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Aza-Michael Addition of Amines to α,β-Unsaturated Compounds Using MolecularIodine as CatalystKalyan Jyoti Borah a , Mridula Phukan a & Ruli Borah aa Chemical Sciences Department , Tezpur University, Napaam ,Tezpur, Assam, IndiaPublished online: 25 Aug 2010.

To cite this article: Kalyan Jyoti Borah , Mridula Phukan & Ruli Borah (2010) Aza-Michael Addition ofAmines to α,β-Unsaturated Compounds Using Molecular Iodine as Catalyst, Synthetic Communications:An International Journal for Rapid Communication of Synthetic Organic Chemistry, 40:19, 2830-2836,DOI: 10.1080/00397910903320241

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AZA-MICHAEL ADDITION OF AMINES TOa,b-UNSATURATED COMPOUNDS USINGMOLECULAR IODINE AS CATALYST

Kalyan Jyoti Borah, Mridula Phukan, and Ruli BorahChemical Sciences Department, Tezpur University, Napaam, Tezpur,Assam, India

Aza-Michael adducts are obtained in very good yields by the conjugate addition of aliphatic

amines to a,b-unsaturated compounds using molecular iodine as catalyst in dichloromethane

at room temperature. Aromatic amines were found to be reactive under reflux in toluene.

Keywords: Amine; b-amino carbonyl compound; aza-Michael addition; iodine; a,b-unsaturated compounds

INTRODUCTION

The conjugate addition of a nitrogen nucleophile to a a,b-unsaturated carbonylcompound leads to the formation of a b-amino carbonyl compound, which is knownas Aza-Michael addition.[1] b-Amino carbonyl compounds have been considered notonly as building units of biologically important natural products including b-lactambut also versatile nitrogen-containing intermediates such as b-amino alcohol, b-aminoacids, b-lactam antibiotics, and 1,2-diamines.[2] Among the methods for generating b-amino carbonyl compounds, the Mannich reaction is a classical method for the prep-aration of these derivatives. The conjugate addition of nitrogen nucleophiles to anunsaturated system requires either basic or acidic catalysts.[3] Lewis acids catalyst, suchas SnCl4, AlCl3, or TiCl4, have been employed to effect this addition, but their use in stoi-chiometric amounts often poses severe environmental problems inwaste streams. Severalgroups have reported[4] substoichiometric use of someLewis acids, such as InCl3, BiNO3,Cu(OTf)2, Bi(OTf)2, LiClO4, and hydrated CeCl3-NaI supported on silica gel or clay,over the past few years.

In continuation of our earlier studies on iodine,[5] we wanted to extend thecatalytic activity of iodine on the conjugate addition of nitrogen nucleophiles toa,b-unsaturated carbonyl compounds.

RESULTS AND DISCUSSION

Initially, we studied the addition of aliphatic amines to an a,b-unsaturatedsystem in dichloromethane at room temperature in the presence of iodine as catalyst.

Received May 6, 2009.

Address correspondence to Dr. Ruli Borah, Department of Chemical Sciences, Tezpur University,

Napaam, Tezpur 784028, Assam, India. E-mail: ruli@tezu.ernet.in

Synthetic Communications1, 40: 2830–2836, 2010

Copyright # Taylor & Francis Group, LLC

ISSN: 0039-7911 print=1532-2432 online

DOI: 10.1080/00397910903320241

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In a typical procedure, treatment of 0.1mmol of iodine with a mixture of diethylamine (3mmol) and methyl acrylate (3.3mmol) in dichloromethane (3ml) at ambi-ent temperature gave the corresponding b-aminocarbonyl compound in 93% yield(Scheme 1) within 15min. The same reaction was done at room temperature in

Scheme 1. Synthesis of methyl 3-(N,N-diethylamino)-propionate using I2 as catalyst.

Table 1. I2-catalyzed aza-Michael addition of aliphatic amine in dichloromethane at ambient temperature

Entry Amine Olefin Product Time Yielda,b (%)

1 Et2NH A 15min 93

2 Et2NH B 15min 92

3 Et2NH C 25min 89

4 Et2NH E N=A 48h N=A

5 n-BuNH2 A 3h 86

6 n-BuNH2 B 3h 85

7 (iPr)2NH A 40min 82

8 (iPr)2NH B 20min 90

9 (iPr)2NH C 30min 87

10 (iPr)2NH D N=A 48h N=A

11 A 20min 85

12 B 15min 90

13 C 30min 91

14 A 15min 89

15 B 15min 90

16 C 25min 91

(Continued )

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Table 1. Continued

Entry Amine Olefin Product Time Yielda,b (%)

17 PhCH2NH2 A 2.5 h 75

18 PhCH2NH2 B 2.5 h 70

aAll the products were characterized by 1H NMR, IR, and mass spectrometry.bIsolated yields.

