Facile syntheses of 2,2-dimethyl-6-(2-oxoalkyl)-1,3-dioxin-4-ones and the corresponding 6-substituted 4-hydroxy-2-pyrones

Article abstract of DOI:10.1021/jo050307m

A variety of 2,2-dimethyl-6-(2-oxoalkyl)-1,3-dioxin-4-ones 5a-l and the corresponding 6-substituted 4-hydroxy-2-pyrones 3a-l were prepared in high yields under mild reaction conditions by the reaction of 2,2,6-trimethyl-1,3- dioxin-4-one 4 with 1-acylbenz

Full text of DOI:10.1021/jo050307m

SCHEME 1
Facile Syntheses of
2,2-Dimethyl-6-(2-oxoalkyl)-1,3-dioxin-4-ones
and the Corresponding 6-Substituted
4-Hydroxy-2-pyrones
Alan R. Katritzky,*,§ Zuoquan Wang,§ Mingyi Wang,§,‡
C. Dennis Hall,§ and Kazuyuki Suzuki§
2-pyrones have been known for more than 100 years, due
to their inaccessibility, studies before the 1960s were
limited to a small group of 6-unsubstituted 2-pyrones.
Over recent decades the chemistry of 6-unsubstituted
2-pyrones has been investigated intensively and has led
to the development of 2-pyrone chemistry.7
Center for Heterocyclic Compounds,
Department of Chemistry, University of Florida,
Gainesville, Florida 32611-7200
katritzky@chem.ufl.edu
By contrast, relatively few examples of the preparation
of 6-substituted 2-pyrones have been reported. 1,3-
Dioxin-4-ones including 2,2-dimethyl-6-(2-oxoalkyl)-1,3-
dioxin-4-ones are versatile synthons which can be pre-
pared with a variety of substitution patterns. Facile ring
opening of dioxinone 1 to acylketene 2 under either
thermal or photochemical conditions allows cyclization
to 6-substituted-4-hydroxy-2-pyrones 3 (Scheme 1). Tra-
ditionally, the synthesis of 2,2-dimethyl-6-(2-oxoalkyl)-
1,3-dioxin-4-ones 5 has been accomplished either by
electrophilic addition of acyl halides or anhydrides to the
γ-position of the lithium enolate of 4 (38% to 69%
yields),8,9 or by a two-step procedure involving vinylogous
Mukaiyama aldol addition of (2,2-dimethyl-6-methylene-
6H-1,3-dioxin-4-yloxy)trimethylsilane 6 to aldehydes to
give alcohols 7, followed by oxidation of the latter to give
5 using the Dess-Martin method. Ketones 5 then un-
derwent thermal cyclization to give 6-substituted-4-
hydroxy-2-pyrones 3 (Scheme 2).8,10
Received February 17, 2005
A variety of 2,2-dimethyl-6-(2-oxoalkyl)-1,3-dioxin-4-ones
5a-l and the corresponding 6-substituted 4-hydroxy-2-
pyrones 3a-l were prepared in high yields under mild
reaction conditions by the reaction of 2,2,6-trimethyl-1,3-
dioxin-4-one 4 with 1-acylbenzotriazoles 9 in the presence
of LDA followed by thermal cyclization of 5a-l to 3a-l.
Synthesis of novel 6-(1-benzoylalkyl)-2,2-dimethyl-1,3-dioxin-
4-ones 12a-c was achieved by alkylation of dioxinone 5a
and their subsequent cyclization gave 5-alkyl-4-hydroxy-2-
pyrones 13a-c.
Problems with handling and storing acyl halides, and
their incompatibility with acid-sensitive functional groups,
prompted our search for alternatives.11 Benzotriazole acts
as a good leaving group and has been employed exten-
sively as a synthetic auxiliary.12 1-Acylbenzotriazoles are
advantageous carboxylic acid derivatives in that they are
stable and readily prepared in one step from carboxylic
acids even in cases where an acid-sensitive functionality
is present.13 They have been widely used in many N-,13b,14
C-,15 O-,15d,16 and S-acylation reactions.17
2-Pyrones represent an important class of lactones that
are substructures of many natural products1 showing a
wide range of biological activity, such as potent nonpep-
tidic HIV protease inhibitory,2 antimicrobial,3 androgen-
like,4 antifungal,5 and pheromonal6 effects. Although
* Corresponding author.
