Efficient synthesis of a trisubstituted 1,6-naphthyridone from acetonedicarboxylate and regioselective Suzuki arylation

Article abstract of DOI:10.1021/jo0514927

An efficient five-step synthesis of 1,6-naphthyridone 3b, a p38 mitogen-activated protein (MAP) kinase inhibitor intermediate, in 32% overall yield starting from acetonedicarboxylate (ADC) is described. The synthesis began with a selective monoamidation o

Full text of DOI:10.1021/jo0514927

Efficient Synthesis of a Trisubstituted 1,6-Naphthyridone from
Acetonedicarboxylate and Regioselective Suzuki Arylation
John Y. L. Chung,* Chaoxian Cai, J. Christopher McWilliams, Robert A. Reamer,
Peter G. Dormer, and Raymond J. Cvetovich
Process Research, Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07965
john_chung@merck.com
Received July 18, 2005
An efficient five-step synthesis of 1,6-naphthyridone 3b, a p38 mitogen-activated protein (MAP)
kinase inhibitor intermediate, in 32% overall yield starting from acetonedicarboxylate (ADC) is
described. The synthesis began with a selective monoamidation of ADC dimethyl ester enolate 9.
A novel concomitant enamine formation and an imide cyclization afforded the nitrogen differentially
protected enamide imide 12. Treatment of 12 with KOtBu and 3-ethoxyacrylate produced lactam
15 quantitatively, which was converted to tetrachloronaphthyridone 19 via a one-pot p-methoxy-
benzyl (PMB) deprotection and bischlorination. A highly regioselective Pd(OAc)2/IMes-catalyzed
Suzuki coupling completed the synthesis.
Introduction
pharmaceutical agents.1-6 Recently, our laboratories have
disclosed an expedient synthesis of N-aryl-substituted
naphthyridones 3a from N-aryl pyridinone 2a, which in
turn was prepared from enaminone 1a and methyl
propiolate.7 Key to the cyclization of sterically hindered
N-aryl enaminone 1a with methyl propiolate was the use
of solid NaOH (Scheme 1). In connection with our p38
kinase inhibitor program,8 we were interested in applying
this methodology to 2,4-difluorophenyl-substituted enam-
inone 1b for the preparation of pyridinone 2b and
ultimately trisubstituted 1,6-naphthyridone 3b. However,
under a variety of reaction conditions, 1b underwent
1,6-Naphthyridones have recently emerged as impor-
tant heterocyclic cores present in many biologically active
agents. This heterocycle is most notably prevalent in
many kinase inhibitors1 and anti-infective agents2 and
is increasingly adapted in many cardiovascular,3 central
nervous system (CNS),4 and metabolic-related agents.5
As a result, the preparation of this heterocycle has
become of great interest for the design of potential
(1) (a) Silver, P. J.; Lepore, R. E.; Canniff, P. C.; O’Connor, B.; Lemp,
B.; Harris, A. L. Drug Dev. Res. 1990, 21, 105-17. (b) Thompson, A.
M.; Showalter, H. D. H.; Denny, W. A. J. Chem. Soc., Perkin Trans. 1
2000, 12, 1843-1852. (c) Ding, Q.; Xie, Y.; Gray, N. S.; You, S.;
Chopiuk, G.; Jiang, J.; Liu, Y.; Steensma, R.; Wang, X.; Sim, T. WO
Patent 2005034869, 2005; Chem. Abstr. 2005, 142, 411341.
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Betebenner, D. A.; Donner, P. L.; Green, B. E.; Kempf, D. J.; McDaniel,
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(6) (a) Huang, Q.; Hunter, J. A.; Larock, R. C. Org. Lett. 2001, 3,
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(3) Lee, K. C.; Ezrin, A. M.; Pagani, E. D.; Canniff, P. C.; Hamel, D.
W.; Fort, D. J.; Silver, P. J. Drug Dev. Res. 1990, 21, 119-23.
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41, 857-865. (b) Clark, J. D.; Davis, J. M.; Favor, D.; Fay, L. K.;
Franklin, L.; Henegar, K. E.; Johnson, D. S.; Nichelson, B. J.; Ou, L.;
Repine, J. T.; Walters, M. A.; White, A. D.; Zhu, Z. U.S. Patent 043309,
2005; Chem. Abstr. 2005, 142, 261526.
