Solid-supported Robinson annulation under microwave irradiation.

Article abstract of DOI:10.1248/cpb.51.455

Robinson annulation on alumina occurred efficiently on heating with microwave irradiation.

Full text of DOI:10.1248/cpb.51.455

April 2003
Notes
Chem. Pharm. Bull. 51(4) 455—457 (2003)
455
Solid-Supported Robinson Annulation under Microwave Irradiation
Kazuhiko TAKATORI, Masayasu NAKAYAMA, Naoko FUTAISHI, Saori YAMADA, Shinobu HIRAYAMA, and
Masahiro KAJIWARA*
Department of Medicinal Chemistry, Meiji Pharmaceutical University; 2–522–1 Noshio, Kiyose, Tokyo 204–8588, Japan.
Received November 29, 2002; accepted January 6, 2003
Robinson annulation on alumina occurred efficiently on heating with microwave irradiation.
Key words Robinson annulation; microwave; alumina; solid-support; dry media
Heating of organic reaction mixtures with microwave irra- Hajos–Parrish ketone (8) and the indan derivative 10 oc-
diation is an easy and rapid procedure that can be used in curred in low yield, since the reverse reaction, hydration of
place of conventional heating with an oil bath, water bath, or the double bond in the ketone (8) followed by retro-aldol re-
sand bath. It has been applied in the solution phase or with action, tended to occur in this condition (entries 3, 4). The
solid-supported dry media.1,2) We have employed the mi- reaction of 6-membered ring b-ketoester 11 and b-ketoamide
crowave-accelerated Diels–Alder reaction for the synthesis of 1814) with methyl vinyl ketone (2) or ethyl vinyl ketone (5)
a compactin intermediate.3) The Diels–Alder reaction4) and yielded good results (entries 5, 6, 9). The required microwave
Robinson annulation4—7) are useful methods for the synthesis irradiation time and the yield were markedly dependent on
of natural products consisting of fused-ring systems, such as the structure in the case of a,b-unsaturated ketones. The
terpenes and alkaloids.8) In this paper, we report on solid- simple a,b-unsaturated ketone 2 reacted smoothly and the
supported Robinson annulation under microwave yield was good. The bulkier a- or b-substituted a,b-unsatu-
irradiation.9) The usual conditions of Robinson annulation rated ketones 14 and 16 gave poor results (entries 7, 8). This
are as follows. Michael addition of 2-methyl-1,3-cyclohexa- reason for this is presumably the ease of occurrence of the
nedione (1) to methyl vinyl ketone (2) with KOH in refluxed Michael addition. The Michael addition of the b-ketoester 11
methanol for 1—3 h, and after evaporation, aldol condensa- to 2 and 5 on alumina at ambient temperature gave the
tion and dehydration with pyrrolidine under reflux with adduct in 94% and 96% yield, respectively, after elution with
azeotropic distillation in benzene for 1 h give Wieland–Mi- AcOEt. On the other hand, the Michael addition of 11 to the
escher ketone (3) in 63—65% yield.6)
bulkier a,b-unsaturated ketones 14 and 16 scarcely pro-
In the initial investigation of Robinson annulation, 2- ceeded under this condition. The reaction of 11 and 14 gave
methyl-1,3-cyclohexanedione (1) and methyl vinyl ketone (2) a trace amount of the adduct, and adduct formation between
were absorbed on activated acidic, neutral, or basic alumina, 11 and 16 was not detected. These reactions did not proceed
silica gel, Florisil®, or Montmorillonite K10. When alumina easily even under microwave irradiation.15) Therefore, simple
was used, the Michael addition proceeded at ambient temper- alkyl vinyl ketones are the best choice for the a,b-unsatu-
ature without microwave irradiation to afford the correspond- rated ketone.
ing Michael adduct.10,11) Activated basic alumina was the
Pyrrolidine as the catalyst was required for most, but not
most effective.12,13) Other supports did not promote the all, of the reactions. Other secondary amines were also effec-
Michael addition even under microwave irradiation. Mi- tive as the catalyst for the complete reaction (Table 2).
crowave irradiation of the mixture of the Michael adduct and
In summary, the methodology presented provides an oper-
basic alumina for 3 min in a domestic microwave oven re- ationally very simple and rapid Robinson annulation on acti-
sulted in intramolecular aldol condensation and subsequent vated basic alumina under microwave.
partial dehydration to give a mixture of the Wieland–Mi-
Experimental
escher ketone (3) and alcohol 4. In the presence of a catalytic
amount of pyrrolidine, the dehydration completed under mi-
Instruments Unless otherwise noted, all materials were obtained from
commercial suppliers and used without purification. Microwave irradiation
crowave irradiation for 3 min and the reaction afforded only
the Wieland–Miescher ketone (3) in 52% yield (Fig. 1).
Microwave irradiation sufficed for the complete reaction
only after addition of pyrrolidine (Table 1 entry 1), and the
temperature immediately after microwave irradiation was ca.
155 °C. When this reaction was performed by heating in an
oil bath at 155 °C for 3 min after the addition of pyrrolidine,
the annulation was not completed and afforded the Michael
adduct and the ketone 3 in 33% and 19% yield, respectively.
Microwave heating was effective for the dry media reaction.
The reaction of several structurally diverse 1,3-dicarbonyl
compounds and a,b-unsaturated ketones was also performed
in this condition (Table 1). All the reactions proceeded
rapidly. The usable 1,3-dicarbonyl compounds included 1,3-
diketone, b-ketoester, and b-ketoamide. The formation of
was carried out in a Mitsubishi RO-F6 domestic microwave oven (500 W,
2450 Hz). Column chromatography and TLC were performed on silica gel
Fig. 1
* To whom correspondence should be addressed. e-mail: kajiwara@my-pharm.ac.jp
© 2003 Pharmaceutical Society of Japan

