Oxidative aza Michael addition of nitrogen-containing heterocycles to kojic acid-derived Baylis-Hillman adducts

Article abstract of DOI:10.1515/hc-2014-0197

The oxidation of Baylis-Hillman adducts, obtained by the reaction of 5-benzyloxy-2-formyl-4-pyrone, with o-iodoxybenzoic acid generates β-ketomethylene intermediates that in situ undergo conjugative attack of NH-containing heterocycles such as imidazole a

Full text of DOI:10.1515/hc-2014-0197

Heterocycl. Commun. 2015; 21(1): 37–41
Zarrin Ghasemi* and Hasan Kalantar Esfangare
Oxidative aza Michael addition of nitrogen-
containing heterocycles to kojic acid-derived
Baylis-Hillman adducts
Abstract: The oxidation of Baylis-Hillman adducts, 1,1-dicarbonylethenes, their formation is often followed by
obtained by the reaction of 5-benzyloxy-2-formyl-4-pyrone, sequential reactions, for example, Diels-Alder cyclization,
with o-iodoxybenzoic acid generates β-ketomethylene and formation of heterocyclic products [21–23].
intermediates that in situ undergo conjugative attack
Oxidation of the Baylis-Hillman alcohols, as useful
of NH-containing heterocycles such as imidazole and and interesting β-hydroxycarbonyls, is a satisfactory
pyrazoles.
alternative to the synthesis of the discussed methylene
intermediates. High selectivity and mild conditions of
Keywords: Baylis-Hillman adducts; β-dicarbonyls; o-iodoxybenzoic acid (IBX)-induced oxidation of Baylis-
2-methylene-1,3-dicarbonyls; oxidative Michael addition.
Hillman adducts, which has gained considerable interest
in recent years, allow for in situ domino reactions of the
generated 2-methylene-1,3-dicarbonyl compounds [24–
27]. One-pot oxidative Michael reaction of Baylis-Hillman
alcohols followed by the addition reaction with a suitable
nucleophile is a developed pathway for trapping of the
generated methylene species [28–31].
DOI 10.1515/hc-2014-0197
Received December 5, 2014; accepted December 23, 2014
Introduction
Kojic acid (5-hydroxy-2-hydroxymethyl-4-pyrone) is a
natural antioxidant and metabolic compound that is pro-
1,3-Dicarbonyl derivatives constitute important synthetic duced by several species of fungi. Its derivatives, which
reagents, incorporating multiple functionalities in a large are widely represented in various biologically relevant
variety of synthetic transformations [1–7]. Moreover, they compounds and pharmaceuticals, have been the subject
exhibit antioxidant, antitumor, and antibacterial activi- of several synthetic studies [32–36]. Our recent results
ties [8, 9] and are also key intermediates to various het- on the synthesis of new heterocyclic derivatives of kojic
erocyclic compounds [10–13]. Reaction of enolates with acid, based on Baylis-Hillman chemistry [37, 38], encour-
acylating reagents (such as esters, acid halides, and aged us to further develop this area of research. Herein we
acylimidazoles) and oxidation of β-hydroxycarbonyls report oxidative aza Michael reactions of azoles such as
using mild oxidants (such as hypervalent iodine rea- imidazole and various pyrazoles with kojic acid-derived
gents or dimethyl sulfoxide-based systems) are the major Baylis-Hillman adducts in the presence of IBX, as a supe-
available routes for the synthesis of β-dicarbonyl com- rior oxidant, with the hope that combining the structural
pounds [14–16]. Furthermore, many improved approaches properties of these azaaryls with the kojic acid backbone
have been recently developed for preparation of these will result in new products with interesting properties.
species [17–19]. 2-Methylene-1,3-dicarbonyls are also
O
O
valuable and reactive intermediates in organic synthe-
sis. These compounds are usually generated by the Kno-
evenagol reaction between 1,3-dicarbonyl compounds
and formaldehyde [20]. Because of the instability of the
BnO
BnO
o-iodoxybenzoic acid (IBX)
EtOAc, 70oC, 3 h
H
O
O
OH
R
O
1
2
O
O
*Corresponding author: Zarrin Ghasemi, Faculty of Chemistry,
Department of Organic and Biochemistry, University of Tabriz, Tabriz
5166614766, Iran, e-mail: z.ghasemi@tabrizu.ac.ir
Hasan Kalantar Esfangare: Faculty of Chemistry, Department of
Organic and Biochemistry, University of Tabriz, Tabriz 5166614766,
Iran
3a
: R = OMe
BnO
3b: R = OEt
3c
: R = OBu
3d: R = Me
R
O
DABCO
OH
O
Scheme 1ꢀPreparation of Baylis-Hillman adducts 3a–d.