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McCormick, S. X.; Pivnichny, J. V.; Hop, C. E. C. A.; Kumar, S.; Wang,
Z.; O’Keefe, S. J.; O’Neill, E. A.; Porter, G.; Thompson, J. E.; Woods,
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467-470. (b) Doherty, J. B.; Stelmach, J. E.; Chen, M.-H.; Liu, L.; Hunt,
J. A.; Ruzek, R. D.; Goulet, J. L.; Wisnoski, D. D.; Natarajan, S. R.;
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10.1021/jo0514927 CCC: $30.25 © 2005 American Chemical Society
Published on Web 11/16/2005
10342
J. Org. Chem. 2005, 70, 10342-10347

Efficient Synthesis of 1,6-Naphthyridone from ADC
SCHEME 1. Fate of Two Different Aryl
Enaminones
SCHEME 2. Bisdichlorophenyl Naphthyridone
TABLE 1. Monoamidation of ADC Dimethyl Ester
M in
enolate 9 solubility isolated yield
base
enolate 9a
in THF at 22 °C
10
MgCl2/NH4OH
NaH
Mg
Na
Li
Na
K
+
41%
81%
79%
78%
<2%
++
+++
++
-
LiOtBu
NaOtBu
KOtBu
predominantly nucleophilic aromatic substitution cycliza-
tion, affording quinolinone 4 as the major product.9
a Magnesium enolate was isolated. All other enolates were
generated in situ.
Results and Discussion
To avoid this problem, we sought to prepare simple
enaminones without the difluorophenyl group and install
this moiety at a later stage of the synthesis. However,
all attempts to form the N-aryl enaminones of 3-oxobu-
tanoates or its equivalents such as cyanoacetone and
3-aminocrotonitrile with 2,6-dichloroaniline gave no reac-
tion, presumably because of poor nucleophilicity of the
2,6-dichloroaniline nitrogen.
To remedy this problem, we investigated activated
acetonedicarboxylate (ADC) derivatives,10 which had the
added advantage of containing all the carbons required
for the B-ring of naphthyridone (Scheme 2). Treatment
of ADC with 2,6-dichloroaniline and catalytic TsOH in
refluxing toluene with azeotropic removal of water gave
initially enamine diester 5. However, imide formation
was competitive and ultimately afforded enamine imide
6 as the major product, which precipitated upon cooling
to 22 °C in 51% yield. Formation of imide 6 was a fatal
flaw of this approach because, after conversion to imide
8 (Scheme 2), all attempts to excise the dichloroaniline
group from imide 8 failed.11
as a way to introduce a removable imide nitrogen
protecting group. Methods were investigated to selec-
tively monoamidate ADC dimethyl ester with p-meth-
oxybenzylamine (PMB-NH2) via enolate 9 as a way to
differentiate the two esters (Table 1). Initial experiments
with the magnesium enolate12 gave a variable ∼50% yield
of 10. The sodium13 and the lithium enolates generated
in situ using NaH, NaOtBu, or LiOtBu gave consistently
good yields of 10, whereas the potassium enolate gener-
ated with KOtBu gave almost no reaction. The poor yields
for the magnesium and potassium enolates were mainly
due to poor solubility in THF. Thus, the one-pot treat-
ment of ADC dimethyl ester with 1.25 equiv of NaH,
NaOtBu, or LiOtBu in THF followed by 1.05 equiv of
PMB-NH2 afforded ADC ester amide 10 in 80% yield.
In these reactions, a small amount (2-3%) of bisamide
11 was also formed, which was removed by simple
filtration during extraction.
To overcome these problems, we turned our attention
to the synthesis and the utility of ADC ester amide 10
The condensation of ester amide 10 with 2,6-dichlo-
roaniline (1.2 equiv) in refluxing toluene in the presence
of 5 mol % TsOH underwent a concomitant enamine and
imide formation to produce imide 12 in 65-68% yield
(Scheme 3). Small amounts (5%) of bis(PMB) adduct 13
were also produced but easily removed by crystallization
of 12 from acetonitrile. As far as we are aware, this type
(9) Chu, D. T. W.; Nordeen, C. W.; Hardy, D. J.; Swanson, R. N.;
Giardina, W. J.; Pernet, A. G.; Plattner, J. J. J. Med. Chem. 1991, 34,
168-74.
(10) Charvat, T.; Potacek, M.; Marek, J. Monatsh. Chem. 1995, 126,
333-40.
(11) For example, basic conditions, such as aqueous NaOH, NH4-
OH, or NH2NH2 up to 120 °C or NaBH4, gave no reaction. In fact, the
sodium enolate of 8 could be isolated as a solid from the NaOH reaction.
Acidic conditions, such as 30% H2SO4 or 6 N HCl, gave no reaction at
<80 °C and gave complete decompostion at 120 °C, in which only 1,6-
dichloroaniline was detected, indicative of total destruction of the
naphthyridone ring system.
