2
NH2
HN
HN
HN
4
5
6
3
Scheme 2 Reagents and conditions: (i) t-BuCOCl, Et3N, toluene, reflux, 3.5 h; (ii) H2, 5% Pd/C, MeOH, 40 °C, 5 h; (iii) 1. 3-chlorobutan-
2-one, toluene, reflux, 6 h; 2. concd NH3, H2O, r.t., 69% from 4.
plexed by N,N,N¢,N¢-tetramethylethylenediamine (3 tetrahydrofuran at –75 °C and the resulting solution was
equiv)6b at –78 °C followed by addition of tributylchlo- subsequently quenched with deuterium oxide. The analy-
rostannane at 0 °C. After one hour at room temperature, a sis of the crude reaction product by 1H NMR spectroscopy
1:1 mixture of the 5- and 7-tributylstannyl derivatives 7 revealed that the deprotonation had occurred unselective-
and 8 was obtained, along with a large amount (50%) of ly in the 5- and 7-positions of 3 giving rise to a 1:1 mixture
unreacted starting material 3 (Scheme 3, condition A). of the 5- and 7-deuterated derivative together with various
Further attempts to increase the conversion of 3 by ex- bis(deuterated) products. On the other hand, when diethyl
tending the reaction time after the addition of n-butyllith- ether was used instead of tetrahydrofuran, deprotonation
ium or by running the reaction at higher temperature again occurred predominantly in the 7-position of 3 to
proved unsuccessful. However, when the metalation of give a 4:1 mixture of the 7- and 5-deuterated derivative,
compound 3 was carried out with tert-butyllithium (3 respectively (Scheme 4). Presumably the kinetically pre-
equiv) at –78 °C and the intermediate trapped with tribu- ferred 7-deprotonated anion is not exposed to the equilib-
tylchlorostannane, the conversion of starting material 3 rium with the thermodynamically favored 5-deprotonated
increased (90%) and the ratio of the regioisomeric stan- anion, since the former anion precipitates in diethyl ether
nanes 7 and 8 was clearly improved to 9:1 (Scheme 3, at the low reaction temperature.
condition B).
With these excellent results in hand, we began our studies
Additional experiments were conducted to investigate the on the Stille cross coupling of the 7-(tributylstannyl)imi-
influence of the solvent. Therefore, the imidazo[1,2-a]py- dazo[1,2-a]pyridine 7 with substituted cinnamoyl chlo-
ridine 3 was reacted with tert-butyllithium (2.8 equiv) in rides 9a–d (Scheme 5). Although the Stille cross-
coupling reaction of aryl- and heteroarylstannanes with
SnBu3
5
acyl chlorides has been extensively studied over the past
three decades,9 only a few examples of such reactions
N
N
N
conditions
A or B
7
with a,b-unsaturated acyl chlorides are described in the
literature.10 Initial experiments concerning the cross cou-
pling of 7-(tributylstannyl)imidazo[1,2-a]pyridine 7 with
cinnamoyl chloride 9a were carried out with dichloro-
bis(triphenylphosphine)palladium (10%) in tetrahydrofu-
ran at 50–60 °C and led to complete destannylation of the
starting material 7. Several modifications of the reaction
conditions, including change of catalysts [Pd(PPh3)4,
PdCl2(MeCN)2, PdCl2(dppf)] or solvent (toluene, NMP),
were unsuccessful. However, when bis(acetoni-
trile)dichloropalladium [PdCl2(MeCN)2, 15%] was used
as a catalyst in the presence of an excess of cinnamoyl
N
N
Bu3Sn
+
N
HN
HN
HN
O
O
O
3
7
8
Scheme 3 Reagents and conditions: (A) 1.6 M n-BuLi in hexane (3
equiv), TMEDA (3 equiv), Et2O, –78 °C to 0 °C followed by addition
of Bu3SnCl (3 equiv), 30 min, then r.t., 1 h, crude 1:1 mixture of 7 and
8; (B) 1.5 M t-BuLi in pentane (3 equiv), Et2O, –78 °C followed by
addition of Bu3SnCl (3 equiv), 1h , then r.t., overnight, crude mixture
of 7 and 8, 9:1; 7 was obtained in 41% yield.