Table 2. I2-catalyzed aza-Michael addition of aromatic amine under reflux condition using toluene as

solvent

Entry Amine Olefin Product Time (h) Yielda,b (%)

1 PhNH2 A 7 70

2 PhNH2 B 8 65

3 4-NO2C6H4NH2 A N=A 20 N=A

4 2-NO2C6H4NH2 A N=A 20 N=A

5 4-MeO C6H4NH2 A 7 85

6 4-MeO C6H4NH2 B 8 65

7 4-Cl C6H4NH2 A 9 60

8 A 9 50

9 B 10 48

10 C 12 49

aAll the products were characterized by 1HNMR, IR, and mass spectrometry.bIsolated yields.

2832 K. J. BORAH, M. PHUKAN, AND R. BORAH

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the absence of iodine, and after 5 h, 60% of b-aminocarbonyl compound wasisolated. Various acyclic and cyclic aliphatic amines showed excellent 1,4-additionwith a range of a,b-unsaturated compounds to yield the corresponding adducts(Table 1). The reaction completed within 15–40min for secondary aliphatic aminesin the presence of methyl acrylate, acrylonitrile, and methyl merthacrylate. However,with the primary amine (entries 5, 6, 17, and 18), the reaction was sluggish andtook 3 hr.

To extend the scope of this methodology, we tested the catalytic activity of iod-ine for aniline and methyl acrylate condensation. At room temperature, no conden-sation occurred; however, in refluxing toluene, the reaction went satisfactorily. Wehave summarized the results of other aromatic amines in Table 2.

EXPERIMENTAL

All reactions were monitored by thin-layer chromatography (TLC) using silicagel (Merck, 60–120 mesh). 1HNMR spectra were recorded on a Varian 400-MHzFT-NMR spectrometer using CdCl3 as solvent and tetramethylsilane (TMS) asinternal standard. Mass spectrometry data were obtained on a Perkin-Elmer Clarus600C mass spectrometer. Infrared (IR) data were recorded on a Nicolet instruments410 Fourier transform (FT)–IR spectrophotometer using KBr optics. All productswere characterized by comparison of their IR, 1H NMR, and mass spectra withthose of authentic samples.[4e,6] The starting chemicals were obtained from commer-cial suppliers and used without further purification.

General Procedure for the Synthesis of b-Amino CarbonylCompound

Iodine-catalyzed aza-Michael addition of aliphatic amine. A mixture ofaliphatic amine (3mmol), a,b-unsaturated compound (3.3mmol), and I2 (0.1mmol)in dichloromethane (3ml) was stirred at ambient temperature for a definite period.The progress of the reaction was monitored by TLC. After completion, the reactionmixture was diluted with 10ml of distilled water and washed with an aqueous sol-ution of sodium thiosulfate for removal of iodine. Then the mixture was extractedwith dichloromethane (3� 10ml). The dichloromethane extracts were dried overanhydrous sodium sulfate and removed in a rotary evaporator under reduced press-ure. The crude reaction mixture was further purified by silica-gel column chromato-graphy with different ratios of n-hexane and ethyl acetate as solvent system. Theproduct was isolated in pure form.

Iodine-catalyzed aza-Michael addition of aromatic amine. A mixture ofaromatic amine (3mmol), a,b-unsaturated compound (3.3mmol), and I2 (0.1mmol)in toluene (3ml) was refluxed at 110 �C for a definite period. The progress of thereaction was monitored by TLC. After completion, the reaction mixture was dilutedwith 10ml of distilled water and washed with an aqueous solution of sodium thiosul-fate for removal of iodine. Then the mixture was extracted with ethyl acetate(3� 10ml). The ethyl acetate extracts were dried over anhydrous sodium sulfateand removed in a rotary evaporator under reduced pressure. The crude reaction

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mixture was further purified by silica-gel column chromatography with differentratios of n-hexane and ethyl acetate as solvent system. The product was isolatedin pure form.

Spectral Data for Selected Compounds

3-(N,N-Diethylamino)-propionitrile (Table 1, entry 2)[6d]. Oil, IR (neat)cm�1: 2978, 2916, 2244. 1H NMR (CdCl3): d 2.67 (t, J¼ 7.0Hz, 2H), 2.40 (q,J¼ 7.3Hz, 4H), 2.30 (t, J¼ 7.0Hz, 2H), 0.92 (t, J¼ 7.3Hz, 6H). MS (EI, 70 eV):m=z¼ 127 (Mþ 1).

3-Butylaminopropionitrile (Table 1, entry 6)[6a]. Oil, IR (neat) cm�1: 3440,2960, 2916, 2253. 1HNMR (CdCl3): d 2.92 (t, J¼ 6.65Hz, 2H), 2.59 (t, J¼ 7.15Hz,2H), 2.5 (t, J¼ 6.64Hz, 2H), 1.43–1.47 (m, 2H), 1.33–1.37 (m, 2H), 0.92(t, J¼ 7.5Hz, 3H). MS (EI, 70 eV): m=z¼ 127 (Mþ 1).

