New synthesis of carbazoles from novel exo-2-oxazolidinone dienes

Article abstract of DOI:10.1055/s-1998-1571

A new synthesis of carbazoles, via regioselective Diels-Alder reaction of novel exo-2-oxazolidinone dienes 1, is described. Cyclization with palladium acetate of the intermediate diaryl amines, obtained by a one-pot three-step procedure from the cycloadducts, yielded the desired substituted carbazoles.

Full text of DOI:10.1055/s-1998-1571

January 1998
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New Synthesis of Carbazoles from Novel exo-2-Oxazolidinone Dienes
Ashis B. Mandal, Francisco Delgado, Joaquín Tamariz*
Department of Organic Chemistry, Escuela Nacional de Ciencias Biológicas, I.P.N. Prol. Carpio y Plan de Ayala, 11340 México, D.F.
Fax: +525-396-3503; e-mail: fdelgado@woodward.encb.ipn.mx
Received 4 September 1997
Abstract: A new synthesis of carbazoles, via regioselective Diels-Alder
reaction of novel exo-2-oxazolidinone dienes 1, is described.
Cyclization with palladium acetate of the intermediate diaryl amines,
obtained by a one-pot three-step procedure from the cycloadducts,
yielded the desired substituted carbazoles.
methylation of 7 with dimethyl sulfate in sodium hydroxide gave diaryl
amines 3. In spite of the very clean transformation to diaryl amines 3,
the yields were low, probably because of formation of polar by-products
soluble in the aqueous phase. The preparation of 3 was improved by
carrying out the hydrolysis and methylation of adducts 4/5 in the same
13
flask, without isolating compounds 7 (Table 2).
In the past two decades, a great number of carbazole alkaloids have been
1
isolated from natural sources. Many of them possess an aromatic
framework, highly substituted, mainly in positions 1, 2, 3, 6, and 7, by
oxygenated, carbonylated, halogenated and alkylated substituents. An
interesting class of these compounds is that of the 1-oxygenated and 2-
2
methylated carbazoles, such as the marine alkaloids hyellazoles,
3
4
5
6
carbazomycins, carbazoquinocins, carazostatin, and antiostatins.
7
8
Clausines and clausenal are characterized by the presence of a
carbonylic substituent in position 3. These alkaloids have attracted
considerable interest because of their pharmacological properties, such
1a,3b,8
as antifungal, gram-positive and gram-negative antibacterial,
1f
1d
1b,1c
antimalarial, antiviral, and antiyeast activities.
They have also
4,6,9
shown a strong inhibitory effect against lipid peroxidation,
along
7
with vasocontraction. Several synthetic strategies have been developed
8,10
towards their total syntheses.
Recently, we achieved a one-pot synthesis of novel N-substituted 4,5-
dialkylidene 2-oxazolidinones 1, from α-diketones and the
11
corresponding isocyanates. Dienes 1 proved to be very reactive and
regioselective in Diels-Alder reactions with unsymmetrical olefins,
providing functionalized cyclohexenes. As a demonstration of the
synthetic potential of these dienes, and of their application in the
preparation of biologically active natural products, herein we describe a
concise route to carbazoles, employing the approach outlined in Scheme
1. Carbazoles 2 would be accessed via palladium-promoted cyclization
of the diaryl amine intermediates 3, which in turn would be derived
from the cycloadduct of a suitable N-aryl exo-2-oxazolidinone diene 1.
Scheme 2
Scheme 1
Thermal cycloaddition of dienes 1 with methyl vinyl ketone (MVK)
furnished the desired ortho-adducts as diasteromeric endo/exo 4/5
12
mixtures (Table 1, Scheme 2), the endo isomer being the major, in
11a
agreement with the previous report. Surprisingly, basic hydrolysis of
these mixtures did not provide the expected α-amino cyclohexenones 6,
but the aromatic amino phenols 7. It appears that the cyclohexane ring
was rapidly oxidized under the reaction conditions, since all attempts of
isolating or detecting compounds 6 by NMR were unsuccessful. Thus,

88
LETTERS
SYNLETT
14
α-Amino ketones are very susceptible to aerial oxidation. This is
T.; Nakamura, S.; Hirata, T.; Suga, T. J. Antibiot. 1988, 41, 602.