D
5
N
N
N
i
7
N
N
+
others
+
D
N
HN
HN
HN
O
3
O
O
solvent
THF
25%
82%
23%
18%
53%
Et2O
< 3%
Scheme 4 Lithiation of 3. Reagents and conditions: 1.7 M t-BuLi in pentane (2.8 equiv), THF or Et2O, –75 °C, 15 min followed by quenching
with D2O.
Synthesis 2008, No. 19, 3065–3070 © Thieme Stuttgart · New York

PAPER
Synthesis of Substituted Imidazonaphthyridines via DOM
3067
chloride (3 equiv), the hydrochloride of the product 2a order to avoid the handling of environmentally hazardous
precipitated from the reaction mixture on cooling to yield tin organyls on large scale and contamination of the final
26% of 2a. This result prompted us to examine briefly the product with traces thereof. In fact, reaction of the lithiat-
influence of chloride being present in the reaction mixture ed derivative of compound 3 with cinnamaldehyde to the
on the conversion of starting material 7. Since it is also alcohol 10 and subsequent oxidation with manganese di-
known that added halides can strongly influence reaction oxide proved to be an alternative approach and delivered
rates and that the presence of lithium chloride is often nec- the 7-cinnamoyl-substituted imidazo[1,2-a]pyridine 2a in
essary when coupling aryl triflates in ethereal solvents,11 good yield (Scheme 6).
we added lithium chloride to the reaction mixture in order
to improve the conversion of 7. In fact, running the reac-
tion with PdCl2(MeCN)2 (10%), cinnamoyl chloride (1.1
N
N
equiv), and lithium chloride (1.1 equiv) as additive result-
ed in almost complete conversion of the starting material
7 (>90%). Under optimized reaction conditions and with
tris(dibenzylideneacetone)dipalladium [Pd2(dba)3] as cat-
alyst, the desired product 2a was isolated in 66% yield on
a multigram scale. Likewise, further substituted cin-
namoyl chlorides 9b–d were reacted with stannane 7 un-
der similar conditions as for 2a to provide the
corresponding 7-acylated compounds 2b–d in moderate
yields (Table 1).
N
HO
O
N
N
N
i
ii
HN
HN
HN
O
O
O
3
10
2a
Scheme 6 Reagents and conditions: (i) 1. 1.5 M t-BuLi in pentane,
Et2O, –78 °C; 2. PhCH=CHCHO, –78 °C, 1 h and r.t., 1 h, 60%; (ii)
MnO2, CHCl3, r.t., 16 h, 75%.
Table 1 Synthesis of Compounds 1a–d and 2a–d
The straightforward and convenient synthesis of a series
of substituted imidazonaphthyridines serving as precur-
sors of gastric H+/K+-ATPase inhibiting drugs has been
successfully worked out. Selective directed ortho-metala-
tion (DOM) of 2,3-dimethyl-8-(pivaloylamino)imida-
zo[1,2-a]pyridine 3 with tert-butyllithium and tri-
butylchlorostannane, followed by Stille cross-coupling
and acid-catalyzed cyclization of the corresponding un-
saturated 7-acyl compounds led to the highly substituted
imidazo[1,2-h][1,7]naphthyridines 1a–d. The develop-
ment of a scaled-up route for compound 1a avoiding toxic
tin organyls proved to be possible by direct reaction of the
lithiated derivative of 3 with cinnamaldehyde followed by
clean oxidation of the hydroxy function of alcohol 10. The
synthesis of enantiomerically pure analogues of 1 as well
as their conversion into highly active H+/K+-ATPase in-
hibitors, which eventually led to the discovery of the clin-
ically studied analogue Soraprazan,12 will be described in
a forthcoming full paper.
Ar
Product Yield Mp
Product Yield Mp
(%)
(°C)
(%)
69
73
41
41
(°C)
Ph
2a
2b
66
177–179 1a
158–160 1b
138–140
80–82
2-ClC6H4
4
2,6-Cl2C6H3 2c
2-CF3CC6H4 2d
a Crude yield.
50a
50a
n.d.
n.d.
