Pyridone annulation by 4 + 2 coupling of dienolates with nitriles and nitrile equivalents. A solution to the acetonitrile problem

Full text of DOI:10.1021/jo0157876

6826
J . Org. Chem. 2001, 66, 6826-6828
P yr id on e An n u la tion by 4 + 2 Cou p lin g of
Dien ola tes w ith Nitr iles a n d Nitr ile
Equ iva len ts. A Solu tion to th e Aceton itr ile
P r oblem
Yanping Chen, Tindy Li, and Scott McN. Sieburth*,1
Department of Chemistry, State University of New York at
Stony Brook, Stony Brook, New York 11794-3400
F igu r e 1. A nitrile-dienolate condensation approach to
pyridone construction. The dienolate can take several forms.
is the culprit. The acid dianion methodology7 is one of
the more effective methods, but yields with acetonitrile
are low (vide infra).
sieburth@temple.edu
Received May 23, 2001
We required a 6-methyl-2-pyridone, with four ring
carbons derived from a butenoic acid and one from
acetonitrile, or their equivalents. During the course of
this investigation we have surveyed the known ap-
proaches and report here an alternative two-step solution
that provides reasonable overall yields.
As outlined in Figure 1, the dienolate component 3 can
be derived from an acid, an ester, or an amide. For
“simple” ester dienolates 3b, condensation with nitriles
would be expected to be unfavorable, based on pKa values
alone.9-11 In the cases of the dienolates prepared from
acids 3a , and primary and secondary amides 3c, the
reactive species would be a dianion, with presumably
enhanced nucleophilicity. A potential complication of this
reaction is the well-known selectivity of dienolates for
R-alkylation.12 The selectivity with acylating reagents,
however, with their potential for reversibility, has not
been fully addressed.13
In tr od u ction
Assembly of 2-pyridones can be accomplished in a
variety of ways, with many approaches described in
Tieckelmann’s extensive 1974 review.2 New variations
have been reported since, and additional reviews have
appeared.3 During the course of our investigations of
2-pyridone photochemistry,4 we had the opportunity to
explore the formation of a 2-pyridone by coupling a nitrile
with a dienolate, retrosynthetically depicted in Figure
1. Several examples of this reaction are known. Conden-
sation of nitriles with benzyl anions derived from o-
methyl benzamides to form isoquinolinones has been
described by a number of laboratories.5 Condensation of
nitriles with â-keto ester dianions (3b, R4 ) O-) leads to
4-hydroxy-2-pyridones.6 More recently, the dienolate
dianions 3a , prepared from unsaturated carboxylic acids,
have been coupled with nitriles to yield pyridones.7 These
nitrile condensations often give high yields of pyridones
when the nitrile substituent R6 is aromatic or another
nonenolizable group. When the nitrile is aliphatic, how-
ever, the yields suffer, and for acetonitrile (R6 ) methyl)
some reactions are reported to fail.5a,7 The reasonable
speculation has been that deprotonation of the aliphatic
nitriles by the nucleophile, followed by self-condensation,8
Resu lts a n d Discu ssion
We began with 2-methylcyclopentenoic acid14 4 and its
condensation with benzonitrile and acetonitrile, Scheme
1, following the method of Brun.7 In each instance the
desired pyridone was formed in yields comparable to
those reported. Benzonitrile gave the pyridone 5a in good
yield. Unfortunately, simple changes in reaction condi-
tions failed to improve the miserable yields of 5b from
acetonitrile. Reasoning that an amide-derived dienolate
would be sufficiently nucleophilic, we also tried nitrile
condensations with N,N-dimethyl amide 6. This proved
to be significantly better than with 4, and with chiral
substrate 715 the yield from acetonitrile was 44%. Nev-
ertheless, much room for improvement remained.
(1) Address correspondence to this author at Department of Chem-
istry, 201 Beury Hall, 1901 N. 13th Street, Temple University,
Philadelphia, PA 19122.
