A general preparation of pyridines and pyridones via the annulation of ketones and esters

Article abstract of DOI:10.1021/jo0155198

A general preparation of pyridines 4a-f from stabilized ketones 3a-c and aryl ketones 3d-f is described. The annulation of stabilized esters 3g,h gives access to the corresponding 2-pyridones 4g,h. The annulation reactions proceed in fair to excellent yie

Full text of DOI:10.1021/jo0155198

4194
J . Org. Chem. 2001, 66, 4194-4199
A Gen er a l P r ep a r a tion of P yr id in es a n d P yr id on es via th e
An n u la tion of Keton es a n d Ester s
J ean-Franc¸ois Marcoux,* Fe´lix-Antoine Marcotte, J immy Wu, Peter G. Dormer,
Ian W. Davies, David Hughes, and Paul J . Reider
Department of Process Research, Merck & Co., Inc., P.O. Box 2000, Rahway, New J ersey 07065
jeff_marcoux@merck.com
Received J anuary 11, 2001
A general preparation of pyridines 4a -f from stabilized ketones 3a -c and aryl ketones 3d -f is
described. The annulation of stabilized esters 3g,h gives access to the corresponding 2-pyridones
4g,h . The annulation reactions proceed in fair to excellent yields (46-87%) with vinamidinium
hexafluorophosphate salts 2a -d containing electron-withdrawing groups at the â-position. The
mechanism of the reaction was investigated by NMR and proceeds through the formation of a
dienaminone intermediate.
Sch em e 1
In tr od u ction
For the past century, classical methods for the forma-
tion of pyridines have been used extensively. Such
methods include the Friedla¨nder condensation of enami-
noketones or â-ketoesters with 1,3-diketones,1 the Hantz-
sch pyridine synthesis from â-dicarbonyl compounds in
the presence of an aldehyde and ammonia,2 and the
related Knoevenagel cyclization of â-aminoacrylates with
R,â-unsaturated carbonyl compounds.3 Despite the nu-
merous studies and applications that have appeared in
the literature,4,5 most methods are still severely limited
in their use by the lack of generality, the harsh reaction
conditions involved, the poor yields, or the formation of
complex mixtures of side products. New methodologies
alleviate some of these limitations.5 They include the
inverse electron-demand Diels-Alder cycloaddition of
triazines with electron-rich alkenes,6 the cycloaddition
of azadienes with Fisher carbenes,7 and the sequential
reaction of metalated phosphonates with nitriles and
unsaturated carbonyl compounds.8
We have recently described how the COX-2 specific
inhibitor Etoricoxib can be assembled by construction of
the central pyridine ring with the introduction of the C-5
substituent in a single step from the readily accessible
ketone 1, 2-chloro-N,N-dimethylamino trimethinium
hexafluorophosphate salt 2a (CDT-phosphate) and am-
monia (Scheme 1).9 As a result of these studies, CDT-
phosphate (2a ) has become available in commercial
quantities. The â-substituted vinamidinium hexafluoro-
phosphate salts 2 are accessible in good yield by reacting
the corresponding acetic acids or acetyl chlorides with
phosphorus oxychloride in DMF at 70 °C followed by
quenching in aqueous HPF6.10,11 The convenient prepara-
tion and stability of hexafluorophosphate vinamidinium
salts renders their use very attractive in synthesis.
We have recently applied this methodology to the
preparation of substituted pyridine derivatives via the
annulation of ketones with vinamidinium salts (Scheme
2).12 The chloropyridine derivatives, which are accessible
(1) (a) Friedla¨nder, P.; Gohring, C. F. Ber. 1883, 16, 1833. For
reviews see: (b) Cheng, C. C.; Yan, S. J . Org. React. 1982, 28, 37. (c)
Caluwe, P. Tetrahedron 1980, 36, 2359.
(2) (a) Hantzsch, A. Liebigs Ann. Chem. 1882, 215, 1. For reviews
on formation of 1,4-dihydropyridines including Hantzsch synthesis
see: (b) Eisner, U.; Kuthan, J . Chem. Rev. 1972, 72, 1. (c) Singh, B.;
Lesher, G. Y. J . Heterocycl. Chem. 1980, 17, 1109.
(3) (a) Knoevenagel, E.; Fries, A. Ber. Dtsch. Chem. Ges. 1898, 31,
761. (b) Mumm, O.; Hu¨neke, H. Ber. Dtsch. Chem. Ges. 1917, 50, 1568.
(c) Mumm, O.; Bo¨hme, O. Ber. 1921, Dtsch. Chem. Ges. 54, 726. (d)
Bohlmann, F. (E. Merck A-G.) German Patent 1190646, 1965. (e)
Kochetkov, N. K.; Khomutova, E. D.; Likhosherstov, L. M. Zh. Obshch.
