Iodine-Catalyzed Conversion of b-Dicarbonyl Compounds into b

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Sep 24, 2009 - catalytic amounts of iodine under solvent-free conditions at room temperature ... ation reactions,[17] Ferrier reactions,[8] oxidation reactions,[19] ...
Synthetic Communicationsw, 35: 2811–2818, 2005 Copyright # Taylor & Francis, Inc. ISSN 0039-7911 print/1532-2432 online DOI: 10.1080/00397910500290557

Iodine-Catalyzed Conversion of b-Dicarbonyl Compounds into b-Enaminones Within a Minute Under Solvent-Free Conditions Siddhartha Gogoi, Ranjana Bhuyan, and Nabin C. Barua Natural Products Chemistry Division, Regional Research Laboratory (CSIR), Jorhat, Assam, India

Abstract: Synthesis of b-enaminones from b-dicarbonyl compounds has been achieved in high yields within a minute using primary and aromatic amines and catalytic amounts of iodine under solvent-free conditions at room temperature. Keywords: Amines, b-diketones, b-enaminones, b-ketoesters, iodine

b-Enaminones are versatile intermediates for the synthesis of many bioactive molecules with a heterocyclic unit. Their basic structural units RNH–C55C–Z (Z ¼ –COCH3 or –COOC2H5) are responsible for the synthesis of many therapeutic agents from both natural and synthetic sources including taxol,[1] anticonvulsivant,[1a,2] antiinflammatory,[1a,3] and duocarmycin classes of antitumor agents[1a,4] as well as quinoline antibacterials[1a,5] and quinoline antimalarials. In addition, chiral enaminones that can be easily synthesized from optically active compounds are generally used as ligands for diastereoselective synthesis. Because of the stability of enaminones under simulated physiological pH conditions and low toxicity,[2,6] the synthesis of b-enaminones is receiving much attention in recent times. There are several methods reported in the literature Received in India May 25, 2005 Address correspondence to Nabin C. Barua, Natural Products Chemistry Division, Regional Research Laboratory (CSIR), Jorhat 785006 Assam, India. Tel.: þ91-23762370121; Fax: þ91-2376-2370011; E-mail: [email protected] 2811

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for the preparation of b-enaminones. Among them, the oldest and most general method for the preparation of enaminones is the direct condensation of amines and dicarbonyl compounds under reflux in aromatic solvent with azeotropic removal of water.[1c,7] Other procedures using Al2O3,[1b] SiO2,[8] montmorillonite K-10/microwave or ultrasound,[9] NaAuC14,[10] Zn(ClO4)2 . 6H2O,[11] acetic acid under ultrasound,[12] and CeC13 . 7H2O[13] have also been reported in the literature. However, most of these procedures suffer from drawbacks such as reflux temperatures, low yields of the products, the use of expensive or less easily available reagents, the use of toxic solvents (benzene, toluene, etc.) and long reaction times. In this context, we felt the need for a mild and efficient procedure for the preparation of b-enaminones because in many cases b-enaminones are used as intermediates in organic synthesis. We observed that when b-dicarbonyl compounds were mixed with amines and a catalytic amount of iodine under solvent-free conditions, the corresponding b-enaminones were obtained in excellent yields at room temperature (Scheme 1). In recent times, because of its easily availability, low cost, low toxicity, and environmentally friendly character, iodine is widely used by organic chemists as a catalyst for various transformations.[14] It is mostly used as a Lewis acid catalyst for the selective protection of alcohol groups[15] and carbonyl groups,[14e,16] acetylation reactions,[17] Ferrier reactions,[8] oxidation reactions,[19] allylation reactions,[14d] three-component allylations of imines,[20] and so forth. Herein we report a very fast iodine-catalyzed conversion of b-dicarbonyl compounds into b-enaminones under mild and solvent-free conditions at room temperature. As shown in Table 1, we performed this reaction with both b-ketoesters and 1,3-diketones. In both the cases, the only isolable products were b-enaminones. This is probably because of differences in reactivity between the acetyl carbonyl and the ester carbonyl; the former is more reactive than the latter. Resonance and conjugation effect also help the formation of b-enaminones as the sole product. In the case of more nucleophilic amines (entries 1, 2, 5, 7, 8, and 11), the yields of the corresponding b-enaminones are higher in our procedure than the reported protocols, and the time required for completion of the reaction is also much less (1 min. or less). In the case of very weak amines such as aniline (entries 3 and 9), the reaction

Scheme 1.

Entry

Synthesis of b-enamino esters and b-enamino ketones from amines and dicarbonyl compounds under solvent-free conditions Substrates

Amines

Productsa

Reaction time (min)

Yieldsb (%) [ref.]