(2) Tieckelmann, H. Pyridinols and Pyridones. In Heterocyclic
Compounds; Abramovitch, R. A., Ed.; J ohn Wiley & Sons: New York,
1974; Vol. 14, part 3, pp 597-1180.
(3) Meyers, A. I.; Sircar, J . C. Additions to the Cyano Group to Form
Heterocycles. In The Chemistry of the Cyano Group; Rappoport, Z., Ed.;
Interscience: New York, 1970; pp 341-421. McKillop, A.; Boulton, A.
J . Synthesis of Six-membered Rings. In Comprehensive Heterocyclic
Chemistry; Katritzky, A. R., Rees, C. W., Eds.; Pergamon: New York,
1984; Vol. 2, pp 67-98. J ones, G. Pyridines and their Benzo Deriva-
tives: (v) Synthesis. In Comprehensive Heterocyclic Chemistry; Katrit-
zky, A. R., Rees, C. W., Eds.; Pergamon: New York, 1984; Vol. 2, pp
395-510. See also: ref 4.
Attempts to capitalize on the moderate success with 6
and 7, using the dianion of N-methyl amide 9 or the
diisopropylamide 10, failed completely. A similar disap-
pointment met our attempts to employ a zinc dienolate
(4) Sieburth, S. M. The Inter- and Intramolecular [4 + 4] Photo-
cycloaddition of 2-Pyridones and Its Application to Natural Product
Synthesis. In Advances in Cycloaddition; Harmata, M., Ed.; J AI:
Greenwich, CT, 1999; Vol. 5, pp 85-118.
(9) Streitwieser, A., J r.; J uaristi, E.; Nebenzahl, L. L. Equilibrium
Carbon Acidities in Solution. In Comprehensive Carbanion Chemistry,
Studies in Organic Chemistry; Buncel, E., Durst, T., Eds.; Elsevier:
New York, 1980; pp 323-381.
(10) Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456-463.
(11) Activated nitriles can react with less nucleophilic enolates: Lee,
L. F.; Normansell, J . E. J . Org. Chem. 1990, 55, 2964-2967.
(12) Savu, P. M.; Katzenellenbogen, J . A. J . Org. Chem. 1981, 46,
239-250.
(13) J ohnson, P. R.; White, J . D. J . Org. Chem. 1984, 49, 4424-
4429.
(14) Hiranuma, S.; Shibata, M.; Hudlicky, T. J . Org. Chem. 1983,
48, 5321-5326.
(15) White, J . D.; Ruppert, J . F.; Avery, M. A.; Torii, S.; Nokami, J .
J . Am. Chem. Soc. 1981, 103, 1813-1821.
(5) (a) Poindexter, G. S. J . Org. Chem. 1982, 47, 3787-3788. (b) Cho,
W.-J .; Park, M.-J .; Chung, B.-H.; Lee, C.-O. Bioorganic Med. Chem.
Lett. 1998, 8, 41-46.
(6) Huckin, S. N.; Weiler, L. Can. J . Chem. 1974, 52, 1343-1351.
Also â-enamino ketone dianions: Bartoli, G.; Bosco, M.; Cimarelli, C.;
Dalpozzo, R.; De Munno, G.; Guercio, G.; Palmieri, G. J . Org. Chem.
1992, 57, 6020-6025.
(7) Brun, E. M.; Gil, S.; Mestres, R.; Parra, M. Synlett 1999, 1088-
1090.
(8) Schaefer, F. C. Nitrile Reactivity. In The Chemistry of the Cyano
Group; Rappoport, Z., Ed.; Interscience: New York, 1970; pp 239-
305.
10.1021/jo0157876 CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/07/2001

Notes
Sch em e 1. An n u la tion of Acid a n d Am id e
J . Org. Chem., Vol. 66, No. 20, 2001 6827
the yields of 13 are quite reasonable. Heating 13b and
13c with ethanolic ammonia led to a high yield of
pyridones 5b and 5c. The chiral ester 14 also condensed
well with the Weinreb acetamide 12b and was readily
converted to pyridone 8 in high yield. Condensation of
the Weinreb acetamide 12b with N,N-dimethyl amide 7
proceeded in good yield, but attempts to convert the keto-
tertiary amide product to a pyridone with ammonia was
unsuccessful.