1c
248–249
184–185
1d
The a,b-unsaturated acyl-substituted imidazo[1,2-a]py-
ridines 2a–d were then finally cyclized to the target com-
pounds 1a–d under acidic conditions. Thus, heating
compounds 2a–d with concentrated hydrochloric acid
(2a, 2b) or 50% sulfuric acid (2c, 2d) led to cleavage of
the pivaloylamino protective group and concomitant cy-
clization to the respective 9-arylimidazonaphthyridines
1a–d in good to moderate yields (Scheme 5, Table 1).3
Melting points were taken in open capillaries on a Büchi B-540
melting point apparatus and are uncorrected. All NMR spectra were
recorded in DMSO-d6 on a Bruker DPX 200 or Avance 400 spec-
trometer and are referenced to TMS or the 13C signal of the solvent
(d = 39.5). The 13C peak assignments are based on 2D HSQC and
Finally, we focused on the scaleup of compound 1a which
was required in multigram amounts for further modifica-
tions to form active H+/K+-ATPase inhibitors.3 For this
purpose, it was necessary to establish a tin-free process in
O
Cl
N
O
N
N
O
O
N
N
N
i
ii
Bu3Sn
+
HN
HN
NH
Ar
O
Ar
Ar
7
9a–d
2a–d
1a–d
Scheme 5 Reagents and conditions: (i) Pd2(dba)3 (7–12.5%), ArCH=CHCOCl (1–1.28 equiv), LiCl (1–1.28 equiv), THF, 60 °C; (ii) 2a, 2b:
concd HCl, 100 °C, 4 h; 2c, 2d: 50% H2SO4, 100 °C, 3–4 h; for details see experimental part.
Synthesis 2008, No. 19, 3065–3070 © Thieme Stuttgart · New York

3068
J. Senn-Bilfinger et al.
PAPER
HMBC spectra. Elemental analyses were performed on a Carlo
Erba 1106 C, H, N analyzer at the Institut für Organische Chemie,
Universität Stuttgart.
poured into H2O and extracted with Et2O (2 ×). The combined or-
ganic phases were dried (Na2SO4) and evaporated. The residue was
purified by column chromatography (light petroleum ether–EtOAc,
3:2) to give 7 (54.9 g, 41%) as an oil with a purity of 87% (1H
NMR). The product was used without further purification in the
next step.
1H NMR (200 MHz, DMSO-d6): d = 0.82–1.72 (m, 18 H, CH2), 0.85
(t, 7.2 Hz, 9 H, w-CH3) 1.30 [s, 9 H, (CH3)3], 2.30 (s, 3 H, 2-CH3),
2.36 (s, 3 H, 3-CH3), 6.77 (d, JHH = 6.6 Hz, Sn satellites: JSnH = 33.5
Hz, 1 H, H6), 7.95 (d, JHH = 6.6 Hz, Sn satellites: JSnH = 6.4 Hz, 1
H, H7), 9.12 (s, 1 H, NH)
2,2-Dimethyl-N-(2-nitropyridin-3-yl)propanamide (5)
To a suspension of 2-nitropyridin-3-amine (4, 12.0 kg, 86.3 mol) in
toluene (36 L) were successively added Et3N (14.7 L, 105 mol) and
trimethylacetyl chloride (12.8 L, 105 mol). The mixture was re-
fluxed for 3.5 h and then cooled to 25 °C and extracted with H2O
(14.4 L). The organic layer was separated, washed with H2O (14.4
L), and evaporated. Co-evaporation with MeOH (6 L) left an oily
residue of crude 5 (20.5 kg) which was used directly in the next step.
N-{2,3-Dimethyl-7-[(2E)-3-phenylprop-2-enoyl]imidazo[1,2-
a]pyridin-8-yl}-2,2-dimethylpropanamide (2a); Typical
Procedure
N-(2-Aminopyridin-3-yl)-2,2-dimethylpropanamide (6)
To a soln of crude 5 (20.5 kg) in MeOH (100 L) was added 5% Pd/
C (0.96 kg, 50 wt% in H2O) and the mixture was hydrogenated (1–
1.5 bar H2) while the inner temperature was maintained at 35–40 °C.
After complete uptake of H2, stirring was continued overnight at r.t.
The catalyst was filtered off, washed with MeOH (6 L) and the fil-
trate was evaporated. After co-evaporation with toluene (36 L), a
precipitate began to form, which was collected and washed with tol-
uene to yield 6 (10.97 kg). A second crop of the product 6 (3.7 kg)
was obtained from the mother liquor on evaporation. The combined
crude product (14.67 kg) was used directly in the next step.