(12) Yamato, M.; Kusunoki, Y. Chem. Pharm. Bull. 1981, 29, 2832-
2836.
(13) (a) Bertz, S. H.; Rihs, G.; Woodward, R. B. Tetrahedron 1982,
38, 63-70. (b) Szychowski, J.; Wojtasiewicz, K. Pol. J. Chem. 1994,
68, 2741-2743.
J. Org. Chem, Vol. 70, No. 25, 2005 10343

Chung et al.
SCHEME 3. Enamine Imide Formation
SCHEME 5. PMB Deprotection-Bischlorination
olate, and the ADC route also eliminated the use of
expensive Bredereck’s reagent ((Me2N)2CHOCMe3) which
was used in the open-chained enaminones method for the
conversion of 2a to 3a.
The optimized condition involves slow addition of 1.1
equiv of ethyl 3-ethoxyacrylate to a solution of 12 and
1.4 equiv of KOtBu/THF in NMP at 100 °C and aging for
3 h to complete the cyclization of 14. After dilution with
water and adjustment to pH 2, naphthyridone 15 pre-
cipitates from the mixture in 92% yield.
SCHEME 4. Annulation of Lactam Ring
Removal of the PMB group in naphthyridone 15 was
achieved by treatment with TFA at 120 °C or MsOH at
22 °C to cleanly afford 18 (Scheme 5). After evaporation
of TFA, chlorination of the residue with POCl3 and Me4N-
Cl15 at 140 °C afforded tetrachloronaphthyridone 19.
Alternatively, it was found that conversion of imide 15
to 19 could be achieved in one step using the chlorination
conditions in 70% yield.
To complete the synthesis of 3b, a regioselective Suzuki
coupling of 19 with 2,4-difluorophenylboronic acid (20)
was explored. In initial studies using 1.6 equiv each of
20 and Cs2CO3 and 4 mol % Pd(dppf)Cl2 in refluxing
toluene, the starting materials were completely consumed
within 1 h, affording a 1:0.1:1 mixture of desired monoad-
duct 3b, undesired monoadduct 21, and bis adduct 22
(Table 2, entry 1). When the reaction temperature was
lowered to 85 °C and 1.2 equiv of 20 was used, the
reaction proceeded to 70% conversion with a 3.8:1 ratio
of 3b to 22 with no undesired monoadduct 21 (Table 2,
entry 2). Assignments of regioisomers 3b and 21 were
made using detailed NMR studies including 2-D hetero-
nuclear multiple-bond correlation (HMBC) and gradient-
enhanced nuclear Overhauser effect (NOE) experiments.
In 3b, a NOE enhancement was observed from H-4 to
H-6′′. In addition, a spin-spin coupling constant of 3.3
of reaction is unprecedented. We have observed that,
when a solution of 10 was washed only once with aqueous
HCl solution during its isolation, compound 13 was
produced as the major product. When a solution of 10
was washed three times with aqueous HCl solution, then
the amount of 13 was reduced to 5%. Presumably, this
is due to the organic solubility of the sodium enolate,
which could undergo self-condensation and release PMB-
NH2. It is known that acetonedicarboxylate diester self-
condenses at elevated temperatures to produce phenolic
products only when alkali metals are present.14
With 12 in hand, annulation of the lactam ring with
methyl propiolate was carried out in a fashion similar to
that for 6-8 (Scheme 4). However, the formation of large
amounts of the double-addition adducts 16 and 17
resulted in only 20-40% yields of the desired 15. This is
most likely due to the less sterically demanding PMB
group in 14 relative to 2,6-dichlorophenyl in 7 and the
high reactivity of methyl propiolate. To address this
problem, we examined the less reactive methyl 3-meth-
oxyacrylate and ethyl 3-ethoxyacrylate. Gratifyingly, the
reaction of 12 with these two acrylates in NMP with KOt-
Bu gave clean reactions, and the desired product 15 was
obtained in >90% yield. These acrylates are at least an
order of magnitude less expensive than methyl propi-
Hz was observed between H-4 and F-2′′ (verified via 19
F
decoupling). In compound 21, a NOE enhancement was
observed from H-8 to H-6′′. In the 13C spectrum of 21, a
four-bond spin-spin coupling was observed between C-8
and F-2′′ (JCF ) 13.6 Hz). These analyses firmly estab-
lished that the connectivity of the 2,4-difluorophenyl
groups in compounds 3b and 21 are as drawn.