Dien ola tes w ith Nitr iles
Con clu sion s
The condensation of Weinreb amides with dienolates
is a useful and practical approach to pyridone annulation,
particularly for enolizable substrates. On the basis of the
work of Turner, it is likely that an excess of dienolate
would enhance the condensation yields.19 For all the
reactions described here, a small excess of the electrophile
was employed. Condensations of N,N-dimethyl amide
derived dienolates with nitriles should prove useful as
well.
Sch em e 2. Un su ccessfu l Con d en sa tion Attem p ts
Exp er im en ta l Section
3-P h en yl-2,5,6,7-tetr a h yd r o-[2]p yr in d in -1-on e (5a ). To a
-78 °C solution of 6 (107 mg, 0.70 mmol) in THF (8 mL) was
added dropwise a solution of LDA (5 mL of a 0.25 M solution in
THF, 1.25 mmol) and the mixture stirred for 1 h. A solution of
benzonitrile (0.097 mL, 0.957 mmol) in THF (3 mL) was added
dropwise, and the mixture was allowed to warm to room
temperature and stirred for 24 h. After dilution with 10% HCl
and extraction with ethyl acetate, the combined organics were
dried and concentrated to give 5a (135.8 mg, 92%) as a light
yellow solid. Recrystallization from methanol/ethyl acetate gave
colorless needles. Rf ) 0.21 (silica gel, 1:19 methanol/methylene
in a vinylogous Blaise reaction16 with acetonitrile (Scheme
2). The simple expedient of condensing ester 11 with
benzonitrile also failed, as expected.
1
chloride). mp ) 214-5 °C (lit. 210-1 °C20). H NMR (CDCl3) δ
11.15 (s, 1H), 7.70 (m, 2H), 7.48 (m, 3H), 6.48 (s, 1H), 2.89 (m,
4H), 2.13 (m, 2H). 13C NMR (CDCl3) δ 162.5, 157.2, 144.9, 133.9,
130.7, 129.6, 129.0, 128.5, 127.3, 126.4, 103.2, 34.4, 29.4, 23.5.
On the other hand, ester enolates (but not dieno-
lates17,18) have been successfully condensed with Weinreb
amides.19 The resulting δ-keto acrylates would be readily
convertible to pyridones. Reaction of the dienolate derived
from 11 with N-methoxy-N-methyl acetamide 12a and
butyramide 12b both gave modest yields of the δ-keto
esters 13b and 13c. Unreacted 11 was also isolated,
consistent with the report that conversion of ester eno-
lates with Weinreb amides are often difficult to drive to
completion.19 On the basis of unrecovered starting 11,
IR (neat): 1633, 1609, 1597 cm-1
.
3-Meth yl-2,5,6,7-tetr a h yd r o-[2]p yr in d in -1-on e (5b fr om
6). Following the procedure used for 5a , using 6 (135.4 mg, 0.885
mmol) and acetonitrile (0.15 mL, 2.9 mmol) gave 5b (0.05 g, 38%)
as a colorless solid. Recrystallization from ethyl acetate gave
colorless needles. Rf ) 0.45 (silica gel, 1:19 methanol/methylene
1
chloride), mp ) 158-9 °C (lit. 160-1 °C20). H NMR (CDCl3) δ
12.24 (s, 1H), 6.02 (s, 1H), 2.79 (t, 4H), 2.32 (s, 3H), 2.04 (m,
2H). 13C NMR (CDCl3) δ 163.3, 157.8, 143.5, 128.2, 104.2, 34.2,
29.2, 23.5, 18.9. IR (neat): 1648, 1566, 1466 cm-1. MS (EI+)
Sch em e 3. Con d en sa tion of Dien ola tes w ith En oliza ble Wein r eb Am id esa
a
Conversion-based yields are in parentheses.