Brought to you by | New York University Bobst Library Technical Services
Authenticated
Download Date | 2/10/15 9:17 AM

ꢁꢁꢁꢂ
38ꢀ
ꢀZ. Ghasemi and H.K. Esfangare: Oxidative aza Michael addition
R1
Y
O
O
O
O
O
BnO
BnO
BnO
N
O
X
R
azaaryl
IBX
R
R
CH3CN
O
O
O
OH
O
O
3a-d
azaaryl: imidazole
pyrazole
3-methylpyrazole
4-methylpyrazole
R1
Y
O
BnO
N
X
: R = OMe; X = CH; Y = N; R1 = H
: R = OEt; X = N; Y = CH; R1 = 4-Me
: R = OBu; X = CH; Y = N; R1 = H
R
4a
4h
4i
O
: R = OMe; X = N; Y = CH; R1 = H
4c: R = OMe; X = N; Y = CH; R1 = 3-Me
4d: R = OMe; X = N; Y = CH; R1 = 4-Me
4e: R = OEt; X = CH; Y = N; R1 = H
4b
OH
4a-n
O
4j: R = OBu; X = N; Y = CH; R1 = H
4k: R = OBu; X = N; Y = CH; R1 = 3-Me
4l: R = OBu; X = N; Y = CH; R1 = 4-Me
: R = OEt; X = N; Y = CH; R1 = H
: R = Me; X = N; Y = CH; R1 = H
4f
4m
1
: R = OEt; X = N; Y = CH; R = 3-Me
: R = Me; X = N; Y = CH; R1 = 4-Me
4n
4g
Scheme 2ꢀOxidative aza Michael reaction of azoles with Baylis-Hillman alcohols.
Results and discussion
Conclusions
Scheme 1 shows the preparation and Baylis-Hillman reac- A series of 1,3-dicarbonyls containing 4-pyrone and azole
tions of aldehyde 2. Oxidation of kojic acid-benzyl ether 1 (imidazole or pyrazole) moieties were synthesized by
in the presence of IBX (3 equiv) in ethyl acetate at 70°C for oxidative Michael addition of the azoles to the oxidized
3 h gave the desired aldehyde 2 in 98% yield. This is a suc- Baylis-Hillman alcohols. The products are enol tautomers.
cessful alternative to the MnO2-promoted benzylic oxida-
tion of 1, in which the maximum yield of 50% is obtained
[37]. The Baylis-Hillman adducts 3a–d (Scheme 1) were
Experimental
obtained in good yields as reported [37, 38].
The IBX-promoted oxidation reactions of the Baylis-
Melting points were determined on a Electrothermal MEL-TEMP appa-
Hillman alcohols 3 was then examined. Initially, 3a was
ratus (model 1202D) and are uncorrected. FT-IR spectra were obtained
treated with 2 equiv of IBX at 70°C in acetonitrile for
in KBr pellets with a Bruker Tensor 27 spectrometer. H and 13C NMR
1
2 h. Although only a single product was detectable by
TLC of the crude reaction mixture, the workup resulted
in decomposition of the product and formation of new
compounds. The reactions of other substrates 3b–d also
yielded similar complex mixtures. For trapping of the
unstable 1,1-dicarbonylethene intermediate, compound
3a was allowed to react with IBX in acetonitrile at 70°C
in the presence of imidazole. This treatment yielded the
sole product 4a in 69% yield (Scheme 2). Employment of
other solvents such as ethyl acetate, acetone, 1,2-dichlo-
roethane, and chloroform resulted in lower yields. Lower
temperatures resulted in lower yields as well. The alcohol
3a was also treated with pyrazole, 3-methylpyrazole, and
4-methylpyrazole under similar conditions, and similar
results were obtained. Under optimal conditions, these
reactions were conducted in acetonitrile at 70°C for 4–5 h
in the presence of 2.5 equiv of IBX. Benzimidazole did not
spectra were recorded in CDCl3 at 298 K on a Bruker Spectrospin Avance
400 spectrometer operating at 400 and 100 MHz, respectively. Elemen-
tal analyses were obtained using a Vario EL III apparatus (Elementar
Co.). Preparative thin-layer chromatography was done with home-
made glass-backed plates (20 ꢀ×ꢀ 20 cm, 500 μm) using silica gel (Merk
Kieselgel 60 PF254+366). IBX was synthesized by oxidation of 2-iodoben-
zoic acid using KBr3 according to the literature [39]. The Baylis-Hillman
alcohols 3a–d were synthesized as previously described [37, 38].
General procedure for the synthesis of compounds 4a–n
To a solution of a Baylis-Hillman alcohol 3a–d (1.0 mmol) in acetoni-
trile (12 mL) and imidazole, pyrazole, or methylpyrazole (1.2 mmol),
IBX (2.5 mmol) was added, and the mixture was stirred for 5 h at 70°C.
Afer filtration of o-iodobenzoic acid, the solution was concentrated
under reduced pressure to give the crude product, which was puri-
fied by preparative TLC using n-hexane/acetone (2:1) as eluent.
Methyl 3-[5-benzyloxy-4-oxo-4H-pyran-2-yl]-2-[(imidazol-1-yl)met-
hyl]-3-oxopropanoate (4a):ꢁThis compound was obtained from
3a and imidazole in 69% yield (0.26 g) as a pale yellow solid; mp
1
react, even at higher temperatures. The H NMR spectra
are fully consistent with the presence of enol forms in all
products 4a–n.
