Dienediolates of α,β-unsaturated carboxylic acids in synthesis: A new synthetic method to 2-pyridones

Article abstract of DOI:10.1055/s-1999-2763

We report a simple procedure for the preparation of 4,6-disubstituted and 3,4,6-trisubstituted-2-pyridones and 3-substituted-1-isoquinolones, in good yields, from lithium dienediolates of α,β-unsaturated carboxylic acids and nitriles.

Full text of DOI:10.1055/s-1999-2763

1088
LETTER
Dienediolates of a,b-Unsaturated Carboxylic Acids in Synthesis: A New
Synthetic Method to 2-Pyridones
Eva M. Brun, Salvador Gil, Ramón Mestres, Margarita Parra*
Departament de Química Orgánica, Universitat de València, Burjassot, València, Spain
Fax: +34 (96) 3983152; E-mail: Margarita.Parra@uv.es
Received 23 April 1999
Abstract: We report a simple procedure for the preparation of 4,6-
O
disubstituted and 3,4,6-trisubstituted-2-pyridones and 3-substitut-
ed-1-isoquinolones, in good yields, from lithium dienediolates of
α,β-unsaturated carboxylic acids and nitriles.
O
H
N
R1
R2
2 Et2NLi
THF
R-CN
R1
OH
CH3
a) R = CH(CH3)2
b) R = CH2CH3
R
R2
Key words: pyridones, isoquinolones, lithium enolates, carboxylic
acids
c) R =
Cl
1, R1 = R2 = H (E)
6, R1 = R2 = H (E)
7, R1 = H ; R2 = CH3
2, R1 = CH3 ; R2 = H (E)
3, R1 = H ; R2 = CH3
4, R1 , R2 = CH2CH2CH2
5, R1, R2= o-C6H4
8, R1 , R2 = CH2CH2CH2
9, R1, R2= o-C6H4
Versatile methods of preparation of functionalized 2-pyri-
dones is an important area of interest due to the high num-
ber of biologically active compounds containing this
structure1 and to the easy conversion of pyridones to the
corresponding pyridines.2 Thus, despite the large number
of methods developed for the synthesis of functionalized
2-pyridones,3 new procedures are being developed contin-
uously.4
d)
CN
Br
O
R2
R1
OH
R2
O
Here we wish to report a new, convenient synthesis of 4,6-
disubstituted and 3,4,6,-trisubstituted 2-pyridones from
α,β-unsaturated carboxylic acids and nitriles.
CN
OH
+
R1
14, R1 = R2 = H (E)
15, R1 = CH3 ; R2 = H (E)
16, R1 = H ; R2 = CH3
NC
11, R1 = R2 = H (E)
12, R1 = CH3 ; R2 = H (E)
13, R1 = H ; R2 = CH3
It is well known that unsaturated carboxylic acids are syn-
thetically useful building blocks. Double deprotonation
by lithium dialkylamides generate their lithium diene-
diolates that behave as ambident nucleophiles, through ei-
ther their α or γ carbon atoms, leading to single or
predominant compounds when allowed to react with elec-
trophiles under adequate conditions.5 Thus, α attack is
favoured for irreversible reactions,6 whereas γ-adducts are
obtained when reversible additions to carbonylic com-
pounds are carried out under equilibrium conditions.7,8
Scheme 1
For the acids 1 and 2, which usually afford E-γ-adducts,9
(Scheme 2) mainly starting material was recovered (en-
tries 1, 2, 4, 5) which was consistent with no addition or
with a low equilibrium constant in the reversible addition
process.
Reactions of these dienediolates with aryl or alkylnitriles
has however remained unexplored. In this particular case
reversible addition leading to γ-adducts might be expected
to prevail. Buten-2-oic acids with an alkyl or aryl substit-
uent at C-3 usually afford Z-γ-adducts. This aspect has led
to cyclized products upon Michael-Dieckmann addition
to unsaturated carboxylic acid lithium salts.9 It is reason-
able therefore that the primary γ-adducts resulting from
these C-3 substituted acids or o-toluic acid and nitriles
would afford pyridine rings (Scheme 1).
R
NLi
R
R1-CN
OLi
OLi
O
R1
OLi
S-trans
R = H
R1
NLi
R1-CN
OLi
OLi
O
The present, preliminary results, summarised in table 1,
show the wide applicability of the method as several α,β-
unsaturated carboxylic acids (1-5) and both alkyl (a, b) or
arylnitriles (c) can be used leading, in a versatile way, to
substituted 2-pyridones (6-8) and 1-isoquinolones (9),
easily isolated as pure compounds in most cases.10
R
R
OLi
S-cis
R = H
Scheme 2
Synlett 1999, No. 07, 1088–1090 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Dienediolates of α,β-Unsaturated Carboxylic Acids in Synthesis
1089
Despite the poor yields found for the latter addition it is of
interest as it shows that both s-cis and s-trans diene-
diolates add to the cyano group. In addition, the highly