In these initial Suzuki experiments, high monoselec-
tivity was observed during the early stages of the
reaction, but the electron-deficient difluorophenyl group
in product 3b activated the remaining chloride toward a
second coupling to give bis adduct 22. A literature survey
indicated that regioselectivity is highly substrate de-
pendent.16 Woodward and co-workers17 have shown that
coupling of electronic-neutral and -rich arylboronic acids
to 1,3-dichloroisoquinoline led exclusively to 1-aryl-3-
(14) (a) Gordon, P. N. J. Org. Chem. 1957, 22, 1006-1007. (b)
Yamato, M.; Kusunoki, Y. Chem. Pharm. Bull. 1981, 29, 1214-1220.
(c) Stone, M. J.; Maplestone, R. A.; Rahman, S. K.; Williams, D. H.
Tetrahedron Lett. 1991, 32, 2663-2666. (d) Nishiwaki, N.; Yagi, H.;
Shinkawa, T.; Matsumoto, M.; Tamura, M.; Ariga, M. J. Oleo Sci. 2005,
54, 461-464.
(15) (a) Henegar, K. E.; Ashford, S. W.; Baughman, T. A.; Sih, J.
C.; Gu, R.-L. J. Org. Chem. 1997, 62, 6588-6597. (b) Adamczyk, M.;
Akireddy, S. R.; Reddy, R. E. Org. Lett. 2000, 2, 3421-3423.
10344 J. Org. Chem., Vol. 70, No. 25, 2005

Efficient Synthesis of 1,6-Naphthyridone from ADC
TABLE 2. Selectivity of Suzuki-Miyaura Cross-Coupling
entry
ligand
Pd complex
base
solvent
toluene
toluene
IPA
toluene or DMF
DMF
temp
conversion
3b/21/22
1a
2b
3c
4d
5e
(dppf)
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Cs2CO3
Cs2CO3
K3PO4
K3PO4
K3PO4
110 °C
85 °C
100 °C
35 °C
97%
70%
93%
88%
95%
1:0.1:1
3.8:0:1
2:0.2:1
7:0.5:1
50:0.9:1
(dppf)
Ph3P
SPhos
IMes‚HCl
50f80 °C
a Reactions were carried out in toluene (0.14 M) with 4 mol % Pd(dppf)Cl2, 1.6 equiv of 20, and 1.6 equiv of Cs2CO3 at 110 °C for 1 h.
b Reactions were carried in toluene (0.14 M) with 4 mol % Pd(dppf)Cl2, 1.2 equiv of 20, and 1.2 equiv of Cs2CO3 at 85 °C for 8 h. c Reactions
were carried out in 2-propanol (0.36 M) with 5 mol % Pd(OAc)2, 15 mol % Ph3P, 1.2 of equiv 20, and 2.2 equiv of K3PO4 at 100 °C for 3
h. The mixture was cooled to room temperature and 0.3 equiv of 20 were added. Then, the reaction was carried out at 100 °C for 2 h.
d Reactions were carried out in toluene or DMF (0.33 M) with 4 mol % Pd(OAc)2, 8 mol % SPhos, 1.1 equiv of 20, and 2.2 equiv of K3PO4
at 22 °C for 1 h and at 35 °C for 22 h. e See Supporting Information for reaction conditions.
chloroisoquinolines, but no example with electronic-
deficient arylboronic acids was included. In comparative
cross-coupling studies, 19 was found to be a more reactive
and a less selective substrate than 1,3-dichloroisoquino-
line. We screened over 50 ligands with Pd with various
bases and solvents,18 and selected results are shown in
Table 2. Some improvements were observed with the
monodentate ligands. Ph3P and Pd(OAc)2 at 100 °C
afforded a 2:0.2:1 ratio of 3b/21/22 (Table 2, entry 3).
Using the highly activating SPhos,19 we could lower the
reaction temperature to 35 °C to give an improved
selectivity of 7:0.5:1 (Table 2, entry 4) at 88% conversion.
The most surprising and pleasing results were with the
N-heterocyclic carbene derived from 1,3-bis(2,4,6-tri-
methylphenyl)imidazolium chloride (IMes‚HCl),20 which
gave a 50:0.9:1 ratio of 3b/21/22 and 3b isolated in 94%
yield (Table 2, entry 5). It is noteworthy to point out that
these results were obtained only when IMes/Pd(OAc)2
ratios were g2.5. When the ratios were e2, boronic acid
20 rapidly degraded to 1,3-difluorobenzene, resulting in
poor conversions.
etonedicarboxylate (ADC). ADC ester amide 10, prepared
by a selective monoamidation of ADC enolate with PMB-
NH2, underwent an enamine formation with 2,6-dichlo-
roaniline and cyclization to afford PMB-protected enam-
ine imide 12. A highly efficient lactam ring annulation
was accomplished with 3-ethoxyacrylate to afford naph-
thyridone imide 15 in excellent yield. A one-pot PMB
deprotection/bischlorination using POCl3-Me4NCl af-
forded tetrachloro-1,6-naphthridone 19. Finally, this
material underwent a highly selective Suzuki coupling
with 2,4-difluorophenylboronic acid catalyzed by IMes/
Pd(OAc)2, thus completing the synthesis.