(c) Kondo, S.; Katayama, M.; Marumo, S. J. Antibiot. 1986, 39,
727. (d) Yamasaki, K.; Kaneda, M.; Watanabe, K. Ueki, Y.;
Ishimaru, K.; Nakamura, S.; Nomi, R.; Yoshida, N.; Nakajima, T.
J. Antibiot. 1983, 36, 552.
promoted by the generation of superoxide species in aerobial basic
solutions. The initial product of oxidation of 6 is presumably the α-
imino ketone which would be enolyzed to the dihydrobenzene
15
16
derivative, and then aromatized to the amino phenol 7.
The intramolecular cyclization to the carbazole was achieved by
palladium-promoted stoichiometric oxidative coupling of amines 3,
(4) Tanaka, M.; Shin-ya, K.; Furihata, K.; Seto, H. J. Antibiot. 1995,
48, 326.
using 1.5 mol equivalents of Pd(OAc) in the presence of acetic acid.
2
(5) Kato, S.; Kawai, H.; Kawasaki, T.; Toda, Y.; Urata, T.;
This method has proved to be efficient for coupling monosubstituted
diaryl amines. Besides, it was also used for the cyclization of
Hayakawa, Y. J. Antibiot. 1989, 42, 1879.
17
(6) Mo, C.-J.; Shin-ya, K.; Furihata, K.; Furihata, K.; Shimazu, A.;
18
19
indolyl, and benzoquinoyl aryl amines. However, moderate to low
yields have been reported when more complex diaryl amines were
Hayakawa, Y.; Seto, H. J. Antibiot. 1990, 43, 1337.
(7) Wu, T.-S.; Huang, S.-C.; Wu, P.-L.; Teng, C.-M. Phytochemistry
1996, 43, 133.
20
employed. In contrast, we isolated carbazoles 2a-2e as crystalline
solids in good yields (Table 3).
21
(8) Chakraborty, A.; Saha, C.; Podder, G.; Chowdhury, B. K.;
Bhattacharyya, P. Phytochemistry 1995, 38, 787.
(9) Hook, D. J.; Yacobucci, J. J.; O'Connor, S.; Lee, M.; Kerns, E.;
Krishnan, B.; Matson, J.; Hesler, G. J. Antibiot. 1990, 43, 1347.
(10) Choshi, T.; Sada, T.; Fujimoto, H.; Nagayama, C.; Sugino, E.;
Hibino, S. J. Org. Chem. 1997, 62, 2535, and references cited
therein. Choshi, T.; Sada, T.; Fujimoto, H.; Nagayama, C.;
Sugino, E.; Hibino, S. Tetrahedron Lett. 1996, 37, 2593. Knölker,
H.-J.; Schlechtingen, G. J. Chem. Soc., Perkin Trans. 1 1997, 349,
and references cited therein. Knölker, H.-J.; Fröhner, W.
Tetrahedron Lett. 1997, 38, 1535. Choshi, T.; Fujimoto, H.;
Sugino, E.; Hibino, S. Heterocycles 1996, 43, 1847.
In summary, we have developed a concise and versatile synthesis of
carbazoles, starting from the novel exo-2-oxazolidinone dienes 1, in
only three steps. In principle, a broad variety of carbazoles could be
prepared by this route, inasmuch as modified dienes and other
dienophiles are used. Efforts are being undertaken to prepare natural
carbazole alkaloids. The results will be reported in due course.
(11) (a) Mandal, A. B.; Gómez, A.; Trujillo, G.; Méndez, F.; Jiménez,
H. A.; Rosales, M. J.; Martínez, R.; Delgado, F.; Tamariz, J.
J. Org. Chem. 1997, 62, 4105. (b) Hernández, R.; Sánchez, J. M.;
Gómez, A.; Trujillo, G.; Aboytes, R.; Zepeda, G.; Bates, R. W.;
Tamariz, J. Heterocycles 1993, 36, 1951.
(12) All new compounds were fully characterized by spectroscopic
1
13
techniques (IR, H NMR, C NMR, MS) and gave correct
elemental analyses.
Acknowledgments. We are grateful to Dr. Hugo A. Jiménez-Vázquez
and Dr. Björn C. Söderberg for helpful comments. We thank Fernando
Labarrios for his help in spectrometric measurements. J.T.
acknowledges DEPI/IPN (Grant 916510) for financial support. A.B.M.
thanks CONACYT for a postdoctoral fellowship awarded (Cátedra
Patrimonial Nivel II, 940240).