Khim. 1959, 29, 1657 (Chem. Abstr. 1960, 54, 8815). (f) J u¨tz, C.;
Lo¨bering, H. G.; Trinkl, K.-K. Synthesis 1977, 326.
(4) For an extensive review on the preparation of pyridines and their
benzo derivatives, see: J ones, G. In Comprehensive Heterocyclic
Chemistry; Katritzky, A. R., Rees, C. W., Eds.; Pergamon Press:
Oxford, 1984; Vol. 2, Chapter 8, pp 395-510.
(8) Palacios, F.; de Renanta, A. M. O.; Oyarzabal, J . Tetrahedron
Lett. 1996, 37, 4577.
(5) (a) Larsen, R. D.; Marcoux, J .-F. In Progress in Heterocyclic
Chemistry; Gribble, G. W., Gilchrist, T. L., Eds.; Pergamon: Oxford,
2000; Vol. 12, Chapter 6.1, in press. (b) Larsen, R. D.; Davies, I. W. In
Progress in Heterocyclic Chemistry; Gribble, G. W., Gilchrist, T. L.,
Eds.; Pergamon: Oxford, 1999; Vol. 11, Chapter 6.1, pp 230-255 and
prior years.
(6) (a) Barlow, M. G.; Sibous, L.; Suliman, N. N. E.; Tipping, A. L.
J . Chem. Soc., Perkin Trans. 1 1996, 519. (b) Seitz, G.; Siegl, J . Z.
Naturforsch. 1997, 52b, 851. (c) Iwamoto, K.-I.; Uishi, E.; Sano, T.;
Tsuchiya, A.; Suzuki, Y.; Higashimo, T.; Miyashita, A. Heterocycles
1997, 45, 1551.
(9) Davies, I. W.; Marcoux, J .-F.; Corley, E. G.; J ournet, M.; Cai,
D.-W.; Palucki, M.; Wu, J .; Larsen, R. D.; Rossen K.; Pye, P. J .;
DiMichele, L.; Dormer, P.; Reider, P. J . J . Org. Chem. 2000, 65, 8415.
(10) Davies, I. W.; Marcoux, J .-F.; Wu, J .; Palucki, M.; Corley, E.
G.; Robbins, M. A.; Tsou, N.; Ball, R. G.; Dormer, P.; Larsen, R. D.;
Reider, P. J . J . Org. Chem. 2000, 65, 4571.
(11) Davies, I. W.; Taylor, M.; Marcoux, J .-F.; Wu, J .; Dormer, P.;
Hughes, D.; Reider, P. J . J . Org. Chem. 2001, 66, 251.
(12) Marcoux, J .-F.; Corley, E. G.; Rossen, K.; Pye, P. J .; Wu, J .;
Robbins, M. A.; Davies, I. W.; Larsen, R. D.; Reider, P. J . Org. Lett.
2000, 2, 2339. For preparation of pyridine N-oxide derivatives, see:
Davies, I. W.; Marcoux, J .-F.; Reider, P. J . Org. Lett. 2001, 3, 209-
211.
(7) Barluenga, J .; Tomas, M.; Lopez-Pelegrin, J . A.; Rubio, E.
Tetrahedron Lett. 1997, 38, 3981.
10.1021/jo0155198 CCC: $20.00 © 2001 American Chemical Society
Published on Web 05/15/2001

General Preparation of Pyridines and Pyridones
J . Org. Chem., Vol. 66, No. 12, 2001 4195
Sch em e 2
Sch em e 3
from CDT-phosphate, are of interest to us and can be
further functionalized via efficient palladium-catalyzed
carbon-carbon and carbon-nitrogen coupling reactions13
as recently reported by Buchwald14 and Fu.15 Although
this new reaction allows the direct formation of pyridines
from ketones, it was limited to R-aryl ketones or alde-
hydes and required the use of excess carboxylic acid (7-8
equiv) and ammonium hydroxide (10 equiv). The exten-
sion of the methodology to a broader range of carbonyl
compounds is of strategic interest since it would be
amenable to the generation of combinatorial libraries.
Moreover, the simplicity of the reaction allows the large-
scale preparation of substituted pyridines in a very
straightforward manner.
Although other bases such as triethylamine and pyridine
could also be used, DABCO gave the best results.
