Synthesis of 3,5,6-trisubstituted α-pyrones from Baylis-Hillman adducts

Article abstract of DOI:10.1016/j.tetlet.2006.11.180

3,5,6-Trisubstituted α-pyrones were synthesized starting from the Baylis-Hillman adducts. The synthesis was carried out via the sequential introduction of ketone at the primary position of Baylis-Hillman adduct, lactonization, and the following oxidation

Full text of DOI:10.1016/j.tetlet.2006.11.180

Tetrahedron Letters 48 (2007) 1069–1072
Synthesis of 3,5,6-trisubstituted a-pyrones from
Baylis–Hillman adducts
Seong Jin Kim, Hyun Seung Lee and Jae Nyoung Kim*
Department of Chemistry and Institute of Basic Science, Chonnam National University, Gwangju 500-757, Republic of Korea
Received 6 November 2006; revised 22 November 2006; accepted 24 November 2006
Available online 22 December 2006
Abstract—3,5,6-Trisubstituted a-pyrones were synthesized starting from the Baylis–Hillman adducts. The synthesis was carried out
via the sequential introduction of ketone at the primary position of Baylis–Hillman adduct, lactonization, and the following oxida-
tion with PCC.
Ó 2006 Elsevier Ltd. All rights reserved.
Recently, considerable efforts have been devoted to the
synthesis of a-pyrones and related compounds by
numerous approaches involving transition metal-cata-
lyzed reactions.1–3 a-Pyrones have been used as syn-
thetic intermediates4 and are found in a wide variety
of biologically active natural products.1–3,5
3a in our hands, we examined the lactonization reaction,
which occurred easily by treatment of 3a with TFAA
(trifluoroacetic anhydride) in CH2Cl2 at room tempera-
ture to give 3-benzylidene-5,6-diphenyl-3,4-dihydro-
pyran-2-one (4a) in 83% yield.8,9
At the earliest stage of this project, we expected that we
could prepare 3-benzyl-5,6-diphenyl-a-pyrone (5a), the
double bond-isomerized compound. However, 4a was
not converted to 5a under various acidic or basic condi-
tions. In addition, compound 4a has limited stability
and decomposed slowly even at room temperature to
many intractable mixtures. Thus, we examined the oxi-
dation of 4a with a variety of conditions. Among the
conditions, PCC oxidation10 was found to be the best
one and to our delight we could obtain 3-benzoyl-5,6-di-
phenyl-a-pyrone (6a)11 in 59% yield from 4a.10,11 Such
an allylic oxidation accompanying the isomerization of
double bond has been reported10a,f and the structure
of 6a was confirmed by comparison with the reported
spectroscopic data.9,11
Recently, a variety of chemical transformations using
the Baylis–Hillman adducts have been investigated thor-
oughly.6,7 Especially the usefulness of the Baylis–Hill-
man adducts for the synthesis of many heterocyclic
compounds is noteworthy.6,7 Basavaiah and Satyanara-
yana have reported the synthesis of functionalized [4.4.3]
and [4.4.4]propellano-bislactones starting from the Bay-
lis–Hillman acetate and indanone derivatives.8 Based on
the Basavaiah’s brilliant paper8 and our recent studies
on the chemical transformations of the Baylis–Hillman
adducts,7 we found an effective route to a-pyrone deriv-
atives from the acetate of the Baylis–Hillman adducts as
shown in Scheme 1.
The reaction of Baylis–Hillman acetate 1a and deoxy-
benzoin (2a) in the presence of t-BuOK in THF afforded
the corresponding methyl ester of 3a together with some
hydrolyzed compound 3a in a variable ratio. We con-
verted the ester derivative into the acid compound 3a
by NaOH hydrolysis of the crude reaction mixture after
simple aqueous extractive workup. With this compound
Encouraged by the successful results, we examined the
reactions of Baylis–Hillman acetates 1a–d and various
ketone derivatives 2a–f and the results are summarized
in Table 1. As ketone compounds we examined deoxy-
benzoin (2a), desoxyanisoin (2b), propiophenone (2c),
acetophenone (2d), cyclohexanone (2e), and a-tetralone
(2f) as the representative examples. As shown in Table
1, the 3-arylidene-3,4-dihydropyran-2-one derivatives
4a–h were obtained in moderate to good yields
(50–83%). The following oxidations of 4a–h with PCC
afforded the desired a-pyrones 6a–h in moderate yields
(51–64%).
Keywords: a-Pyrones; Baylis–Hillman adducts; Lactonization; TFAA;
PCC oxidation.
