An unexpected ring-opening of a 2-pyrone ring at low temperatures. A mild and expeditious synthesis of novel coumarins

Article abstract of DOI:10.1016/S0040-4039(01)00456-7

When the iminium salts of ortho-hydroxy arylaldehydes were condensed with a 4-hydroxy-2-pyrone at room temperature or well below, a series of unique coumarins were isolated via a translactonization at the expense of an unexpected ring-opening of the 2-pyr

Full text of DOI:10.1016/S0040-4039(01)00456-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 3283–3286
An unexpected ring-opening of a 2-pyrone ring at low
temperatures. A mild and expeditious synthesis of novel
coumarins
Ossama Saleh Darwish, Kirsten A. Granum, Quang Tan† and Richard P. Hsung*
Department of Chemistry, University of Minnesota, Minneapolis, MN 55455, USA
Received 5 February 2001; accepted 12 March 2001
Abstract—When the iminium salts of ortho-hydroxy arylaldehydes were condensed with a 4-hydroxy-2-pyrone at room
temperature or well below, a series of unique coumarins were isolated via a translactonization at the expense of an unexpected
ring-opening of the 2-pyrone nucleus. © 2001 Elsevier Science Ltd. All rights reserved.
Coumarin is an important structural motif present in a
variety of natural and unnatural products that possess
significant biological activities.1–3 Given its immense
medicinal value, new protocols for the preparation of
coumarins have been continuously sought after, rang-
ing from transition metal-catalyzed processes4 to classi-
cal lactonizations.5 We have been studying reactions of
a,b-unsaturated iminium salts with various 1,3-diketo
equivalents.6–9 These reactions proceed in a tandem
process consisting of a Knoevenagel condensation,10,11
followed by a 6p-electron electrocyclic ring-closure,12
leading to unique approaches for constructing complex
heterocycles. These studies led us to also examine the
use of iminium salts generated from aromatic
aldehydes.13
As shown in Scheme 1, we envisioned that reactions of
4-hydroxy-2-pyrones, such as 1, with the iminium salt 2
or 3 could lead to Knoevenagel condensation products
4 or 5, and subsequent ring-closure and/or lactol for-
mation could lead to intermediates such as 6, 7, or 8.
Aromatization and/or nucleophilic additions could lead
Scheme 1.
* Corresponding author.
† 1999 McNair Undergraduate Summer Research Fellow from St. Olaf College.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00456-7

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O. S. Darwish et al. / Tetrahedron Letters 42 (2001) 3283–3286
to useful heterocycles such as 9 and 10.14 However,
instead we isolated a product that was neither 9 nor 10
but a coumarin as a result of translactonization due to
an unexpected ring-opening of the 2-pyrone ring under
neutral conditions and at temperatures even well below
room temperature. We report here our findings and its
application as a mild and expeditious synthesis of vari-
ous novel coumarins.
Knoevenagel condensation–lactonization using acyclic
b-ketoesters is known to be very useful for the synthesis
of coumarins.5 However, a similar sequence that would
involve ring-opening of a 2-pyrone ring is unusual at
temperatures well below room temperature and, in this
case, many elegant tandem processes involving the
Knoevenagel condensation and 4-hydroxy-2-pyrones
(and its equivalents) would not have become syntheti-
cally attractive.10,11 While the mechanism leading to the
coumarin 16 is quite straightforward after its structural
elucidation, it is still noteworthy that none of the other
commonly expected products13 were seen under these
conditions.
When 6-methyl-4-hydroxy-2-pyrone 11 was heated at
78°C with 1.0 equiv. of the iminium salt 2, generated in
situ by using 0.24 equiv. of piperidinium acetate,15 and
3.0 equiv. of PhSH in EtOH, the only identifiable
product was the pyrone 12 in 46% yield (Scheme 2).13a
On the other hand, under the identical conditions, the
iminium salt 13 provided the coumarin 1615 in 75%
yield, but the product structure was not assigned until it
was revealed by X-ray crystal structure analysis. The
same product was also observed in 60% yield in the
absence of PhSH.
These results led us to explore the generality of this
reaction for the preparation of useful coumarins. As
shown in Scheme 3, coumarins such as 17–19 may be
prepared readily in high yields at room temperature by
using the appropriate ortho-hydroxy arylaldehydes
treated with 0.24 equiv. of piperidinium acetate. Com-
pound 19 closely represents the AB ring of recently
isolated sesquiterpene coumarins, pallidones A and B,3c
and, thus, the methodology described here can be a
useful approach to these new natural products.
Given the structural assignment of 16, it can be sug-
gested that a translactonization had occurred via the
intermediate 15 after the initial Knoevenagel condensa-
tion, thereby resulting in a rather unexpected ring-
opening of the pyrone nucleus in 15. More significantly,
although such a process had been noted by Moreno-
Man˜as in his studies as a caution at much higher
temperatures,13b–d we found that it occurs rapidly even
at temperatures well below room temperature, and that
the nature of the solvents made no apparent differences
(Scheme 2).
We have described here an efficient synthesis of cou-
marins via an unexpected ring-opening of a 2-pyrone
nucleus at low temperatures. Given the availability of
both starting materials, the ortho-hydroxy arylalde-
hydes and 4-hydroxy-2-pyrones, and given the impor-
tance of coumarins, this mild preparation should be
synthetically useful leading to coumarin derivatives of
high value in medicinal chemistry.
Scheme 2.