456
Vol. 51, No. 4
Table 1. Robinson Annulation under Microwave Irradiation
Entry
1,3-Dicarbonyl compound
a,b-Unsaturated ketone
Pyrrolidine (eq.)
0.05
Time (min)
3
Product
Yield (%)a)
1
54
51
2
1
0.40
5
2
ꢂ
3
4
5
6
7
2
2
2
5
0.07
0.09
0.05
0.05
none
3
3
3
3
45
32
86
11
11
11
87
3
3
28b)
ꢂ
8
9
0.05
3
5
ꢂ ꢂ
7
11c)
73
2
none
3
a) Isolated yield. b) Single isomer. The stereochemistry was not determined. c) A 1 : 1 diastereomer mixture. The ratio was estimated by 1H-NMR spectrum.
Table 2. Effect of Various Amines in Robinson Annulation of 11 and 2
mina from Wako Pure Chemical Industries, Ltd. (200 mesh for column chro-
matography) could be used instead of Merck alumina.
Amine (0.05 eq)
Time (min)
Yield (%)
Ethyl 6-Methyl-7-oxo-1,3,4,5,6,7-hexahydro-2H-naphthalene-4a-carboxy-
late (15): Slightly yellow oil. IR (neat) cmꢁ1: 2936, 2862, 1725, 1677, 1631,
1452, 1368, 1292, 1258, 1232, 1203, 1188, 1154, 1134, 1087, 1021, 865.
1H-NMR (CDCl3) d: 1.08 (3H, d, Jꢀ6.6 Hz), 1.28 (3H, t, Jꢀ7.1 Hz), 1.23—
1.48 (4H, m), 1.74 (1H, m), 1.89 (1H, m), 2.24—2.50 (5H, m), 4.17—4.29
(2H, m), 5.91 (1H, s). EI-MS m/z (%): 236 (Mꢂ, 55), 194 (50), 163 (100),
138 (37), 91 (13). HR-MS m/z: 236.1408 (Calcd for C14H20O3: 236.1412).
N-(2,6-Dimethylphenyl)-2-oxocyclohexanecarbamide (18): White nee-
dles. mp 135.8—136.6 °C (benzene). IR (KBr) cmꢁ1: 3416, 3233, 3040,
2945, 2869, 1708, 1647, 1542, 1478, 1376, 1129, 769, 690. 1H-NMR
(CDCl3) d: 1.71—1.93 (2H, m), 1.94—2.20 (3H, m), 2.23 (6H, s), 2.42—
2.65 (3H, m), 3.41 (1H, dd, Jꢀ6.0, 11.5 Hz), 7.04—7.13 (3H, m), 8.64 (1H,
br s). EI-MS m/z (%): 245 (Mꢂ, 38), 147 (37), 121 (100), 98 (23), 55 (12).
HR-MS m/z: 245.1412 (Calcd for C15H19NO2: 245.1416).
N-(2,6-Dimethylphenyl)-7-oxo-1,3,4,5,6,7-hexahydro-2H-naphthalene-
4a-carbamide (19): White needles. mp 213.3—214.5 °C (benzene). IR (KBr)
cmꢁ1: 3311, 2941, 2859, 1664, 1540, 1264, 1220, 782. 1H-NMR (CDCl3) d:
1.30—2.28 (6H, m), 2.22 (6H, s), 2.29—2.88 (6H, m), 6.13 (1H, s), 7.02—
7.15 (3H, m), 7.92 (1H, s). EI-MS m/z (%): 297 (Mꢂ, 27), 151 (11), 150
(100), 149 (12), 148 (14), 147 (53), 132 (18), 122 (15), 121 (18), 119 (24),
118 (17), 108 (36), 107 (11), 105 (12), 93 (25), 91 (20), 79 (19), 77 (14).
HR-MS m/z: 297.1728 (Calcd for C19H23NO2: 197.1729). Anal. Calcd for
C19H23NO2: C, 76.73; H, 7.80; 4.71. Found: C, 76.71; H, 7.87; N, 4.51.
Piperidine
Morpholine
Diisopropylamine
Diethylamine
3
3
3
3
66
66
72
69
60N (spherical, neutral, 40—50 mm, Kanto Chemical) and on percolated sil-
ica gel 60F254 plates (Merck), respectively. Melting points (mp) were mea-
sured on a Yanaco micro melting point apparatus and are uncorrected. IR
spectra were recorded on a JASCO VALOR-III Fourier-transform spectrom-
1
eter. H-NMR spectra were recorded on a Varian Gemini 2000 (300 MHz)
Fourier-transform spectrometer. The chemical shifts are reported in d values
relative to tetramethylsilane (TMS) at 0 ppm. Electron-impact MS (EI-MS)
and high resolution MS (HR-MS) were obtained with a JEOL JMS-DX-302
double-focusing spectrometer. Elemental analysis was performed with a
Perkin-Elmer Model 240B elemental analyzer.
A Typical Procedure. Wieland–Miescher Ketone (3) A mixture of ac-
tivated basic alumina (4.0 g, 70—230 mesh, Aluminum oxide 90 active,
basic, Blockmann type I activity) and 2-methyl-1,3-cyclohexanedione (1,
1.00 g, 8.0 mmol) was placed in a glass or Teflon® vessel. Methyl vinyl ke-
tone (2, 0.91 ml, 11.2 mmol) was added. The mixture was shaken for 10 min
to allow the Michael addition to proceed. Pyrrolidine (0.03 ml, 0.36 mmol)
was added. The mixture was shaken for 10 min and irradiated with mi-
crowaves for 3 min. The product was eluted with ethyl acetate and the eluate
was evaporated. The residue was purified by column chromatography on sil-
ica gel (hexane : ethyl acetateꢀ2 : 1) to give 3 (0.75 g, 54%). Activated alu-
Acknowledgments This work was supported by a Grant-in-Aid for En-
couragement of Young Scientists No. 12771368 from the Ministry of Edu-
cation, Culture, Sports, Science and Technology, Japan.