Preformation of the enolate with t-BuOK was essential
for the reaction to proceed. The addition of DBU or
stronger bases such as alkoxides or amides to the
preformed enolate/CDT mixture led to extensive decom-
position of CDT. The reaction did not proceed in toluene,
dichloromethane, or DMSO. Although DMF is a suitable
solvent, it was used only when a higher temperature of
cyclization was required (vide infra) since under other-
wise identical conditions the enolate reaction was slower
and translated into lower conversions. The reaction is
slow and incomplete when conducted in wet solvents.17
The ketoamide 3b reacted in excellent yield under the
reaction conditions (entry 3). 1,3-Diketones reacted more
slowly, and the conversion was incomplete. In this case,
the addition of DABCO did not accelerate or drive the
reaction to completion. The annulation of 1,3-cyclohexa-
dione proceeded in an unoptimized 46% assay yield to
give the azatetralone 4c in a single step. The azatetralone
is an intermediate in the synthesis of an aldose reductase
inhibitor, which was previously prepared in five steps
from 3-bromo-5-chloro-2-pyridone.18 Replacement of the
CDT by the more electrophilic nitro-substituted iminium
salt 2b allowed a complete consumption of the enolate
in few minutes at room temperature and increased the
yield of cyclization to 80% (Scheme 4). Nitropyridines are
useful precursors to 3-aminopyridines. This result is
significant since the â-phthalimidyl vinamidinium salt
behaves poorly (vide infra) and alternative 2-amino
vinamidinium salts did not react under standard condi-
tions.19
In this paper, we report the annulation of stabilized
ketones and esters with vinamidinium salts under sim-
plified reaction conditions to give the corresponding
substituted pyridines and pyridones in fair to excellent
yields.
Resu lts a n d Discu ssion
Enolates of aldehydes, ketones, and esters are known
to add to vinamidinium salts to produce dienaminones
in moderate to good yields.16 For initial studies, methyl
acetoacetate (3a ) was chosen as a representative ketone.
The ketone was reacted with CDT-phosphate (2a ) ac-
cording to the Nair procedure16 in the presence of sodium
hydride and pyridine in THF, and the resulting inter-
mediate was reacted in situ with an excess of ammonium
hydroxide at reflux to give 27% assay yield of the desired
2-methyl-3-methoxycarbonyl-5-chloropyridine (4a ). Pre-
forming the enolate with t-BuOK followed by reaction in
THF at 40-65 °C gave improved results, with the yield
of 4a increasing to 60%, although substantial starting
material remained unreacted. Upon further optimization,
it was found that addition of an equimolar amount of
DABCO to the mixture of preformed potassium enolate
and CDT-phosphate in THF for 3 h at 45 °C gave com-
plete conversion (Scheme 3).
Acyclic diketones such as dibenzoylmethane, trifluo-
romethylacetylacetone, and acetylacetone were unreac-
tive and failed to give preparatively useful yields of the
cyclized products. Enolates that are unstabilized reacted
in lower yields. While the less stabilized enolate meth-
oxymethyl phenyl ketone (Table 1, entry 6) proceeded in
modest yield (36%), the condensation of acetophenone
and 2-acetyl pyridine proceeded in only 14-15% to give
the pyridines 4e-f (entries 7 and 8). This is a limitation
of the current methodology, but studies are underway to
extend the reactivity of unstabilized enolates with related
vinamidinium analogues.20
The disappearance of the starting material was moni-
1
tored by H NMR. Ammonium acetate was added to the
resulting adduct, and ring closure to the pyridine oc-
curred upon heating at reflux in THF for a few hours to
give the desired pyridine 4a in 84% isolated yield (Table
1, entry 1). DABCO accelerated the addition reaction and
led to complete consumption of the preformed potassium
enolate. The reaction conducted with t-BuOK in the
absence of DABCO did not go to completion and resulted
in 68% assay yield of the desired pyridine (entry 2).
Significantly, the reaction is not limited to ketones
but can also be applied to esters. 3-Phenyl-5-chloropyri-
(13) The palladium-catalyzed Suzuki coupling of 4a with 4-meth-
oxyphenyl boronic acid using (di-tert-butylphosphino)biphenyl as a
ligand under reactions conditions reported in ref 14 gave the corre-
sponding aryl pyridine in an unoptimized 60% yield.
(14) Wolfe, J . P.; Singer, R. A.; Young, B. H., Buchwald, S. L. J .
Am. Chem. Soc. 1999, 121, 9550.
(15) Littke, A. F.; Dai, C.; Fu, G. C. J . Am. Chem. Soc. 2000, 122,
2040.
(16) Nair, V.; Cooper, C. S. J . Org. Chem. 1981, 46, 4759.
(17) Solvents that contain >300 µg H2O/mL as determined by Karl
Fisher titration.