§ University of Florida.
‡ Present address: Tyger Scientific Inc., 324 Stokes Avenue, Ewing,
NJ 08638.
We now describe the facile syntheses of 2,2-dimethyl-
6-(2-oxoalkyl)-1,3-dioxin-4-ones 5 and the corresponding
(1) Marrison, L. R.; Dickinson, J. M.; Ahmed, R.; Fairlamb, I. J. S.
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513. (b) Simon, A.; Dunlop, R. W.; Ghisalberti, E. L.; Silvasithamparam,
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(8) Sato, M.; Sakaki, J.-i.; Sugita, Y.; Yasuda, S.; Sakoda, H.;
Kaneko, C. Tetrahedron 1991, 47, 5689-5708.
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Perkin Trans. 1 1992, 2855-2861. (b) Sakaki, J.-i.; Sugita, Y.; Sato,
M.; Kaneko, C. J. Chem. Soc., Perkin Trans. 1 1991, 434-435. (c)
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Lett. 1990, 901-904.
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(11) Katritzky, A. R.; Denisko, O. V.; Fang, Y.; Zhang, L.; Wang, Z.
Arkivoc 2001, 11, 41-48.
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1991, 47, 2683-2732. (b) Katritzky, A. R.; Lan, X.; Fan, W.-Q.
Synthesis 1994, 445-456. (c) Katritzky, A. R.; Lan, X.; Yang, J. Z.;
Denisko, O. V. Chem. Rev. 1998, 98, 409-548.
10.1021/jo050307m CCC: $30.25 © 2005 American Chemical Society
Published on Web 05/13/2005
4854
J. Org. Chem. 2005, 70, 4854-4856

SCHEME 2
TABLE 1. Preparation of 1,3-Dioxin-4-ones 5 and
2-Pyrones 3
SCHEME 3
entry
R (9: RCOBt)
Ph
4-MeC6H4
4-ClC6H4
Ph2CH
5, yield %
3, yield %
ref
a
b
c
d
e
f
g
h
i
65
58
61
58
65
53
52
51
51
37a
66
60
82
77
75
85
66b
70
86
53
64
73
61
82
8
19
20
â-Naphthyl
n-C6H13
tBu
2-pyrones 3 by a selective vinylogous addition process of
1-acylbenzotriazoles 9 to the γ-position of the lithium
enolate of 4, followed by thermal cyclization by heating
under reflux in toluene.
iPr
CH2dCH-(CH2)8
PhCHdCH
2-Furyl
j
k
l
10a
10a
Results and Discussion. 1-Acylbenzotriazoles 9a-n
were readily prepared by treating the corresponding
carboxylic acids either (i) with thionyl chloride and
benzotriazole in methylene chloride at 25 °C13c or (ii) in
THF with 1-(methylsulfonyl)-1H-1,2,3-benzotriazole in
the presence of triethylamine under reflux overnight.13b
Treatment of dioxinone 4 with 1.3 equiv of LDA
(prepared in situ at -78 °C) resulted in formation of the
dark brown lithium enolate of 4. Subsequent reaction
with 1-acylbenzotriazoles 9a-l between -78 °C and
ambient temperature overnight yielded 2,2-dimethyl-6-
(2-oxoalkyl)-1,3-dioxin-4-ones 5a-l in 37-66% yields
(Scheme 3 and Table 1). The structures of 5a-l were
supported by 1H and 13C NMR data (see the Supporting
Information).
2-Thienyl
a Byproduct N,N-diisopropyl-3-phenyl-3-(2,2,6-trimethyl-4-oxo-
4H-1,3-dioxin-5-yl)propanamide (b1) was isolated in 21% yield.
b Byproduct (Z)-4-hydroxy-4-(2-naphthyl)-3-buten-2-one (b2) was
isolated in 14% yield.