6828 J . Org. Chem., Vol. 66, No. 20, 2001
Notes
m/z (%): 149 (M+, 71), 148 (100), 134 (9), 120 (8). Exact mass
(M - H) m/z: calculated 148.0762, found: 148.0768.
cyclopentenecarboxylic acid15 (4.35 g, 25 mmol) in benzene (50
mL) was slowly added thionyl chloride (10.9 mL) in benzene (15
mL). The solution was heated to reflux for 4 h, evaporated, and
redissolved in benzene (50 mL). The solution was cooled in an
ice bath and dimethylamine (11 mL in 20 mL benzene) was
added dropwise. After stirring for 1 h the mixture was diluted
with water and extracted with ethyl acetate. The combined
organics were washed with water, dried over Na2SO4, and
concentrated in vacuo to give a dark oil which was purified by
flash chromatography (1:19 methanol/methylene chloride) to give
unsaturated amide 7 (4.3 g, 96%). Rf ) 0.47 (silica gel, 1:19
3-Meth yl-2,5,6,7-tetr a h yd r o-[2]p yr in d in -1-on e (5b fr om
11). To a -78 °C solution of 11 (420 mg, 3.0 mmol) in THF (3
mL) was added dropwise to a -78 °C solution of LDA (4.5 mmol
in 20 mL of THF). After 1.5 h, a solution of N-methoxy-N-methyl
acetamide (460 mg, 4.5 mmol) was added and stirring continued
at -78 °C for 2 h. A 10% HCl solution (5 mL) was added, the
mixture was warmed to room temperature and then diluted with
sat. NH4Cl. The aqueous phase was extracted with ethyl acetate,
the combined organics were dried over MgSO4 and purified by
flash chromatography, initially with 1:19 ethyl acetate/hexanes,
to give recovered 11 (232 mg, 55%) and then with 3:17 ethyl
acetate/hexanes, to give methyl 2-(2-oxo-propyl)-1-cyclopentene-
carboxylate 13b (202 mg, 37%; 67% based on recovered 11). Rf
1
methanol/methylene chloride). H NMR (CDCl3) δ 2.99 (s, 7H),
2.27 (m, 2H), 1.90 (m, 1H), 1.78 (m, 1H), 1.66 (s, 3H), 1.58 (m,
1H), 0.88 (d, J ) 6.6 Hz, 3H), 0.74 (d, J ) 6.9 Hz, 3H). 13C NMR
(CDCl3) δ 170.4, 140.0, 134.6, 54.4, 37.6. 37.3, 34.1, 30.3, 24.2,
1
20.9, 17.9, 15.3. IR (neat): 1621, 1445, 1391, 1367 cm-1
.
) 0.35 (silica gel, 1:4 ethyl acetate/hexanes), H NMR (CDCl3):
δ 3.769 (s, 2H), 3.710 (s, 3H), 2.662 (t, J ) 7.5 Hz, 2H), 2.515 (t,
J ) 7.8 Hz, 2H), 2.193 (s, 3H), 1.873 (m, 2H). 13C NMR (CDCl3):
204.9, 166.0, 151.8, 130.1, 51.0, 44.9, 39.0, 33.2, 29.9, 21.3. IR
(neat): 2952, 1713, 1644, 1434, 1358, 1298, 1265 cm-1. MS (EI)
m/z (%): 182 (M+, 5), 150 (100), 108 (42), 81 (70), 43 (64). Exact
mass m/z: calculated 182.0943, found 182.0944.
Keto ester 13b (80 mg, 0.44 mmol) was dissolved in absolute
ethanol (5 mL) in a resealable tube. The solution was saturated
with ammonia, sealed, and heated to 130 °C for 4 h. Removal of
the solvent gave 5b (58 mg, 88%).
N,N-Dim eth yl 2-Meth yl-1-cyclop en ten eca r boxa m id e (8
fr om 7). Following the procedure used for 5a , using 7 (171 mg,
0.88 mmol) and acetonitrile (0.46 mL, 8.8 mmol), gave 8 (73 mg,
44%) as a faintly yellow solid. Rf ) 0.24 (silica gel, 1:19 methanol/
methylene chloride). mp ) 100-102 °C. [R]D ) 28° (CHCl3, 0.08).