substituted polycyclic 2-pyridones which may be easily
obtained from carboxylic acids and 1,2-dicyano com-
pounds and could be of interest in evaluating new reaction
conditions in order to obtain better yields and selectivity
of formation.
In summary, we have found a simple procedure for prep-
aration of 4,6-disubstituted and 3,4,6-trisubstituted-2-py-
ridones from lithium dienediolates, derived from α,β-
unsaturated carboxylic acids and nitriles as starting mate-
rials, which are either commercially available or conve-
niently prepared by conventional or well stabilised
procedures. The method may also be extended to 2-alkyl-
benzoic acids leading to the 1-isoquinolone moieties. In
addition, both 2-pyridones and 1-isoquinolones are easily
isolated from the reaction mixture, as they precipitate on
work-up with water and can be easily purified by a simple
crystallisation.
Acknowledgement
The present research has been financed by DCICYT (PB-95-1121-
C02-01). One of us (E.M.B.) acknowledges a grant by DGICYT.
References and Notes
We expected the addition of dienediolates to nitriles to be
a slow process as it has been described that cyano alde-
hydes led, with good yield, to the corresponding cyano
hydroxy acids.8 However being reversible additions it is
not clear if it is a kintically preferred attack to the carbonyl
moiety. Taking into account that the alkylation of a benz-
ylic substrate is an irreversible reaction, we examined a
competition reaction using 2-cyanobenzylbromide (en-
tries 3, 6 and 10). Only 2-cyano alkylation products (11 to
16) were obtained (Scheme1), showing that alkylation is
faster than addition to the nitrile.6 The isoindole corre-
sponding to an addition to the nitrile and intramolecular
substitution of the bromide by the nitrogen atom has not
been detected in the reaction products.
(1) Schultz, A. G. Chem. Rev. 1973, 73, 385-405. Williams, D. R;
Lowder, P. D.; Gu, Y-G. Tetrahedron Lett. 1997, 38, 327-330.
Kozikowski, A. P.; Campiani, G.; Sun, L-Q.; Wang, S.;
Saxena, A.; Doctor, B.P. J. Am. Chem. Soc. 1996, 118, 11357-
11362. Curran, D. P.; Liu, H. J. Am. Chem. Soc. 1992, 114,
5863-5864.
(2) Murray, T. J.; Zimmerman, S. C. Tetrahedron Lett. 1995, 36,
7627-7630. Lee, L. F.; Normansell, J. E. J. Org. Chem. 1990,
55, 2964-2967.
(3) Meislich, H. In Pyridine and its derivatives, vol. 3;
Klingsberg, E., Ed.; Interscience: New York, 1962; p 509-
890. Jones, G. In Comprehensive Heterocyclic Chemistry II;
Katritzky, A.; Rees, C. W.; Scriven, E. F., Ed.; Pergamon
Press: Oxford, 1996; p 395-510.
(4) Jain, R.; Roschangar, F.; Ciufolini, M. A. Tetrahedron Lett.
1995, 36, 3307-3310. Tohda, Y.; Yanagidani, T.; Hiramatsu,
S-i.; Nishiwaki, N.; Tani, K.; Ariga, M. Bull. Chem. Soc. Jpn.
1997, 70, 2781-2790.
(5) Mekelburger, H. B.; Wilcox, C. S. In Comprehensive Organic
Synthesis; Trost, B. M.; Fleming, I., Ed.; Pergamon
Press:Oxford, 1991; p 99-131. Thomson, C. M. Dianion
Chemistry in Organic synthesis; CRS Press: Boca Raton
(Florida), 1994; p 88-129. Aurell, M. J.; Gaviña, P.; Mestres,
R. Tetrahedron 1994, 50, 2571-2582. Brun, E. M.; Gil, S.;
Mestres, R.; Parra, M.; Villar, F. Tetrahedron Lett. 1998, 39,
1055-1058. Aurell, M. J.; Ceita, L.; Mestres, R.; Parra, M.;
Tortajada, A. Tetrahedron 1995, 51, 3915-3928.
(6) Cainelli, G.; Cardillo, G.; Contento, M.; Umani-Ronchi, A.
Gazz. Chim. Ital. 1974, 104, 625-627. Katzenellenbogen, J.
A.; Savu, P. M. J. Org. Chem. 1981, 239-250. Brun, E. M.;
Gil, S.; Mestres, R.; Parra, M. Tetrahedron 1998, 54, 15305-
15320.
Additions to acetonitrile have not been included because
a polymeric material was formed, and the corresponding
pyridones cannot be the obtained reliably.
We have extended this method to include 1,2-dicyano-
benzene (Scheme 3) and here surprisingly products 17 and
18 were isolated upon addition to lithium dienediolates of
acids 2 and 3, in 9% and 39% yield, respectively.
O
CN
CN
NH
O
R1
R2
R1
R2
N
OH
CH3
Et2NLi
2, R1 = CH3 ; R2 = H (E)
3, R1 = H ; R2 = CH3
17, R1 = CH3 ; R2 = H
18, R1 = H ; R2 = CH3
(7) Cainelli, G.; Cardillo, G.; Contento, M.; Umani-Ronchi, A. J.
Chem. Soc. Perkin Trans I 1973, 400-404. Johnson, P. R;
White, J. D. J. Org. Chem. 1984, 49, 4424-4429.
Scheme 3
Synlett 1999, No. 07, 1088–1090 ISSN 0936-5214 © Thieme Stuttgart · New York

