ZrOCl2·8H2O as a highly efficient and the moisture tolerant Lewis acid catalyst for Michael addition of amines and indoles to α, β-unsaturated ketones under solvent-free conditions

Journal of Molecular Catalysis A: Chemical 252 (2006) 150–155

ZrOCl2·8H2O as a highly efficient and the moisture tolerant Lewis acid catalyst for Michael addition of amines and indoles to ␣, ␤-unsaturated ketones under solvent-free conditions Habib Firouzabadi ∗ , Nasser Iranpoor, Maasoumeh Jafarpour, Arash Ghaderi Department of Chemistry, College of Sciences, Shiraz University, Shiraz 71454, Iran Received 27 September 2005; received in revised form 27 September 2005; accepted 16 November 2005 Available online 29 March 2006

Abstract The 1,4-conjugate addition of indoles and amines to cyclic and acyclic ␣, ␤-unsaturated ketones for C–N bond formation was efficiently carried out under solvent-free conditions at 50 ◦ C using a catalytic amount of ZrOCl2 ·8H2 O as a moisture tolerant Lewis acid. The reusability of the catalyst has been successfully examined without noticeable loss of its catalytic activity. © 2006 Elsevier B.V. All rights reserved. Keywords: ZrOCl2 ·8H2 O; Michael reaction; Amine; Indole; ␣, ␤-Unsaturated ketones; Solvent-free

1. Introduction In recent years, considerable attention has been focused on the development of efficient and operationally simple protocols for carbon–carbon and carbon–heteroatom bonds formation for the construction of valuable molecules. For example, carbon–carbon bond formation through the addition of electrophiles to the C-3 position of the indoles leading to the bioactive indole alkaloids [1]. However, the carbon–heteroatom bondforming reactions especially are of concern, since the resulting functionality can be readily manipulated to produce many classes of compounds of especial importance [2]. In addition, nitrogen-containing compounds are of significant importance in human life and also they are useful as biologically active substances, dyes, and fine chemicals [3]. For instance, the ␤-amino carbonyl group is a common moiety in a large variety of biologically active compounds such as alkaloids and polyketides [4–7]. They are also attractive precursors in preparation of ␥amino alcohols, ␤-lactams, ␤-aminoacid derivatives and chiral auxiliaries [8–13], many of which serve as powerful antibiotics or other drugs [14]. The acid or base-induced conjugate addition of nucleophiles to ␣, ␤-unsaturated carbonyl compounds,

∗

Corresponding author. E-mail address: [email protected] (H. Firouzabadi).

1381-1169/$ – see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.molcata.2005.11.025

Michael reaction, is among the most useful carbon–carbon and carbon–heteroatom bond forming reaction. To avoid problems rising from the addition of stoichiometric amounts of the acidic or basic catalysts or reagents [15], a number of methods has been developed. Thus, in this regard, Lewis acids such as FeCl3 , LiCl, HgCl2 [16,17], lantanide salts (Ln = La, Sm, Yb) [18], InCl3 and InBr3 [19], Pd [20], CeCl3 [21], Bi(NO3 )3 [22], Bi(OTf)3 [23], Sc(DS)3 [24], copper salts [25] and acidic clays [26], have attracted much attention because of their unique reactivities and selectivities. However, the requirement of anhydrous conditions in most of cases and also the practice of expensive and toxic metal precursors such as lantanide triflates has restricted the use of some Lewis acids in the conjugate addition of nucleophiles to ␣, ␤-unsaturated compounds. Recently, the use of CeCl3 /NaI [27] supported on silica-gel has been introduced as a relatively non-toxic and a rather inexpensive catalytic system for Michael addition of indoles, but, the use of high percentage of CeCl3 /NaI (30 mol%) combined with the relatively harsh reaction conditions accompanied with the long reaction times, present disadvantages of this catalytic system. Thus, the addition of a safe and a cheap catalytic system, which is not a moisture and air sensitive system with high catalytic activity is of practical value. Very recently, we have developed two efficient catalytic methods for Michael addition of indoles [28], amines and thiols [29] to ␣, ␤-unsaturated ketones in an aqueous media. In continuation of our work upon new applications of Zr(IV) com-