1
130–132°C; IR: ν 3086, 2924, 1733, 1646 cm-1; H NMR: δ 3.82 (s, 3H,
Brought to you by | New York University Bobst Library Technical Services
Authenticated
Download Date | 2/10/15 9:17 AM

ꢂꢁꢁꢁ
Z. Ghasemi and H.K. Esfangare: Oxidative aza Michael additionꢀ
ꢀ39
CO2CH3), 5.15 (s, 2H, OCH2Ph), 5.72 (s, 2H, CH2-N), 6.32 (s, 1H, H-4 Im), for C21H20N2O6 (396.40): C, 63.63; H, 5.05; N, 7.07. Found: C, 63.42; H,
7.04 (s, 1H, H-3), 7.32–7.41 (m, 5H, H phenyl), 7.45 (s, 1H, H-5 Im), 7.60 5.31; N, 7.29.
(s, 1H, H-6), 7.68 (s, 1H, H-2 Im); 8.15 (s, 1H, OH); 13C NMR: δ 50.9,
52.9, 70.8, 107.5, 114.0, 126.7, 127.4, 127.7, 128.6, 131.3, 133.4, 134.6, 140.5, Ethyl 3-[5-benzyloxy-4-oxo-4H-pyran-2-yl]-3-oxo-2-[(3-methylpyra-
146.8, 162.4, 163.5, 169.1, 172.9. Anal. Calcd for C20H18N2O6 (382.38): C, zol-1-yl)methyl]propanoate (4g):ꢁThis compound was obtained
62.83; H, 4.71; N, 7.33. Found: C, 62.52; H, 4.75; N, 7.29.
from 3b and 3-methylpyrazole in 58% yield (0.24 g) as brown oil; IR:ν
3073, 2984, 1703, 1644 cm-1; 1H NMR: δ 1.25 (t, 3H, J ꢀ=ꢀ 7.1 Hz, CH3), 2.09
Methyl 3-[5-benzyloxy-4-oxo-4H-pyran-2-yl]-3-oxo-2-[(pyrazol-1-yl) (s, 3H, CH3–3 Py), 4.24 (q, 2H, J ꢀ=ꢀ 7.1 Hz, CH2), 5.12 (s, 2H, OCH2Ph),
methyl]propanoate (4b):ꢁThis compound was obtained from 3a and 5.69 (s, 2H, CH2-N), 6.18 (d, 1H, J ꢀ=ꢀ 2.5 Hz, H-4 Py), 7.05 (s, 1H, H-3),
pyrazole in 67% yield (0.25 g) as yellow oil; IR: ν 3083, 2982, 1727, 7.32–7.41 (m, 5H, H phenyl), 7.49 (d, 1H, J ꢀ=ꢀ 2.5 Hz, H-5 Py), 7.58 (s, 1H,
1
1645; H NMR: δ 3.80 (s, 3H, CO2CH3), 5.10 (s, 2H, OCH2Ph), 5.80 (s, H-6), 8.00 (s, 1H, OH); 13C NMR: δ 12.5, 13.1, 54.6, 60.8, 70.8, 106.1,
2H, CH2-N), 6.47 (s, 1H, br, H-4 Py), 7.02 (s, 1H, H-3), 7.32–7.42 (m, 5H, H 109.3, 114.9, 126.7, 127.5, 127.7, 129.2, 131.9, 134.2, 139.8, 140.7, 142.9,
phenyl), 7.54 (s, 1H, br, H-3 Py), 7.57 (s, 1H, H-6), 7.84 (s, 1H, br, H-5 Py), 156.6, 163.0, 174.1. Anal. Calcd for C22H22N2O6 (410.30): C, 64.39; H,
8.11 (s, 1H, OH); 13C NMR: δ 51.2, 54.3, 70.9, 107.2, 113.4, 116.0, 126.8, 5.36; N, 6.83. Found: C, 64.16; H, 5.28; N, 6.68.
127.5, 127.7, 128.5, 131.3, 135.7, 139.5, 141.0, 143.8, 156.6, 163.7, 174.1. Anal.
Calcd for C20H18N2O6 (382.38): C, 62.83; H, 4.71; N, 7.33. Found: C, 62.48; Ethyl 3-[5-benzyloxy-4-oxo-4H-pyran-2-yl]-3-oxo-2-[(4-methylpyra-
H, 4.77; N, 7.45.