Experimental Section
Methyl
5-[(4-Methoxybenzyl)amino]-3,5-dioxopen-
tanoate (10). To a mixture of 60% NaH (3.0 g, 75 mmol) in
t
THF (42 mL), 30% BuONa/THF (26.4 mL, 75 mmol) in THF
(49 mL), or 1 M BuOLi/THF (75 mL, 75 mmol) was slowly
t
added dimethyl acetonedicarboxylate (10.8 g, 60 mmol) over
1 h at 20-25 °C. After stirring at 22 °C for 0.5-1 h,
4-methoxybenzylamine (8.85 g, 63 mmol) was added in one
portion. The reaction was monitored by high-pressure liquid
chromatography (HPLC) condition A. After complete consump-
tion of ADC (4-18 h), the reaction mixture (83% assayed yield)
was poured into a 10 °C mixture of EtOAc (100 mL), 3 N HCl
(50 mL), and saturated aqueous NaCl solution. After stirring
for 0.5-1 h at 20 °C, the mixture was filtered to remove some
insoluble solids (bisamide 11: HRMS-FAB (m/z) [M + H]+
calcd for C21H25N2O5 385.1764, found 385.1759), and the solid
was washed with EtOAc (30 mL) and water (10 mL). The
organic layer of the filtrate was washed twice with a mixture
of saturated aqueous NaCl (35 mL) and 3 N HCl (15 mL), twice
with a mixture of saturated aqueous NaCl (35 mL) and water
(15 mL), and once with saturated aqueous NaCl (50 mL). The
organic phase was filtered and concentrated, and the residue
was dried by diluting with isopropyl acetate (60 mL) and
concentrating several times. After concentrating to near dry-
In summary, we have developed an efficient five-step
synthesis to trisubstituted naphthyridone 3b from ac-
(16) (a) For a review, see: Schroter, S.; Stock, C.; Bach, T. Tetra-
hedron 2005, 61, 2245-2267. (b) Maerten, E.; Hassouna, F.; Couve-
Bonnaire, S.; Mortreux, A.; Carpentier, J.-F.; Castanet, Y. Synlett 2003,
1874-1876.
(17) Ford, A.; Sinn, E.; Woodward, S. J. Chem. Soc., Perkin Trans.
1 1997, 927-934.
(18) The full screening studies will be disclosed in a future publica-
tion.
(19) Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L.
J. Am. Chem. Soc. 2005, 127, 4685-4696.
(20) (a) Singh, R.; Viciu, M. S.; Kramareva, N.; Navarro, O.; Nolan,
S. P. Org. Lett. 2005, 7, 1829-1832. (b) Navarro, O.; Oonishi, Y.; Kelly,
R. A.; Stevens, E. D.; Briel, O.; Nolan, S. P. J. Organomet. Chem. 2004,
689, 3722-3727. (c) Grasa, G. A.; Viciu, M. S.; Huang, J.; Zhang, C.;
Trudell, M. L.; Nolan, S. P. Organometallics 2002, 21, 2866-2873.
J. Org. Chem, Vol. 70, No. 25, 2005 10345

Chung et al.
ness, the residue was taken up in heptane (70 mL) and the
solid was filtered and dried in vacuo, affording 14-15 g of 10
as a beige solid (85-95% purity by HPLC condition A; 75-
80% corrected yield). This material was used as is in the next
step. An analytical pure sample of 10 was obtained by
crystallization from 1:1 EtOAc/heptane: 1H NMR (CD3CN) δ
7.21 (d, J ) 8.7, 2H), 7.00 (br S, NH), 6.88 (d, J ) 8.7, 2H),
4.28 (d, J ) 6.0, 2H), 3.77 (s, 3H), 3.66 (s, 3H), 3.60 (s, 2H),
3.45 (s, 2H); traces of two enol forms were also detected, 6.75
(br s, NH), 5.17 (s), 5.09 (s), 4.31 (d, J ) 6.0), 3.17 (s), 3.10 (s);
13C NMR (CD3CN) δ 198.3, 167.5, 165.5, 158.9, 131.0, 128.9,
113.8, 54.9, 51.8, 50.2, 48.9, 42.3; LC-MS (API-ES+) m/z [M
+ Na]+ 302, [M + Na-CH3OH]+ 270; HRMS-FAB (m/z) [M
+ H]+ calcd for C14H18NO5 280.1185, found 280.1183.