(18) (a) Quallich, G. J .; Fox, D. E.; Friedmann, R. C.; Murtiashaw,
C. W. J . Org. Chem. 1992, 57, 761-764. (b) Quallich, G. J . (Pfizer Inc.)
U.S. Patent 5677458, 1997.
(19) For the preparation of 2-amino vinamidinium salts, see: Arnold,
Z. Collect. Czech. Chem. Commun. 1973, 38, 1168.
(20) For the preparation and reactivity of vinamidinium analogues,
see ref 11.

4196 J . Org. Chem., Vol. 66, No. 12, 2001
Marcoux et al.
Ta ble 1. An n u la tion of Keton es a n d Ester s w ith N,N-Dim eth yl-2-ch lor o-tr im eth in iu m Hexa flu or op h osp h a te
(CDT-p h osp h a te) 2a a
a
Unless otherwise noted, all reactions were conducted in THF using 1.05 equiv of 20 wt % t-BuOK/THF and 1.5 equiv of CDT-phosphate.
Assay determined by HPLC using an analytically pure sample of the final product as standard. c 1.0 equiv of DABCO was added to the
b
CDT-enolate mixture. 1.0 equiv of 3c and 0.5 equiv of CDT-phosphate were used (yield based on CDT-phosphate). e The cyclization
d
with ammonium acetate was performed at 120 °C in DMF.
Ta ble 2. An n u la tion of Meth yl Acetoa ceta te w ith
Su bstitu ted N,N-Dim eth yla m in ovin a m id in iu m
Hexa flu or op h osp h a te Sa ltsa
Sch em e 4
done 4g was formed cleanly from ethyl phenylacetate
(entry 9). The cyclization on the ester required a solvent
switch to DMF prior to the addition of ammonium acetate
and heating at a temperature of 120 °C for 12 h. Dimethyl
malonate reacted under similar reaction conditions to
give 3-hydroxycarbonyl-5-chloro-2-pyridone 4h in 78%
yield after hydrolysis of the ester moiety (entry 10).
The scope of the reaction was examined by reacting
methyl acetoacetonate with various substituted methin-
ium salts (Table 2). As previously reported in the case of
R-aryl ketones,12 the reaction was highly sensitive to the
nature of the substituent at the â-position of the vina-
midinium salts. Although excellent yields are obtained
with CDT (entry 1), the replacement of chloride by a nitro
group led to a very reactive electrophile that, in contrast
with cyclohexanedione, reacted unselectively with methyl
acetoacetonate to give a mixture of products.21
The reaction did proceed in good yields in the case of
aryl-substituted salts (entries 2-4). Previously, aryl-
substituted vinamidinium salts were found to be unre-
active when treated with the potassium enolate of
ketosulfone 1 followed by quench in acetic acid and
TFA.12 The yields obtained are directly linked to the
capacity of the â-substituent to stabilize a negative
(21) The major product identified was methyl 3-nitro-4-N,N-dim-
ethylaminobenzoate and was isolated in 71% yield. A more detailed
account of this work will be reported in due course.

General Preparation of Pyridines and Pyridones
J . Org. Chem., Vol. 66, No. 12, 2001 4197
Sch em e 5
Sch em e 6
charge; the more electron-withdrawing p-nitrophenyl
substituent gave the highest yield at 67%. The unsub-
stituted phenyl group gave 61%, and the electron-
donating p-methoxyphenyl substituent gave 46% yield
(entries 2-4). The lower yield obtained using a phthal-
imidyl group is partly attributed to the weak electrophi-
licity of the substituent but also to partial decomposition
via hydrolysis of the phthalimide moiety under the
reaction conditions (entry 5). As expected, the methyl-
substituted and unsubstituted methinium salts (R ) H,
Me) were unreactive.
The results reported in Table 2 show that the electron-
accepting character of the â-substituent has a dramatic
effect on the rate and the yield of the reaction. Moreover,
no reaction occurs unless an electron-stabilizing group
is present at the â-position. Taken together, these
observations suggest that the vinamidinium salt behaves
as a Michael-type acceptor and that the transition state
involves the formation of a partial negative charge at the
â-carbon of the vinamidinium salt. Studies on unsym-
metrically 1,3-disubstituted vinamidinium salts are cur-
rently underway to further study this mechanistic hy-
pothesis.
Typically, the adduct 9 is not detected by NMR analysis
of the crude reaction mixture and it undergoes elimina-
tion of dimethylamine to form the corresponding di-
enamine (Scheme 6). In some instances where the proton
R to the carbonyl is less acidic, the elimination is
noticeably slower and can be accelerated by addition of
a base such as DABCO. In the case of ketone 1, the
intermediate 7, which required the use of an acid quench
to drive the elimination, was isolated and characterized
by NMR and HRMS.