zol-1-yl)methyl]propanoate (4h):ꢁThis compound was obtained
from 3b and 4-methylpyrazole in 59% yield (0.24 g) as brown oil; IR:
Methyl 3-[5-benzyloxy-4-oxo-4H-pyran-2-yl]-3-oxo-2-[(3-methylpy- ν 3099, 2981, 1739, 1647 cm-1; 1H NMR: δ 1.25 (t, 3H, J ꢀ=ꢀ 7.1 Hz, CH3), 2.02
razol-1-yl)methyl]propanoate (4c):ꢁThis compound was obtained (s, 3H, CH3–4 Py), 4.16 (q, 2H, J ꢀ=ꢀ 7.1 Hz, CH2), 5.11 (s, 2H, OCH2Ph),
from 3a and 3-methylpyrazole in 73% yield (0.29 g) as yellow oil; 5.78 (s, 2H, CH2-N), 7.00 (s, 1H, H-3), 7.38–7.42 (m, 5H, H phenyl), 7.54
1
IR: ν 3072, 2990, 1725, 1650; H NMR: δ 2.05 (s, 3H, CH3), 3.79 (s, 3H, (s, 1H, H-3 Py), 7.59 (s, 1H, H-6), 7.63 (s, 1H, H-5 Py); 8.23 (s, 1H, OH);
CO2CH3), 5.10 (s, 2H, OCH2Ph), 5.82 (s, 2H, CH2-N), 6.19 (d, 1H, J ꢀ=ꢀ 1.8 13C NMR: δ 7.7, 13.1, 54.7, 61.2, 70.7, 114.1, 115.7, 126.4, 126.8, 127.4, 127.7,
Hz, H-4 Py), 7.02 (s, 1H, H-3), 7.35–7.38 (m, 5H, H phenyl), 7.48 (s, 1H, 133.9, 138.8, 139.7, 144.6, 149.5, 154.6, 161.2, 163.9, 172.9. Anal. Calcd
br, H-5 Py), 7.56 (s, 1H, H-6), 8.00 (s, 1H, OH); 13C NMR: δ 12.6, 51.7, 55.7, for C22H22N2O6 (410.30): C, 64.39; H, 5.36; N, 6.83. Found: C, 64.20; H,
70.9, 109.5, 115.2, 126.8, 127.5, 127.7, 131.9, 134.3, 135.9, 140.3, 147.4, 152.6, 5.18; N, 6.71.
154.2, 161.2, 163.5, 172.9. Anal. Calcd for C21H20N2O6 (396.40): C, 63.63;
H, 5.05; N, 7.07. Found: C, 63.42; H, 5.29; N, 7.28.
Butyl 3-[5-benzyloxy-4-oxo-4H-pyran-2-yl]-2-[(imidazol-1-yl)meth-
yl]-3-oxopropanoate (4i):ꢁThis compound was obtained from 3c
Methyl 3-[5-benzyloxy-4-oxo-4H-pyran-2-yl]-3-oxo-2-[(4-methylpy- and imidazole in 72% yield (0.30 g) as colorless oil; IR: ν 3400, 2956,
razol-1-yl)methyl]propanoate (4d):ꢁThis compound was obtained 1719, 1646 cm-1; H NMR: δ 0.90 (t, 3H, J ꢀ=ꢀ 7.3 Hz, CH3), 1.37 (m, 2H,
1
from 3a and 4-methylpyrazole in 70% yield (0.28 g) as yellow oil; IR: CH2CH3), 1.62 (m, 2H, CH2CH2CH2), 4.22 (t, 2H, J ꢀ=ꢀ 6.6 Hz, CO2CH2), 5.11
ν 3088, 2955, 1738, 1641 cm-1; 1H NMR: δ 2.08 (s, 3H, CH3), 3.61 (s, 3H, (s, 2H, OCH2Ph), 5.81 (s, 2H, CH2-N), 6.31 (s, 1H, H-4 Im), 7.11 (s, 1H,
CO2CH3), 5.07 (s, 2H, OCH2Ph), 5.80 (s, 2H, CH2-N), 7.02 (s, 1H, H-3), 7.20 H-3), 7.32–7.41 (m, 5H, H phenyl), 7.45 (s, 1H, H-5 Im), 7.58 (s, 1H, H-6),
(s, 1H, H-3 Py), 7.35–7.41 (m, 5H, H phenyl), 7.50 (s, 1H, H-5 Py), 7.68 (s, 7.66 (s, 1H, H-2 Im), 8.73 (s, 1H, OH); 13C NMR: δ 12.6, 18.0, 29.4, 54.6,
1H, H-6), 8.01 (s, 1H, OH); 13C NMR: δ 7.82, 47.8, 51.1, 70.5, 90.3, 113.3, 64.9, 70.7, 108.7, 114.1, 126.8, 127.4, 127.7, 131.6, 131.7, 133.2, 134.6, 139.5,
115.3, 126.2, 126.8, 126.9, 127.5, 127.7, 139.7, 139.9, 140.0, 140.7, 161.2, 140.4, 146.6, 161.2, 163.2, 172.9. Anal. Calcd for C23H24N2O6 (424.46): C,
163.1, 172.3. Anal. Calcd for C21H20N2O6 (396.40): C, 63.63; H, 5.05; N, 65.09; H, 5.66; N, 6.60. Found: C, 64.78; H, 5.38; N, 6.87.