4-[(2,6-Dichlorophenyl)amino]-1-(4-methoxybenzyl)-
pyridine-2,6-(1H,3H)-dione (12). A mixture of ADC ester
amide 10 (8.52 g, 90 wt %, 27.5 mmol), 2,6-dichloroaniline (5.75
g, 34.5 mmol), toluene (36 mL), and p-toluenesulfonic acid
monohydrate (0.26 g, 1.38 mmol) was heated at 60 °C for 2.5
h and then at reflux (117 °C) under a Dean-Stark trap for 20
h under N2. The mixture was allowed to cool slowly to 22 °C,
and the product precipitated. After stirring for 2-3 h, the solid
was filtered, washed with toluene (25 mL), and dried in vacuo,
affording 9.3 g of 12 (75% purity by HPLC condition A; 65%
corrected yield). The purity of crude product ranged from 70
to 92%, contained 2-10% 1-(4-methoxybenzyl)-4-[(4-methoxy-
phenyl)amino]pyridine-2,6-(1H,3H)-dione (13), and was used
as is in the next step without problem. A pure sample was
obtained by crystallization from acetonitrile: 1H NMR (CD3-
CN) δ 7.50 (d, J ) 8.1, 2H), 7.33 (t, J ) 8.1, 1H), 7.23 (d, J )
8.7, 2H), 7.0 (s, NH), 6.83 (d, J ) 8.7, 2H), 4.84 (s, 2H), 4.57
(s, 1H), 3.74 (s, 3H), 3.62 (s, 2H); 13C NMR (CD3CN) δ 168.4,
166.3, 158.8, 153.1, 134.3, 132.8, 130.4, 129.7, 129.4, 129.2,
128.8, 125.3, 113.6, 89.4, 54.9, 41.2, 35.2; LC-MS (API-ES+)
m/z [M + H]+ 391, [M + Na]+ 413; HRMS-FAB (m/z) [M +
H]+ calcd for C19H17Cl2N2O3 391.0616, found 391.0620.
ES+) m/z [M + H]+ 323; HRMS-FAB (m/z) [M + H]+ calcd
for C14H9Cl2N2O3 322.9990, found 322.9987.
5,7-Dichloro-1-(2,6-dichlorophenyl)-1,6-naphthyridin-
2-(1H)-one (19). In a sealed tube was charged naphthyridon-
etrione 15 (5.0 g, 90%, 10.2 mmol), tetramethylammonium
chloride (1.23 g, 11.05 mmol), and phosphorus oxychloride (20
mL, 212.4 mmol). The brown solution was heated at 140 °C
for 21 h. After cooling to room temperature, the reaction
mixture was quenched into ice water (300 g). The suspension
was stirred for 6 h at 22 °C. The solid was filtered, washed
with water (80 mL × 3), and dried in vacuo, affording 5.9 g of
crude 19 as brown solid (44% purity by HPLC condition A).
The crude solid along with NaHCO3 (5.9 g) was triturated with
isopropyl acetate (IPAC) (125 mL) over 2 days. After filtration
and washing with isopropyl acetate (25 mL × 2), the filtrate
was evaporated to dryness, affording 3.4 g of 19 as light brown
solid (76% purity by HPLC condition A; 70% corrected yield).
A pure sample was obtained by flash chromatography (20-
35% IPAC/heptane): 1H NMR (CDCl3) δ 8.20 (d, J ) 10.0, 1H),
7.61 (d, J ) 8.0, 2H), 7.52 (t, J ) 8.0, 1H), 6.89 (d, J ) 10.0,
1H), 6.36 (s, 1H); 13C NMR (CDCl3) δ 159.6, 150.6, 150.1, 147.7,
136.5, 134.7, 131.8, 131.5, 129.6, 124.2, 113.7, 108.1; LC-MS
(API-ES+) m/z [M + H]+ 359; HRMS-FAB (m/z) [M + H]+
calcd for C14H7Cl4N2O 358.9312, found 358.9309.
7-Chloro-1-(2,6-dichlorophenyl)-5-(2,4-difluorophenyl)-
1,6-naphthyridin-2-(1H)-one (3b). A mixture of Pd(OAc)2
(2.7 mg, 0.01 mmol), IMes‚HCl (9.1 mg, 0.025 mmol), K3PO4
(122 mg, 0.557 mmol), and DMF (0.75 mL) was stirred under
a N2 stream at room temperature for 1 h. Tetrachloronaph-
thyridinone 19 (100 mg, 99%, 0.253 mmol) and 2,4-difluo-
rophenylboronic acid (44 mg, 0.278 mmol) were added and
heated at 50 °C for 3.5 h. To drive the reaction to e5% starting
material, more 2,4-difluorophenylboronic acid (20 mg, 0.126
mmol) was added and heating was increased to 60 °C for 8 h.