3a-l in 53-86% yields (Scheme 3 and Table 1). The
1
structures of 3a-l were supported by H and 13C NMR
data (see the Supporting Information). In a NOE experi-
ment on 3e irradiation of the OH signal at C-4 enhanced
both H3 and H5 of the pyrone ring, thus offering an
unequivocal confirmation of the 2-pyrone structure in
accord with previous studies.2d,18 gHMBC spectra on 3e
show 3-bond coupling of H-1 and H-3 of the naphthalene
ring with C-6 of the pyrone ring, and 2-bond coupling of
H3 and H5 with C-4 and 2-bond coupling of H3 with C-2
of the pyrone ring, thus confirming the assignment of C-2
at 163.1 ppm and C-4 at 170.6 ppm.
Heating solutions of 5a-l in toluene under reflux for
20-30 min produced 4-hydroxy-6-substituted-2-pyrones
(13) (a) Katritzky, A. R.; Shobana, N.; Pernak, J.; Afridi, A. S.; Fan,
W.-Q. Tetrahedron 1992, 48, 7817-7822. (b) Katritzky, A. R.; He, H.-
Y.; Suzuki, K. J. Org. Chem. 2000, 65, 8210-8213. (c) Katritzky, A.
R.; Zhang, Y.; Singh, S. K. Synthesis 2003, 2795-2798.
(14) (a) Katritzky, A. R.; Levell, J. R.; Pleynet, D. P. M. Synthesis
1998, 153-156. (b) Katritzky, A. R.; Wang, M.; Yang, H.; Zhang, S.;
Akhmedov, N. G. Arkivoc 2002, 8, 134-142. (c) Katritzky, A. R.;
Rogovoy, B. V.; Kirichenko, N.; Vvedensky, V. Bioorg. Med. Chem. Lett.
2002, 12, 1809-1811. (d) Katritzky, A. R.; Suzuki, K.; Singh, S. K.
Synthesis 2004, 2645-2652. (e) Katritzky, A. R.; Hoffmann, S.; Suzuki,
K. Arkivoc 2004, 12, 14-22.
(15) (a) Katritzky, A. R.; Pastor, A. J. Org. Chem. 2000, 65, 3679-
3682. (b) Katritzky, A. R.; Abdel-Fattah, A. A. A.; Wang, M. J. Org.
Chem. 2003, 68, 1443-1446. (c) Katritzky, A. R.; Abdel-Fattah, A. A.
A.; Wang, M. J. Org. Chem. 2003, 68, 4932-4934. (d) Katritzky, A.
R.; Wang, Z.; Wang, M.; Wilkerson, C. R.; Hall, C. D.; Akhmedov, N.
G. J. Org. Chem. 2004, 69, 6617-6622. (e) Katritzky, A. R.; Suzuki,
K.; Singh, S. K.; He, H.-Y. J. Org. Chem. 2003, 68, 5720-5723. (f)
Katritzky, A. R.; Suzuki, K.; Singh, S. K. Croat. Chem. Acta 2004, 175-
178.
A limitation to the above method was found when
1-(1H-1,2,3-benzotriazol-1-yl)-2-[1,1′-biphenyl]-4-yl-1-eth-
anone 9m and 1-(1H-1,2,3-benzotriazol-1-yl)-2-(phenyl-
sulfanyl)-1-ethanone 9n were employed as electrophiles
in the reaction. Neither of the desired 2-pyrones 5m or
5n was detected in the corresponding reaction mixtures,
but instead, N,N-diisopropylacetamides 10m and 10n
were isolated as the major products in 37% and 41%
yields, respectively, together with some unreacted dioxi-
none 4 (Scheme 4). The mechanism for the formation of
10m,n is presumably as shown in Scheme 5. Due to the
existence of active R-hydrogens in 1-acylbenzotriazoles
9m,n, anion exchange occurs between the anion of 4 and
9m,n to give ketenes 11m,n, which then add to N,N-
diisopropylamine to yield acetamides 10m and 10n.