7.07. Found: C, 63.44; H, 5.32; N, 7.26.
Butyl 3-[5-benzyloxy-4-oxo-4H-pyran-2-yl]-3-oxo-2-[(pyrazol-1-yl)
Ethyl 3-[5-benzyloxy-4-oxo-4H-pyran-2-yl]-2-[(imidazol-1-yl)meth- methyl]propanoate (4j):ꢁThis compound was obtained from 3c and
yl]-3-oxopropanoate (4e):ꢁThis compound was obtained from 3b pyrazole in 69% yield (0.29 g) as colorless oil; IR: ν 3090, 2986, 1721,
and imidazole in 68% yield (0.27 g) as brown oil; IR: ν 3083, 2982, 1645 cm-1; 1H NMR: δ 0.80 (t, 3H, J ꢀ=ꢀ 7.0 Hz, CH3), 1.15 (m, 2H, CH2CH3),
1
1727, 1645 cm-1; H NMR: δ 1.44 (t, 3H, J ꢀ=ꢀ 7.1 Hz, CH3), 4.46 (q, 2H, 1.41 (m, 2H, CH2CH2CH2), 4.03 (t, 2H, J ꢀ=ꢀ 7.0 Hz, CO2CH2), 5.12 (s, 2H,
J ꢀ=ꢀ 7.1 Hz, CH2), 5.13 (s, 2H, OCH2Ph), 5.68 (s, 2H, CH2-N), 6.35 (s, 1H, OCH2Ph), 5.49 (s, 2H, CH2-N), 6.85 (s, 1H, H-4 Py), 7.05 (s, 1H, H-3),
H-4 Im), 7.02 (s, 1H, H-3), 7.32–7.41 (m, 5H, H phenyl), 7.46 (s, 1H, H-5 7.34–7.40 (m, 5H, H phenyl), 7.50 (s, 1H, H-3 Py), 7.56 (s, 1H, H-6), 7.67
Im), 7.59 (s, 1H, H-6), 7.68 (s, 1H, H-2 Im); 8.32 (s, 1H, OH); 13C NMR: δ (s, 1H, H-5 Py), 8.07 (s, 1H, OH); 13C NMR: δ 12.7, 18.1, 29.5, 54.8, 61.7,
13.1, 54.8, 61.0, 70.9, 106.1, 113.2, 126.8, 127.0, 127.8, 128.6, 130.9, 132.8, 70.9, 105.9, 108.7, 114.3, 126.5, 127.2, 127.9, 130.9, 131.8, 133.3, 134.4,
134.4, 145.1, 147.8, 154.0, 162.8, 163.0, 172.9. Anal. Calcd for C21H20N2O6 139.8, 145.8, 162.2, 163.6, 172.9. Anal. Calcd for C23H24N2O6 (424.46): C,
(396.40): C, 63.63; H, 5.05; N, 7.07. Found: C, 63.39; H, 5.22; N, 7.34.
65.09; H, 5.66; N, 6.60. Found: C, 64.71; H, 5.43; N, 6.71.
Ethyl 3-[5-benzyloxy-4-oxo-4H-pyran-2-yl]-3-oxo-2-[(pyrazol-1-yl) Butyl 3-[5-benzyloxy-4-oxo-4H-pyran-2-yl]-3-oxo-2-[(3-methylpyra-
methyl]-propanoate (4f):ꢁThis compound was obtained from 3b zol-1-yl)methyl]-propanoate (4k):ꢁThis compound was obtained
and pyrazole in 64% yield (0.25 g) as brown oil; IR: ν 3099, 2981, 1739, from 3c and 3-methylpyrazole in 70% yield (0.31 g) as colorless oil;
1
1647 cm-1; 1H NMR: δ 1.06 (t, 3H, J ꢀ=ꢀ 7.1 Hz, CH3), 4.05 (q, 2H, J ꢀ=ꢀ 7.1 Hz, IR: ν 3396, 3089, 2978, 1722, 1646 cm-1; H NMR: δ 0.90 (t, 3H, J ꢀ=ꢀ 7.3
CH2), 5.09 (s, 2H, OCH2Ph), 5.77 (s, 2H, CH2-N), 6.31 (s, 1H, H-4 Py), Hz, CH3), 1.37 (m, 2H, CH2CH3), 1.62 (m, 2H, CH2CH2CH2), 2.07 (s, 3H,
7.06 (s, 1H, H-3), 7.35–7.41 (m, 5H, H phenyl), 7.50 (d, 1H, J ꢀ=ꢀ 2.0 Hz, H-3 CH3–3 Py), 4.12 (t, 2H, J ꢀ=ꢀ 6.6 Hz, CO2CH2), 5.11 (s, 2H, OCH2Ph), 5.88
Py), 7.57 (s, 1H, H-6), 7.69 (d, 1H, J ꢀ=ꢀ 2.0 Hz, H-5 Py), 8.07 (s, 1H, OH); (s, 2H, CH2-N), 6.91 (s, 1H, H-4 Py), 7.04 (s, 1H, H-3), 7.32–7.42 (m, 5H,
13C NMR: δ 12.7, 54.8, 66.9, 70.9, 108.8, 113.2, 115.5, 126.8, 127.5, 127.7, H phenyl), 7.49 (s, 1H, H-6), 7.60 (s, 1H, H-5 Py), 8.03 (s, 1H, OH);
128.5, 131.3, 135.7, 139.5, 140.0, 143.8, 156.8, 163.6, 174.1. Anal. Calcd 13CNMR: δ 12.4, 12.6, 17.6, 29.1, 54.6, 64.5, 70.9, 105.8, 107.9, 114.1, 126.8,
Brought to you by | New York University Bobst Library Technical Services
Authenticated
Download Date | 2/10/15 9:17 AM

ꢁꢁꢁꢂ
40ꢀ ꢀZ. Ghasemi and H.K. Esfangare: Oxidative aza Michael addition
127.4, 127.7, 131.8, 134.2, 134.6, 135.6, 139.9, 147.4, 161.2 163.7, 172.9. Anal.