April 2003
457
References and Notes
8) Ho T.-L., “Carbocycle Construction in Terpene Synthesis,” VCH Pub-
lishers Inc., New York, 1988.
9) Another Robinson annulation under microwave irradiation, see: Rissafi
B., Louzi A. E., Loupy A., Petit A., Soufiaoui M., Tétouani S. F., Eur.
J. Org. Chem., 2002, 2518—2523 (2002).
1) Caddlick S., Tetrahedron, 51, 10403—10432 (1995).
2) Loupy A., Petit A., Hamelin J., T.-Boullet F., Jacquault P., Mathé D.,
Synthesis, 1998, 1213—1234 (1998).
3) Takatori K., Hasegawa K., Narai S., Kajiwara M., Heterocycles, 42,
525—528 (1996).
10) Ranu B. C., Bhar S., Sarkar D. C., Tetrahedron Lett., 32, 2811—2812
(1991).
4) Comprehensive Organic Synthesis: Selectivity, Strategy, and Effi-
ciency in Modern Organic Chemistry, Vol. 2, 4, eds. by Trost B. M., 11) Ranu B. C., Bhar S., Tetrahedron, 48, 1327—1332 (1992).
Fleming I., Pergamon Press, New York, 1991.
5) Rapson W. S., Robinson R., J. Chem. Soc., 1935, 1285—1288 (1935).
12) For organic reaction on alumina, see: Posner G. H., Angew. Chem. Int.
Ed. Engl., 17, 487—496 (1978).
6) Ramachandran S., Newman M. S., “Organic Syntheses,” Coll. Vol. V, 13) For organic reaction on alumina, see: Kabalka G. W., Pagni R. M.,
ed. by Baumgarten H. E., John Wiley and Sons, Inc., New York, 1973,
pp. 486—488.
7) For solvent-free Robinson annulation with sodium methoxide, see:
Miyamoto H., Kanetaka S., Tanaka K., Yoshizawa K., Toyota S., Toda
F., Chem. Lett., 2000, 888—889 (2000).
Tetrahedron, 53, 7999—8065 (1997).
14) Amide 18 was prepared from the ester 11 and 2,6-xylidine under mi-
crowave irradiation, see: Suri O. P., Satti N. K., Suri K. A., Syn. Com-
mun., 30, 3709—3718 (2000).
15) Ranu B. C., Saha M., Bhar S., Syn. Commun., 27, 621—626 (1997).