To a soln of 7 (54.4 g, 87% purity, 89 mmol) in THF (0.6 L) was
added Pd2(dba)3·CHCl3 (1.0 g, 1.0 mmol) and LiCl (5.5 g, 130
mmol) under argon. A soln of cinnamoyl chloride (21.7 g, 130
mmol) in THF (50 mL) was added and the mixture was refluxed for
2.5 h during which time a thick yellow precipitate was formed. The
mixture was stirred at r.t. overnight and the precipitate was collect-
ed and washed with Et2O. The crude product was suspended in H2O
(0.6 L) and the pH was adjusted to pH 10 with aq 2 M NaOH. The
mixture was extracted with CH2Cl2 (4 ×) and the combined organic
phases were washed with sat. aq NaHCO3, dried (Na2SO4), and con-
centrated in vacuo. The residue was crystallized (EtOAc–Et2O) to
give 2a (21.9 g, 66%) as a yellow solid; mp 177–179 °C.
N-(2,3-Dimethylimidazo[1,2-a]pyridin-8-yl)-2,2-dimethylpro-
panamide Hydrochloride (3·HCl)
To a suspension of crude 6 (14.67 kg) in toluene (96 L) was added
3-chlorobutan-2-one (96 wt%, 11.8 L, 112 mol) and the mixture
was refluxed using a Dean–Stark trap. After 1 h, additional 3-chlo-
robutan-2-one (1.4 L, 13 mol) was added and heating was continued
for 6 h. After removal of 8–10 L toluene by distillation, precipita-
tion of 3·HCl began and the mixture was allowed to cool to r.t. over-
night. The precipitate was collected, washed with toluene (6 L) and
dried in vacuo at 50–60 °C to yield 3·HCl (16.9 kg, 70% based on
4).
1H NMR (400 MHz, DMSO-d6): d = 1.12 [s, 9 H, (CH3)3], 2.38 (s,
3 H, 2-CH3), 2.45 (s, 3 H, 3-CH3), 7.01 (d, JHH = 7.1 Hz, 1 H, H6),
7.20 (d, JHH = 16.1 Hz, 1 H, PhCH=CHCO), 7.39–7.43 (m, 3 H, m-
H, p-H), 7.45 (d, JHH = 16.1 Hz, 1 H, PhCH=CHCO), 7.65–7.69 (m,
2 H, o-H), 8.13 (d, JHH = 7.1 Hz, 1 H, H5), 9.50 (s, 1 H, NH).
13C NMR (100 MHz, DMSO-d6): d = 8.03 (3-CH3), 13.20 (2-CH3),
26.95 [3 C, C(CH3)3], 38.94 [C(CH3)3], 110.62 (C6), 118.48 (C3),
120.77 (C5), 124.24 (C8), 125.23 (PhCH=CHCO), 126.17 (C7),
128.24 (2 C, o-C), 128.81 (2 C, m-C), 130.21 (p-C), 134.65 (phenyl
Cq), 139.01 (C8a), 140.39 (C2), 141.71 (PhCH=CHCO), 176.52
(NHC=O), 190.25 (C=O).
N-(2,3-Dimethylimidazo[1,2-a]pyridin-8-yl)-2,2-dimethylpro-
panamide (3)
To a suspension of 3·HCl (260 g, 0.92 mol) in H2O (1 L) and CH2Cl2
(0.4 L) was added concd NH3 (75 mL) until pH 10. The organic lay-
er was separated and the aqueous layer was extracted with CH2Cl2
(3 ×). The combined organic layers were washed with H2O (2 ×),
dried (Na2SO4), and evaporated to half of its volume. Upon addition
of light petroleum ether, the product began to crystallize. The pre-
cipitate was collected, washed with light petroleum ether, and dried
in vacuo at 45 °C to yield 3 as a beige solid (220 g, 97%); mp 91–
93 °C.
1H NMR (400 MHz, DMSO-d6): d = 1.30 [s, 9 H, (CH3)3], 2.33 (s,
3 H, 2-CH3), 2.38 (s, 3 H, 3-CH3), 6.84 (dd, JHH = 7.5, 6.8 Hz, 1 H,
H6), 7.86 (dd, JHH = 7.5, 0.8 Hz, 1 H, H7), 7.89 (dd, JHH = 6.8, 0.8
Hz, 1 H, H5), 8.85 (s, 1 H, NH).