Calcd for C24H26N2O6 (438.48): C, 65.75; H, 5.94; N, 6.39. Found: C,
65.53; H, 5.88; N, 6.21.
[5] Langer, P. Regio- and diastereoselective cyclization reactions
of free and masked 1,3-dicarbonyl dianions with 1,2-dielectro-
philes. Chem. Eur. J. 2001, 7, 3858–3866.
[6] Simon, C.; Constantieux, T.; Rodriguez, J. Utilisation of
1,3-dicarbonyl derivatives in multicomponent reactions. Eur. J.
Org. Chem. 2004, 24, 4957–4980.
Butyl 3-[5-benzyloxy-4-oxo-4H-pyran-2-yl]-3-oxo-2-[(4-methylpyra-
zol-1-yl)methyl]-propanoate (4l):ꢁThis compound was obtained
from 3c and 4-methylpyrazole in 71% yield (0.31 g) as colorless oil;
IR: ν 3089, 2960, 1737, 1648 cm-1; 1H NMR: δ 0.79 (t, 3H, J ꢀ=ꢀ 7.0 Hz, CH3),
1.43 (m, 2H, CH2CH3), 1.85 (m, 2H, CH2CH2CH2), 2.03 (s, 3H, CH3–4 Py),
4.03 (t, 2H, J ꢀ=ꢀ 6.6 Hz, CO2CH2), 5.01 (s, 2H, OCH2Ph), 5.72 (s, 2H, CH2-
N), 7.04 (s, 1H, H-3), 7.14–7.35 (m, 5H, H phenyl), 7.52 (s, 1H, H-3 Py),
7.58 (s, 1H, H-6), 7.62 (s, 1H, H-5 Py), 9.69 (s, 1H, br, OH); 13C NMR: δ
7.60, 12.3, 17.8, 29.2, 54.3, 64.4, 70.7, 90.7, 114.6, 119.5, 126.6, 127.6, 129.1,
135.8, 139.4, 139.8, 140.4, 145.1, 147.2, 162.8, 164.8, 172.9. Anal. Calcd
[7] LoPachin, R. M.; Gavin, T.; Geohagen, B. C.; Zhang, L.; Casper,
D. β-Dicarbonyl enolates: a new class of neuroprotectants.
J. Neurochem. 2011, 116, 132.
[8] Kel,in, A. V. Recent advances in the synthesis of 1,3-diketones.
Curr. Org. Chem. 2003, 7, 1691–1711.
[9] Kel,in, A. V.; Maioli, A. Recent advances in the chemistry of
1,3-diketones: structural modifications and synthetic applica-
tions. Curr. Org. Chem. 2003, 7, 1855–1886.
for C24H26N2O6 (438.48): C, 65.75; H, 5.94; N, 6.39. Found: C, 65.58; H, [10] Cai, S.; Wang, F.; Xi, C. Synthesis of 3-substituted isocoumarin
5.73; N, 6.14.
derivatives via CuI-catalyzed reaction of o-bromobenzamides
with 1,3-diketones. Synthesis 2012, 44, 1892.
1-[5-Benzyloxy-4-oxo-4H-pyran-2-yl]-2-[(pyrazol-1-yl)methyl]- [11] Liu, Y.; Wan, J. P. Advances in copper-catalyzed C-C coupling
butane-1,3-dione (4m):ꢁThis compound was obtained from 3d and
reactions and related domino reactions based on active meth-
ylene compounds. Chem. Asian J. 2012, 7, 1488–1501.
pyrazole in 66% yield (0.24 g) as yellow oil; IR: ν 3020, 2960, 1716,
1
1646 cm-1; H NMR: δ 2.34 (s, 3H, CH3), 5.05 (s, 2H, OCH2Ph), 5.81 (s, [12] Dang, H. V.; Habib, N. S.; Stadlbauer, W. Synthesis and struc-
2H, CH2-N), 6.42 (s, 1H, H-4 Py), 7.00 (s, 1H, H-3), 7.34–7.38 (m, 5H, H
ture elucidation of 3,4-dihydroxy-2-quinolin-2-ylpyrido[3,2,1-jk]
carbazol-6-ones. J. Heterocycl. Chem. 2007, 44, 161–165.
phenyl), 7.53 (s, 1H, H-6), 7.65 (d, 1H, J ꢀ=ꢀ 2.4 Hz, H-3 Py), 7.78 (s, 1H,
H-5 Py), 8.02 (s, 1H, OH); 13C NMR: δ 26.5, 51.8, 71.0, 109.2, 115.2, 122.5, [13] Klappa, J. J.; Rich, A. E.; McNeill, K. One-step synthesis of 3,5-dis-
126.8, 127.6, 127.7, 127.8, 131.6, 134.3, 135.3, 140.3, 147.6, 156.2, 173.8,
185.5. Anal. Calcd for C20H18N2O5 (366.38): C, 65.57; H, 4.92; N, 7.65.
Found: C, 65.29; H, 5.18; N, 7.45.
ubstituted-2-pyridylpyrroles from the condensation of 1,3-diones
and 2-(aminomethyl)pyridine. Org. Lett. 2002, 4, 435–437.