1090
E. M. Brun et al.
LETTER
–78 °C to room temperature over 24h and then poured into
(8) Parra, M.; Mestres, R.; Aparicio, D.; Durana, N.; Rubiales, G.
J. Chem. Soc. Perkin Trans. I 1989, 327-332.
water (50 mL). In most cases the 2-pyridone crystallize from
this mixture and can be directly isolated, otherwise it was
extracted with ethyl acetate. When the reaction fails to go to
completion, the acidic products are extracted, from the
aqueous layer, by acidification with conc. hydrochloric acid at
0ºC and extracted with ethyl acetate. The combined organic
layers were washed with brine to neutral pH and dried
(MgSO4). Evaporation of solvent, gave the crude acidic
fraction.
(9) Aurell, M. J.; Gaviña, P.; Gil, S.; Parra, M.; Tortajada, A.;
Mestres, R. Synth. Commun. 1991, 1825-1831. Aurell, M. J.;
Gaviña, P.; Mestres, R. Tetrahedron 1994, 50, 2571-2582.
Aurell, M. J.; Gil, S.; Mestres, R.; Parra, M.; Tortajada, A.
Tetrahedron 1994, 50, 5109-5118.
(10) Typical Reaction procedure: Diethyl amine (1 mmol) in THF
(2 mL) was added dropwise at -78° C to butyllithium 1.6 M in
THF (5 mmol) and the solution was stirred for 1/2h at 0 °C.
The unsaturated carboxylic acid (2.25 mmol) in THF (2 mL)
was then added dropwise at –78° C. After 1/2h at 0° C a
solution of nitrile (2.25 mmol. in 2 mL of THF) was added at
–78° C. The mixture was stirred and gradually warmed from
Article Identifier:
1437-2096,E;1999,0,07,1088,1090,ftx,en;L04699ST.pdf
Synlett 1999, No. 07, 1088–1090 ISSN 0936-5214 © Thieme Stuttgart · New York