1

C6H11NH2

1

92[22]

2

CH3(CH2)4CH2NH2

0.5

94[13]

3

PhNH2

3

79[22]

4

CH3NH2

1

90[22]

5

PhCH2NH2

0.30

98[22]

6

NH2(CH2)2NH2

1

95[21]

7

C6H11NH2

0.4

97[12] 2813

(continued )

Conversion of b-Dicarbonyl Compounds

Table 1.

Entry

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Table 1.

Continued Substrates

Amines

Productsa

Reaction time (min)

Yieldsb (%) [ref.]

CH3(CH2)4CH2NH2

0.5

95[12]

9

PhNH2

2.5

81[12]

10

CH3NH2

1

92[22]

11

PhCH2NH2

0.30

99[12]

12

NH2(CH2)2NH2

1

97[21]

All the products were characterized by 1H NMR, IR, mass, and CHN analysis.[12,13,21,22] Yields are of pure isolated products.

a b

S. Gogoi, R. Bhuyan, and N. C. Barua

8

Conversion of b-Dicarbonyl Compounds

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Scheme 2.

took somewhat longer time (2 – 3 min) and gave comparatively better yields than the reported methods. When we performed this reaction with symmetrical diamines (entries 6 and 12), the corresponding dimerized products were obtained in high yield (95% and 97%). In all these cases, the chemoselectivity was very good, that is, only Z-b-enaminones were formed predominantly as confirmed by 1H NMR spectra of the crude products. We also observed that this reaction proceeds with unsymmetrical b-ketoesters and 1,3-diketones with equal ease. However, in the case of aryl-b-ketoesters (Scheme 2), the reactions were somewhat slow but the yields were good (85–95%). In the case of phenylacetylacetone, the yields were good to excellent (92–98%) (Scheme 3). In these cases, the regiochemistry was controlled by the more reactive carbonyl groups, which underwent preferential attack on the amine. As for the mechanism of this reaction, we believe that the enol or enolate form of A reacts with iodine and drives the reaction toward formation of the iodinated product B. The lone pair on nitrogen of the amine then undergoes nucleophilic addition to the more active carbonyl to give species C. The IQ ion present in the reaction mixture then picks up iodine with concomitant dehydration driven by more stabilized product with liberation of iodine to give the desired product as shown in Scheme 4. In conclusion, we have demonstrated a very mild and efficient method for the conversion of b-ketoesters and b-diketones to b-enaminones in the presence of amines using a catalytic amount of iodine at room temperature within a minute under solvent-free conditions. The yields of the products are quite good in comparison to other methods reported in the literature. Because iodine is a less expensive, easily available, and environmentally friendly catalyst, this method may find wide acceptance among organic chemists.

Scheme 3.

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Scheme 4.

EXPERIMENTAL NMR spectra were recorded in Bruker DPX-300 NMR machine in deuteriochloroform and chemical shift values were recorded in d relative to TMS as the internal standard. IR spectra were recorded on Perkin-Elmer 1640 FTIR spectrometer on chloroform. Mass spectra were recorded in a Brucker Daltonic Data Analysis 2.0 spectrometer. All reagents were of commercial quality from freshly opened containers and were purchased from Aldrich Chemical Company and used without further purification. General Procedure for the Formation of Enaminones Iodine (20 mol%) was added to a mixture of ethyl acetoacetate or acetylacetone (1.5 mmol) and amine (1.5 mmol) [but in the case of aniline and ethylene diamine (entries 3, 6, 9 and 12), iodine was first added to the substrates, the mixture was cooled to 58C, and then amine was added dropwise]. When iodine was added, heat evolved (exothermic reaction). Then, the reaction mixture was cooled under tap water. During this period, the reaction completed, which was indicated by TLC. Then, the reaction mixture was diluted with CH2Cl2 and washed with water. The extract was dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by preparative TLC on silica gel using n-hexane/EtO Ac (1 : 1), which gave the pure b-enaminones (79–99%). Spectral Data of Selected Compounds (3Z)-4-(Cyclohexylamino)-3-penten-2-one (entry 1): IR (thin film, CHCl3): 1606, 1577 cm21. 1H NMR (300 MHz, CDCl3) d (ppm): 1.27 – 1.86 (m, 10H),

