Unique tandem heck-lactamization naphthyridinone ring formation between acrylanilides and halogenated pyridines

Article abstract of DOI:10.1021/jo0613479

The Heck coupling of acrylanilides with 4-bromo-2-chloro-3-iodo-pyridine using palladium acetate can produce bis-Heck products or undergo an unusual tandem Heck-lactamization ring formation to generate 5-chloro-1-aryl-1,6- naphthyridin-2(1H)-ones.

Full text of DOI:10.1021/jo0613479

SCHEME 1. Potential Route to p38 Kinase Inhibitor
Naphthyridinones
Unique Tandem Heck-Lactamization
Naphthyridinone Ring Formation between
Acrylanilides and Halogenated Pyridines
Raymond J. Cvetovich,* Robert A. Reamer, Lisa DiMichele,
John Y. L. Chung, and Jennifer R. Chilenski
Merck Research Laboratories, Merck & Co., Inc., P.O. Box
2000, Rahway, New Jersey 07065
raymond_cVetoVich@merck.com
ReceiVed June 29, 2006
SCHEME 2. Potential Synthetic Route to Naphthyridinone
7ga
The Heck coupling of acrylanilides with 4-bromo-2-chloro-
3-iodo-pyridine using palladium acetate can produce
bis-Heck products or undergo an unusual tandem Heck-
lactamization ring formation to generate 5-chloro-1-aryl-1,6-
naphthyridin-2(1H)-ones.
a (i) NaNO2, 48% HBr, H2O, 25 °C; (ii) LDA, THF, -70 °C, I2.
and tetrazole-ligand Pd(II),4e as well as with aryl bromides using
palladacycle.5 1,6-Naphthyridin-2(1H)-ones have been success-
fully synthesized by Hunt,2 Savarin,6a Larock,6b Erian,6c and
Chung.6d Separately, 1,8-,7a,b 1,5-,7b and 1,7- 7b naphthyridinones
have been synthesized utilizing a number of different ap-
proaches.
Discussion
Trihalopyridine 4 provides a useful substitution pattern about
the pyridine ring to allow the Heck coupling with 2′,6′-
dichloroacrylanilide (5g) at the 3-iodo position to form 6 which
would then be ring closed to synthesize 2-chloro-N-aryl-
naphthyridinone 7. Trihalopyridine 4 was readily synthesized
(see Scheme 2) from 4-amino-2-chloropyridine (2) via Sand-
meyer reaction with NaNO2/aq HBr/KBr at 25 °C (in the
absence of copper catalysts) to make 4-bromo-2-chloropyridine
(3)8 in >98% yield. Deprotonation/iodination using LDA/I2 in
THF at -70 °C produced trihalopyridine 4 in 69% isolated yield
as a crystalline solid.
p38 Mitogen-activated protein (MAP) kinase inhibitors are
known to positively regulate the release of tumor necrosis
factor-R (TNF-R) and interleukin-1 (IL-1) in response to stress.
Therapeutic strategies to target these cytokines have been
clinically validated with biological agents that sequester TNF-
R, resulting in efficacy in the treatment of rheumatoid arthritis
(RA), Crohn’s disease, and psoriasis.1 N-aryl-1,6-naphthyridin-
2(1H)-ones, exemplified by structure 1, have been reported to
be potent p38 MAP kinase inhibitors.2 A synthetic strategy
toward N-arylnaphthyridinones such as 1 could progress from
the Heck coupling of acrylanilides with halo-substituted py-
ridines, followed by cyclization (see Scheme 1). The use of
acrylanilides in Heck coupling reactions has received little
attention in the literature,3 although acrylamide has been
successfully coupled with aryl iodides using palladium acetate,4a
immobilized palladium,4b,c cyclopalladated ferrocenylimines,4d
When acrylanilide 5g reacted with trihalopyridine 4 in DMAC
at 120 °C, in the presence of Pd(OAc)2 and DIPEA, a slow
(4) (a) Zhao, H.; Cai, M.-Z.; Peng, C.-Y.; Song, C.-S. J. Chem. Res.,
Synop. 2002, 1, 28. (b) Zhuangyu, Z.; Yi, P.; Hongwen, H.; Tsi-yu, K.
Synth. Commun. 1990, 20, 3563. (c) Cai, M.-Z.; Zhou, J.; Zhao, H.; Song,
C.-S. J. Chem. Res. Synop. 2002, 2, 76. (d) Wu, Y.; Hou, J.; Yun, H.; Cui,
X.; Yuan, R. J. Organomet. Chem. 2001, 637-639, 793. (e) Gupta, A. K.;
Song, C. H.; Oh, C. H. Tetrahedron Lett. 2004, 45, 4113.