[14] Bartlett, S. L.; Beaudry, C. M. High-yielding oxidation of
β-hydroxyketones to β-diketones using o-iodoxybenzoic acid.
J. Org. Chem. 2011, 76, 9852–9855.
1-[5-Benzyloxy-4-oxo-4H-pyran-2-yl]-2-[(4-methylpyrazol-1-yl)
methyl]-butane-1,3-dione (4n):ꢁThis compound was obtained from [15] Jeyakumar, K.; Chand, D. K. Molybdenum(VI) dichloride dioxide
3d and 4-methylpyrazole in 62% yield (0.23 g) as yellow oil; IR: ν
3089, 2926, 1706, 1642 cm-1; 1H NMR: δ 2.06 (s, 3H, CH3–4 Py), 2.31 (s,
3H, CH3), 5.07 (s, 2H, OCH2Ph), 5.72 (s, 2H, CH2-N), 6.99 (s, 1H, H-3),
catalyzed conversion of β-hydroxy-carbonyls into α-bromo
1,3-dicarbonyls by n-bromosuccinimide. Synthesis 2009, 2,
306–310.
7.34–7.38 (m, 5H, H phenyl), 7.56 (s, 1H, H-3 Py), 7.61 (s, 1H, H-6), 7.94 [16] Yuasa, Y.; Kato, Y. New oxidation of β-hydroxy α-methyl
(s, 1H, H-5 Py); 8.69 (s, 1H, br, OH); 13C NMR: δ 7.7, 26.4, 48.9, 70.9,
115.0, 120.2, 121.2, 126.8, 127.7, 127.9, 129.5, 134.2, 135.6, 139.8, 145.5,
147.5, 156.2, 173.9, 185.7. Anal. Calcd for C21H20N2O5 (380.40): C, 66.31; [17] Lim, D.; Fang, F.; Zhou, G.; Coltart, D. M. Direct carbon-carbon
H, 5.26; N, 7.37. Found: C, 66.09; H, 5.17; N, 7.60.
ketones: a convenient synthesis of 3-methylalkane-2,4-diones.
Org. Proc. Res. Dev. 2002, 6, 628–631.
bond formation via soft enolization: a facile and efficient syn-
thesis of 1,3-diketones. Org. Lett. 2007, 9, 4139–4142.
[18] Sato, K.; Yamazoe, S.; Yamamoto, R.; Ando, A. Direct synthe-
sis of 1,3-diketones by Rh-catalyzed reductive α-acylation of
enones. Org. Lett. 2008, 10, 2405–2408.
Acknowledgments: The authors thank Research Affairs of
University of Tabriz for financial support.
[19] Sada M.; Matsubara, S. A tandem reaction initiated by
1,4-addition of bis(iodozincio)methane for 1,3-diketone forma-
tion. J. Am. Chem. Soc. 2010, 132, 432–433.
[20] Nenajdenko, V. G.; Statsuk, A. V.; Balenkova, E. S. Reaction of
2-methylene-1,3-dicarbonyl compounds containing a CF3-
group with 1,3-dienes. Tetrahedron 2000, 56, 6549–6556.
[21] Yamauchi, M.; Katayama, S.; Baba, O.; Watanabe, T. Reactivity
of 2-methylene-1,3-dicarbonyl compounds. Inverse electron-
demand Diels-Alder reactions with alkyl vinyl ethers. J. Chem.
Soc. Perkin Trans. 1, 1990, 1990, 3041–3044.
[22] Yamauchi, M.; Honda, Y.; Matsuki, N.; Watanabe, T. Reactivity
of 2-methylene-1,3-dicarbonyl compounds. Stereoselective
and asymmetric Diels-Alder reactions. J. Org. Chem. 1996, 61,
2719–2725.
[23] Yamauchi, M. Reactivity of 2-methylene-1,3-dicarbonyl com-
pounds. 1,3-Dipolar cycloaddition reaction with nitrile oxide.
J. Heterocycl. Chem. 2002, 39, 1013–1018.
References
[1] Li, H.; Li, W.; Liu, W.; He, Z.; Li, Z. An efficient and general iron-
catalyzed C-C bond activation with 1,3-dicarbonyl units as a
leaving groups. Angew. Chem. 2011, 123, 3031–3034.
[2] Dhiman, S.; Ramasastry, S. S. V. Acid catalyzed ring transforma-
tion of benzofurans to tri- and tetrasubstituted furans. J. Org.
Chem. 2013, 78, 10427–10436.