H. Firouzabadi et al. / Journal of Molecular Catalysis A: Chemical 252 (2006) 150–155

151

Scheme 1.

pounds [30], we first examined the conjugate addition of amines and indoles to ␣, ␤-unsaturated ketones in the presence of catalytic amounts of ZrCl4 in the absence of solvent. We found that the reactions in the presence of catalytic amounts of this compound did not proceed cleanly and a mixture of unidentified products was produced. Then we used zirconyl chloride octahydrate (ZrOCl2 ·8H2 O) as a catalyst for the addition of amines and indoles to ␣, ␤-unsaturated ketones under non-solvent conditions with success. The reactions proceeded smoothly at 50 ◦ C and the desired Michael adducts were produced in high yields in short reaction times (Scheme 1). Reports on the safety of Zr(IV) salts show that their LD50 is high [LD50 [ZrOCl2 ·8H2 O, oral rat] = 2950 mg/Kg] [31]. ZrOCl2 ·8H2 O with a rather high LD50 and low toxicity should not be that much harmful to mammalians. ZrOCl2 ·8H2 O is a highly water tolerant material therefore, its handling does not need especial precautions. This material is a commercially available and a cheap compound. Literature survey shows that only a very few reports are available dealing with the catalytic activity of this compound [32].

Scheme 2.

lated in good to excellent yields in short reaction times (Table 2, entries 1–12). Surprisingly, in the presence of this catalyst, 4nitroaniline which is a rather weak nucleophile, reacted with both methyl vinyl ketone and cyclohexenone in short reaction times 12 and 20 min, respectively, and the adducts were isolated in excellent yields (Table 2, entries 10 and 11). However, the addition of indole and 2-methyl indole to methyl vinyl ketone was also investigated. We found that indole reacted with methyl vinyl ketone after 120 min and the adduct was isolated in 77% yield. 2-Methyl indole was reacted with methyl vinyl ketone in a shorter reaction time (30 min) and the adduct was isolated in 95% yield. Reaction of 2-methyl indole with cyclohexenone was also proceeded well within a short reaction time (50 min) and the corresponding adduct was isolated in 94% yield (Table 2, entries 13–15). The addition of thiols and alcohols to methyl vinyl ketone, as a reaction model, under similar condition, was also investigated. The reaction of thiols with this ␣, ␤-unsaturated ketone was a non-selective and the two unidentified products were produced (1,2-addition and 1,4-addition). Alcohols, under similar condition, remained almost intact in appropriate reaction times. Therefore, addition of amines in the presence of alcohols would be a highly selective reaction. For this purpose, the reaction of aniline in the presence of equimolar amount of benzyl alcohol was studied. The results show that the reaction proceeded with absolute chemoselectivity and the amino-adduct was produced quantitatively whereas, the alcohol was remained intact (GC). This chemoselectivity is presented by Scheme 2. Recycling of the catalyst is important for the large-scale operation and industrial point of view. To check the possibility of the catalyst recycling, addition of methyl vinyl ketone with aniline at 50 ◦ C under solvent-free conditions in the presence of 2 mol% of ZrOCl2 ·8H2 O was studied. After completion of the reaction and

2. Results and discussion Initial studies to examine the effect of temperature as well as catalyst loading were carried out using methyl vinyl ketone and aniline as a model reaction. Investigation of the different amounts of ZrOCl2 ·8H2 O at different temperatures under solvent-free conditions led us to methyl vinyl ketone (1.1 mmol), aniline (1 mmol) and ZrOCl2 ·8H2 O (2 mol%) at 50 ◦ C as the optimized condition. The data presented in Table 1, show the promising feature of this method in terms of molar ratio of the catalyst, reaction rate and the yield of the product compared with those reported in the literature [18,19,21,27,33]. The work-up was easy and the catalyst was simply filtered from the reaction mixture. Then the generality of the procedure was evaluated by the reaction of a number of ␣, ␤-unsaturated cyclic and acyclic ketones with structurally and electronically diverse amines. The reactions proceeded easily and the adducts were iso-

