Synthesis of 6-substituted 4-hydroxy-2-pyrones from aldehydes by addition of an acetoacetate equivalent, Dess-Martin oxidation and subsequent cyclization

Article abstract of DOI:10.1055/s-2001-18759

A three step procedure for the synthesis of 6-substituted 4-hydroxy-2-pyrones 2 from aldehydes 1 is described. An acetoacetate equivalent 3 was added to the corresponding aldehyde (10 examples) in a vinylogous Mukaiyama aldol addition (72-99%). The intermediate alcohols 4 were oxidized to the ketones 5 using the Dess-Martin method (67%-quant,). A final thermal cyclization of compounds 5 yielded the title compounds 2 (61-92%; 40-85% overall).

Full text of DOI:10.1055/s-2001-18759

1974
LETTER
Synthesis of 6-Substituted 4-Hydroxy-2-pyrones from Aldehydes by Addition
of an Acetoacetate Equivalent, Dess–Martin Oxidation and Subsequent
Cyclization
S
ynthesis of 6-S
h
ubstituted 4-
o
Hydroxy-2-
r
s
from
A
lde
t
hydes en Bach,* Stefan Kirsch
Lehrstuhl für Organische Chemie I, Technische Universität München, Lichtenbergstr. 4, 85747 Garching, Germany
Fax +49(89)28913315; E-mail: thorsten.bach@ch.tum.de
Received 20 August 2001
yielding, mild conversions: Carbonyl addition of an ace-
toacetate equivalent, Dess–Martin oxidation and thermal
cyclization.
Abstract: A three step procedure for the synthesis of 6-substituted
4-hydroxy-2-pyrones 2 from aldehydes 1 is described. An acetoac-
etate equivalent 3 was added to the corresponding aldehyde (10 ex-
amples) in a vinylogous Mukaiyama aldol addition (72–99%). The
intermediate alcohols 4 were oxidized to the ketones 5 using the
Dess–Martin method (67%–quant.). A final thermal cyclization of
compounds 5 yielded the title compounds 2 (61–92%; 40–85%
overall).
The addition of the easily available ketene acetal 38 to var-
ious aldehydes 1 proceeded readily employing TiCl4 (1.1
equiv) as the Lewis acid (Scheme 2).8,9 Only 1.7 equiva-
lents of the reagent were required to ensure complete con-
version.10 The yields of isolated products were high for a
broad range of substrates (Table). The oxidation step
turned out to be more subtle and required some optimiza-
tion. We found that the Dess–Martin conditions11 were
ideally suited for the desired conversion of alcohol 4 to the
cyclization precursor 5.12 The choice of the protected 1,3-
dicarbonyl building block 3 was crucial to the success of
the oxidation. As briefly mentioned above, all attempts to
oxidize unprotected -hydroxy- -ketocarboxylates re-
mained unsuccessful in our hands. In the oxidation step
stoichiometric amounts (1.3 equiv) of the reagent were
sufficient for a complete conversion. In several instances
the oxidation product was not isolated (entries 1, 2, 7, and
10) but was directly converted further to the pyrone 2 by
the known3b,13 thermal cyclization reaction14 of 6-(2-
oxoalkyl)-1,3-dioxin-4-ones.15 An overview of the reac-
tions we have conducted so far is provided in Scheme 2
and in the Table.16
Key words: aldehydes, heterocycles, oxidations, pyrones, ring clo-
sure
The conversion of aldehydes 1 to biologically relevant 6-
substituted 4-hydroxy-2-pyrones 21,2 generally requires
three steps (Scheme 1): Oxidation, C–C bond formation
and cyclization. Whereas the C–C bond formation step
has obviously to occur prior to cyclization, the oxidation
step can occur at any stage of the sequence. An initial ox-
idation to a carboxylic acid requires further transforma-
tions of the acid into an acylating agent, i.e. an acid
chloride,3 an ester,4 or an amide.4c,5 A final oxidation, i.e.
the conversion of a dihydropyrone to a pyrone, requires
drastic conditions6 which may not be compatible with sen-
sitive substrates.