(1) Chen, Z.; Gibson, T. B.; Robinson, F.; Silvestro, L.; Pearson, G.;
Xu, B.; Wright, A.; Vanderbilt, C.; Cobb, M. H. Chem. ReV. 2001, 101,
2449.
(5) Nejjar, A.; Pinel, C.; Djakovitch, L. AdV. Synth. Catal. 2003, 345,
612.
(2) (a) Bao, J.; Hunt, J. A.; Miao, S.; Rupprecht, K. M.; Stelmach, J. E.;
Liu, L.; Ruzek, R. D.; Sinclair, P. J.; Pivinchny, J. V.; Hop, C. E. C. A.;
Kumar, S.; Zaller, D. M.; Shoop, W. L.; O’Neill, E. A.; O’Keefe, S. J.;
Thompson, C. M.; Cubbon, R. M.; Wang, R.; Zhang, W. X.; Thompson, J.
E.; Doherty, J. B. Bioorg. Med. Chem. Lett. 2005, 16, 64. (b) Hunt, J. A.;
Kallashi, F.; Ruzek, R. D.; Sinclair, P. J.; Ita, I.; 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, A.; Zaller, D. M.;
Doherty, J. B. Bioorg. Med. Chem. Lett. 2003, 13, 467.
(6) (a) Savarin, C. G.; Murry, J. A.; Dormer, P. G. Org. Lett. 2002, 4,
2071. (b) Kadnikov, D. V.; Larock, R. C. J. Org. Chem. 2004, 69, 6772.
(c) Erian, A. W.; Sherif, S. M.; Alassar, A.-Z. A.; Elkholy, Y. M.
Tetrahedron 1994, 50, 1877. (d) Chung, J. Y. L.; Cai, C.; McWilliams, J.
C.; Reamer, R. A.; Dormer, P. G.; Cvetovich, R. J. J. Org. Chem. 2005,
70, 10342.
(7) (a) Manley, P. J.; Bilodeau, M. T. Org. Lett. 2004, 6, 2433. (b)
Sherlock, M. H.; Kaminski, J. J.; Tom, W. C.; Lee, J. F.; Wong, S.-C.;
Kreutner, W.; Bryant, R. W.; McPhail, A. T. J. Med. Chem. 1988, 31, 2108.
(3) Hegedus, L. S.; Holden, M. S. J. Org. Chem. 1986, 51, 1171.
10.1021/jo0613479 CCC: $33.50 © 2006 American Chemical Society
Published on Web 10/04/2006
8610
J. Org. Chem. 2006, 71, 8610-8613

SCHEME 3. Acrylanilide 5a-g Productsa
reaction ensued. Multiple products were formed but a minor
product was isolated in ∼10% yield that was identified by NMR
and MS analysis as 2-chloro-naphthyridinone 7g, the structure
of which was confirmed by single-crystal X-ray analysis. Small
amounts of Heck product 6g were found in the reaction mixture
as well as bis-Heck analogue 8g. No known precedents for this
tandem Heck cyclization are known, although intramolecular
cyclization of benzamides have been reported by Buchwald et
al. using palladium catalysis9 and Hunt2 has successfully
cyclized dichloroanilides onto bromopyridines using copper
catalysis,2 with neither procedure involving the use of R,â-
unsaturated amides.
Optimization of reaction conditions led to the use of ethylene
carbonate (EC) as solvent in the presence of dichloroacrylanilide
(2 equiv), Pd(OAc)2 (3 mol %), sodium acetate (3 equiv),
potassium bromide (6 equiv) and water (10 v%). Among the
solvents screened (DMF, DMAC, DMSO, toluene, water,
alcohols, gycol), ethylene carbonate was superior in increasing
the reaction rate, especially in combination with KBr and water
which allowed reaction completion in 3 h at 90 °C and produced
naphthyridinone 7g in yields of up to 85%. The use of other
salts, such as LiBr, CsBr, tetrabutylammonium bromide, and
tetrabutylammonium iodide were compared. While some minor
rates differences were observed, the best additive was KBr, with
yield and reaction rate favored with the use of 6-10 equiv of
KBr. The presence of phosphine ligands or the attempted use
of Hermann’s catalyst led to polymerization of di-chloro-
acrylanilide with the formation of little or no desired product.
The use of nonphosphine ligands, such as neocuproine (2,9-
dimethyl-1,10-phenanthroline) did not result in useful rates but
did favor the production of mono-Heck coupling to give 6g as
the major product. No discernible deviation was observed when
using either a nitrogen atmosphere or allowing exposure to air.