Conversion of b-Dicarbonyl Compounds

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1.95 (s, 3 H), 1.98 (s, 3H), 3.34 –3.38 (m, 1H), 4.91 (s, 1H), 11.00 (br, s, 1H). 13 C NMR (75 MHz, CDCl3) d (ppm): 18.25, 24.07, 24.99, 28.34, 33.46, 51.13, 94.59, 161.56, 193.91. MS (ESI): m/z 204 [M+ + Na]. Anal calcd. for C11H19NO: C, 72.79; H, 10.47; N, 7.68. Found: C, 72.88; H, 10.56; N, 7.73. (3Z)-4-(Methylamino)-3-penten-2-one (entry 4): IR (thin film, CHCl3): 1610, 1572 cm21. 1H NMR (300 MHz, CDCl3) d (ppm): 10.64 (br s, 1H, NH), 4.91 (s, 1H), 2.86 (d, 3H, J ¼ 5.4 Hz), 1.94 (s, 3H), 1.83 (s, 3H). 13C NMR (75 MHz, CDCl3) d (ppm): 194.4, 164.0, 94.7, 29.4, 28.4, 18.5 MS (ESI): m/z 136 (M+ + Na). Anal calcd. for C6H11NO: C, 63.62; H, 9.75; N, 12.32. Found: C, 63.69; H, 9.80; N, 12.38. (3Z)-4-(Benzylamino)-3-penten-2-one (entry 5): IR (thin film, CHCl3): 1607, 1572 cm21. 1H NMR (300 MHz, CDCl3) d (ppm): 11.15 (br s, 1H, NH), 7.22– 7.34 (m, 5H, C6H5), 5.04 (s, 1H), 4.41 (d, J ¼ 6.5 Hz, 2H) 2.01 (s, 3H), 1.89 (s, 3H) 13C NMR (75 MHz, CDCl3) d (ppm): 195.3, 162.8, 137.7, 128.6, 127.2, 126.5, 95.7, 46.5, 28.7, 18.7. Anal calcd. for C12H15NO: C, 76.09; H, 8.01; N, 7.32. Found: C, 76.16; H, 7.99; N, 7.40. Ethyl (2Z)-3-(cyclohexylamino) but-2-enoate (entry 7): IR (thin film, CHCl3): 1658, 1605 cm21. 1H NMR (300 MHz, CDCl3) d (ppm): 1.24 (t, 3H, J ¼ 7.1 Hz), 1.25– 1.88 (m, 10H), 1.93 (s, 3H), 3.29– 3.33 (m, 1H), 4.07 (q, 2H, J ¼ 7.1 Hz), 4.38 (s, 1H), 8.64 (br, s, 1H). 13C NMR (75 MHz, CDCl3) d (ppm): 14.73, 19.21, 24.71, 25.47, 34.56, 51.41, 58.23, 60.36, 81.78, 160.79, 170.63. MS (ESI): m/z 234 [M+ + Na]. Anal calcd. for C12H21NO2: C, 68.13; H, 9.91; N, 6.59. Found: C, 68.21; H, 10.02; N, 6.63. Ethyl (2Z)-3-(Methylamino)-2-butenoate (entry 10): IR (thin flim, CHCl3): 1651, 1610 cm21. 1H NMR (300 MHz, CDCl3) d (ppm): 8.42 (br s, 1H, NH), 4.41 (s, 1H), 4.01 (q, 2H, J ¼ 7.0 Hz), 2.85 (d, 3H, J ¼ 5.5), 18.2 (s, 3H), 1.21 (t, 3H, J ¼ 7.0 Hz) 13C NMR (75 MHz, CDCl3) d (ppm): 170.4, 162.5, 81.7, 58.21, 29.4, 19.0, 14.5. MS (ESI): m/z 166 (M+ + Na). Anal calcd. for C7H13NO2: C, 58.67; H, 9.11; N, 9.69. Found: C, 58.72; H, 9.15; N, 9.78. Ethyl (2Z)-3-(benzylamino) but-2-enoate (entry 11): IR (thin film, CHCl3): 1655, 1605 cm21. 1H NMR (300 MHz, CDCl3) d (ppm): 1.25 (t, 3H, J ¼ 7.1 Hz), 1.90 (s, 3H), 4.10 (q, 2H, J ¼ 7.1 Hz), 1.90 (s, 3H), 4.10 (q, 2H, J ¼ 7.1 Hz), 4.42 (d, 2H, J ¼ 6.4 Hz), 4.55 (s, 1H), 7.22– 7.40 (m, 5H), 8.95 (br s, 1H, NH) 13C NMR (75 MHz, CDCl3) d (ppm): 14.7, 19.5, 24.1, 46.8, 58.5, 83.2, 126.8, 127.4, 128.8, 138.8, 161.0, 170.6. MS (ESI): m/z 242 (M+ + Na) Anal calcd. for C13H17NO2: C, 71.16; H, 7.89; N, 6.31. Found: C, 71.21; H, 7.81; N, 6.39.