Methyl-3-piperidinyl-propionate (Table 1, entry 11)[6d]. Oil, IR (neat)cm�1: 2936, 2856, 1738. 1H NMR (CdCl3): d 3.63 (s, 3H), 2.62 (t, J¼ 8.0Hz, 2H),2.45 (t, J¼ 8.0Hz, 2H), 2.32–2.34 (m, 4H), 1.55–1.34 (m, 6H). MS (EI, 70 eV): m=z¼ 172 (Mþ 1).

(3-Piperidin-1-yl)propionitrile (Table 1, entry 12)[6a]. Oil, IR (neat) cm�1:2934, 2857, 2806, 2244. 1H NMR (CdCl3): d 2.65–2.70 (m, 2H), 2.51 (m, 2H), 2.43(m, 4H), 1.55–1.57 (m, 4H), 1.44 (m, 2H). MS (EI, 70 eV) m=z¼ 139 (Mþ 1).

Methyl-3-pyrrolidinyl-propionate (Table 1, entry 14)[6d]. Oil, IR (neat)cm�1: 3410, 2959, 2872, 1736. 1H NMR (CdCl3): d 3.67 (s, 3H), 2.88 (t, J¼ 7.0Hz,Hz, 2H), 2.26–2.35 (m, 6H), 1.18 (m, 4H); MS (EI, 70 eV): m=z¼ 158 (Mþ 1).

Methyl (2-methyl-3-pyrrolidinyl)-propionate (Table 1, entry 16)[6d]. Oil,IR (neat) cm�1: 3405, 2966, 1738. 1H NMR (CdCl3): d 3.67 (s, 3H), 2.82–2.40 (m,7H), 1.75 (m, 4H), 1.15 (d, J¼ 8.5Hz, 3H). MS (EI, 70 eV) m=z¼ 173 (Mþ 1).

Methyl-3-phenylaminopropionate (Table 2, entry 1)[6e]. Oil, IR (neat)cm�1: 3377, 2929, 2727, 1736.1H NMR (CdCl3): d 7.16–7.23 (m, 2H), 6.67 (m,1H), 6.63 (d, J¼ 7.7Hz, 2H), 4.00 (br, 1H), 3.68 (s, 3H), 3.47 (t, J¼ 6.5Hz, 2H),2.65 (t, J¼ 6.5Hz, 2H). MS (EI, 70 eV): m=z¼ 180 (Mþ 1).

3-Phenylaminopropionitrile (Table 2, entry 2)[6a]. Oil, IR (neat) cm�1:3356, 2960, 2926, 2245. 1H NMR (CdCl3): d 7.18–7.25 (m, 2H), 6.75–6.77 (m,1H), 6.67–6.63 (d, J¼ 7.6Hz, 2H), 4.00 (br, 1H), 3.47 (t, J¼ 6.5Hz, 2H), 2.61 (t,J¼ 6.5Hz, 2H). MS (EI, 70 eV): m=z¼ 147 (Mþ 1).

3-(4-Methoxyphenylamino)propionitrile (Table 2, entry 6)[6a]. Oil, IR(neat) cm�1: 3357, 2959, 2828, 2243. 1H NMR (CdCl3): d 2.62 (t, J¼ 6.5Hz, 2H),3.45 (t, J¼ 6.5Hz, 2H), 3.76 (s, 3H), 6.54 (d, J¼ 8.8Hz, 2H), 6.80 (d, J¼ 8.8Hz,2H). MS (EI, 70 eV): m=z¼ 177 (Mþ 1).

Methyl-3-(imidazol-1-yl)propionate (Table 2, entry 8)[6f]. Oil, IR (neat)cm�1: 1732, 1509. 1H NMR (CdCl3): d 7.54 (s, 1H), 7.05 (s, 1H), 6.93 (s, 1H),

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4.27 (t, J¼ 6.6Hz, 2H), 3.70 (s, 1H), 2.78 (t, J¼ 6.6Hz, 2H). MS (EI, 70 eV):m=z¼ 155 (Mþ 1).

CONCLUSION

In conclusion, we have developed a mild and efficient Aza-Michael addition ofaliphatic and aromatic amines to a,b-unsaturated compounds in organic solventusing molecular iodine as catalyst. The advantages of this method include excellentyield, simple workup procedure, good product selectivity, inexpensive catalyst, shortreaction time for aliphatic amines, and most importantly reactivity toward aromaticamine at higher temperatures.

ACKNOWLEDGMENTS

The authors are thankful to the Council of Scientific and Industrial Research,New Delhi, India, for Research Project Grant No. 01(2067)=06=EMR-II to R. B.and to Central Instrument Facility, Indian Institute of Technology, Guwahati, fortheir cooperation in sample analysis.

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