Anal. Calcd for C23H25N3O2: C, 73.58; H, 6.71; N, 11.19. Found: C,
73.42; H, 6.62; N, 11.20.
N-{7-[(2E)-3-(2-Chlorophenyl)prop-2-enoyl]-2,3-dimethylimi-
dazo[1,2-a]pyridin-8-yl}-2,2-dimethylpropanamide (2b)
1H NMR (200 MHz, DMSO-d6): d = 1.12 [s, 9 H, (CH3)3], 2.37 (s,
3 H, 2-CH3), 2.44 (s, 3 H, 3-CH3), 7.05 (d, JHH = 7.0 Hz, 1 H, H-6),
7.30 (d, JHH = 15.9 Hz, 1 H, PhCH=CHCO), 7.42 (m, 2 H, Harom),
7.53 (m, 1 H, Harom), 7.77 (d, JHH = 15.9 Hz, 1 H, PhCH=CHCO),
7.85 (m, 1 H, Harom), 8.14 (d, JHH = 7.0 Hz, 1 H, H-5), 9.54 (s, 1 H,
NH).
N-{7-[(2E)-3-(2,6-Dichlorophenyl)prop-2-enoyl]-2,3-dimeth-
ylimidazo[1,2-a]pyridin-8-yl}-2,2-dimethylpropanamide (2c)
1H NMR (400 MHz, DMSO-d6): d = 1.12 [s, 9 H, (CH3)3], 2.37 (s,
3 H, 2-CH3), 2.45 (s, 3 H, 3-CH3), 7.08 (d, JHH = 7.0 Hz, 1 H, H-6),
7.38 (d, JHH = 16.2 Hz, 1 H, PhCH=CHCO), 7.40 (t, JHH = 8.2 Hz,
1 H, p-H), 7.56 (d, JHH = 16.2 Hz, 1 H, PhCH=CHCO), 7.57 (d,
JHH = 8.2 Hz, 2 H, m-H), 8.15 (d, JHH = 7.0 Hz, 1 H, H-5), 9.62 (s,
1 H, NH).
13C NMR (100 MHz, DMSO-d6): d = 7.90 (3-CH3), 12.92 (2-CH3),
27.08 [3 C, C(CH3)3], 39.43 [C(CH3)3], 108.60 (C7), 111.40 (C6),
117.18 (C3), 118.49 (C5), 125.85 (C8), 136.95 (C8a), 137.31 (C2),
176.49 (C=O).
Anal. Calcd for C14H19N3O: C, 68.54; H, 7.81; N, 17.13. Found: C,
68.42; H, 7.85; N, 17.31.
N-[2,3-Dimethyl-7-(tributylstannyl)imidazo[1,2-a]pyridin-8-
yl]-2,2-dimethylpropanamide (7)
To a soln of 3 (53.5 g, 0.22 mol) in anhyd Et2O (1.3 L) was added
dropwise 1.5 M t-BuLi in pentane (0.44 L, 0.66 mol) at –78 °C over
a period of 1.5 h. After a further 1 h at –78 °C, Bu3SnCl (187 mL,
0.66 mol) was slowly added to the suspension and stirring was con-
tinued at –78 °C for 1 h and at r.t. overnight. The mixture was
N-(2,3-Dimethyl-7-{(2E)-3-[2-(trifluoromethyl)phenyl]prop-2-
enoyl}imidazo[1,2-a]pyridin-8-yl)-2,2-dimethylpropanamide
(2d)
1H NMR (200 MHz, DMSO-d6): d = 1.10 [s, 9 H, (CH3)3], 2.38 (s,
3 H, 2-CH3), 2.45 (s, 3 H, 3-CH3), 7.01 (d, JHH = 7.0 Hz, 1 H, H-6),
7.35 (d, JHH = 15.6 Hz, 1 H, PhCH=CHCO), 7.57–7.86 (m, 4 H,
Synthesis 2008, No. 19, 3065–3070 © Thieme Stuttgart · New York

PAPER
Synthesis of Substituted Imidazonaphthyridines via DOM
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Harom and PhCH=CHCO), 8.16 (d, JHH = 7.0 Hz, 1 H, H-5), 9.53 (s,
1 H, NH).
Anal. Calcd for C18H17N3O: C, 74.21; H, 5.88; N, 14.42. Found: C,
74.07; H, 5.91; N, 14.22.