*
Corresponding author. Tel.: +82 62 530 3381; fax: +82 62 530
3389; e-mail: kimjn@chonnam.ac.kr
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.11.180

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S. J. Kim et al. / Tetrahedron Letters 48 (2007) 1069–1072
OAc
O
COOMe
Ph
1.
t
-BuOK (1.1 equiv)
TFAA (2.0 equiv)
CH2Cl2, rt, 2 h
COOH
O
Ph
O
Ph
THF, rt, 5 h
1a
+
Ph
Ph
2. NaOH, aq MeOH
rt, 24 h
3. aq HCl
O
Ph
Ph
Ph
4a (83%)
3a (68%)
Ph
2a
PCC (2.0 equiv)
CH2Cl2, rt, 12 h
O
O
O
Ph
O
Ph
O
Ph
Ph
Ph
Ph
5a
6a (59%)
Scheme 1.
Table 1. Synthesis of benzylidene lactones 4 and 3-arol-a-pyrones 6
OAc
1a: R1 = H, R2 = Me
1b: R1 = Me, R2 = Me
1c: R1 = Cl, R2 = Me
1d: R1 = H, R2 = Et
2a: deoxybenzoin
2b: desoxyanisoin
2c: propiophenone
2d: acetophenone
2e: cyclohexanone
2f: α-tetralone
COOR2
R1
1a-d
Entry
Substrates
Acid 3a (%)
Lactone 4b (%)
a-Phyrone 6c (%)
1
2
3
4
5
6
7
8
9
1a + 2a
1b + 2a
1c + 2a
1d + 2a
1a + 2b
1a + 2c
1a + 2d
1a + 2e
1a + 2f
3a (68)
3b (70)
3c (—)d
3a (—)d
3d (—)d
3e (—)d
3f (18)
4a (83)
4b (80)
4c (50)
4a (61)
4d (50)
4e (70)
4f (51)
4g (52)
4h (72)
6a (59)
6a (55)
6c (60)
e
—
6d (64)
6e (58)
6f (51)
e
3g (43)
3h (44)
–
6h (52)
a Conditions: (i) t-BuOK (1.1 equiv), dry THF, rt, 5 h; (ii) NaOH (3.0 equiv), H2O/MeOH, rt, 24 h; and (iii) aq HCl.
b Conditions: TFAA (2.0 equiv), CH2Cl2, rt, 2 h.
c Conditions: PCC (2.0 equiv), CH2Cl2, rt, 12 h.
d Yield was not determined.
e Oxidation was not tried.
COOH
(i) t-BuOK (2.2 equiv)
THF, rt, 5 h
Ph
O
1a (2.0 equiv)
+
2d (1.0 equiv)
COOH
Ph
O
+
Ph
COOH
(ii) NaOH (5.0 equiv)
H2O/MeOH, rt, 24 h
(iii) aq HCl
Ph
3f (18%, entry 7)
7 (55%)
Ph
TFAA
O
Ph
O
O
O
O
Ph
+
O
no
reaction
PCC
Ph
COOH
Ph
Ph
8 (38%)
9 (25%)
Ph
Scheme 2.

S. J. Kim et al. / Tetrahedron Letters 48 (2007) 1069–1072
1071
Ph
Ph
(i)
t
-BuOK (1.1 equiv)
1a (2.0 equiv)
+
2f (1.5 equiv)
COOH
O
THF, rt, 5 h
COOH
COOH
Ph
+
O
(ii) NaOH (5.0 equiv)
H2O/MeOH, rt, 24 h
(iii) aq HCl
3h (44%, entry 9)
10 (27%)
TFAA
O
O
O
O
11 (53%)
Ph
Ph
Scheme 3.
(i) ref.12
(ii) hydrolysis
O
O
O
O
COOH
O
Ph
1a
+
TFAA
PCC
Ph
O
Ph
acetylacetone (2g)
3i (76%)
6i (64%)
4i (60%)
Scheme 4.
When we used acetophenone (2d), we could not obtain
the mono-adduct 3f in good yield. Instead bis-adduct 7
was isolated as the major product (Scheme 2). As
already shown in entry 7 in Table 1, compound 3f
showed similar reactivity in the following reactions.
Bis-adduct 7 could be converted into bicyclic compound
8 (38%) according to the similar mechanism reported8
together with mono-cyclic compound 9 (25%).
References and notes
1. For some references of traditional approaches, see: (a)
Kotretsou, S. I.; Georgiadis, M. P. Org. Prep. Proced. Int.