Table 1 Comparison of catalytic activity of ZrOCl2 ·8H2 O with respect to the other catalysts used for the addition of amines and 2-methylindole to methyl vinyl ketone Catalyst

ZrOCl2 ·8H2 O SmI3 [18] InCl3 [19] CeCl3 ·7H2 O [21,27] Nafion SAC-13 [33]

mol%

2 10 10 30 10

Solvent

None CH3 CN CH2 C12 None CH3 CN

2-Methylindole

Pipiridine

Time (min)

Yield (%)

30 60 150 1200 –

95 95 92 98 –

Time (min)

Aniline Yield (%)

Time (min)

95 –

8

–

–

94 –

360 –

87 –

– 720

– 98

3

Yield (%)

152

H. Firouzabadi et al. / Journal of Molecular Catalysis A: Chemical 252 (2006) 150–155

Table 2 Michael addition of amines and indoles to ␣, ␤-unsaturated ketones catalyzed by ZrOCl2 ·8H2 O under solvent-free conditionsa Entry

Substrate

␣, ␤-Enone

Product

Time (min)

Isolated yield (%)

1

5

95

2

8

94

3

8

95

4

12

94

5

8

94

6

15

84

7

15

85

8

2

95

9

8

94

10

12

95

H. Firouzabadi et al. / Journal of Molecular Catalysis A: Chemical 252 (2006) 150–155

153

Table 2 (Continued) Entry

Substrate

␣, ␤-Enone

Product

Time (min)

Isolated yield (%)

11

20

94

12

20

75

13

120

77

14

120

mixture of unidentified products

15

30

95

16

50

94

All products were identified by their spectroscopic data and their comparison with known samples. a The molar ratio of nucleophile: ␣, ␤-unsaturated ketonecatalyst was 100:110:2 and the reactions were carried out under solvent-free conditions at 50 ◦ C.

the addition of the solvent to the reaction mixture, the catalyst was separated by simple filtration. The isolated ZrOCl2 ·8H2 O was dried and reused for five runs without noticeable drop in the product yield and its catalytic activity.

3. Conclusions We have introduced ZrOCl2 ·8H2 O as a highly efficient, cheap, moisture resistant catalyst for C–N bond formation using Michael addition reactions. In the presence of this catalyst, structurally diverse amines were added to different ␣, ␤-unsaturated ketones successfully in short reaction times in the absence of solvent. The use of a safe catalyst and its insensitivity towards moisture combined with an easy work-up procedure are the strong points of the presented methodology for C–N bond formation via Michael addition reactions.

4. Experimental ZrOCl2 ·8H2 O, amines and indoles were purchased from Merck or Fluka Chemical Companies. Purity determinations of the products were accomplished by GLC on a Shimadzu model GC-14 A instrument or by TLC on silica-gel polygram SIL G/UV 254 plates. NMR spectra were recorded on a Brucker Avance DPX 250 MHz instrument. Mass spectra were recorded on a Shimadzu GC-MS-QP 1000PX. 4.1. General procedure for the Michael addition of amines to α, β-unsaturated carbonyl compounds To a mixture of amine (1 mmol) and ␣, ␤-unsaturated carbonyl compound (1.1 mmol) was added ZrOCl2 ·8H2 O (2 mol%). Reaction mixture was stirred at 50 ◦ C for appropriated reaction time, which was monitored by TLC and GC (Table 2).

