Electron Deficient Dienes. 2. One Step Synthesis of a Coumarin ...

LETTER 477
Electron Deficient Dienes.
2. One Step Synthesis of a Coumarin-Fused Electron Deficient Diene and its
Inverse Electron Demand Diels-Alder Reactions with Enamines.
Graham J. Bodwell, * Zulan Pi, Ian R. Pottie
Chemistry Department, Memorial University of Newfoundland, St. John’s, Newfoundland, Canada, A1B 3X7
Fax: +1 (709)-737-3702; E-mail: gbodwell@morgan.ucs.mun.ca
Received 1 December 1998
Abstract: A coumarin-fused electron deficient diene was prepared
by the base-induced reaction of dimethyl glutaconate and salicaldehyde.
Its inverse electron demand Diels-Alder reactions with enamines
give, after in situ elimination and dehydrogenation,
benzocoumarins.
Key words: Diels-Alder, inverse electron demand, coumarins,
enamines
In an effort to expand the field of inverse electron demand
Diels-Alder (IEDDA) chemistry, 1 we are engaged in research
concerned with the synthesis and IEDDA reactions
of electron deficient dienes that bear electron withdrawing
groups at the 1 and 3 positions, i.e. 1. 2-5 Our first paper in
this area described the synthesis and some IEDDA reactions
of the electron deficient diene 2, 6 which was prepared
in five steps from 2-cyclohexen-1-one.
With an eye to the development of a more expedient synthetic
route to derivatives of 1, an investigation of vinylogous
Knoevenagel condensations between glutaconate
esters and aldehydes was initiated (Scheme 1). The reactions
of dimethyl glutaconate 3 with aldehydes 4a-c each
resulted in the complete consumption of the reactants and
the formation of intractable materials. Some simple members
of the family defined by 1 have been reported to be
unstable, 3 so it may be that the desired products 5a-c reacted
further under the conditions of their formation. Diene
5c has been previously reported, 5 but no comment was
made regarding its stability. 7
The failure of these reactions led to an investigation the
use of salicaldehyde 4d. This worked quite well, giving
the coumarin-fused 5d in 69% yield. 8 The partial aromatic
character of the 2-pyrone moiety likely contributes to the
enhanced stability of 5d (> 6 months in air) compared to
2 (a few days in air) as well as lower IEDDA reactivity.
Whereas 2 reacts with ethyl vinyl ether, 6 5d is unreactive
under the same conditions. Attempts to promote this reaction
by Yb(OTf) 3 or Eu(hfc) 3 catalysis 9 also failed.
Diene 2 reacts readily with enamine 6 in hot acetonitrile
solution to afford the tricycle 9 (45%) (Scheme 2). Under
these conditions, neither the adduct 7 nor the new diene 8,
which results from the elimination of morpholine from 7,
is observed. The apparently facile dehydrogenation of 8 is
interesting. Since no reduced disproportionation products
were observed, it would seem, as Danishefsky speculated
for a related system, 10 that the aromatization probably occurs
by a process other than disproportionation.
Scheme 2
Scheme 1
Diene 5d reacts with a variety of enamines to give substituted
benzocoumarins (Table 1), which presumably arise
from successive IEDDA reaction, elimination of R 2 NH
and dehydrogenation, analogous to the sequence shown in
Scheme 2. In every case, no other products derived from
5d were isolated.
Under the same conditions used for the reaction between
2 and 6, diene 5d reacted with enamine 10 (Entry 1) to
give benzocoumarin 16 in 45% yield. After some experi-
Synlett 1999, No. 4, 477–479 ISSN 0936-5214 © Thieme Stuttgart · New York

478 G. J. Bodwell et al. LETTER
Table 1
mentation with the reaction conditions (Entries 2-6), it
was found that equivalent yields could be obtained at
room temperature after just 1 h by using CH 2 Cl 2 as the solvent.
The greater solubility of 5d in CH 2 Cl 2 allowed the
reaction to be run at higher concentration than in CH 3 CN.
Changing the amine portion of the enamine from morpholine
to pyrrolidine led to a significant increase in the yield
(64%, Entry 7). Again CH 2 Cl 2 was found to be a better
solvent. Worthy of note is that the corresponding reaction
in CH 3 CN (Entry 8) afforded a small quantity of a byproduct
17. That this compound is the hydrogenated selfcondensation
product of acetophenone may provide some
clue as to how the dehydrogenations are occurring. At this
point room temperature reaction in CH 2 Cl 2 was chosen as
our standard reaction conditions. 11
Reaction of enamine 12 with 5d under standard conditions
(Entry 9) gave 18 (43%). With its geminal methyl groups,
enamine 13 (Entry 10) was not expected to react with 5d
to give an aromatized product, but rather diene 19 (cf. 8).
However the only product isolated was 20 (51%). Its formation
can be explained by a [1,5]-H shift of 19. More extended
conjugation and lesser steric congestion between
one of the geminal methyl groups and the nearby aryl-H
atom in 20 may well be responsible for the readiness with
which the [1,5]-H shift occurs. AM1 calculations using
the Spartan package of software indicated that 20 is 7.9
kcal/mol lower in energy than 19.
Ketene aminal 14 12 reacted with 5d under standard conditions
to afford the aromatized product 21 in 48% yield
(Entry 9). None of the product 22 was obtained, which
suggests that the dehydrogenation of its direct precursor
(cf. 8) occurs more quickly than a [1,5]-H shift. This process
would afford a compound that could aromatize via
the elimination of a second molecule of piperidine.