(13) 3-Acetyl-6-m-chlorophenylamino-1-methoxy-2-methylbenzene
(3b). A mixture of 4b/5b (96:4) (0.229 g, 0.75 mmol) in ethanol
(95%) (10 mL) and NaOH (0.15 g, 3.75 mmol) was stirred at
room temperature for 12 h. The solution was concentrated under
vacuo, water (2 mL) added, cooled to 0 °C, and (CH ) SO added
3 2
4
(0.47 g, 3.75 mmol) dropwise for 10 min. The stirring was
continued for 4 h at 5 °C and then for another 4 h at rt. The crude
mixture was extracted with EtOAc (50 mL), washed with water
(2 x 10 mL) and dried over Na SO . The solvent was removed
References and Notes
(1) (a) Chakraborty, A.; Chowdhury, B. K.; Bhattacharyya, P.
Phytochemistry 1995, 40, 295. (b) Sakano, K.; Ishimaru, K.;
Nakamura, S. J. Antibiot. 1980, 33, 683. (c) Sakano, K.;
Nakamura, S. J. Antibiot. 1980, 33, 961. (d) TePaske, M. R.;
Gloer, J. B.; Wicklow, D. T.; Dowd, P. F. J. Org. Chem. 1989, 54,
4743. (e) TePaske, M. R.; Gloer, J. B.; Wicklow, D. T.; Dowd, P.
F. Tetrahedron Lett. 1989, 30, 5965. (f) Bringmann, G.;
Ledermann, A.; François, G. Heterocycles 1995, 40, 293.
(g) Chakraborty, D. P., in The Alkaloids; Cordell, G. A., Ed.;
Academic Press: New York, 1993; Vol. 44, Ch. 4.
(h) Chakraborty, D. P., in Prog. Chem. Org. Nat. Prod.; Herz, W.;
Grisebach, H.; Kirby, G. W., Eds.; Springer: Wien, 1977; p. 299.
(i) Chakraborty, D. P.; Roy, S., in Prog. Chem. Org. Nat. Prod.;
Herz, W.; Grisebach, H.; Kirby, G. W., Eds.; Springer: Wien,
1991; p. 71. (j) Faulkner, D. J. Nat. Prod. Rep. 1997, 14, 259.
2
4
under vacuo, purified by column chromatography over silica gel
(hexane/EtOAc, 19:1), and the solid product recrystallized
(CH Cl /hexane, 1:4) to give 0.115 g (53%) of 3b as colorless
2
2
crystals. R
0.47 (hexane/EtOAc, 4:1); m.p. 94-95 °C; IR (KBr)
f
-1
1
3340, 2930, 1660, 1590, 1520, 1480, 1350, 1260, 1030 cm ; H
NMR (300 MHz, CDCl ) δ 2.53 (s, 3H, Me), 2.54 (s, 3H,
3
CH CO), 3.75 (s, 3H, MeO), 6.59 (br s, 1H, NH), 7.02 (ddd, J =
3
8.0, 1.9, 0.9 Hz, 1H), 7.07 (ddd, J = 8.1, 2.1, 0.9 Hz, 1H), 7.12 (d,
J = 8.6 Hz, 1H), 7.22 (dd, J = 2.1, 1.9, 1.9 Hz, 1H), 7.26 (dd, J =
13
8.1, 8.0 Hz, 1H), 7.52 (d, J = 8.6 Hz, 1H);
C NMR (75 MHz,
CDCl
) δ 13.8, 29.0, 60.0, 110.0, 118.1, 119.9, 122.7, 127.7,
3
130.0, 130.4, 133.1, 135.1, 139.6, 142.1, 146.8, 199.3; MS (70
+
+
eV) 291 (M +2, 33), 289 (M , 100), 274 (74), 239 (75), 224 (17),
207 (23), 196 (8), 167 (11), 111 (7), 77 (10), 65 (10), 51 (9); Anal.
Calcd for C
H ClNO : C, 66.32; H, 5.57; N, 4.83. Found: C,
16 16 2
(2) Cardellina, J. H.; Kirkup, M. P.; Moore, R. E.; Mynderse, J. S.;
66.50; H, 5.76; N, 4.96.
Seff, K.; Simmons, C. J. Tetrahedron Lett. 1979, 4915.
(14) Julian, P. L.; Meyer, E. W.; Magnani, A.; Cole, W. J. Am. Chem.
Soc. 1945, 67, 1203.