154

H. Firouzabadi et al. / Journal of Molecular Catalysis A: Chemical 252 (2006) 150–155

After completion of the reaction, CH2 Cl2 (10 mL) was added and filtered. Evaporation of the solvent of filtered solution under vacuum on a rotary evaporator afforded the desired product in high purity in excellent yield (Table 2). Further purification was performed by column chromatography eluted with petroleum ether/EtOAc (2/1). Structural assignments of the products are based on their 1 H NMR, 13 C NMR, MS spectra and elemental analysis. 4.2. General procedure for the Michael addition of indoles to α, β-unsaturated carbonyl compounds To a mixture of indole (1 mmol) and ␣, ␤-unsaturated carbonyl compound (1.1 mmol) was added ZrOCl2 ·8H2 O (2 mol%). Reaction mixture was stirred at 50 ◦ C for appropriated reaction time, which was monitored by TLC and GC (Table 2). After completion of the reaction, CH2 Cl2 (10 mL) was added and filtered. Evaporation of the solvent of filtered solution under vacuum on a rotary evaporator afforded the desired product in high purity in excellent yield (Table 2). Further purification was performed by column chromatography eluted with petroleum ether/EtOAc (2/1). Structural assignments of the products are based on their 1 H NMR, 13 C NMR, MS spectra and elemental analysis. 4.3. Selected spectral data (Table 2, entry 10). 1 H NMR (CDC13 , TMS, 250 MHz): δ (ppm) 2.19 (s, 3H), 2.78 (t, 2H), 3.48 (t, 2H), 5.05 (b, 1H), 6.51 (d, 2H), 8.01 (d, 2H); 13 C NMR (CDCl3 , TMS, 62.9 MHz): δ (ppm) 30.24, 37.633, 42.07, 111.01, 126.42, 138.2, 152.99, 208; MS (70 eV), m/e: 208 [M+ ]. Anal. Calcd. for (C10 H12 N2 O3 ): C, 57.68; H, 5.81; Found: C, 57.7; H, 5.82. (Table 2, entry 12). 1 H NMR (CDC13 , TMS, 250 MHz): δ (ppm) 2.15 (s, 3H), 2.68 (t, 2H), 2.88 (s, 3H), 3.61 (t, 2H), 6.61–6.75 (m, 3H), 7.19–7.27 (m, 2H); 13 C NMR (CDC13 , TMS, 62.9 MHz): δ (ppm) 30.57, 38.50, 40.30, 47.34, 112.52, 116.72, 129.28, 148.63, 207.95; MS (70 eV), m/e: 177 [M+ ]. Anal. Calcd. for (C11 H15 NO): C, 74.54; H, 8.53; Found: C, 74.51; H, 8.53. (Table 2, entry 13). 1 H NMR (CDC13 , TMS, 250 MHz): δ (ppm) 2.19 (s, 3H), 2.85 (t, 2H), 3.07 (t, 2H), 6.97 (s, 1H), 7.1–7.2 (dd, 2H), 7.33 (d, 1H), 7.59 (d, 1H), 8.05 (b, 1H); 13 C NMR (CDCl3 , TMS, 62.9 MHz): δ (ppm) 19.36, 30.05, 44.09, 111.20, 115.11, 118.65, 119.27, 121.51, 122.02, 127.17, 136.32, 209; MS (70 eV), m/e: 187 [M+ ]. Anal. Calcd. for (C12 H13 NO): C, 76.98; H, 7.00; Found: C, 76.97; H, 7.02. (Table 2, entry 15). 1 H NMR (CDC13 , TMS, 250 MHz): δ (ppm) 2.05 (s, 3H), 2.35 (s, 3H), 2.75 (t, 2H), 2.9 (t, 2H), 7.05–7.15 (m, 3H), 7.40 (m, 1H), 7.75 (br s, 1H, NH); 13 C NMR (CDCl3 , 63 MHz): δ (ppm) 11.5, 19.8, 41.54, 79.51, 111.35, 114.46, 118.91, 119.95, 121.58, 122.69, 126.11, 127.53, 127.44, 128.89, 136.49, 139.2, 208.5; MS (70 eV) m/z: 201 [M]+ . Anal. Calcd. for (C13 H15 NO): C, 77.58; H, 7.51; Found: C, 77.60; H, 7.53. (Table 2, entry 16). 1 H NMR (CDC13 , TMS, 250 MHz): δ (ppm) 1.75–1.65 (m, 1H), 1.93–1.88 (m, 2H), 2.19–2.08 (m,