The extension of this unique tandem Heck-lactamization
cyclization reaction to acrylanilides bearing differing aryl substi-
tution was then examined (see Scheme 3). The series of acryl-
anilides 5a-g was prepared by stirring the corresponding aniline
in DMAC and adding acryloyl chloride, followed by crystal-
lization with water.10 In this way each acrylanilide was prepared
in 85-95% yield. Each acrylanilide (2 equiv) was then heated
with trihalopyridine 4 using the conditions described above.
The Heck reaction with acrylanilides 5a-g showed a clear
reaction rate difference that was dependent on the electron
donating/withdrawing ability of the substituents with the fastest
rates of the Heck reaction achieved with electron donating
groups attached to the aryl ring. In most cases two major
products (see Scheme 4) were identified: 2-chloro-naphthyri-
dinone 7a-g and bis-Heck product 8a-g. The selectivity was
observed to vary, with the highest conversions to naphthyridi-
none 7 occurring with the stronger electron withdrawing groups
of acrylanilide 5f and 5g, and bis-Heck byproduct formation
being significant with acrylanilides 5a-e.
a
(i) Ethylene carbonate, NaOAc, KBr, H2O, Pd(OAc)2, 90 °C.
SCHEME 4. Effect of Base on Product Formationa
a (i) Ethylene carbonate, base, KBr, H2O, Pd(OAc)2, 90 °C, 2 h.
were identified, particularly mono-Heck products 6a-f as well
as very small amounts of debrominated mono-Heck products
9a-f (proposed structure based on LCMS of reaction mixtures).
With difluoroacrylanilide 5f and dichloroacrylanilide 5g, the
yields of naphthyridinone 7f and 7g decreased, but remained
the major products.
The effect of base strength was examined in the reaction of
acrylanilide 5c with trihalopyridine 4, using NaOAc, Na2CO3,
K2CO3, Cs2CO3, NaOH, and KOH. Rates and selectivity
differences were readily observed by varying the choice of base
(see Scheme 4). Sodium acetate gave the slowest rate of
consumption of trihalopyridine 4 and produced the greatest
amount of bis-Heck product 8c. Sodium carbonate was faster
than sodium acetate and produced less bis-Heck product. But
potassium carbonate was much faster than sodium carbonate
producing mostly naphthyridinone 7c, similar to NaOH and
KOH. The effect of sodium versus potassium was also seen
between NaOH and KOH, with KOH producing less bis-Heck
coupling and an 88% yield of naphthyridinone 7c. Cesium
carbonate was quite different. Reactions with cesium carbonate
produced naphthyridinone 7c along with a large amount of
debrominated mono-Heck 9c. The variation of base in the
reaction of acrylanilide 7g with trihalopyridine 4 showed little
or no effect, presumably owing to its higher acidic strength and
the effectiveness of NaOAc as a base in that reaction.
When the stoichiometry of the acrylanilide 5a-f was
decreased to 1.1 equiv, yields declined and other byproducts
(8) (a) Talik, T.; Plazek, E. Rocz. Chem. 1955, 29, 1019. (b) Talik, T.;
Talik, Z.; Ban-Oganowska, H. Synthesis 1974, 293. (c) Boucher, E.; Simard,
M.; Wuest, J. D. J. Org. Chem. 1995, 60, 1408. (d) Bouillon, A.; Voisin,
A. S.; Robic, A.; Lancelot, J.-C.; Collot, V.; Rault, S. J. Org. Chem. 2001,
68, 10178.
(9) Wolfe, J. P.; Rennels, R. A.; Buchwald, S. L. Tetrahedron 1996, 52,
7525.
(10) Cvetovich, R. J.; DiMichele, L. Org. Process Res. DeV. 2006, 10,
944.
J. Org. Chem, Vol. 71, No. 22, 2006 8611

SCHEME 5. Formation of Aryl Acrylanilide 6g and 15
brown solid (55.4 g). This was crystallized from methanol (150
mL) by the addition of water (50 mL) to give 41.91 g of tan solids
(69% isolated yield). 1H NMR (400.25 MHz) CDCl3: δ 8.13 (d, J
) 5.1 Hz, 1H), 7.45 (d, J ) 5.1 Hz, 1H). 13C NMR (100.65 MHz)
CDCl3: δ 156.6, 148.6, 143.1, 126.5, 104.1.