Although indoles have been reported to participate as dienophiles
in IEDDA reactions, 13 N-methylindole 11 failed
to react with 5d after 7 d in refluxing CH 2 Cl 2 (Entry 12).
A more comprehensive investigation of the IEDDA
chemistry of 5d and its derivatives is now underway, as
are attempts at using the methodology described above in
the synthesis of heterohelicenes and heterokekulenes.
Acknowledgement
The authors gratefully acknowledge the Natural Sciences and Engineering
Research Council (NSERC) of Canada for financial support
of this work.
References and Notes
(1) Boger, D. L. J. Heterocyclic Chem. 1996, 33, 1519-1531.
van der Plas, H. C. Il Farmaco 1995, 50, 419-424. Afarinkia,
K.; Vinader, V.; Nelson, T. D.; Posner, G. H. Tetrahedron
1992, 48, 9111-9171. Boger, D. L. Bull. Soc. Chim. Belg.
1990, 99, 599-615. Boger, D. L.; Weinreb, S. M. Hetero
Diels-Alder Methodology in Organic Synthesis; Academic
Press: New York, 1989. Boger, D. L. Chem. Rev. 1986, 86,
781-793. Boger, D. L. Tetrahedron, 1983, 39, 2869-2939.
(2) Prinzbach, H.; Auge, W.; Basbudak, M. Helv. Chim. Acta
1971, 54, 759-764.
(3) Ahn, K.-D.; Hall, H. K. J. Polym. Sci., Polym. Chem. 1981,
19, 629-644.
(4) Padwa, A.; Gareau, Y.; Harrison, B.; Rodriguez, A.
J. Org. Chem. 1992, 57, 3540-3545. Padwa, A.; Gareau, Y.;
Harrison, B.; Norman, B. H. J. Org. Chem. 1991, 56, 2713-
2720. Padwa, A.; Harrison, B.; Norman, B. H. Tetrahedron
Lett. 1989, 30, 3259-3262. Padwa, A.; Norman, B. H. Tetrahedron
Lett. 1988, 29, 2417-2420.
(5) Rossi, R.; Carpita, A.; Bellina, F.; Cossi, P. J. Organomet.
Chem. 1993, 451, 33-43. Bellina, F.; Carpita, A.; Santis, M.
D.; Rossia, R. Tetrahedron, 1994, 50, 12029-12046.
(6) Bodwell, G. J.; Pi, Z. Tetrahedron Lett. 1997, 38, 309-312.
Synlett 1999, No. 4, 477–479 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER One Step Synthesis of a Coumarin-Fused Electron Deficient Diene 479
(7) 5c was reportedly (ref. 5) purified by column chromatography
and thus exhibits at least a reasonable degree of stability.
(8) Experimental procedure for 5d. To a magnetically stirred,
room temperature solution of salicaldehyde (20.0 g, 0.164
mol) and dimethyl glutaconate (25.9 g, 0.164 mol) in anhydrous
THF (300 mL) was added dropwise piperidine (2.81 g,
0.033 mol). The mixture was stirred for 48 h at reflux, cooled
and concentrated to ca. 40 mL volume under reduced pressure.
The resulting slurry was cooled at 0 °C for about 10 min
and then suction filtered. The precipitate was washed with
cold ether (3 x 10 mL) and then dried under high vacuum to
afford 6d as a pale yellow, analytically pure solid (26.1 g,
69%): m.p. 176-178 °C; 1 H NMR (300 MHz, CDCl 3 ) d 7.88
(s, 1H), 7.62-7.55 (m, 2H), 7.57 (d, J = 15.9 Hz, 1H), 7.37-
7.30 (m, 2H), 7.11 (d, J = 15.7 Hz, 1H), 3.81 (s, 3H); 13 C NMR
(75 MHz, CDCl 3 ) d 167.3, 159.0, 153.5, 143.6, 138.0, 132.9,
128.5, 124.8, 123.2, 122.2, 118.9, 116.9, 116.6, 51.8; IR (nujol)
n = 1727 cm -1 ; UV-Vis (CH 3 OH) l max (log e) 290 (3.63),
315 (3.62) nm; EIMS (70 eV) m/z (%) 230 (M + , 16), 199 (12),
172 (12), 171 (100), 115 (24); Anal. Calcd for C 13 H 10 O 4 : C,
67.82; H, 4.38. Found: C, 67.71; H, 4.27.
(9) Marko, I. E.; Evans, G. R.; Declercq, J. P. Tetrahedron, 1994,
50, 4557-4574.
(10) Danishefsky, S.; Cunningham, R. J. Org. Chem. 1965, 30,
3676-3678.
(11) General procedure for the reaction of 5d with enamines: To a
magnetically stirred, room temperature solution of diene 5d
(1.00 g, 4.34 mmol) in CH 2 Cl 2 (25 mL) was added dropwise
over 15 min a solution of the dienophile (6.51 mmol) in
CH 2 Cl 2 (5 mL). After stirring at room temperature for 3 h, the
solvent was removed under reduced pressure and the residue
was chromatographed (SiO 2 , 4% ethyl acetate / CH 2 Cl 2 ).
(12) Baganz, H.; Domaschke, L. Chem. Ber. 1962, 95, 2095-2096.
(13) Wan, Z.-K; Snyder, J. K. Tetrahedron Lett. 1998, 39, 2487-
2490.
Synlett 1999, No. 4, 477–479 ISSN 0936-5214 © Thieme Stuttgart · New York