The intermediates 10, 11, and 12 were isolated by
concentration of the crude reaction mixture followed by
purification on silica gel (1% Et3N, in EtOAc/hexanes)
in 35%, 86%, and 98% yields, respectively (Scheme 6).
The yield of formation of dienaminones 10 and 11 is
within experimental error of the assay yields reported
for the formation of pyridines 4c and 4a from the
corresponding starting ketones. The cyclization of the two
dienaminones 10 and 11, when heated at reflux in THF
in the presence of NH4OAc, proceeded in almost quan-
Mech a n istic Con sid er a tion s
Single-crystal X-ray structure determination revealed
that vinamidinium salts adopt a symmetrical, planar “W”
trans configuration.10-11,22 Although the reaction of the
enolate with the vinamidinium salt leads to the enamine
intermediate 9, two different transitions state models
may be envisaged (Scheme 5). Reaction of the enolate via
a 1,2-type addition on the imine function would go
through the transition state 7, decreasing the positive
charge on the nitrogen atom. A 1,4-addition of the enolate
(Michael-type) on the enaminone moiety leading to the
transition state 8 can also be envisaged. This transition
state would be stabilized by the presence of an electron-
stabilizing substituent attached at the â-position (R3).
(22) CDT-phosphate 2a was shown to have an all “W” conformation
with bond lengths and bond angles within the expected range. The
phenyl and 4-fluorophenyl vinamidinium salts also have identical
conformations (see ref 10-11). See also: Koziol, A.; Palenik, G. J .;
Marson, C. M.; Katritzky, A. R. Acta Crystallogr. 1990, C46, 1282.

4198 J . Org. Chem., Vol. 66, No. 12, 2001
Marcoux et al.
F igu r e 1. 1H NMR data of 11 recorded at 27 °C in d7-DMF in the presence of 1 equiv of NH4OAc. The content of the tube was
heated at 45-65 °C for a period of 15-30 min between each accumulation.
titative yields, whereas in the presence of NH4OH the
reaction proceeded very slowly to give ca. 25% conversion
after 2 days at 65 °C. Although high yields are obtained
for the cyclization of dienamines onto a keto group, the
cyclization on an ester or carboxylate is slower and
proceeds in lower yields. The cyclization of the diester
12 does not proceed in THF at reflux, and a higher
temperature of reaction in DMF is required.
Exp er im en ta l Section
Elemental analyses were performed by Quantitative Tech-
nologies, Inc., Whitehouse, NJ . High-resolution mass spectra
were obtained from M-Scan, Inc., West Chester, PA. Water
content was determined by Karl Fischer titration on a Metro-
hm 737 KF coulometer.
Gen er a l Exp er im en ta l P r oced u r e for th e An n u la tion
of Keton es. To a suspension of the ketone (25 mmol) in dry
THF (50 mL) at 0 °C was added dropwise a 20 wt % solution
of t-BuOK in THF (16.4 mL, 26.3 mmol, 1.05 equiv). The slurry
was stirred at room temperature for 45 min, and the vinami-
dinium hexafluorophosphate salt (11.5 g, 37.5 mmol, 1.5 equiv)
was added in one portion. The resulting mixture was stirred
at 45 °C for 3 h (in the presence of 1.0 equiv of DABCO when
specified), and ammonium acetate (2 equiv) was added in one
portion. The resulting dark solution was heated at reflux for
6 h and concentrated under reduced pressure. The residue was
directly purified by chromatography on silica gel (CH2Cl2 or
CHCl3/MeOH was used as eluent). Alternatively, the residue
after evaporation of the THF can be extracted with ethyl
acetate and washed with water and saturated sodium chloride
solution prior to the purification.
2-Meth yl-5-ch lor o Meth yln icotin a te (4a ). Mp 186-187
°C. 1H NMR (400 MHz, CDCl3): δ 8.58 (d, J ) 2 Hz, 1H), 8.18
(d, J ) 2 Hz, 1H), 3.94 (s, 3H), 2.81 (3H). 13C NMR (100 MHz
CDCl3): δ 165.6, 157.9, 150.5, 137.7, 129.1, 125.9, 52.4, 24.1.
IR (cm-1): 3074, 3036, 3000, 2957, 2925, 2858, 1732. Anal.
Calcd for C8H8ClNO2: C, 51.77; H,4.34; N, 7.55. Found: C,
51.98; H, 4.43; N, 7.44.