Diethyl{2-[(2,6-dichlorophenyl)amino]-2-oxoethyl}phos-
phonate (13). To a solution of diethylphosphonoacetic acid (2 mL,
11.9 mmol) in dichloromethane (10 mL) was added oxalyl chloride
(2.2 mL, 23.9 mmol) at 22 °C under nitrogen. The mixture was
stirred overnight and then concentrated. The brown oil was stirred
under house vacuum for 1 h and then diluted with dichloromethane
(10 mL), followed by the addition of 2,6-dichloroaniline (1.97 g,
11.9 mmol). Pyridine (2.0 mL, 23.9 mmol) was slowly added over
10 min, maintaining <35 °C using a water bath. After stirring for
4-5 h, the reaction mixture was quenched with 1.5 N HCl (16
mL) and brine (20 mL) and extracted with EtOAc (60 mL). The
mixture was filtered to facilitate phase separation. The organic layer
was washed with brine (15 mL), dried (Na2SO4), and evaporated
to dryness to give 4 g of oil. Purification by flash chromatography
(50 to 100% EtOAc/heptane) afforded 2.42 g (60%) of pure product
Unsaturated anilide 6g was prepared by the Emmon-
Wadsworth condensation (see Scheme 5) of aldehyde 12 with
phosphonate 13 then resubjected to the Heck reaction conditions,
but no desired cyclization product was detected. Instead, a slow
steady degradation took place in the absence of acrylanilide 5g,
and bis-Heck products were formed in its presence. In a similar
fashion, the iodoanalogue 15 was prepared from aldehyde 14.11
It likewise failed to cyclize to naphthyridinone 7g when
subjected to the Heck cyclization conditions described above.
In each case, prolonged heating led to unidentified degradates.
While no definitive mechanism can be deduced from the data
available, it appears that following the initial Heck coupling at
the pyridyl iodide position a nondisassociated palladium inter-
mediate is involved in the subsequent ring closure onto the
bromide position.
1
as a white solid. H NMR (400.25 MHz) CDCl3: δ 8.84 (1H),
7.29 (d, J ) 8.1, 2H), 7.12 (t, J ) 8.1, 1H), 4.21-4.14 (om, 4H),
3.09 (d, J ) 20.9, 2H), 1.33 (t, J ) 7.1, 6H). 13C NMR (100.65
MHz) CDCl3: δ 162.4 (J ) 3.7), 133.8, 132.2, 128.6, 128.5, 63.07
(J ) 6.5), 35.05 (J ) 31.0, 16.45 (J ) 6.3). LCMS: C12H16Cl2-
NO4P; m/e 362.0 (10) ) M + Na. HRMS (ES+): calcd for C12H17-
Cl2NO4P (M + 1), 340.02668; found, 340.02755; calcd for
C12H16Cl2NO4PNa (M + Na), 362.00862; found, 362.00889.
(2E)-3-(4-Bromo-2-chloropyridin-3-yl)-N-(2,6-dichlorophe-
nyl)acrylamide (6 g). Potassium tert-butoxide (1 M) in THF (11.5
mL) was added over 5 min to a solution of phosphonoanilide 13
(3.40 g, 10.0 mmol) cooled at 0 °C. The solution was stirred for
1.5 h, then pyridylaldehyde 12 (2.67 g, 10 mmol) as a solid was
added. The resulting solution was warmed to 22 °C and stirred for
2.5 h. Water (125 mL) was added to form a precipitate which was
filtered and washed with water (3 × 50 mL). The product was dried
in Vacuo at 55 °C to give 3.7 g of crystalline white product (93%
yield). 1H NMR (400.25 MHz) d6-DMSO: δ 10.37 (1H), 8.26 (d,
J ) 5.2, 1H), 7.88 (d, J ) 5.2, 1H), 7.59-7.55 (om, 3H), 7.39 (t,
J ) 8.1, 1H), 6.99 (d, J ) 6.1, 1H). 13C NMR (100.65 MHz) d6-
DMSO: δ 162.3, 149.5, 149.2, 135.1, 134.8, 133.4, 132.6, 130.7,
129.7, 129.4, 128.6, 128.2. LCMS: C14H8BrCl3N2O; m/e 406.9
(100) ) M + 1, 408.9 (65), 405.0 (45). HRMS (ES+): calcd for
C14H9BrCl3N2O (M + 1), 404.89584; found, 404.89640.
Summary
A unique tandem Heck-lactamization ring formation of
naphthryidinones in the reaction of acrylanilides with 4-bromo-
2-chloro-3-iodo-pyridine catalyzed by Pd(OAc)2 was discovered
and optimized to produce 5-chloro-1-aryl-1,6-naphthyridin-
2(1H)-ones in good to excellent yields. The effects of solvents,
ring substitution, additives, and choice of base were examined
in optimizing the reaction for reaction rates and yield.