(3) (a) Kaneda, M.; Sakano, K.; Nakamura, S.; Kushi, Y.; Iitaka, Y.
Heterocycles 1981, 15, 993. (b) Kaneda, M.; Naid, T.; Kitahara,

January 1998
SYNLETT
89
(15) Lee-Ruff, E. Chem. Soc. Rev. 1977, 6, 195. Buehler, C. A. Chem.
Rev. 1964, 64, 7.
(21) 3-Acetyl-7-chloro-1-methoxy-2-methylcarbazole (2b). A mixture
of 3b (0.058 g, 0.2 mmol), palladium acetate (0.067 g, 0.3 mmol),
and glacial acetic acid (2.5 mL) was placed in a sealed tube under
(16) Few examples describing oxidation and aromatization of α-amino
ketones have been reported: Kornfeld, E. C.; Fornefeld, E. J.;
Kline, G. B.; Mann, M. J.; Morrison, D. E.; Jones, R. G.;
Woodward, R. B. J. Am. Chem. Soc. 1956, 78, 3087.
N atmosphere, and heated at 110 °C for 3 h. After cooling, the
2
solution was filtered, diluted with water (10 mL), and neutralized
with saturated aqueous solution of NaHCO . The precipitate thus
3
obtained was filtered, extracted with EtOAc (2 x 20 mL), and
(17) Åkermark, B.; Eberson, L.; Jonsson, E.; Pettersson, E. J. Org.
Chem. 1975, 40, 1365. See also: Hegedus, L. S. Angew. Chem.
Int. Ed. Engl. 1988, 27, 1113..
dried over Na SO . The solvent was removed under vacuo and the
2
4
residue was purified by column chromatography over silica gel
(hexane/EtOAc, 9:1). The solid product was recrystallized
(acetone/hexane) to give 0.037 g (65%) of 2b as colorless crystals.
(18) Harris, W.; Hill, C. H.; Keech, E.; Malsher, P. Tetrahedron Lett.
1993, 34, 8361. Black, D. St. C.; Keller, P. A.; Kumar, N.
Tetrahedron 1993, 49, 151. Srinivasan, P. C.; Jeevanandam, A.
Synth. Commun. 1995, 25, 3427.
R 0.37 (hexane/EtOAc, 4:1); m.p. 168-169 °C;
f
IR (KBr) 3250, 2920, 1640, 1600, 1560, 1430, 1360, 1230, 1030
-1
1
cm ; H NMR (300 MHz, CDCl ) δ 2.63 (s, 3H, Me), 2.72 (s, 3H,
3
(19) Knölker, H.-J.; O’Sullivan, N. Tetrahedron 1994, 50, 10893.
Åkermark, B.; Oslob, J. D.; Heuschert, U. Tetrahedron Lett. 1995,
36, 1325.
CH CO), 3.92 (s, 3H, MeO), 7.23 (dd, J = 8.3, 1.8 Hz, 1H), 7.44
3
(d, J = 1.8 Hz, 1H), 7.94 (d, J = 8.3 Hz, 1H), 8.22 (s, 1H), 8.53 (br
13
s, 1H, NH); C NMR (75 MHz, CDCl ) δ 13.7, 22.7, 60.8, 111.3,
3
(20) Miller, R. B.; Moock, T. Tetrahedron Lett. 1980, 21, 3319.
Hellwinkel, D.; Kistenmacher, T. Liebigs Ann. Chem. 1989, 945.
Chunchatprasert, L.; Dharmasena, P.; Oliveira-Campos, A. M. F.;
Queiroz, M. J. R. P.; Raposo, M. M. M.; Shannon, P. V. R.
J. Chem. Res. (S) 1996, 84. Morel, S.; Boyer, G.; Coullet, F.;
Galy, J.-P. Synth. Commun. 1996, 26, 2443.
118.8, 120.8, 121.1, 121.3, 122.5, 128.9, 131.91, 131.93, 135.5,
140.2, 143.7, 200.0; MS (70 eV) 289 (M +2, 15), 287 (M , 53),
272 (100), 229 (12), 214 (16), 201 (9), 166 (11), 139 (12), 128 (5),
+
+
100 (5), 82 (8), 75 (7), 43 (38); Anal. Calcd for C
H ClNO : C,
16 14 2
66.79; H, 4.90; N, 4.87. Found: C, 67.00; H, 5.00; N, 4.94.