2-Meth yl-5-ch lor o Dim eth yln icotin a m id e (4b). 1H NMR
(400 MHz, CDCl3): δ 8.47 (d, J ) 2 Hz, 1H), 7.48 (d, J ) 2 Hz,
1H), 3.13 (s, 3H), 2.86 (s, 3H), 2.47 (s, 3H). 13C NMR (100 MHz
CDCl3): δ 168.0, 152.5, 148.1, 133.4, 132.6, 129.2, 38.2, 34.7,
21.5. IR (cm-1): 3245, 3044, 3017, 2939, 1624, 1500, 1438,
1407, 1272, 1180, 1072, 914, 841. Anal. Calcd for C9H11ClN2O
C, 54.42; H, 5.58; N, 14.10. Found: C, 54.85; H, 5.72; N, 13.72
3-Ch lor o-7,8-d ih yd r o-5(6H)-qu in olon e (4c). 1H NMR
(400 MHz, CDCl3): δ 8.63 (d, J ) 2 Hz, 1H), 8.23 (d, J ) 2 Hz,
1H), 3.12-3.16 (m, 2H), 2.67-2.71 (m, 2H), 2.16-2.24 (m, 2H).
13C NMR (100 MHz CDCl3): δ 196.7, 161.3, 152.1, 134.1, 130.7,
The cyclization of intermediate 11 in the presence of
1
ammonium acetate was followed by NMR (300 MHz H
and 13C) in d7-DMF (Figure 1). The reaction mixture was
heated at 45-65 °C for a period of 15-30 min between
each accumulation. The 1H NMR spectra in Figure 1
show the appearance of an intermediate which was
assigned to 13 (peaks B), along with the formation of
dimethylamine (peak at 2.42 ppm). The concentration of
the species 13 remains more or less constant during the
whole transformation as the cyclization proceeds starting
at a temperature of 45 °C. Coherent with our proposed
mechanism, the concentration of dimethylamine, as
measured by integration at any point during the reaction,
equals the sum of the concentrations of 13 and the final
pyridine 4a . No evidence of attack of ammonia on the
ketone moiety to form an imine intermediate was de-
1
tected by H or 13C NMR.
In conclusion, ketones and esters react with vinami-
dinium salts to give the corresponding pyridine and
pyridone rings with high regioselectivity in fair to excel-
lent yields. The reaction is dependent upon the nature
of the substituent at the â-position of the vinamidinium
species. This methodology represents a novel method to
access the pyridine/pyridone systems and should find
widespread application in heterocyclic chemistry. Further
work is in progress to expand the scope of the reaction
and explore the reactivity of structurally modified me-
thinium reagents.

General Preparation of Pyridines and Pyridones
J . Org. Chem., Vol. 66, No. 12, 2001 4199
128.6, 38.1, 31.8, 21.5. Anal. Calcd for C9H8ClNO: C, 59.52;
H, 4.44; N, 7.71. Found: C, 59.63; H, 4.63; N, 7.55.
2-Meth yl-5-(4-n itr op h en yl) m eth yln icotin a te (6a ). Mp
180-182 °C. 1H NMR (400 MHz, CDCl3): δ 8.89 (d, J ) 2 Hz,
1H), 8.44 (d, J ) 2 Hz, 1H), 8.34-8.38 (m., 2H), 7.76-7.80
(m, 2H), 3.99 (s, 3H), 2.92 (s, 3H). 13C NMR (100 MHz CDCl3):
δ 166.6, 160.4, 150.0, 147.8, 143.2, 137.0, 131.9, 127.8, 125.6,
124.5, 52.6, 24.7. IR (cm-1): 3074, 3036, 3000, 2957, 2928,
1731, 1602, 1518, 1349, 1256, 1234, 1089, 856, 754. Anal. Calcd
for C14H12N2O4 C, 61.76; H, 4.44; N, 10.29. Found: C, 60.73;
H, 4.44; N, 9.76.
2-Meth yl-5-p h en yl Meth yln icotin a te (6b). Mp 85-85.5
°C.1H NMR (400 MHz, CDCl3): δ 8.85 (d, J ) 2 Hz, 1H), 8.40
(d, J ) 2 Hz, 1H), 7.61-7.62 (m., 2H), 7.59-7.60 (m, 2H), 7.47-
7.50 (m, 1H), 3.96 (s, 3H), 2.89 (s, 3H). 13C NMR (100 MHz
CDCl3): δ 166.9, 158.4, 149.9, 136.7, 136.6, 134.0, 129.1, 128.2,
126.9, 125.1, 52.2, 24.4. IR (cm-1): 3058, 3031, 3003, 2975,
2948, 2843, 1728, 1455, 1437, 1319, 1247, 1230, 1085, 761, 698.
Anal. Calcd for C14H13NO2 C, 73.99; H, 5.77; N, 6.16. Found:
C, 73.95; H, 5.97; N, 6.10.