ACKNOWLEDGMENT The authors gratefully acknowledge the Director, Regional Research Laboratory (CSIR), Jorhat, Assam, India, for providing facilities for this work. S. G. and R. B. thank the CSIR, New Delhi, India, for the financial assistance.

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REFERENCES 1. (a) Michael, J. P.; Koning, C. B.; Hosken, G. D.; Stanbury, T. V. Tetrahedron 2001, 57, 9635– 9648; (b) Valduga, C. J.; Braibante, H. S.; Braibante, E. F. J. J. Heterocycl. Chem. 1998, 35, 189– 192; (c) Ferraz, H. M. C.; Oliveira, E. O.; Payret-Arrua, M. E.; Brandt, C. A. J. Org. Chem. 1995, 60, 7357– 7359. 2. Azzaro, M.; Geribaldi, S.; Videau, B. Synthesis 1981, 880– 881. 3. Dannhardt, G.; Bauer, A.; Nowe, U. J. Perkt. Chem. 1998, 340, 356– 358. 4. Boger, D. L.; Ishizaki, T.; Wysocki, J. R. J.; Munk, S. A.; Kitos, P. A.; Suntornwat, O. J. Am. Chem. Soc. 1989, 111, 6461– 6463. 5. (a) Appelbaum, F. C.; Hunter, P. A. Int. J. Antimicrob. Agents 2000, 16, 5 – 7; (b) Wang, Y. F.; Izawa, T.; Kobayashi, S.; Ohno, M. J. Am. Chem. Soc. 1982, 104, 6465– 6466. 6. Naringrekar, V. H.; Stella, V. J. J. Pharm. Sci. 1990, 79, 138– 146. 7. (a) Amougay, A.; Letsch, O.; Pete, J. P. Tetrahedron 1996, 52, 2405– 2420; (b) Martin, D. F.; Janusonis, G. A.; Martin, B. B. J. Am. Chem. Soc. 1961, 83, 73 – 75; (c) Arend, M.; Westermann, B.; Risch, N. Angew. Chem., Int. Ed. 1998, 37, 1044– 1070. 8. Rechsteimer, B.; Texier-Boullet, F.; Hamelin, J. Tetrahedron Lett. 1993, 34, 5071 –5074. 9. (a) Braibante, M. E. F.; Braibante, H. T. S.; Salvatore, S. J. S. Quim. Nova 1990, 13, 67 – 69; (b) Braibante, M. E. F.; Braibante, H. T.S.; Missio, L.; Andricopulo, A. Synthesis 1994, 898– 900. 10. Arcadi, A.; Bianchi, G.; Di Giuseppe, S.; Marinelli, F. Green Chem. 2003, 64 – 66. 11. Bartoli, G.; Bosco, M.; Locatelli, M.; Marcantoni, E.; Melchiorre, P.; Sambri, L. Synlett 2004, 239– 242. 12. Brandt, C. A.; Da Silvar, A. C. M. P.; Pancote, C. G.; Brito, C. L.; Da Silveira, M. A. B. Synthesis 2004, 1557– 1559. 13. Khodaei, M. M.; Khosropour, A. R.; Kookhazadeh, M. Synlett 2004, 1980– 1984. 14. (a) Yadav, J. S.; Reddy, B. V. S.; Rao, C. V.; Reddy, M. S. Synthesis 2003, 277– 279; (b) Karimi, B.; Golshani, B. Synthesis 2002, 784– 788; (c) Basu, M. K.; Samajdar, S.; Becker, F. F.; Banik, B. K. Synlett 2002, 319– 321; (d) Yadav, J. S.; Chand; Pratap, K.; Anjaneyula, S. Tetrahedron Lett. 2002, 43, 3783– 3784; (e) Firouzabadi, H.; Iranpoor, N.; Hazarkhani, H. J. Org. Chem. 2001, 66, 7527– 7529. 15. Deka, N. J.; Sarma, J. C. J. Org. Chem. 2001, 66, 1947– 1948. 16. Kalita, D. J.; Borah, R.; Sarma, J. C. Tetrahedron Lett. 1998, 39, 4573– 4575. 17. Deka, N.; Mariotte, A.-M.; Boumendjel, A. Green Chem. 2001, 3, 263– 264. 18. Koreeda, M.; Housten, T. A.; Shull, B. K.; Klemke, E.; Tuinman, R. J. Synlett 1995, 90 – 92. 19. (a) Yusybov, M. S.-O.; Filimonov, V. D. Synthesis 1991, 131– 132; (b) Gogoi, P.; Sarmah, G. K.; Konwar, D. J. Org. Chem. 2004, 69, 5153– 5154. 20. Phukan, P. J. Org. Chem. 2004, 69, 4005– 4006. 21. Stefani, H. A.; Costa, I. M.; Silva, D. O. Synthesis 2000, 1526– 1528. 22. Gravestock, D.; Dovey, M. C. Synthesis 2003, 523– 530.