N-{7-[(2E)-1-Hydroxy-3-phenylprop-2-enyl]-2,3-dimethylimi-
dazo[1,2-a]pyridin-8-yl}-2,2-dimethylpropanamide (10)
To a soln of 3 (5.0 g, 20 mmol) in anhyd Et2O (200 mL) was added
dropwise 1.5 M t-BuLi in pentane (40 mL, 60 mmol) at –78 °C over
a period of 30 min. After a further 30 min at –78 °C, cinnamalde-
hyde (7.5 mL, 60 mmol) was added slowly to the suspension and
stirring was continued at –78 °C for 1 h and at r.t. for 1 h. The mix-
ture was poured into H2O and neutralized with 6 M HCl. The mix-
ture was extracted with EtOAc (2 ×) and the combined organic
phases were washed with H2O, dried (Na2SO4), and evaporated. The
residue was purified by column chromatography (EtOAc) and crys-
tallized (Et2O) to give 10 (4.5 g, 60%) as a colorless solid; mp 195–
196 °C.
1H NMR (400 MHz, DMSO-d6): d = 1.31 [s, 9 H, (CH3)3], 2.29 (s,
3 H, 2-CH3), 2.36 (s, 3 H, 3-CH3), 5.41 [ddd, JHH = 4.5, 4.5, 1.2 Hz,
1 H, CH(OH)], 5.64 (d, JHH = 4.5 Hz, 1 H, OH), 6.44 (dd,
JHH = 16.0, 4.5 Hz, 1 H, PhCH=CHCO), 6.65 (dd, JHH = 16.0, 1.2
Hz, 1 H, PhCH=CHCO), 6.96 (d, JHH = 7.1 Hz, 1 H, H6), 7.16–7.24
(m, 1 H, p-H), 7.26–7.33 (m, 2 H, m-H), 7.34–7.39 (m, 2 H, o-H),
8.05 (d, JHH = 7.1 Hz, 1 H, H5), 9.16 (s, 1 H, NH).
9-(2-Chlorophenyl)-2,3-dimethyl-9,10-dihydroimidazo[1,2-h]-
1,7-naphthyridin-7(8H)-one (1b)
1H NMR (200 MHz, DMSO-d6): d = 2.32 (s, 3 H, 2-CH3), 2.38 (s,
3 H, 3-CH3), 2.90 (AB; A: dd, JHH = 16.3, 6.9 Hz, B: dd, JHH = 16.3,
6.4 Hz, 2 H, H-8), 5.28 (m, 1 H, H-9), 6.97 (d, JHH = 7.1 Hz, 1 H,
H-6), 7.22–7.50 (m, 4 H, Harom), 7.46 (d, JHH = 7.1 Hz, 1 H, H-5),
7.90 (s, 1 H, NH).
9-(2,6-Dichlorophenyl)-2,3-dimethyl-9,10-dihydroimidazo[1,2-
h]-1,7-naphthyridin-7(8H)-one (1c)
1H NMR (400 MHz, DMSO-d6): d = 2.29 (s, 3 H, 2-CH3), 2.36 (s,
3 H, 3-CH3), 2.54 (ddd, JHH = 16.8, 5.8, 1.1 Hz, 1 H, H-8), 3.31 (dd,
JHH = 16.7, 14.9 Hz, 1 H, H-8), 5.72 (dd, JHH = 14.9, 5.8 Hz, 1 H, H-
9), 7.03 (d, JHH = 7.1 Hz, 1 H, H-6), 7.37 (m, 1 H, p-H), 7.43 (d,
JHH = 7.1 Hz, 1 H, H-5), 7.49 (m, 2 H, m-H), 7.93 (s, 1 H, NH).