O
O
O
TiCl4
4
R
H
(CH2Cl2)
O
O
OH
O
O
R
OH
6
1
+
−78 °C
1.5 h
OTMS
R
O
1
2
3
4
Scheme 1
O
O
I
(CH2Cl2)
In light of these facts, the most direct approach for the de-
sired conversion appears to be an oxidation after C-C
bond formation and prior to cyclization. A literature
search surprisingly revealed that there is only limited pre-
cedence for this strategy. The intermediate , -unsubsti-
tuted -hydroxy- -ketocarboxylates are prone to a retro-
aldol fragmentation and have so far only been oxidized
under acidic conditions.7 In the following communication
we present a synthetic sequence which gives general ac-
cess to the title compounds from aldehydes by three high
OAc
AcO OAc
(toluene)
O
O
O
2
25 °C
1-2 h
111 °C
10 min
R
O
5
Scheme 2
In general, each reaction step is fairly independent on the
choice of substrates. Variations of the reaction conditions
have not yet been examined to a large extent. In the case
of silyl ether 1j, the reaction time for the conversion 1j
4j had to be shortened in order to avoid extensive desily-
lation (entry 10). It is remarkable that even the sensitive
Synlett 2001, No. 12, 30 11 2001. Article Identifier:
1437-2096,E;2001,0,12,1974,1976,ftx,en;G17701ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

LETTER
Synthesis of 6-Substituted 4-Hydroxy-2-pyrones from Aldehydes
1975
Table Yields for the Three Individual Steps in the Conversion of
Aldehydes 1a–j to the Corresponding 4-Hydroxy-2-pyrones 2a–j
Acknowledgement
This work was supported by the Bayer AG (Wuppertal) and by the
Fonds der Chemischen Industrie. We would like to thank Olaf Ak-
kermann for skillful technical assistance.
Entry R---
#
Yield 4 Yield 5 Yield 2
[%]a
[%]b
[%]c
1
2
a
85
quant.d 75
quant.d 92
References
b
72
82
(1) General reviews: (a) Moreno-Mañas, M.; Pleixats, R. Adv.
Heterocycl. Chem. 1992, 53, 1. (b) Moreno-Mañas, M.;
Pleixats, R. Heterocycles 1994, 37, 585.
(2) HIV-protease inhibition: (a) Aristoff, P. A. Drugs Fut. 1998,
23, 995. (b) Romines, K. R.; Chrusciel, R. A. Curr. Med.
Chem. 1995, 2, 825.
(3) (a) Chan, T. H.; Brownbridge, P. Can. J. Chem. 1983, 61,
688. (b) Sato, M.; Sakaki, J.-I.; Sugita, Y.; Yasuda, S.;
Sakoda, H.; Kaneko, C. Tetrahedron 1991, 47, 5689.
(4) (a) Huckin, S. N.; Weiler, L. Can. J. Chem. 1974, 52, 1343.
(b) Harris, T. M.; Harris, C. M.; Oster, T. A.; Brown, L. E.
Jr.; Lee, J. Y.-C. J. Am. Chem. Soc. 1988, 110, 6180.
(c) Yamaguchi, M.; Shibato, K.; Nakashima, H.; Minami, T.
Tetrahedron 1988, 44, 4767. (d) Krohn, K.; Roemer, E.;
Top, M. Liebigs Ann. 1996, 271.
(5) (a) Yamaguchi, M.; Shibato, K.; Hirao, I. Chem. Lett. 1985,
1145. (b) Lygo, B. Tetrahedron 1995, 51, 12859.
(c) Hiyama, T.; Reddy, G. B.; Minami, T.; Hanamoto, T.
Bull. Chem. Soc. Jpn. 1995, 68, 350.
3
4
5
c
d
e
98
99
73
67
76
85
83
95
74
81
TBDMS
6
7
f
90
98
g
quant.d 87
8
h
99
90
72
(6) (a) Abramson, H. N.; Wormser, H. C. J. Heterocycl. Chem.
1981, 18, 363. (b) Poulton, G. A.; Cyr, T. D. Can. J. Chem.
1982, 60, 2821.
(7) Hagiwara, H.; Kobayashi, K.; Miya, S.; Hoshi, T.; Suzuki,
T.; Ando, M. Org. Lett. 2001, 3, 251.