Synthetic Communicationsw, 35: 2819–2821, 2005 Copyright # Taylor & Francis, Inc. ISSN 0039-7911 print/1532-2432 online DOI: 10.1080/00397910500290573

Use of Iodosobenzene in Combination with Vilsmeier –Haack Reagent in Carbon – Carbon Bond Cleavage of Dehydroacetic Acid and Its Analogue Om Prakash, Vishwas Chaudhri, and Mayank Kinger Department of Chemistry, Kurukshetra University, Kurukshetra, Haryana, India

Abstract: The reaction of dehydroacetic acid with iodosobenzene in combination with Vilsmeier– Haack reagent offers a new and convenient method for C-C bond cleavage with the formation of 3-chloro-4-hydroxy-6-methyl-2H-pyran-2-one. Keywords: Dehydroacetic acid, hypervalent iodine, iodosobenzene, Vilsmeier – Haack reagent

The application of organohypervalent iodine reagents is a fertile and attractive field of organic synthesis.[1,2] Of the various hypervalent iodine reagents, iodobenzene diacetate (IBD),[3] iodobenzene bis(trifluoro)acetate (IBTA),[4] and [hydroxy(tosyloxy)iodo]benzene (HTIB)[5] have been found to be more versatile than the other reagents, such as iodosobenzene (IOB). The relatively less utility of IOB is due to its polymeric nature,[6] which makes it insoluble in common solvents. To overcome such difficulties, combination reagents were developed. For example, the utility of IOB is greatly enhanced when it is combined with acids,[7] bases,[8] or other catalysts. Continuing our investigations on the use of combination reagents,[9] we became interested in exploring the utility of IOB in combination with Vilsmeier –Haack reagent.[10] Received in India May 24, 2005 Address correspondence to Om Prakash, Department of Chemistry, Kurukshetra University, Kurukshetra, Haryana 136119, India. Fax: 91-1744-238277; E-mail: [email protected] 2819

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Scheme 1.

3-Acetyl-4-hydroxy-6-methyl-2H-pyran-2-one (dehydroacetic acid, DHA, 1a) was treated with a combination of (PhIO)n-POCl3/DMF prepared by the addition of POCl3 to a solution of IOB in DMF. The reaction led to the formation of 3-chloro-4-hydroxy-6-methyl-2H-pyran-2-one (2)[11] in 60% yield. When treated with the DHA analogue 1b, 2 was formed in 55% yield (Scheme 1). It is interesting to mention that the reaction of DHA with POCl3 is known to give 4-chloro-3-(1-chlorovinyl)-6-methyl-2H-pyran-2-one.[12] In the present case, the 4-OH group remains intact. EXPERIMENTAL DHA was purchased from commercial sources (Acros) and used without further purification. Iodosobenzene[13] and compound 1b[14] were prepared according to literature procedure. Melting points were taken in open capillaries and are uncorrected. 1H NMR spectra were recorded on a Brucker 300-MHz instrument using TMS as an internal standard. IR spectra were recorded on a Buck Scientific IR M-500 spectrophotometer. 3-Chloro-4-hydroxy-6-methyl-2H-pyran-2-one (2) from 1a: To a solution of iodosobenzene (2.2 g, 10 mmol) in DMF (25 ml) were added POCl3 (2.29 g, 15 mmol) and DHA (1.68 g, 10 mmol). The reaction mixture was stirred for 2 h and then poured into ice-cold water. The resulting solid was filtered, washed with chloroform, recrystallized from ethyl acetate and then from acetic acid to afford 0.96 g (60%) as grayish white crystals. Mp 238– 2408C, lit mp[12] 242 – 2438C; IR (nmax, KBr): 1700 cm 21 (s, C55O); 1 H NMR (CDCl3, DMSO, 300 MHz, d): 2.13 (s, 3H, CH3), 5.95 (s, 1H,55CH-); mass (m/z): 160. ACKNOWLEDGMENT We are thankful to Defense Research Development Organization (DRDO) (ERIP/ER/0303447/M/01), New Delhi, India, for financial assistance.