Experimental Section
4-Bromo-2-chloropyridine (3).8d 4-Amino-2-chloropyridine (25.0
g, 194 mmol) was dissolved in 48% HBr (170 mL) and water (180
mL) and cooled to 2 °C. A solution of sodium nitrite (22.7 g, 330
mmol) in water (125 mL) was added dropwise over 1 h, then KBr
(25 g, 210 mmol) was added. The heterogeneous mixture was
allowed to warm to 22 °C and stirred overnight. After the mixture
was cooled to 2 °C, the pH was adjusted to 10 using 50% sodium
hydroxide solution (80 g, 1 mol), and MTBE (300 mL) was added.
The organic phase was separated and evaporated in Vacuo, and a
slightly yellow oil was obtained (38.0 g).
4-Bromo-2-chloro-3-iodo-pyridine (4). A solution of n-butyl-
lithium (2.5 M, 82 mL) was added to diisopropylamine (30.1 mL,
215 mmol) in THF (100 mL) that was cooled to -40 °C. After the
mixture was cooled to -70 °C, a solution of 4-bromo-2-chloro-
pyridine (36.5 g, 190 mmol) in THF (100 mL) was added over 2.5
h, and the mixture was stirred a further 2 h at -70 °C. A solution
of iodine (50.6 g, 200 mmol) in THF (100 mL) was added over 2
h, while maintaining the reaction temperature at less than -65 °C.
This mixture was stirred a further 30 min, then poured into a mixture
of 5% sodium thiosulfate (500 mL) and IPAc (500 mL). The organic
phase was washed with water then evaporated in Vacuo to a dark
(2E)-3-(2-Chloro-4-iodopyridin-3-yl)-N-(2,6-dichlorophenyl)-
acrylamide (15). Potassium tert-butoxide (1 M) in THF (11.5 mL)
was added over 5 min to a solution of phosphonoanilide 13 (3.40
g, 10.0 mmol) cooled at 0 °C. The solution was stirred for 1.5 h,
then pyridylaldehyde 14 (2.67 g, 10 mmol) was added as a solid.
The resulting solution was warmed to 22 °C and stirred for 2 h to
give a precipitate. Water (60 mL) was added, and the precipitate
was filtered and washed with a 1/1 mixture of THF/water (40 mL).
The product was dried in Vacuo at 55 °C to give 3.8 g of crystalline
1
white product (83.9% yield). H NMR (400.25 MHz) d6-DMSO:
δ 10.33 (br s, 1H), 8.05 (d, J ) 5.0, 1H), 8.00 (d, J ) 5.0, 1H),
7.57 (d, J ) 8.1, 2H), 7.50 (d, J ) 16.0, 1H), 7.38 (t, J ) 8.1, 1H),
6.85 (d, J ) 16.0, 1H). 13C NMR (100.65 MHz) d6-DMSO: δ
162.3, 148.8, 147.5, 138.9, 134.3, 134.1, 133.5, 132.6, 129.4, 129.3,
128.5, 113.6. LCMS: C14H8Cl3IN2O; m/e 452.8 (100), 454.8 (90).
HRMS (ES+): calcd for C14H9Cl3IN2O (M + 1), 452.88197; found,
452.88388; calcd for C14H9Cl3IN2ONa (M + Na), 474.86391;
found, 474.86351.
Heck Reactions. General Procedure. A mixture of acrylanilide
(2.0 mmol), 4-bromo-2-chloro-3-iodopyridine (1.0 mmol), sodium
acetate (3.0 mmol), potassium bromide (6.0 mmol), ethylene
carbonate (12 g), water (1.2 mL), and palladium acetate (0.03 mmol)
was heated to 90 °C for 3-12 h. The mixture was poured into
water (25 mL) and toluene (25 mL), the phases were separated,
(11) (a) Rocca, P.; Cochennec, C.; Marsais, F.; Thomas-dit-Dumont, L.;
Godard, A.; Queguiner, G. J. Org. Chem. 1993, 58, 7832. (b) Duvey, G.;
Nivoliers, F.; Rocca, P.; Godard, A.; Marsais, F.; Queguiner, G. J.
Heterocycl. Chem. 2001, 38, 1039.
8612 J. Org. Chem., Vol. 71, No. 22, 2006

and the aqueous phase was re-extracted with toluene (25 mL). The
combined toluene phases were washed with water (3 × 25 mL).
The mixture of phases required filtration to isolate the bis-Heck
product which was insoluble. The Heck-cyclization product,
contained in the toluene extract, can be purified via column
chromatography (silica gel 60, ethyl acetate/hexanes). The bis-Heck
product can be purified by applying a THF dissolved sample to
silica gel 60 and eluting with ethyl acetate.
5-Chloro-1-(4-methoxyphenyl)-1,6-naphthyridin-2(1H)-one (7a).