2,3-Dimethyl-9-[2-(trifluoromethyl)phenyl]-9,10-dihydro-
imidazo[1,2-h]-1,7-naphthyridin-7(8H)-one (1d)
1H NMR (400 MHz, DMSO-d6): d = 2.30 (s, 3 H, 2-CH3), 2.38 (s,
3 H, 3-CH3), 2.82 (m, 2 H, H-8), 5.22 (t, JHH = 8.1 Hz, 1 H, H-9),
7.02 (d, JHH = 7.0 Hz, 1 H, H-6), 7.49 (d, JHH = 7.0 Hz, 1 H, H-5),
7.53 (t, JHH = 7.8 Hz, 1 H, Harom), 7.68 (t, JHH = 7.8 Hz, 1 H, Harom),
13C NMR (75 MHz, DMSO-d6): d = 7.99 (3-CH3), 13.15 (2-CH3),
27.45 [3 C, C(CH3)3], 38.76 [C(CH3)3], 67.31 [CH(OH)], 109.56
(C6), 115.98 (C3), 121.59 (C8), 122.04 (C5), 126.10 (2 C, o-C),
127.16 (p-C), 127.42 (PhCH=CHCO), 128.51 (2 C, m-C), 132.21
(PhCH=CHCO), 134.96 (C7), 136.83 (phenyl Cq), 138.34 (C2),
141.03 (C8a), 177.40 (C=O).
7.74 (d, JHH = 7.8 Hz, 1 H, Harom), 7.83 (s, 1 H, NH), 7.89 (d, JHH
7.8 Hz, 1 H, Harom).
=
Acknowledgment
Anal. Calcd for C23H27N3O2: C, 73.18; H, 7.21; N, 11.13. Found: C,
73.13; H, 7.34; N, 10.86.
We would like to thank Mrs. C. Schneider, Mrs. C. Hartbaum, Mr.
B. Grobbel, and Mr. U. Dölling for their skillful technical assistance
in the preparative work. We are also indebted to Professor R. R.
Schmidt, Universität Konstanz, for numerous critical and fruitful
discussions.
N-{2,3-Dimethyl-7-[(2E)-3-phenylprop-2-enoyl]imidazo[1,2-
a]pyridin-8-yl}-2,2-dimethylpropanamide (2a)
To a soln of 10 (93.6 g, 0.25 mol) in CHCl3 (1.6 L) was added MnO2
(282 g, 3.24 mol) and the mixture was stirred overnight at r.t. The
mixture was filtered and the filtrate was evaporated. The residue
was crystallized (EtOAc–Et2O) to give 2a (69.8 g, 75%) as a yellow
solid; mp 184–186 °C.
References
(1) For a review on DOM, see: (a) Gschwend, H. W.;
Rodriguez, H. R. Org. React. 1979, 26, 1. (b) Snieckus, V.
Chem. Rev. 1990, 90, 879. (c) Queguiner, G.; Marsais, F.;
Snieckus, V.; Epsztajn, J. Adv. Heterocycl. Chem. 1991, 52,
187.
(2) Anctil, E. J.-G.; Snieckus, V. Metal-Catalyzed Cross-
Coupling Reactions; De Meijere, A.; Diederich, F., Eds.;
Wiley-VCH: Weinheim, 2004, 761–813.
Anal. Calcd for C23H25N3O2: C, 73.58; H, 6.71; N, 11.19. Found: C,
73.30; H, 6.81; N, 11.06.
2,3-Dimethyl-9-phenyl-9,10-dihydroimidazo[1,2-h][1,7]naph-
thyridin-7(8H)-one (1a); Typical Procedure
To an ice-cold soln of 2a (33.3 g, 88.6 mmol) in dioxane (250 mL)
was slowly added concd HCl (130 mL) and the mixture was re-
fluxed overnight. The mixture was cooled down, evaporated to a
total volume of 100 mL and neutralized with concd NH3. The result-
ing suspension was extracted with EtOAc (4 ×) and the combined
organic phases were washed with H2O, dried (Na2SO4), and evapo-
rated. The residue was purified by column chromatography
(EtOAc–light petroleum ether, 3:1) and crystallized (i-Pr2O) to give
1a (17.9 g, 69%) as a yellow solid; mp 138–140 °C.
(3) Simon, W.-A.; Postius, S.; Riedel, R.; Senn-Bilfinger, J.;
Grundler, G. WO 9842707, 1998.
(4) See, for example: (a) Donnelly, J. A.; Farrell, D. F. J. Org.
Chem. 1990, 55, 1757. (b) Xia, Y.; Yang, Z.-Y.; Xia, P.;
Bastow, K. F.; Tachibana, Y. J. Med. Chem. 1998, 41, 1155.