2000, 32, 161; (b) Stanovnik, B. J. Heterocycl. Chem. 1999,
36, 1581; (c) Kepe, V.; Polanc, S.; Kocevar, M. Hetero-
cycles 1998, 48, 671.
2. For some transition-metal catalyzed synthesis of a-pyro-
nes, see: (a) Larock, R. C.; Doty, M. J.; Han, X. J. Org.
Chem. 1999, 64, 8770; (b) Larock, R. C.; Han, X.; Doty,
M. J. Tetrahedron Lett. 1998, 39, 5713; (c) Cerezo, S.;
Moreno-Manas, M.; Pleixats, R. Tetrahedron 1998, 54,
7813.
3. Further references on the synthesis of a-pyrone deriva-
tives, see: (a) Yao, T.; Larock, R. C. J. Org. Chem. 2003,
68, 5936; (b) Ma, S.; Yu, S.; Yin, S. J. Org. Chem. 2003,
68, 8996; (c) Zhu, X.-F.; Schaffner, A.-P.; Li, R. C.; Kwon,
O. Org. Lett. 2005, 7, 2977; (d) Bellina, F.; Biagetti, M.;
Carpita, A.; Rossi, R. Tetrahedron 2001, 57, 2857; (e)
Bellina, F.; Biagetti, M.; Carpita, A.; Rossi, R. Tetrahe-
dron Lett. 2001, 42, 2859; (f) Ma, S.; Yin, S.; Li, L.; Tao,
F. Org. Lett. 2002, 4, 505; (g) Biagetti, M.; Bellina, F.;
Carpita, A.; Stabile, P.; Rossi, R. Tetrahedron 2002, 58,
5023; (h) Biagetti, M.; Bellina, F.; Carpita, A.; Viel, S.;
Mannina, L.; Rossi, R. Eur. J. Org. Chem. 2002, 1063; (i)
Biagetti, M.; Bellina, F.; Carpita, A.; Rossi, R. Tetra-
hedron Lett. 2003, 44, 607.
4. (a) Afarinkia, K.; Posner, G. H. Tetrahedron Lett. 1992,
33, 7839; (b) Hsung, R. P.; Shen, H. C.; Douglas, C. J.;
Morgan, C. D.; Degen, S. J.; Yao, L. J. J. Org. Chem.
1999, 64, 690; (c) Chen, C.-H.; Liao, C.-C. Org. Lett. 2000,
2, 2049; (d) Bellina, F.; Carpita, A.; Mannocci, L.; Rossi,
R. Eur. J. Org. Chem. 2004, 2610.
Similar results were observed in the reaction of 1a and a-
tetralone (2f) as in Scheme 3. We obtained mono-adduct
3h (44%) and bis-adduct 10 (27%)8 together. As in entry
9, mono-adduct 3h was converted into 4h and 6h simi-
larly. Bis-adduct 10 gave the tricyclic compound 11 in
53% yield as in Basavaiah’s paper.8
As shown in Scheme 4, we used acetylacetone (2g) in
order to introduce the simplest substituent, acetonyl
group, at the primary position of Baylis–Hillman adduct
as in our previous letter.12 By using compound 3i, we
prepared 4i and 6i similarly in moderate yields.
In summary, we developed a facile and efficient proce-
dure for the synthesis of 3-arylidene-5,6-disubstituted-
3,4-dihydropyran-2-ones and 3,5,6-trisubstituted a-
pyrones starting from the Baylis–Hillman adducts.
Acknowledgments
This study was financially supported by Chonnam
National University (2005). Spectroscopic data were
obtained from the Korea Basic Science Institute,
Gwangju branch.
5. (a) Schlingmann, G.; Milne, L.; Carter, G. T. Tetra-
hedron 1998, 54, 13013; (b) Shi, X.; Leal, W. S.; Liu, Z.;
Schrader, E.; Meinwald, J. Tetrahedron Lett. 1995, 36,
71; (c) Gehrt, A.; Erkel, G.; Anke, T.; Sterner, O. Z.

1072
S. J. Kim et al. / Tetrahedron Letters 48 (2007) 1069–1072
Naturforsch 1998, 53c, 89, and further references were
well cited in Ref. 3a.
7.92 (t, J = 2.7 Hz, 1H); 13C NMR (CDCl3, 75 MHz) d
18.75, 25.41, 97.60, 122.41, 128.46, 129.32, 130.24, 134.70,
141.81, 147.49, 164.43. Anal. Calcd for C13H12O2: C,
77.98; H, 6.04. Found: C, 77.79; H, 6.13.