1H), 2.23 (s, 3H), 2.48–2.36 (m, 3H), 2.99–2.88 (m, 1H), 3.2–3.1 (m, 1H), 7.07–6.98 (m, 2H), 7.01 (d, 2H), 7.59 (d, 1H), 8.33 (s, 1H, NH); 13 C NMR (CDC13 , 63 MHz): δ (ppm) 7.4, 21.4, 26.7, 32.6, 36.7, 43.5, 106.1, 108.6, 114.0, 114.1, 116, 122.1, 125.7, 130.8, 207.5; MS (70 eV) m/z: 227 [M]+ . Anal. Calcd. for (C15 H17 NO): C, 79.26; H, 7.54; Found: C, 79.2; H, 7.52. Acknowledgements The authors are thankful to the Shiraz University Research Council and Iran TWAS Chapter based at ISMO. References [1] (a) V. Snieckus, The Alkaloids, vol. 11, Academic, New York, 1968; (b) G.W. Gribble, Comperhensive Heterocyclic Chemistry, vol. 2, 2nd ed., Pergamon, New York, 1996, p. 203; (c) R. Gibe, M.A. Kerr, J. Org. Chem. 67 (2002) 6247. [2] H.C. Kolb, K.B. Sharpless, in: M. Beller, C Bolm (Eds.), Transition Metals for Organic Synthesis, 2nd ed., Wiley-VCH, D-69469, Weinheim, Germany, 2004. [3] (a) M.S. Gibson, in: S. Patai (Ed.), The Chemistry of Amino Group, Interscience, New York, 1968, p. 61; (b) J. March, Advanced Organic Chemistry, 4th ed., Wiley, New York, 1992, p. 768. [4] R. Baltzly, E. Lorz, P.B. Russell, F.M. Smith, J. Am. Chem. Soc. 77 (1955) 624. [5] C.B. Pollard, G.C. Mattson, J. Am. Chem. Soc. 78 (1956) 4089. [6] P. Traxler, U. Trinks, E. Buchdunger, H. Mett, T. Meyer, M. Muller, U. Regenass, J. Rosel, N. Lydon, J. Med. Chem. 38 (1995) 2441. [7] J. Staunton, B. Wilkinson, Top. Curr. Chem. 195 (1998) 49. [8] M. Tramontini, Synthesis (1973) 703. [9] Y.F. Wang, T. Izawa, S. Kobayashi, M. Ohno, J. Am. Chem. Soc. 104 (1982) 6465. [10] G.I Georg (Ed.), The Organic Chemistry of ␤-Lactams, VCH Publishers, New York, 1993. [11] Y. Hayashi, J.J. Rode, E.J. Corey, J. Am. Chem. Soc. 118 (1996) 5502. [12] E. Juariti (Ed.), Enantioselective Synthesis of ␤-Amino Acids, WileyVCH, New York, 1997. [13] S. Kobayashi, H. Ishitani, Chem. Rev. 99 (1999) 1069 (and references therein). [14] (a) G. Cardillo, C. Tomasini, Chem. Soc. Rev. (1996) 117; (b) A. Graul, J. Castaner, Drugs Future 22 (1997) 956; (c) E. Juaristi, H. Lopez-Ruiz, Curr. Med. Chem. 6 (1999) 983. [15] (a) Z. Iqbal, A.H. Jackson, K.R. Rao, Tetrahedron Lett. 29 (1988) 21; (b) J. Christoffers, Eur. J. Org. Chem. (1998) 1259. [16] J. Cabral, P. Laszlo, L. Mahe, M.-T. Montaufier, S.L. Randriamahefa, Tetrahedron Lett. 30 (1989) 3969. [17] M. Perez, R. Pleixats, Tetrahedron 51 (1995) 8355. [18] (a) S. Matsubara, M. Yoshioka, K. Utimoto, Chem. Lett. (1994) 827; (b) G. Jenner, Tetrahedron Lett. 36 (1995) 233; (c) Z.-P. Zhan, R.-F. Yang, K. Lang, Tetrahedron Lett. 46 (2005) 3859. [19] (a) J.S. Yadav, S. Abraham, B.V.S. Reddy, G. Sabitha, Synthesis (2001) 2165; (b) T.P. Loh, L.-L. Wei, Synlett (1998) 975; (c) M. Bandini, P.G. Cozzi, M.G. Giacomini, P. Melchiorre, S. Selva, A. Umani-Ronchi, J. Org. Chem. 67 (2002) 3700. [20] M. Kawatsura, J.F. Harwig, Organometallics 20 (2001) 1960. [21] G. Bartoli, M. Bosco, E. Marcantoni, M. Pertini, L. Sambri, E. Torregiani, J. Org. Chem. 66 (2001) 9052. [22] N. Srivastava, B.K. Banik, J. Org. Chem. 68 (2003) 2109. [23] (a) R. Varala, M.M. Alam, S.R. Adapa, Synlett (2003) 720; (b) M.M. Alam, R. Varala, S.R. Adapa, Tetrahedron Lett. 44 (2003) 5115.