This was followed by more 2,4-difluorophenylboronic acid (8
mg, 0.054 mmol) and heating at 80 °C for 2 h. The reaction
mixture was cooled to 20 °C, and water (4 mL) was added to
precipitate crude 3b. The solid was filtered, washed with
water, and dried in vacuo to afford 130 mg of crude 3b. The
crude solid was purified by flash chromatography (10-40%
IPAC/heptane) to afford 104 mg of pure 3b as an off-white solid
(94%). The purity by HPLC condition B was 99%: 1H NMR
(CDCl3) δ 7.67 (ddd, J ) 0.8, 3.6, 10.0, 1H), 7.62 (m, 2H), 7.60
(m, 1H), 7.52 (m, 1H), 7.15 (m, 1H), 7.02 (m, 1H), 6.78 (d, J )
10.0, 1H), 6.45 (d, J ) 0.8, 1H); 13C NMR (CDCl3) δ 164.3 (dd,
JCF ) 11.8, 252.6), 159.9, 160.0 (dd, JCF ) 11.8, 252.6), 154.0,
151.9, 147.0, 137.6 (d, JCF ) 3.3), 135.0, 133.4 (dd, JCF ) 4.3,
10.0), 131.85, 131.88, 129.8, 123.5, 121.2 (dd, JCF ) 4.1, 15.1),
114.5, 112.6 (dd, JCF ) 3.7, 21.6), 108.2, 104.7 (t, JCF ) 25.6);
1-(2,6-Dichlorophenyl)-6-(4-methoxybenzyl)-1,6-naph-
thyridone-2,5,7-(1H,6H,8H)-trione (15). To a solution of
enaminone 12 (7.5 g, 90.5%, 17.35 mmol) in anhydrous
t
N-methylpyrrolidine (52.5 mL) was added 1 M BuOK/THF
solution (24.3 mL). The orange solution exothermed from 23
to 34 °C and became a dark green solution. The solution was
heated to 100 °C, and ethyl ethoxyacrylate (2.84 mL, 19.09
mmol) was added over 1 h. The reaction mixture was stirred
at 100 °C for 3 h, cooled to 30 °C, and poured into a solution
of water (342 mL) and NaCl (2.2 g). The aqueous solution was
washed with MTBE (105 mL × 2), and then nitrogen was
bubbled in for 1 h. HCl (3 N, 12.8 mL) was slowly added over
1-2 h to pH e2 with stirring. The suspension was stirred for
2 h, filtered, washed with water (75 mL × 3), and dried in
vacuo, affording 8.93 g of 15 (80% purity by HPLC condition
A; 92% corrected yield): 1H NMR (CD3CN) δ 8.10 (d, J ) 9.7,
1H), 7.64 (d, J ) 7.8, 1H), 7.56 (t, J ) 7.8, 1H), 7.29 (d, J )
8.5, 2H), 6.84 (d, J ) 8.5, 2H), 6.61 (d, J ) 9.7, 1H), 4.94 (s,
2H), 3.74 (s, 3H), 3.41 (s, 2H); 13C NMR (CD3CN) δ 166.3,
163.0, 160.7, 159.1, 147.9, 138.3, 133.7, 132.3, 132.0, 129.8,
129.6, 129.3, 119.5, 113.6, 107.1, 54.9, 48.9, 42.4, 34.8; LC-
MS (API-ES+) m/z [M + H]+ 443, [M + Na]+ 465; HRMS-
FAB (m/z) [M + H]+ calcd for C22H17Cl2N2O4 443.0565, found
443.0558.
19F NMR (CDCl3) δ -107.0 (d, JFF ) 9.0), -110.1 (d, JFF
)
9.0); LC-MS (API-ES+) m/z [M + H]+ 437, [M + Na]+ 459;
HRMS-FAB (m/z) [M + H]+ calcd for C20H10Cl3F2N2O 436.9827,
found 436.9831.