1H NMR (400.25 MHz) CDCl3: δ 8.19 (dd, J ) 10.0, 0.7 Hz,
1H), 8.13 (d, J ) 5.9 Hz, 1H), 7.18-7.08 (m, 4H), 6.87 (d, J )
10.0 Hz, 1H), 5.56 (dd, J ) 5.9, 0.7 Hz, 1H), 3.89 (s, 3H). 13C
NMR (100.65 MHz) CDCl3: δ 162.0, 160.4, 151.0, 148.5, 148.2,
136.3, 129.5 (2C), 128.8, 124.5, 115.9 (2C), 114.5, 110.4, 55.8.
LCMS: C15H11ClN2O2; m/e 287.0 ) M + 1. HRMS (ES+): calcd
for C15H12ClN2O2 (M + 1), 287.05818; found, 287.06099.
(2E,2′E)-3,3′-(2-Chloropyridine-3,4-diyl)bis[N-(4-methoxyphe-
nyl)acrylamide] (8a). 1H NMR (400.25 MHz) d6-DMSO: δ 10.29
(s, 1H), 10.26 (s, 1H), 8.45 (d, J ) 5.2 Hz, 1H), 7.70-7.68 (m,
7H), 6.97 (d, J ) 15.6 Hz, 1H), 6.94-6.89 (m, 4H), 6.49 (d, J )
15.8 Hz, 1H), 3.74 (s, 3H), 3.73 (s, 3H). 13C NMR (100.65 MHz)
d6-DMSO: δ 161.9, 161.6, 155.6 (2C), 150.5, 148.9, 144.3, 134.9,
133.2, 132.21, 132.00, 131.97, 129.7, 129.2, 120.9 (2C), 120.8 (2C),
120.7, 114.0 (4C), 55.1 (2C). LCMS: C25H22ClN3O4; m/e 486.1
) M + Na.
(s, 1H), 10.44 (s, 1H), 8.45 (d, J ) 5.1 Hz, 1H), 7.75-7.66 (om,
7H), 7.20-7.14 (om, 4H), 6.98 (d, J ) 15.6 Hz, 1H), 6.50 (d, J )
15.9 Hz, 1H). 13C NMR (100.65 MHz) d6-DMSO: δ 162.2, 162.0,
158.3 (d, J ) 240.9 Hz, 2C), 150.5, 149.0, 144.3, 135.4, 135.2
(dd, J ) 2.4 Hz, 2C), 133.8, 131.9, 129.6, 128.9, 121.19 (d, J )
8.0 Hz, 2C), 121.10 (d, J ) 8.0 Hz, 2C), 120.8, 115.4 (d, J ) 22.5
Hz, 4H). LCMS: C23H16ClF2N3O2; m/e 462.1 ) M + Na.
5-Chloro-1-(4-chlorophenyl)-1,6-naphthyridin-2(1H)-one (7e).
1H NMR (400.25 MHz) CDCl3: δ 8.20 (dd, J ) 10.0, 0.7 Hz,
1H), 8.14 (d, J ) 5.9 Hz, 1H), 7.61-7.55 (m, 2H), 7.22-7.17 (m,
2H), 6.86 (d, J ) 10.0 Hz, 1H), 6.51 (dd, J ) 5.9, 0.7 Hz, 1H).
13C NMR (100.65 MHz) CDCl3: δ 161.5, 151.1, 148.4, 147.8,
136.6, 136.0, 134.8, 130.9 (2C), 130.0 (2C), 124.4, 114.4, 110.0.
LCMS: C14H8Cl2N2O; m/e 291.0 ) M + 1. HRMS (ES+): calcd
for C14H9Cl2N2O (M + 1), 291.00864; found, 291.00936.
(2E,2′E)-3,3′-(2-Chloropyridine-3,4-diyl)bis[N-(4-chlorophe-
nyl)acrylamide] (8e). 1H NMR (400.25 MHz) d6-DMSO: δ 10.54
(s, 1H), 10.50 (s, 1H), 8.44 (d, J ) 5.1 Hz, 1H), 7.71-7.64 (m,
7H), 7.40-7.35 (m, 4H), 6.97 (d, J ) 15.6 Hz, 1H), 6.49 (d, J )
15.8 Hz, 1H). 13C NMR (100.65 MHz) d6-DMSO: δ 162.4, 162.1,
150.5, 149.0, 144.2, 137.7 (2C), 135.7, 134.1, 131.8, 129.6, 128.8
(5C), 127.4 (2C), 121.0 (2C), 120.9 (2C), 120.8. LCMS: C23H16-
Cl3N3O; m/e 494.0 ) M + Na.
5-Chloro-1-(2,6-difluorophenyl)-1,6-naphthyridin-2(1H)-
1
one (7f). H NMR (400.25 MHz) CDCl3: δ 8.21 (om, 2H), 7.54
5-Chloro-1-(4-methylphenyl)-1,6-naphthyridin-2(1H)-one (7b).