2-Meth yl-5-(4-m eth oxyp h en yl) Meth yln icotin a te (6c).
1H NMR (400 MHz, CDCl3): δ 8.81 (d, J ) 2 Hz, 1H), 8.35 (d,
J ) 2 Hz, 1H), 7.50-7.54 (m., 2H), 6.98-7.01 (m, 2H), 3.94 (s,
3H), 3.85 (s, 3H), 2.85 (s, 3H). 13C NMR (100 MHz CDCl3): δ
167.1, 160.0, 157.8, 149.7, 136.1, 133.7, 129.2, 128.1, 125.2,
114.7, 55.4, 52.3, 24.4. IR (cm-1): 3058, 3048, 3010, 2961, 2928,
2838, 1730, 1612, 1518, 1454, 1249, 1088, 1031, 821, 783. Anal.
Calcd for C15H15NO3 C, 70.02; H, 5.88; N, 5.44. Found: C,
69.81; H, 5.78; N, 5.29.
2-P h en yl-3-m eth oxy-5-ch lor op yr id in e (4d ). 1H NMR
(400 MHz, CDCl3): δ 8.30 (d, J ) 2 Hz, 1H), 7.88-7.92 (m,
2H), 7.39-7.47 (m, 3H), 7.29 (d, J ) 2 Hz, 1H), 3.86 (s, 3H).
13C NMR (100 MHz CDCl3): δ 153.7, 146.5, 139.9, 136.9, 130.7,
129.3, 128.7, 128.1, 118.8, 55.8. LC-MS [M + H]+ 228.7.
2-P h en yl-5-ch lor op yr id in e (4e).23 1H NMR (400 MHz,
CDCl3): δ 8.66 (d, J ) 2 Hz, 1H), 7.96-8.00 (m, 2H), 7.73 (dd,
J ) 8, 2 Hz, 1H), 7.68 (d, J ) 8 Hz, 1H), 7.42-7.52 (m, 3H).
13C NMR (100 MHz CDCl3): δ 155.5, 148.3, 138.0, 136.6, 130.7,
129.4, 128.9, 126.8, 121.2.
2-(P yr id in -2-yl)-5-ch lor op yr id in e (4f).24 1H NMR (400
MHz, CDCl3): δ 8.68 (dd, J ) 5, 1 Hz, 1H), 8.62 (d, J ) 2 Hz,
1H), 8.39 (d, J ) 8 Hz, 1H), 8.38 (dt, J ) 8, 1 Hz, 1H), 7.83
(dt, J ) 8, 1 Hz, 1H), 7.79 (dd, J ) 8, 2 Hz, 1H), 7.32 (ddd, J
) 8,5,1 Hz). 13C NMR (100 MHz CDCl3): δ 155.0, 154.1, 149.0,
147.9, 137.0, 136.5, 132.2, 123.8, 121.8, 121.0.
3-Ca r boxy-5-ch lor o-2-p yr id on e (4h )25 was prepared by
adding dropwise a 20 wt % solution of t-BuOK in THF (26.3
mmol, 1.05 equiv) to a suspension of dimethyl malonate (25
mmol) in dry THF (50 mL) at 0 °C. The reaction mixture was
stirred at room temperature for 45 min, and the vinamidinium
hexafluorophosphate salt (37.5 mmol, 1.5 equiv) was added
in one portion. The resulting mixture was stirred at 45 °C for
6 h. The volatiles were removed in vacuo. DMF was added
(25 mL) followed by ammonium acetate (3 equiv). The resulting
dark solution was heated at 120 °C for 20 h, cooled, and
concentrated under reduced pressure. Water (100 mL) was
added to the black residue, and the mixture was washed with
dichloromethane (3 × 100 mL). The pH of the water solution
was adjusted to 7-8 by addition of aqueous NaOH, and the
solution was further extracted with dichloromethane. The
water layer was concentrated in vacuo until a thick dark oil
was obtained. A brown solid was obtained by vigorous stirring
of the oil in ethyl acetate for several hours at room tempera-
ture. The solid was filtered, and the cake was washed with
ethyl acetate. The resulting beige solid can be recrystallized
from ethyl acetate or IPAc. 1H NMR (400 MHz, CDCl3): δ 9.5-
6.5 (bs, 2H). 13C NMR (100 MHz CDCl3): δ 169.5, 166.8, 148.1,
138.4, 119.0, 115.4. HRMS: calcd for C6H4ClNO3 172.9880,
found 172.9856.