H. Firouzabadi et al. / Journal of Molecular Catalysis A: Chemical 252 (2006) 150–155 [24] K. Manabe, N. Aoyama, S. Kobayashi, Adv. Synth. Catal. 343 (2001) 174. [25] L.W. Xu, J.W. Li, C.G. Xia, S.L. Zhou, X.X. Hu, Synlett (2003) 2425. [26] N.S. Shaikh, V.H. Deshpande, A.V. Bedekar, Tetrahedron 57 (2001) 9045. [27] G. Bartoli, M. Bartolacci, M. Bosco, G. Foglia, A. Giuliani, E. Marcatoni, L. Sambri, E. Torregiani, J. Org. Chem. 68 (2003) 4594. [28] H. Firouzabadi, N. Iranpoor, F. Nowrouzi, Chem. Commun. (2005) 789. [29] H. Firouzabadi, N. Iranpoor, A.A. Jafari, Adv. Synth. Catal. 347 (2005) 655. [30] (a) H. Firouzabadi, N. Iranpoor, B. Karimi, Synlett (1999) 319–320; (b) H. Firouzabadi, N. Iranpoor, B. Karimi, Synlett (1999) 321–323; (c) H. Firouzabadi, N. Iranpoor, M. Jafarpour, Tetrahedron Lett. 45 (2004) 7451–7454;

155

(d) H. Firouzabadi, N. Iranpoor, M. Jafarpour, Tetrahedron Lett. 46 (2005) 4107–4110; (e) H. Firouzabadi, N. Iranpoor, M. Jafarpour, Tetrahedron Lett. (in press); (f) H. Firouzabadi, N. Iranpoor, M. Jafarpour, J. Sulfur Chem. 26 (2005) 313–324. [31] R.J.S.R. Lewis, Dangerous Properties of Industrial Materials, vol. 3, 8th ed., Van Nostrand Reinhold, New York, 1989. [32] (a) R. Ghosh, S. Maiti, A. Chakraborty, Tetrahedron Lett. 46 (2005) 147–151; (b) K. Mantri, K. Komura, Y. Sugi, Green Chem. 7 (2005) 677–682; (c) F. Shirini, M.A. Zolfigol, E. Mollarazi, Synth. Commun. 35 (2005) 1541–1545. [33] T.C. Wabnitz, J.-Q. Yu, J.B. Spencer, Synlett (2003) 1070–1072.