Interestingly, the same reaction was not detected when
(16) (a) Katritzky, A. R.; Pastor, A.; Voronkov, M. V. J. Heterocycl.
Chem. 1999, 36, 777-781. (b) Wedler, C.; Kleiner, K.; Kunath, A.;
Schick, H. Liebigs Ann. 1996, 881-885.
(17) Katritzky, A. R.; Shestopalov, A. A.; Suzuki, K. Synthesis 2004,
1806-1813.
(18) Tori, K.; Hirata, T.; Koshitani, O.; Suga, T. Tetrahedron Lett.
1976, 16, 1311-1314.
J. Org. Chem, Vol. 70, No. 12, 2005 4855

SCHEME 4
SCHEME 5
SCHEME 6
b
a Byproduct 2-butyl-1-phenyl-1,3-butanedione (b3) was isolated in 15% yield. Byproduct 2-pentyl-1-phenyl-1,3-butanedione (b4) was
isolated in 22% yield.
1-acylbenzotriazole 9d was reacted with 1,3-dioxin-4-one
4, even though 9d has a more acidic R-hydrogen. Pre-
sumably steric hindrance by the two phenyl groups in
9d prevents the anion exchange reaction.
acylbenzotriazoles are stable to storage over months
under ambient conditions, (ii) they are sufficiently reac-
tive to form new C-C bonds between -78 °C and ambient
temperature, but stable enough to resist side reactions,
and (iii) the intermediate 1,3-dioxin-4-ones are obtained
in good yields compared with those using the acid
chloride method.
Alkylation of dioxinone 5a was achieved by reactions
with alkyl iodides in THF in the presence of sodium
hydride, which led to novel products 12a-c in 51-62%
yields (Scheme 6). Transformations analogous to those
described in Scheme 3 also succeeded with 12a-c to give
5-alkylated 2-pyrone 13a-c in 26-47% yields. The
Experimental Section
General Methods and Materials. Melting points were
determined on a hot-stage apparatus and are uncorrected. NMR
spectra were recorded in CDCl3 or DMSO-d6 with TMS as the
internal standard for 1H (300 MHz) or CDCl3 or DMSO-d6 as
the internal standard for 13C (75 MHz), unless otherwise
specified. All reactions were carried out under an atmosphere
of nitrogen. Anhydrous THF was obtained by distillation from
sodium/benzophenone ketyl immediately prior to use. Column
chromatography was performed with S733-1 silica gel (200-425
mesh).
1
structures of 12a-c and 13a-c were supported by H
and 13C NMR data (see the Supporting Information).
In conclusion, the facile synthesis described herein
affords a general and versatile approach to the biologi-
cally important class of 2-pyrones. The present method
provides a complementary approach to earlier methods,
specifically those where acid chlorides are employed. The
advantage of this method includes the following: (i) most
Acknowledgment. The authors are grateful to Dr.
(19) Bonsignore, L.; Cabiddu, S.; Loy, G.; Secci, D. Heterocycles 1989,
29, 913-919.
Novruz G. Akhmedov for helpful discussion.
(20) Gorgues, A. Bull. Soc. Chim. Fr. Pt. 2 1973, 4, 1293-1295.
(21) Go¨rlitz, G.; Hartmann, H. Heteroatom Chem. 1997, 8 (2), 147-
155.
Supporting Information Available: Characterization
data for compounds 5a-l, b1; 3a-l, b2; 10m,n; 12a-c; and
13a-c, b3,4. This material is available free of charge via the
Internet at http://pubs.acs.org.
(22) Nakai, T.; Tanaka, K.; Ishikawa, N. Chem. Lett. 1976, 11,
1263-1266.
(23) Choudhary, A.; Baumstark, A. L. Synthesis 1989, 9, 688-690.
(24) Taber, D. F.; Jiang, Q. J. Org. Chem. 2001, 66, 1876-1884.
JO050307M
4856 J. Org. Chem., Vol. 70, No. 12, 2005