2-Meth yl-5-p h th a lym id yl Meth yln icotin a te (6d ). Mp
1
206-208 °C. H NMR (400 MHz, CDCl3): δ 8.77 (s, 1H), 8.36
(s, 1H), 7.96-2.00 (m, 2H), 7.82-7.85 (m, 2H), 3.94 (s, 3H),
2.91 (3H). 13C NMR (100 MHz CDCl3): δ 166.5, 165.9, 159.3,
149.0, 135.7, 134.7, 131.4, 126.3, 125.2, 123.9, 52.4, 24.5. IR
(cm-1): 3058, 3040, 3026, 2960, 2923, 2853, 1728, 1561, 1470,
1381, 1282, 1218, 1085, 877, 714. Anal. Calcd for C16H12N2O4
C, 64.86; H, 4.08; N, 9.46. Found: C, 63.44; H, 4.05; N, 9.06.
Dien a m in e 10. 1H NMR (400 MHz, CDCl3): δ 6.93 (s, 1H),
5.64 (s, 1H), 2.51-2.54 (m, 2H), 2.43 (s, 6H), 2.36-2.40 (m,
2H), 1.96-2.03 (m, 2H). 13C NMR (100 MHz CDCl3): δ 193.9,
171.8, 119.8, 117.9, 109.9, 96.5, 38.2, 36.2, 27.4, 20.8. LC-MS:
[M + H]+ 228.7, [M + Na]+ 250.7.
1
Dien a m in e 11. Approximately 2:1 mixture of isomers. H
NMR (400 MHz, CDCl3): δ 7.17 (s, 0.5H), 6.83 (s, 1H), 6.73
(s, 0.5H), 5.64 (s, 1H), 3.78 (s, 1.5H), 3.69 (s, 3H), 3.18 (s, 3H),
2.47 (s, 6H), 2.34 (s, 3H), 2.18 (s, 1.5H). 13C NMR (400 MHz,
CDCl3) 192.9, 170.0, 165.8, 149.0, 143.3, 125.6 (broad), 121.0,
112.9 (broad), 97.5, 51.8, 51.2, 43.2, 38.7, 26.4, 20.5. Anal.
Calcd for C10H14ClNO3 C, 51.84; H, 6.09; N, 6.05. Found: C,
51.97; H, 6.01; N, 5.93.
3-Nitr o-7,8-d ih yd r o-5(6H)-qu in olon e (5). The general
experimental procedure was followed with the following
modification: the reaction mixture after the addition of the
vinamidinium hexafluorophosphate salt was aged 45 min at
1
20 °C instead of 45 °C. H NMR (400 MHz, CDCl3): δ 9.48 (d,
Dien a m in e 12. 1H NMR (400 MHz, CDCl3): δ 7.26 (s, 1H),
6.66 (s, 1H), 3.82 (s, 3H), 3.75 (s, 3H), 3.19 (s, 6H). 13C NMR
(100 MHz CDCl3): δ 168.4, 166.1, 147.8, 143.7, 111.3, 97.3,
52.0, 51.9, 43.1, 29.6. Anal. Calcd for C10H14ClNO4 C, 48.49;
H, 5.70; N, 5.66. Found: C, 48.52; H, 5.73; N, 5.51.
Dien a m in e 13. 1H NMR (300 MHz, CDCl3): δ 8.58 (s, 1H),
7.84 (s, 1H), 8.36 (s, 1H), 7.46-7.52 (m, 2H), 7.11-7.20 (m,
2H), 3.95 (s, 3H), 2.80 (s, 3H). 13C NMR (75 MHz CDCl3): δ
165.2, 149.4, 139.5, 135.4, 129.5, 128.7, 128.6, 125.3, 116.6,
116.4, 53.0, 14.7. LC-MS: [M++ 1] 262.1.
J ) 2 Hz, 1H), 9.02 (d, J ) 2 Hz, 1H), 3.30 (t, J ) 6 Hz, 2H),
2.79 (t, J ) 6 Hz, 2H), 2.79 (quint., J ) 6 Hz, 2H). 13C NMR
(100 MHz CDCl3): δ 195.5, 169.0, 147.7, 143.4, 129.9, 127.9,
38.0, 32.7, 21.1. Anal. Calcd for C9H8N2O3: C, 56.25; H, 4.20;
N, 14.58. Found: C, 56.40; H, 4.43; N, 14.35.
(23) Ali, N. M.; McKillop, A.; Mitchell, M. B.; Rebelo, R. A.;
Wallbank, P. J . Tetrahedron 1992, 48, 8117.
(24) Uchida, Y.; Kajita, R.; Kawasaki, Y.; Oae, S. Tetrahedron Lett.
1995, 36, 4077.
(25) Gero, T. W.; J aques, L. W.; Mays, R. P.; Reid, D. H. Synth.
Commun. 1989, 19, 553.
J O0155198