1H NMR (CDCl3) δ 11.58 (s, 1H), 5.97 (s, 1H), 3.25 (t, 1H), 2.70
(m, 2H), 2.52 (m, 1H), 2.271 (s, 3H), 1.94 (m, 2H), 0.98 (d, J )
6.9 Hz, 3H), 0.70 (d, J ) 6.9 Hz, 3H). 13C NMR (CDCl3) δ 162.9,
157.9, 143.3, 130.3, 103.9, 48.9, 33.4, 28.7, 23.9, 21.3, 18.9, 16.8.
IR (neat) 1638, 1564, 1465, 1433 cm-1. MS (EI) m/z (%): 191
(M+, 17), 149 (16), 148 (100). Exact mass m/z: calculated
191.1310, found 191.1303.
3-Bu tyl-2,5,6,7-tetr a h yd r o-[2]p yr in d in -1-on e (5c fr om 11).
Following the procedure described for 5b, 11 (420 mg, 3.0 mmol)
and N-methoxy-N-methyl n-pentamide (770 mg, 4.5 mmol) led
to recovered 11 (216 mg) and methyl 2-(2-oxo-hexyl)-1-cyclopen-
tenecarboxylate 13c (159 mg, 24%; 48% based on recovered 11).
Rf ) 0.52 (silica gel, 1:4 ethyl acetate/hexanes), 1H NMR
(CDCl3): δ 3.756 (s, 2H), 3.701 (s, 3H), 2.652 (t, J ) 8.4 Hz,
2H), 2.496 (m, 4H), 1.860 (m, 2H), 1.557 (m, 2H), 1.318 (m, 2H),
0.894 (t, J ) 7.2 Hz, 3H). 13C NMR (CDCl3): δ 107.4, 166.1,
152.1, 130.0, 51.0, 4.1, 42.5, 39.0, 33.2, 25.8, 22.2, 21.4, 13.8. IR
(neat): 2955, 2936, 2871, 1712, 1643, 1434, 1359 cm-1. MS (EI)
m/z (%): 224 (M+, 3), 192 (40), 140 (21), 108 (23), 85 (84), 57
(100). Exact mass m/z: calculated 224.1412, found 224.1412.
Treatment of 13c (57 mg, 0.25 mmol) with ethanolic ammonia
as described for 13b, heating at 130 °C for 6 h, led to isolation
of 5c (42 mg, 86%). Rf ) 0.35 (silica gel, 1:4 methanol/methylene
Meth yl 5-(R)-Isop r op yl-2-(2-oxo-p r op yl)-1-cyclop en ten e-
ca r boxya te (15). To a -78 °C solution of 14 (182.3 mg, 1.00
mmol) in THF (10 mL) was added dropwise a solution of LDA
(0.60 mL of a 2.0 M solution in THF, 1.2 mmol). After 1.5 h, a
solution of N-methoxy-N-methyl acetamide (130 mg, 1.26 mmol)
was added and stirring continued at -78 °C for 2 h. A 10% HCl
solution (1 mL) was added, and the mixture was warmed to room
temperature and then diluted with sat. NH4Cl. The aqueous
phase was extracted with ethyl acetate, and the combined
organics were dried over MgSO4 and purified by Flash chroma-
tography, initially with 1:19 ethyl acetate/hexanes, to give
recovered 14 (54 mg, 30%) and then with 1:4 ethyl acetate/
hexanes, to give 15 (133 mg, 59%). Rf ) 0.39 (silica gel, 1:4 ethyl
acetate/hexanes), [R]D
)
-36.7° (Et2O, 0.105), 1H NMR
1
chloride), H NMR (CDCl3): δ 11.9 (b, 1H), 6.011 (s, 1H), 2.788
(CDCl3): δ 3.78 (d, J ) 15.6, 1H), 3.71 (s, 3H), 3.61 (d, J ) 15.6,
1H), 3.01-3.08 (m, 1H), 2.30-2.60 (m, 2H), 2.19 (s, 3H), 2.02-
2.15 (m, 1H), 1.87 (m, 1H), 1.71 (m, 1H), 0.910 (d, J ) 6.9 Hz),
0.735 (d, J ) 6.9 Hz). 13C NMR (CDCl3): 204.8, 166.2, 151.2,
133.3, 51.6, 50.8, 45.1, 38.2, 29.8, 29.7, 22.3, 21.1, 16.4. IR
(neat): 2956, 1712, 162, 143, 1357, 1298, 1277, 1254 cm-1. MS
(EI) m/z (%): 224 (M+, 2), 192 (59), 149 (100), 107 (34), 43 (29).