1H NMR (400.25 MHz) CDCl3: δ 8.17 (dd, J ) 10.0, 0.6 Hz,
1H), 8.09 (d, J ) 5.9 Hz, 1H), 7.39 (m, 2H), 7.11 (m, 2H), 6.84
(d, J ) 10.0 Hz, 1H), 6.52 (dd, J ) 5.9, 0.6 Hz, 1H), 2.44 (s, 3H).
13C NMR (100.65 MHz) CDCl3: δ 161.6, 150.7, 148.1, 148.0,
139.8, 136.1, 133.5, 131.1 (2C), 128.0 (2C), 124.3, 114.2, 110.2,
21.3 LCMS: C15H11ClN2O; m/e 271.0 ) M + 1. HRMS (ES+):
calcd for C15H12ClN2O (M + 1), 271.06327; found, 271.06531.
(2E,2′E)-3,3′-(2-Chloropyridine-3,4-diyl)bis[N-(4-methylphe-
nyl)acrylamide] (8b). 1H NMR (400.25 MHz) d6-DMSO: δ 10.40
(s, 1H), 10.33 (s, 1H), 8.44 (d, J ) 5.1 Hz, 1H), 7.71-7.57 (m,
7H), 7.18-7.10 (m, 4H), 7.04 (d, J ) 15.6 Hz, 1H), 6.51 (d, J )
15.8 Hz, 1H), 2.26 (s, 3H), 2.25 (s, 3H). 13C NMR (100.65 MHz)
d6-DMSO: δ 162.1, 161.9, 150.5, 148.9, 144.3, 136.4, 136.3, 135.0,
133.4, 132.7 (2C), 132.2, 129.7, 129.2 (5C), 120.7, 119.4 (2C), 119.3
(2C), 20.5 (2C). LCMS: C25H22ClN3O2; m/e 454.1 ) M + Na.
5-Chloro-1-phenyl-1,6-naphthyridin-2(1H)-one (7c). 1H NMR
(400.25 MHz) CDCl3: δ 8.20 (dd, J ) 10.0, 0.6 Hz, 1H), 8.12 (d,
J ) 6.0 Hz, 1H), 6.66-7.53 (om, 3H), 7.26-7.22 (om, 2H), 6.87
(d, J ) 10.0 Hz, 1H), 6.49 (dd, J ) 6.0, 0.6 Hz, 1H). 13C NMR
(100.65 MHz) CDCl3: δ 161.6, 151.0, 148.2, 148.1, 136.4 (2C),
130.6 (2C), 129.8, 128.5 (2C), 124.5, 114.4, 110.2. LCMS: C14H9-
ClN2O; m/e 257.0 ) M + 1. HRMS (ES+): calcd for C14H10-
ClN2O (M + 1), 257.04762; found, 257.04848.
(m, 1H), 7.18-7.12 (m, 2H), 6.86 (d, J ) 10.0 Hz, 1H), 6.55 (m,
1H). 13C NMR (100.65 MHz) CDCl3: δ 160.2, 158.8 (dd, J )
254.9, 3.9 Hz, 2C), 151.2, 149.0, 147.1, 137.1, 132.0 (t, J ) 9.6
Hz), 124.0, 114.7, 113.0 (t, J ) 16.9 Hz), 112.9 (dd, J ) 19.3, 4.0
Hz, 2C), 109.1. LCMS: C14H7ClF2N2O; m/e 293.0 ) M + 1.
HRMS (ES+): calcd for C14H8ClF2N2O (M + 1), 293.02877;
found, 293.03006.
(2E,2′E)-3,3′-(2-Chloropyridine-3,4-diyl)bis[N-(2,6-difluorophe-
1
nyl)acrylamide] (8f). H NMR (400.25 MHz) d6-DMSO: δ 10.2
(s, 2H), 8.48 (d, J ) 5.2 Hz, 1H), 7.75 (d, J ) 5.2 Hz, 1H), 7.73
(d, J ) 15.9 Hz, 2H), 7.43-7.34 (m, 2H), 7.23-7.17 (m, 4H),
7.06 (d, J ) 15.8 Hz, 1H), 6.57 (d, J ) 15.9 Hz, 1H). 13C NMR
(100.65 MHz) d6-DMSO: δ 162.7, 162.4, 157.6 (d, J ) 251.2,
4C), 150.4, 149.2, 144.1 (2C), 136.1, 134.6, 130.4, 129.8, 128.3
(t, J ) 9.6, 2C), 127.4, 120.9, 114.1 (t, J ) 16.9), 112.0 (m, 4C)
LCMS: C23H14ClF4N3O2; m/e 498.1 ) M + Na.