O. S. Darwish et al. / Tetrahedron Letters 42 (2001) 3283–3286
3285
Scheme 3.
Acknowledgements
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R.P.H. would like to thank the National Institutes of
Health (NS38049) and American Chemical Society
Petroleum Research Fund (Type-G) for financial sup-
port. R.P.H. would also like to thank the R. W.
Johnson Pharmaceutical Research Institute for a gener-
ous grant from the Focused Giving Award. The
authors would like to thank the University of Minne-
sota for a Grant-in-Aid of Research, Artistry and
Scholarship (CUFSc: 1003-519-5962). The authors
would also like to thank Drs. Maren Pink and Victor
Young for solving the X-ray structure.
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73, 1865.
Selected characterization. Compound 16: mp 218–220°C;
Rf=0.84 (5% v/v MeOH and 45% EtOAc in Et2O); 1H
NMR (300 MHz, CDCl3): l 2.28 (s, 3H), 7.08 (s, 1H),
7.42 (d, J=9.0 Hz, 1H), 7.59 (ddd, J=1.5, 7.8, 7.8 Hz,
1H), 7.73 (ddd, J=1.8, 7.8, 7.8 Hz, 1H), 7.89 (d, J=8.7
Hz, 1H), 8.05 (d, J=9.0 Hz, 1H), 8.32 (d, J=8.4 Hz,
1H), 9.33 (s, 1H); 13C NMR (75 Hz, CDCl3): l 28.9,
101.6, 113.0, 116.4, 118.8, 121.6, 126.6, 129.1, 129.2,
129.4, 130.2, 135.8, 140.8, 154.8, 158.1, 172.5, 199.4; IR
(thin film): 3059m, 3004m, 2967m, 2924m, 1715s, 1558m
cm−1; MS (EI): m/e (% relative intensity) 280 (26) (M−1)+,
237 (12), 223 (100). Anal. calcd for C17H12O4: C, 72.85;
H, 4.32. Found: C, 72.68; H, 4.45. Compound 17: mp
214–216°C; Rf=0.82 (5% v/v MeOH and 45% EtOAc in
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1
Et2O); H NMR (300 MHz, CDCl3): l 2.29 (s, 3H), 7.07
13. For related studies using aromatic aldehydes, see: (a) de
March, P.; Moreno-Man˜as, M.; Pi, R.; Trius, A. J.
Heterocyclic Chem. 1982, 19, 335; (b) de March, P.;
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(s, 1H), 7.55 (d, J=9.0 Hz, 1H), 7.68 (m, 3H), 7.88 (dd,
J=3.0, 7.5 Hz, 1H), 8.56 (dd, J=2.0, 7.0 Hz, 1H), 8.76
(s, 1H); 13C NMR (75 Hz, CDCl3): l 27.5, 101.4, 114.0,
115.8, 118.4, 122.9, 124.3, 125.0, 127.1, 128.0, 129.8,
136.0, 146.1, 158.4, 172.0, 198.4 (missing one peak due to
overlapping); IR (thin film): 3054m, 2986m, 2305m, 1736s
cm−1; MS (EI): m/e (% relative intensity) 280 (30) (M−1)+,
237 (16), 223 (100). Anal. calcd for C17H12O4: C, 72.85;
H, 4.32. Found: C, 72.66; H, 4.42. Compound 18: mp
210–212°C; Rf=0.71 (50% v/v EtOAc in hexane); 1H
NMR (300 MHz, CDCl3): l 2.28 (s, 3H), 7.03, (s, 1H),
7.34 (ddd, J=1.0 Hz, 6.6 Hz, 9.0 Hz, 2H), 7.63 (ddd,
J=1.0, 6.6, 9.0 Hz, 2H), 8.66 (s, 1H); 13C NMR (75 Hz,
CDCl3): l 27.7, 101.7, 116.7, 118.4, 120.8, 125.0, 129.6,
134.0, 145.5, 154.2, 158.2, 171.8, 199.9; IR (thin film):
3054s, 2987m, 1735s cm−1; MS (EI): m/e (% relative
intensity) 230 (10) (M−1)+, 215 (6), 187 (8), 173 (100).
Anal. calcd for C13H10O4: C, 66.65; H, 4.66. Found: C,
67.00; H, 4.44. Compound 19: mp 174–176°C; Rf=0.64
(50% v/v EtOAc in hexane); 1H NMR (300 MHz,
CDCl3): l 2.28 (s, 3H), 4.00 (s, 3H), 7.05 (s, 1H), 7.19
(ddd, J=1.5, 7.5, 7.8 Hz, 1H), 7.26 (m, 2H), 8.63 (s, 1H);
13C NMR (75 Hz, CDCl3): l 27.7, 56.3, 101.7, 105.1,
115.4, 119.1, 120.8, 124.8, 144.2, 145.7, 157.6, 171.8,
200.0 (missing one peak due to overlapping); IR (thin
film): 3054s, 2987m, 2305m, 1735s cm−1; MS (EI): m/e (%
relative intensity) 260 (20) (M−1)+, 245 (6), 217 (10), 203
(100). Anal. calcd for C14H12O5: C, 64.61; H, 4.87.
Found: C, 64.68; H, 4.91.
15. General procedure. To a stirring solution of 1.00 mmol of
an ortho-hydroxy arylaldehyde and 0.24 mmol of piperi-
dinium acetate salt in 20 ml of an appropriate solvent
was added 1.00 mmol of the 4-hydroxy-2-pyrone 11.
After stirring at 25 or −10°C for 3–10 h, the reaction
mixture was concentrated, and the yellow crude solid was
either recrystallized from MeOH or chromatographed
.
.