Exact mass m/z: calculated 224.1412, found: 224.1423.
(t, J ) 7.5 Hz, 3H), 2.548 (t, J ) 7.5 Hz, 2 H), 2.036 (m, 2H),
1.625 (m, 2H), 1.364 (m, 2H), 0.917 (t, J ) 7.5 Hz, 3H). 13C NMR
(CDCl3): δ 163.1, 157.5, 147.9, 128.5, 103.2, 34.3, 32.7, 30.8, 29.2,
23.5, 22.1, 13.7. IR (NaCl Plate): 2963, 2871, 1632, 1464 cm-1
.
MS (EI) m/z (%): 191 (M+, 31), 162 (10), 149 (100). Exact mass
m/z: calculated 191.1310, found 191.1308.
N,N-Dim eth yl 5-(R)-Isop r op yl-2-m eth yl-1-cyclop en ten e-
ca r boxa m id e (7). To a solution of 5-(R)-isopropyl-2-methyl-1-
Meth yl 5-(R)-Isop r op yl-2-m eth yl-1-cyclop en ten eca r box-
yla t e (8 fr om 15). Keto ester 15 (133 mg, 0.59 mmol) was
dissolved in absolute ethanol (5 mL) in a resealable tube. The
solution was saturated with ammonia, sealed, and heated to 130
°C for 4 h. Removal of the solvent gave 8 (45.2 mg, 85%) which
was pure by NMR.
(16) Hannick, S. M.; Kishi, Y. J . Org. Chem. 1983, 48, 3833-3835.
Lee, A. S.-Y.; Cheng, R.-Y.; Pan, O.-G. Tetrahedron Lett. 1997, 38, 443-
446.
(17) For an R-acylation of an 3-aza dienolate with an enolizable
Weinreb amide, see: Boumendjel, A.; Miller, S. P. F. Tetrahedron Lett.
1994, 35, 819-822.
(18) γ-Condensation of a Weinreb amide with a o-toluamide dian-
ion: Fisher, L. E.; Muchowski, J . M.; Clark, R. D. J . Org. Chem. 1992,
57, 2700-2705.
Ack n ow led gm en t. Support for this research by the
National Institutes of Health is gratefully acknowl-
edged.
(19) Turner, J . A.; J acks, W. S. J . Org. Chem. 1989, 54, 4229-4231.
see also: Dufour, M.-N.; J ouin, P.; Poncat, J .; Pantaloni, A.; Castro,
B. J . Chem. Soc., Perkin Trans. 1 1986, 1895-1899. Campbell, D. A.;
Xiao, X.-Y.; Harris, D.; Ida, S.; Mortezaer, R.; Ngu, K.; Shi, L.; Tien,
D.; Wang, Y.; Navre, M.; Patel, D. V.; Sharr, M. A.; DiJ oseph, J . F.;
Killar, L. M.; Leone, C. L.; Levin, J . I.; Skotnicki, J . S. Bioorg. Med.
Chem. Lett. 1998, 8, 1157-1162. and ref 17.
Su p p or tin g In for m a tion Ava ila ble: Proton NMR spectra
for 5a -c, 7, 8, 13b, 13c, 14, and 15. This material is available
free of charge via the Internet at http://pubs.acs.org.
(20) Davies, L. B.; Leci, O. A.; Sammes, P. G.; Watt, R. A. J . Chem.
Soc., Perkin Trans. 1 1978, 1293-1297.
J O0157876