5-Chloro-1-(2,6-dichlorophenyl)-1,6-naphthyridin-2(1H)-
1
one (7 g). H NMR (400.25 MHz) CDCl3: δ 8.23 (d, J ) 10.0
Hz, 1H), 8.18 (d, J ) 5.8 Hz, 1H), 7.55 (m, 2H), 7.45 (m, 1H),
6.88 (d, J ) 10.0 Hz, 1H), 6.34 (d, J ) 5.8 Hz, 1H). 13C NMR
(100.65 MHz) CDCl3: δ 159.9, 151.1, 149.0, 146.3, 137.1, 134.8
(2C), 132.0, 131.6, 129.5 (2C), 124.3, 114.5, 108.7. HRMS
(ES+): calcd for C14H8Cl3N2O (M + 1), 324.96967; found,
324.97048.
(2E,2′E)-3,3′-(2-Chloropyridine-3,4-diyl)bis(N-phenylacryla-
1
mide) (8c). H NMR (400.25 MHz) d6-DMSO: δ 10.41 (s, 1H),
(2E,2′E)-3,3′-(2-Chloropyridine-3,4-diyl)bis[N-(2,6-dichlo-
1
10.38 (s, 1H), 8.45 (d, J ) 5.1 Hz, 1H), 7.73-7.65 (m, 7H), 7.37-
7.30 (m, 4H), 7.08 (m, 2H), 7.01 (d, J ) 15.6 Hz, 1H), 6.50 (d, J
15.8 Hz, 1H). 13C NMR (100.65 MHz) d6-DMSO; δ 162.3, 162.1,
150.5, 149.0, 144.3, 138.82, 138.80, 135.3, 133.7, 132.1, 129.7,
129.1, 128.8 (4H), 123.8 (2C), 120.8, 119.41 (2H), 119.36 (2H).
LCMS: C23H18ClN3O2; m/e 426.1 ) M + Na.
rophenyl)acrylamide] (8 g). H NMR (400.25 MHz) d6-DMSO:
δ 10.33 (s, 1H), 10.30 (s, 1H), 8.47 (d, J ) 5.1 Hz, 1H), 7.77 (d,
J ) 5.1 Hz, 1H), 7.71 (d, J ) 15.7 Hz, 1H), 7.69 (d, J ) 15.9 Hz,
1H), 7.62-7.50 (m, 4H), 7.43-7. 30 (m, 2H), 7.10 (d, J ) 15.7
Hz, 1H), 6.59 (d, J ) 15.9 Hz, 1H). 13C NMR (100.65 MHz) d6-
DMSO: δ 162.8, 162.4, 150.4, 149.1, 143.9, 135.8, 134.5, 133.6,
132.61, 132.59, 130.7, 130.0, 129.4, 128.62, 128.60, 127.6, 120.7,
114.1. LCMS: C23H14Cl5N3O2; m/e 541.9 (M + 1, 45), 564.0 (M
+ Na, 20), 379.0 (100). HRMS (ES+): calcd for C23H14Cl5N3O2
(M + 1), 539.9606; found, 539.9607.
5-Chloro-1-(4-fluorophenyl)-1,6-naphthyridin-2(1H)-one (7d).
1H NMR (400.25 MHz) CDCl3: δ 8.19 (dd, J ) 10.0, 0.6 Hz,
1H), 8.14 (d, J ) 5.9, 1H), 7.33-7.21 (m, 4H), 6.85 (d, J ) 10.0
Hz, 1H), 6.50 (dd, J ) 5.9, 0.6 Hz, 1H). 13C NMR (100.65 MHz)
CDCl3: δ 163.0 (d, J ) 250.4 Hz), 161.6, 151.1, 148.4, 148.1,
136.5, 132.2 (d, J ) 3.2 Hz), 130.4 (d, J ) 8.8 Hz, 2C), 124.4,
117.7 (d, J ) 23.3 Hz, 2C), 114.4, 110.0. LCMS: C14H8ClFN2O;
m/e 275.0 ) M + 1. HRMS (ES+): calcd for C14H9ClFN2O (M
+ 1), 275.03820; found, 275.03893.
Supporting Information Available: 1H NMR and 13C NMR
spectra for compounds 3, 4, 6g, 7a-g, 8a-g, 13, and 15.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(2E,2′E)-3,3′-(2-Chloropyridine-3,4-diyl)bis[N-(4-fluorophe-
nyl)acrylamide] (8d). 1H NMR (400.25 MHz) d6-DMSO: δ 10.47
JO0613479
J. Org. Chem, Vol. 71, No. 22, 2006 8613