[3] Li, W.; Zheng, X.; Lia, Z. Iron-catalyzed C-C bond cleavage and
C-N bond formation. Adv. Synth. Catal. 2013, 355, 181–190.
[4] Motokura, K.; Fujita, N.; Mori, K.; Mizugaki, T.; Ebitani, K.;
Kaneda, K. Brønsted acid mediated heterogeneous addition
reaction of 1,3-dicarbonyl compounds to alkenes and alcohols.
Angew. Chem. Int. Ed. 2006, 45, 2605–2609.
Brought to you by | New York University Bobst Library Technical Services
Authenticated
Download Date | 2/10/15 9:17 AM

ꢂꢁꢁꢁ
Z. Ghasemi and H.K. Esfangare: Oxidative aza Michael additionꢀ
ꢀ41
[24] Hong, W. P.; Lee, K. J. Baylis-Hillman route to several quinolone
antibiotic intermediates. Synthesis 2006, 6, 963–968.
[25] Yang, J.; Li, H.; Shi, B.; Tian, S.; Zhang, J. Oxidative oxo Diels-
Alder reactions of Baylis-Hillman adducts with electron-rich
alkenes in the presence of IBX. Synth. Commun. 2012, 42,
1567–1576.
[26] Yadav, L. D. S.; Awasthi, C. The first one-pot oxidative
1,2-acetoxysulfenylation and 1,2-disulfenylation of Baylis-
Hillman alcohols in an ionic liquid. Tetrahedron Lett. 2009, 50,
3801–3804.
[32] Farard, J.; Logé, C.; Pfeiffer, B.; Lesur, B.; Duflos, M. A
convenient synthesis of 5-arylamino-4H-pyran-4-ones using
palladium-catalyzed amination. Tetrahedron Lett. 2009, 50,
5729–5732.
[33] Kamino, T.; Kuramochi, K.; Kobayashi, S. A concise approach
to 5-substituted-4-pyrones from kojic acid. Tetrahedron Lett.
2003, 44, 7349–7351.
[34] Xiong, X.; Pirrung, M. C. Modular synthesis of candidate
indole-based insulin mimics by Claisen rearrangement. Org.
Lett. 2008, 10, 1151–1154.
[27] Yadav, L. D. S.; Patel, R.; Srivastava, V. P. One-pot oxidative
conjugate hydrothiocyanation-hydrosulfenylation of Baylis-
Hillman alcohols promoted by a protic ionic liquid. Synlet
2008, 12, 17891792.
[28] Yadav, J. S.; Reddy, B. V. S.; Singh, A. P.; Basak, A. K. The first
one-pot oxidative Michael reaction of Baylis-Hillman adducts
with indoles promoted by iodoxybenzoic acid. Tetrahedron
Lett. 2007, 48, 4169–4172.
[29] Yadav, J. S.; Reddy, B. V. S.; Singh, A. P.; Basak, A. K. IBX/
Sc(OTf)3-promoted one-pot oxidative conjugate addition of
allyltrimethylsilane to Baylis-Hillman adducts. Tetrahedron
Lett. 2007, 48, 7546–7548.
[30] Yadav, L. D. S.; Awasthi, C.; Rai, A. Ionic liquid-promoted
one-pot oxidative Michael addition of TMSCN to Baylis-Hillman
adducts. Tetrahedron Lett. 2008, 49, 6360–6363.
[31] Tan, J. N.; Li, H.; Gu, Y. Water mediated trapping of active meth-
ylene intermediates generated by IBX-induced oxidation of
Baylis-Hillman adducts with nucleophiles. Green Chem. 2010,
12, 1772–1782.
[35] Reddy, B. V. S.; Reddy, M. R.; Madan, C.; Kumar, K. P.; Rao, M.
S. Indium(III) chloride catalyzed three-component coupling
reaction: a novel synthesis of 2-substituted aryl(indolyl)kojic
acid derivatives as potent antifungal and antibacterial agents.
Bioorg. Med. Chem. Lett. 2010, 20, 7507–7511.
[36] Rodrigues, A. P. D.; Carvalho, A. S. C.; Santos, A. S.; Alves, C.
N.; Silva, E. O. Kojic acid, a secondary metabolite from Asper-
gillus sp., acts as an inducer of macrophage activation. Cell
Biol. Int. 2011, 35, 335–343.
[37] Ghasemi, Z.; Eshtad, M.; Mejarshin, F. P. Synthesis of new
N-heteroaryl derivatives of 4-pyrones from kojic acid based
Baylis-Hillman acetates. Chem. Heterocycl. Compd. 2013, 48,
1652–1658.
[38] Shahrisa, A.; Ghasemi, Z. Synthesis of fused pyrimidone
derivatives of 4-pyrones from the acetates of Baylis-Hillman
adducts. Chem. Heterocycl. Compd. 2010, 46, 30–36.
[39] Frigerio, M.; Santagostino, M.; Sputore, S. A user-friendly
entry to 2-iodoxybenzoic acid (IBX). J. Org. Chem. 1999, 64,
4537–4538.
Brought to you by | New York University Bobst Library Technical Services
Authenticated
Download Date | 2/10/15 9:17 AM