5-Chloro-1-(2,6-dichlorophenyl)-7-(2,4-difluorophenyl)-
1,6-naphthyridin-2-(1H)-one (21). An analytical pure sample
was obtained by purification with flash chromatography (10-
40% IPAC/heptane) (95% purity by HPLC condition B): 1H
NMR (CDCl3) δ 8.26 (d, J ) 10.0, 1H), 8.15 (m, 1H), 7.60 (d,
J ) 7.9, 2H), 7.50 (t, J ) 7.9, 1H), 7.00 (m, 1H), 6.94 (d, J )
10.0, 1H), 6.83 (s, 1H), 6.82 (m, 1H); 13C NMR (CDCl3, 150.92
MHz) δ 164.1 (dd, JCF ) 12.2, 254.0), 161.0 (dd, JCF ) 12.2,
254.0), 160.2, 152.0 (d, JCF ) 3.2), 150.8, 147.0, 137.0, 135.0,
132.7 (dd, JCF ) 3.7, 9.9), 132.1, 131.7, 129.6, 124.2, 121.7 (dd,
JCF ) 3.8, 10.4), 113.6, 112.4 (dd, JCF ) 3.5, 21.3), 108.6 (d,
JCF ) 13.6), 104.8 (t, JCF ) 26.3); LC-MS (API-ES+) m/z [M
+ H]+ 437, [M + Na]+ 459; HRMS-FAB (m/z) [M + H]+ calcd
for C20H10Cl3F2N2O 436.9827, found 436.9824.
1-(2,6-Dichlorophenyl)-7-hydroxy-1,6-naphthyridine-
2,5-(1H,6H)-dione (18). Crude compound 18 was obtained by
heating a mixture of naphthyridonetrione 15 (0.4 g, 87%, 0.78
mmol) in TFA (2 mL) in a sealed tube at 120 °C for 6 h and
evaporating to dryness. Alternatively, a solution of naphthy-
ridonetrione 15 (0.1 g, 90%, 0.2 mmol) in methanesulfonic acid
(0.5 mL) was stirred at 22 °C for 2 days. H2O (3 mL) was
added, and the solid was filtered to provide 80 mg of crude
18: 1H NMR (DMSO-d6) δ 7.99 (d, J ) 9.6, 1H), 7.78 (d, J )
8.2, 2H), 7.63 (t, J ) 8.2, 1H), 6.22 (d, J ) 9.6, 1H), 4.60 (s,
1H); 13C NMR (DMSO-d6) δ 161.1, 160.5, 159.2, 150.9, 138.8,
134.1, 133.3, 132.3, 129.9, 113.2, 101.7, 75.9; LC-MS (API-
1-(2,6-Dichlorophenyl)-5,7-bis(2,4-difluorophenyl)-1,6-
naphthyridin-2-(1H)-one (22). An analytical pure sample
was obtained by purification with flash chromatography (10-
40% IPAC/heptane) and recrystallized from acetonitrile (98%
purity by HPLC condition B): 1H NMR (CDCl3) δ 8.13 (m, 1H),
10346 J. Org. Chem., Vol. 70, No. 25, 2005

Efficient Synthesis of 1,6-Naphthyridone from ADC
7.41 (dd, J ) 3.5, 10.0, 1H), 7.66 (m, 1H), 7.63 (m, 2H), 7.51
(m, 1H), 7.12 (m, 1H), 7.04 (m, 1H), 6.97 (m, 1H), 6.90 (s, 1H),
6.82 (m, 1H), 6.81 (d, J ) 10.0, 1H); 13C NMR (CDCl3) δ 164.0
(dd, JCF ) 11.9, 252.0), 163.9 (dd, JCF ) 11.9, 252.0), 161.0
(dd, JCF ) 11.9, 252.0), 160.4, 160.1 (dd, JCF ) 11.9, 252.0),
153.7, 152.5 (d, JCF ) 2.8), 145.7, 137.9 (d, JCF ) 3.1), 135.2,
133.4 (dd, JCF ) 4.6, 9.7), 132.8 (dd, JCF ) 3.9, 9.7), 132.4,
131.6, 129.6, 123.4, 122.9 (dd, JCF ) 3.7, 10.9), 122.5 (dd, JCF
) 3.9, 15.3), 114.3, 112.4 (dd, JCF ) 3.6, 21.3), 112.3 (dd, JCF
) 4.0, 20.9), 108.6 (d, JCF ) 12.3), 104.69 (dd, JCF ) 25.7, 27.3),
104.66 (t, JCF ) 25.7); LC-MS (API-ES+) m/z [M + H]+ 515,
[M + Na]+ 537; HRMS-FAB (m/z) [M + H]+ calcd for C26H13-
Cl2F4N2O 515.0341, found 515.0343.
Supporting Information Available: General experimen-
1
tal methods and H, 13C, and 19F NMR spectra for compound
3b. This material is available free of charge via the Internet
at http://pubs.acs.org.
JO0514927
J. Org. Chem, Vol. 70, No. 25, 2005 10347