6. For the review articles, see: (a) Basavaiah, D.; Rao, A. J.;
Satyanarayana, T. Chem. Rev. 2003, 103, 811; (b) Lee, K.
Y.; Gowrisankar, S.; Kim, J. N. Bull. Korean Chem. Soc.
2005, 26, 1481; (c) Kim, J. N.; Lee, K. Y. Curr. Org. Chem.
2002, 6, 627.
Compound 6a:11 59%; yellow solid, mp 169–170 °C; IR
(film) 1728, 1651, 1523, 1261 cmÀ1 1H NMR (CDCl3,
;
300 MHz) d 7.20–7.63 (m, 13H), 7.91 (d, J = 8.4 Hz, 2H),
7.92 (s, 1H); 13C NMR (CDCl3, 75 MHz) d 118.10, 123.45,
128.25, 128.28, 128.44, 129.09, 129.14, 129.41, 129.53,
130.81, 131.33, 133.49, 135.35, 136.45, 150.71, 158.97,
161.41, 191.71. Anal. Calcd for C24H16O3: C, 81.80; H,
4.58. Found: C, 81.58; H, 4.77.
7. For our recent papers on the chemical transformations of
Baylis–Hillman adducts, see: (a) Park, D. Y.; Lee, M. J.;
Kim, T. H.; Kim, J. N. Tetrahedron Lett. 2005, 46, 8799;
(b) Lee, M. J.; Lee, K. Y.; Park, D. Y.; Kim, J. N.
Tetrahedron 2006, 62, 3128; (c) Lee, M. J.; Lee, K. Y.;
Gowrisankar, S.; Kim, J. N. Tetrahedron Lett. 2006, 47,
1355; (d) Lee, M. J.; Park, D. Y.; Lee, K. Y.; Kim, J. N.
Tetrahedron Lett. 2006, 47, 1833; (e) Lee, K. Y.; Kim, S.
C.; Kim, J. N. Tetrahedron Lett. 2006, 47, 977; (f)
Gowrisankar, S.; Lee, K. Y.; Kim, J. N. Tetrahedron
2006, 62, 4052; (g) Kim, S. C.; Gowrisankar, S.; Kim, J. N.
Tetrahedron Lett. 2006, 47, 3463; (h) Lee, K. Y.; Seo, J.;
Kim, J. N. Tetrahedron Lett. 2006, 47, 3913; (i) Kim, S. C.;
Lee, H. S.; Lee, Y. J.; Kim, J. N. Tetrahedron Lett. 2006,
47, 5681; (j) Gowrisankar, S.; Lee, K. Y.; Kim, T. H.;
Kim, J. N. Tetrahedron Lett. 2006, 47, 5785; (k) Park, D.
Y.; Kim, S. J.; Kim, T. H.; Kim, J. N. Tetrahedron Lett.
2006, 47, 6315; (l) Park, D. Y.; Gowrisankar, S.; Kim, J.
N. Tetrahedron Lett. 2006, 47, 6641; (m) Lee, K. Y.;
Gowrisankar, S.; Lee, Y. J.; Kim, J. N. Tetrahedron 2006,
62, 8798.
Compound 6b: 55%; yellow solid, mp 185–186 °C; IR
(film) 1732, 1657, 1531, 1266 cmÀ1 1H NMR (CDCl3,
;
300 MHz) d 2.43 (s, 3H), 7.20–7.46 (m, 12H), 7.82 (d,
J = 8.1 Hz, 2H), 7.89 (s, 1H); 13C NMR (CDCl3, 75 MHz)
d 21.77, 118.09, 123.84, 128.23, 128.28, 129.09, 129.16,
129.20, 129.43, 129.77, 130.76, 131.40, 133.86, 135.43,
144.58, 150.38, 159.08, 161.16, 191.30. Anal. Calcd for
C25H18O3: C, 81.95; H, 4.95. Found: C, 81.92; H, 5.11.
Compound 6i: 64%; yellow solid, mp 77–78 °C; IR (film)
1729, 1659, 1558, 1281 cmÀ1; 1H NMR (CDCl3, 300 MHz)
d 2.34 (s, 3H), 6.18 (d, J = 6.9 Hz, 1H), 7.42–7.48 (m, 2H),
7.54–7.60 (m, 1H), 7.71 (d, J = 6.9 Hz, 1H), 7.80 (d,
J = 8.4 Hz, 2H); 13C NMR (CDCl3, 75 MHz) d 20.36,
103.67, 122.55, 128.32, 129.31, 133.26, 136.50, 147.31,
159.77, 167.42, 191.92; LCMS m/z 214 (M+). Anal. Calcd
for C13H10O3: C, 72.89; H, 4.71. Found: C, 72.81; H,
4.98.