(8) (a) Grunwell, J. R.; Karipides, A.; Wigal, C. T.; Heinzman,
S. W.; Parlow, J.; Surso, J. A.; Clayton, L.; Fleitz, F. J.;
Daffner, M.; Stevens, J. E. J. Org. Chem. 1991, 56, 91.
(b) Sugita, Y.; Sakaki, J.-I.; Sato, M.; Kaneko, C. J. Chem.
Soc., Perkin Trans. 1 1992, 2855.
(9) (a) Sato, M.; Sunami, S.; Sugita, Y.; Kaneko, C.
Heterocycles 1995, 41, 1435. (b) Krüger, J.; Carreira, E. M.
J. Am. Chem. Soc. 1998, 120, 837.
(10) Representative procedure for the conversion 1 4: At
–78 °C, a solution of ketene acetal 3 (4.25 mmol, 910 mg) in
CH2Cl2 (10 mL) was added dropwise to a solution of
crotonaldehyde 1f (2.5 mmol, 175 mg) and TiCl4 (2.7 mmol,
512 mg) in CH2Cl2 (20 mL). The reaction mixture was
stirred for another 1.5 h at –78 °C and was subsequently
quenched with sat. aq NaHCO3 (10 mL). The organic layer
was separated and the aq layer was extracted with CH2Cl2
(3 5 mL). The combined organic layers were dried
(Na2SO4), filtered and evaporated under reduced pressure to
give the crude product as a pale yellow oil. Purification by
flash chromatography on silica with pentane/EtOAc (80/20)
as eluent gave alcohol 4f9b (477 mg, 2.25 mmol, 90%) as a
colorless oil. 1H NMR (250 MHz, CDCl3): = 1.64 (s, 3 H),
1.65 (s, 3 H), 1.66 (dd, J = 1.4 Hz, J = 6.4 Hz, 3 H), 2.04 (s,
br, 1 H), 2.32–2.47 (m, 2 H), 4.32 (pseudo q, J 7.0 Hz, 1
H), 5.27 (s, 1 H), 5.47 (ddq, J = 1.4 Hz, J = 7.0 Hz, J = 15.3
Hz, 1 H), 5.72 (ddq, J = 0.9 Hz, J = 6.4 Hz, J = 15.3 Hz, 1
H). 13C NMR (62.9 MHz, CDCl3): = 17.6, 24.8, 25.3, 41.5,
69.7, 95.1, 106.6, 128.2, 132.3, 161.1, 168.6.
9
i
99
67
61
92
O
10
j
78e
95d
3
TBDMSO
a 1.7 Equiv 3, 1.1 equiv TiCl4; yield of isolated product after chroma-
tography.10
b 1.3 Equiv periodinane; yield of isolated product after chromato-
graphy.12
c Yield of isolated product after chromatography or recrystalliza-
tion.15
d Yield of crude product.
e 2 Equiv 3, reaction time: 25 min.
furan ring withstands both the oxidation and the ring clo-
sure conditions fairly well (entry 9) although the yields
achieved in these steps are lower than for the other sub-
strates. The total yield for the conversion 1i 2i amount-
ed to 40% whereas an overall yield of > 50% was obtained
in the other nine examples.
The further methylation of 4-hydroxypyrones is well pre-
cedented.17 We have used a standard methylation proce-
dure (Me2SO4, K2CO3 in acetone, 91% yield) to convert
the product 2g into 5,6-dehydrokavain, a naturally occur-
ring pyrone.18 Further applications of the presented meth-
odology in the context of more complex syntheses are
currently under way in our laboratories and will be report-
ed in due course.
(11) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(b) Boeckman, R. B. Jr.; Shao, P.; Mullins, J. J. Org. Synth.
1999, 77, 141.
(12) Representative procedure for the conversion 4 5: Dess–
Martin periodinane (1.5 mmol, 640 mg) was added as a solid
to a solution of compound 4f (1.12 mmol, 238 mg) in 5 mL
of CH2Cl2. The resulting mixture was stirred for 90 min at r.t.