(5) Blewitt, H. L. Special Topics in Heterocyclic Chemistry;
Weissberger, A.; Tailor, E. C., Eds.; Wiley: New York,
1977, 117.
1H NMR (400 MHz, DMSO-d6): d = 2.31 (s, 3 H, 2-CH3), 2.35 (s,
3 H, 3-CH3), 2.93 (AB, A: dd, JHH = 16.3, 6.8 Hz, B: dd, JHH = 16.3,
6.1 Hz, 2 H, H8), 4.99 (ddd, JHH = 6.8, 6.1, 2.6 Hz, 1 H, H9), 6.95
(d, JHH = 7.1 Hz, 1 H, H6), 7.21–7.27 (m, 1 H, p-H), 7.27–7.33 (m,
2 H, m-H), 7.34–7.41 (m, 2 H, o-H), 7.39 (d, JHH = 7.1 Hz, 1 H, H5),
7.85 (s, 1 H, NH).
13C NMR (100 MHz, DMSO-d6): d = 7.92 (3-CH3), 12.86 (2-CH3),
43.14 (C8), 54.51 (C9), 106.44 (C6a), 107.46 (C6), 112.26 (C5),
120.21 (C3), 126.12 (2 C, o-C), 127.23 (p-C), 128.30 (2 C, m-C),
134.59 (C10b), 138.83 (C2), 141.34 (2 C, C10a, phenyl Cq), 188.92
(C=O).
(6) (a) Tamura, Y.; Fujita, M.; Chen, L.-C.; Inoue, M.; Kita, Y.
J. Org. Chem. 1981, 46, 3564. (b) Güngör, T.; Marsais, F.;
Queguiner, G. Synthesis 1982, 499. (c) Turner, J. A. J. Org.
Chem. 1983, 48, 3401.
(7) For related reactions of heterocyclic stannanes with acyl
chlorides, see, for example: (a) Yamamoto, Y.; Yanagi, A.
Chem. Pharm. Bull. 1982, 30, 2003. (b) Arukwe, J.;
Benneche, T.; Undheim, K. J. Chem. Soc., Perkin Trans. 1
1989, 255. (c) Buron, F.; Plé, N.; Turck, A.; Queguiner, G.
J. Org. Chem. 2005, 70, 2616.
Synthesis 2008, No. 19, 3065–3070 © Thieme Stuttgart · New York

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J. Senn-Bilfinger et al.
PAPER
(8) For Stille cross-coupling reaction with imidazo[1,2-
a]pyridines, see, for example: Hervet, M.; Théry, I.;
Gueiffier, A.; Enguehard-Gueiffier, C. Helv. Chim. Acta
2003, 86, 3461.
(9) For a review, see, for exampl: Farina, V.; Krishnamurthy,
V.; Scott, W. J. Org. React. 1997, 50, 1.
(10) (a) Bumagin, N. A.; Bumagina, I. G.; Kashin, A. N.;
Beletskaya, I. P. J. Org. Chem. USSR (Engl. Transl.) 1982,
977. (b) Labadie, S. S.; Teng, E. J. Org. Chem. 1994, 59,
4250.
(11) (a) Scott, W. J.; Stille, J. K. J. Am. Chem. Soc. 1986, 108,
3033. (b) Farina, V.; Krishnan, B.; Marshall, D. R.; Roth, G.
P. J. Org. Chem. 1993, 58, 5434.
(12) (a) Senn-Bilfinger, J.; Postius, S.; Simon, W.-A.; Grundler,
G.; Hanauer, G.; Huber, R.; Kromer, W.; Sturm, E. WO
0017200, 2000. (b) Simon, W.-A.; Herrmann, M.; Klein, T.;
Shin, j. M.; Huber, R.; Senn-Bilfinger, J.; Postius, S.
J. Pharmacol. Exp. Ther. 2007, 321 3, 866. (c) Senn-
Bilfinger, J.; Ferguson, J. R.; Holmes, M. A.; Lumbard, K.
W.; Huber, R.; Zech, K.; Hummel, R.-P.; Zimmermann, P. J.
Tetrahedron Lett. 2006, 47, 3321.
Synthesis 2008, No. 19, 3065–3070 © Thieme Stuttgart · New York