8. Basavaiah, D.; Satyanarayana, T. Org. Lett. 2001, 3, 3619.
9. Spectroscopic data of some selected compounds are as
follows:
Compound 8: 38%; pale yellow solid, mp 84–85 °C; IR
;
(film) 1724, 1612, 1041 cmÀ1 1H NMR (CDCl3,
Compound 4a: 83%; white solid, mp 149–150 °C; IR (film)
300 MHz) d 2.79–2.82 (m, 4H), 2.88–2.96 (m, 1H), 7.25–
7.54 (m, 15H), 8.10 (t, J = 2.1 Hz, 2H); 13C NMR (CDCl3,
75 MHz) d 27.39, 33.94, 105.33, 121.18, 125.41, 128.73,
128.94, 129.83, 129.90, 130.46, 134.22, 137.94, 144.83,
164.19; LCMS m/z 422 (M+). Anal. Calcd for C28H22O4:
C, 79.60; H, 5.25. Found: C, 79.45; H, 5.31.
1728, 1612, 1192 cmÀ1 1H NMR (CDCl3, 300 MHz) d
;
3.87 (d, J = 2.4 Hz, 2H), 7.11–7.27 (m, 10H), 7.37–7.45
(m, 5H), 8.03 (t, J = 2.4 Hz, 1H); 13C NMR (CDCl3,
75 MHz) d 32.96, 113.35, 122.57, 127.38, 127.80, 128.49,
128.61, 128.71, 128.92, 129.04, 129.61, 130.42, 133.14,
134.68, 138.44, 142.13, 145.35, 164.17; LCMS m/z 338
(M+). Anal. Calcd for C24H18O2: C, 85.18; H, 5.36.
Found: C, 85.02; H, 5.53.
10. For similar PCC oxidation in a allylic system, see: (a)
Dauben, W. G.; Lorber, M. E.; Fullerton, D. S. J. Org.
Chem. 1969, 34, 3587; (b) Parish, E. J.; Chitrakorn, S.;
Wei, T.-Y. Synth. Commun. 1986, 16, 1371; (c) Parish, E.
J.; Wei, T.-Y. Synth. Commun. 1987, 17, 1227; (d)
Fernandes, R. A.; Kumar, P. Tetrahedron Lett. 2003, 44,
1275; (e) Cuellar, M. A.; Moreno, L. E.; Preite, M. D.
Arkivoc 2003(x), 169; (f) Page, P. C. B.; McCarthy, T. J. In
Comprehensive Organic Synthesis; Trost, B. M., Fleming,
I., Eds.; Pergamon Press: Oxford, 1991; Vol. 7, pp 99–
113.
Compound 4b: 80%; white solid, mp 164–165 °C; IR (film)
1726, 1603, 1192 cmÀ1 1H NMR (CDCl3, 300 MHz) d
;
2.38 (s, 3H), 3.86 (d, J = 2.7 Hz, 2H), 7.11–7.27 (m, 12H),
7.36 (d, J = 8.1 Hz, 2H), 8.01 (t, J = 2.7 Hz, 1H); 13C
NMR (CDCl3, 75 MHz) d 21.46, 33.11, 113.35, 121.45,
127.34, 127.78, 128.44, 128.60, 128.94, 129.04, 129.46,
130.59, 131.95, 133.20, 138.55, 140.13, 142.24, 145.29,
164.32. Anal. Calcd for C25H20O2: C, 85.20; H, 5.72.
Found: C, 85.38; H, 5.86.
11. Kollenz, G.; Terpetschnig, E.; Sterk, H.; Peters, K.; Peters,
E.-M. Tetrahedron 1999, 55, 2973.
12. Im, Y. J.; Lee, C. G.; Kim, H. R.; Kim, J. N. Tetrahedron
Lett. 2003, 44, 2987.
Compound 4i: 60%; colorless oil; IR (film) 1719, 1577,
1169 cmÀ1
;
1H NMR (CDCl3, 300 MHz) d 1.89 (s, 3H),
3.32–3.36 (m, 2H), 4.89–4.93 (m, 1H), 7.34–7.45 (m, 5H),