Synlett 2001, No. 12, 1974–1976 ISSN 0936-5214 © Thieme Stuttgart · New York

1976
T. Bach, S. Kirsch
LETTER
The mixture was diluted with 30 mL of ether and 6 mL of a
sat. aq NaHCO3-solution containing 5% sodium thiosulfate
was added. After stirring for 20 min, the clear organic layer
was separated. The organics were dried over Na2SO4,
filtered and evaporated. The residue was purified by flash
chromatography on silica with pentane–EtOAc (80:20) to
yield compound 5f (197 mg, 1.1 mmol, 95%) as a colorless
mg) was added within 5 min to refluxing toluene (20 mL).
After additional 10 min at reflux, the mixture was allowed to
cool to r.t. The precipitated solid was collected and
recrystallized from pentane/CH2Cl2 to give 97 mg (0.64
mmol, 81%) of pyrone 2f as a crystalline solid. Mp
(decomp.): 190 °C (ref.19: 191–194 °C). 1H NMR (250
MHz, d6-DMSO): = 1.89 (d, J = 7.0 Hz, 3 H), 5.30 (d,
J = 1.5 Hz, 1 H), 6.05 (d, J = 1.5 Hz, 1 H), 6.21 (d, J = 15.5
Hz, 1 H), 6.53 (dq, J = 7.0 Hz, J = 15.5 Hz, 1 H), 11.69 (s,
br, 1H). 13C NMR (62.9 MHz, d6-DMSO): = 18.4, 89.7,
100.1, 123.7, 134.0, 159.3, 163.3, 170.7. Anal. Calcd for
C8H8O3 (152.15): C, 63.15; H, 5.30. Found: C, 62.97; H,
5.25.
liquid which was taken directly into the cyclization step.15 1
H
NMR (250 MHz, CDCl3): = 1.65 (s, 6 H), 1.89 (dd, J = 1.5
Hz, J = 6.7 Hz, 3 H), 3.41 (s, 2 H), 5.30 (s, 1 H), 6.12 (dq,
J = 1.5 Hz, J = 15.7 Hz, 1 H), 6.88 (dq, J = 6.7 Hz, J = 15.7
Hz, 1 H). 13C NMR (62.9 MHz, CDCl3): = 18.3, 24.9, 44.5,
96.6, 107.1, 130.8, 145.4, 160.7, 164.9, 192.3.
(13) For a related thermal cyclization, see: Lokot, I. P.;
Pashkovsky, F. S.; Lakhvich, F. A. Tetrahedron 1999, 55,
4783.
(16) (a) Literature references to those compounds in the table
which have been previously prepared: 2a: ref.13; 2f: ref.19.
(b) 2g: Resplandy, A. Bull. Soc. Chim. Fr. 1965, 525.
(c) 2h see ref.3b,4b and: Butt, M. A.; Elvidge, J. A. J. Chem.
Soc. 1963, 4483. (d) 4f, 4g, 4i: ref.9b; 4h: ref.8b,9b; 5h: ref.3b.
(17) Bu’Lock, J. D.; Smith, H. G. J. Chem. Soc. 1960, 502.
(18) (a) Adityachaudhyvy, N.; Das, A. K.; Daskanungo, P. Indian
J. Chem. 1976, 14B, 909. (b) Ichino, K.; Tanaka, H.; Ito, K.
Tetrahedron 1988, 44, 3251. (c) Ali, M. S.; Tezuka, Y.;
Awale, S.; Banskota, A. H.; Shigtoshi, S. J. Nat. Prod. 2001,
64, 289.
(14) For references on the DBU-mediated cyclization of , -
diketocarboxylates, see: (a) Oppolzer, W.; Moretti, R.;
Bernardinelli, G. Tetrahedron Lett. 1986, 27, 4713.
(b) Marquet, J.; Moreno-Mañas, M.; Prat, M. Tetrahedron
Lett. 1989, 30, 3105. (c) Ishibashi, Y.; Ohba, S.; Nishiyama,
S.; Yamamura, S. Tetrahedron Lett. 1996, 37, 2997.
(d) Smith, A. B. III.; Kinsho, T. Tetrahedron Lett. 1996, 37,
6461.
(15) Representative procedure for the conversion 5 2: A
toluene (5 mL) solution of compound 5f (0.79 mmol, 166
(19) Kato, K.; Hirata, Y.; Yamamura, S. J. Chem. Soc. C 1969,
1997.
Synlett 2001, No. 12, 1974–1976 ISSN 0936-5214 © Thieme Stuttgart · New York