ZrOCl2$8H2O on montmorillonite K10 accelerated conjugateaddition of amines to a,b-unsaturated alkenes under

solvent-free conditions

Mohammed M. Hashemi,* Bagher Eftekhari-Sis, Amir Abdollahifar and Behzad Khalili

Department of Chemistry, Sharif University of Technology, PO Box 11365-9516, Tehran, Iran

Received 14 July 2005; revised 20 September 2005; accepted 6 October 2005

Available online 28 October 2005

Abstract—At room temperature, ZrOCl2$8H2O on montmorillonite K10 efficiently catalyzes conjugate addition of amines to a variety ofconjugated alkenes such as a,b-unsaturated carbonyl compounds, carboxylic esters, nitriles and amides under solvent-free conditions. Thecatalyst can be recycled for subsequent reactions without any appreciable loss of efficiency.q 2005 Elsevier Ltd. All rights reserved.

1. Introduction

The development of new synthetic methods leading tob-amino ketones or their derivatives has attracted muchattention in organic synthesis. These b-amino ketones areattractive targets for chemical synthesis because of theirprevalence and wide utility. Among the methods forgenerating b-amino ketones, the Mannich reaction is aclassic method for the preparation of these derivatives.1

However, due to the drastic reaction conditions and the longreaction times, the classic Mannich reaction presents seriousdisadvantages.1 The approach based on conjugate additionof amines to a,b-unsaturated carbonyl compounds is one ofthe most simple and effective alternative methods forpreparing b-amino ketones.2

The Michael reaction, which was discovered many yearsago, has been used as one of the most useful methods foreffecting carbon–carbon bond formation and later has alsobeen efficiently manipulated for carbon-sulfur and carbon-nitrogen bond forming processes.2 This reaction is usuallycarried out under acid or base catalysis.3 However, to avoidside reactions, occasionally encountered in the presence of astrong acid or a base, a number of alternative procedureshave been developed in the past few years and in particular,various Lewis acid-induced reactions have been reported.4

Unfortunately, many of these procedures often require alarge excess of reagents, long reaction time and drastic

0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.doi:10.1016/j.tet.2005.10.006

Keywords: Conjugate addition; Amine; a,b-Unsaturated olefins; Zirconiumoxychloride; Solvent free.* Corresponding author. Tel.: C98 21 661 65313; fax: C98 21 660 05718;

e-mail: mhashemi@sharif.edu

reaction conditions in acetonitrile or 1,2-dichloroethanewhich are toxic. In some cases, a stoichiometric amount ofLewis acid such as AlCl3, TiCl4 or SnCl4 are required.4

The use of zirconium(IV) salts as an efficient Lewis acid forvarious transformations, such as electrophilic aminationof activated arenes,5 transthioacetylization of acetals,6

deoxygenation of heterocyclic-N-oxides,7 reduction ofnitro compounds,8 conversion of carbonyl compounds to1,3-oxathiolanes,9 selective oxidation of primary andbenzylic alcohols,10 synthesis of nitriles from O-arylal-doximes,11 chemoselective N-nitrosation of secondaryamines,12 Michael reaction of 1,3-dicarbonyls and enones,13

opening of epoxide rings by amines,14 reactions of indole,1-methylindole, and pyrrole with a,b-unsaturated ketone15

and Friedel-Crafts reactions has been well documented inthe literature.

Synthetic chemists have been using highly dispersedmineral solids with extensive specific areas, for aconsiderable time. Many organic reactions have beendevised in which the reagents are deposited on variousinorganic solid supports. These reagents have advantagesover the conventional homogeneous solution techniques:easy set-up and work-up, mild experimental conditions,high yields and/or selectivity.16 Montmorillonite K10 had agreat impact in organic synthesis and has offered majorbreakthroughs for the fine chemicals manufacturingindustries.17

As part of our research on chemical transformations,18 inthis paper we report a simple and environmentally benign

Tetrahedron 62 (2006) 672–677

M. M. Hashemi et al. / Tetrahedron 62 (2006) 672–677 673

methodology for the conjugate addition of amines to a,b-unsaturated esters, nitriles, amides and ketones underneutral, solvent-free conditions and at room temperatureusing ZrOCl2$8H2O on montmorillonite K10 as catalyst.

2. Results and discussion

Different types of amines (primary and secondary) weresubjected to conjugate addition reactions on the clay-supported zirconium oxychloride. The overall reaction is asshown in Scheme 1.

We started to study the conjugate addition catalyzed byZrOCl2 supported on the montmorillonite K10 by examin-ing the conditions required for the reaction involvingpiperidine and methylacrylate to afford adduct 1a. Asummary of the results obtained is provided in Table 1.Entries 1–7 show the effect of various solvents on the yieldof the reaction. Although acetonitrile, dichloromethane andsolvent-free conditions afforded the product in high yields,we chose solvent-free conditions for economical andenvironmental acceptability. Entry 7 describes the yieldsof four consecutive additions leading to 1a. In theseexperiments the product was isolated by filtration, thesolid residues washed with dichloromethane, and theremaining catalyst reloaded with fresh reagents for furtherruns, follows reactivation (80 8C, vacuum). No decrease inthe yield was observed demonstrating that ZrOCl2/mont-morillonite K10 can be reused as a catalyst in conjugateadditions. The optimum amount of catalyst (0.15 mmol ofZrOCl2$8H2O on 0.1 g montmorillonite K10) was deter-mined from experiments corresponding to entries 7–9.Entries 10, 11 and 12 show the effect of montmorilloniteK10 and the catalytic effect of ZrOCl2$8H2O/

+

X

ZrOCl2 / Mont

r.t

R'

RR1R

2NH

R = H, Me, Ph; R' = H, Me; X =

Scheme 1.

Table 1. Conjugate addition of piperidine (3 mmol) to methylacrylate (2 mmol)

Entry Solvent ZrOCl2$8H2O(mmol)

Mo

1 H2O 0.152 CH2Cl2 0.153 CH3CN 0.154 THF 0.155 EtOH 0.156 DMF 0.157 Solvent free 0.158 Solvent free 0.109 Solvent free 0.2010 Solvent free 0.1511 Solvent free 012 Solvent free 0

a Isolated yield.b Catalyst was used over four runs.

montmorillonite K10 in the conjugate addition of piperidineto methylacrylate, respectively.

The conjugate reaction of piperidine with methylacrylate inthe presence of ZrOCl2$8H2O/montmorillonite K10 gavethe conjugate adduct in high yield and in a short time. Theresults are summarized in Table 2. The data in Table 2clearly show that the reaction of different aliphatic aminesand a,b-unsaturated esters give the corresponding b-aminoester in high yield at room temperature without using anysolvent. Primary amines, such as benzylamine, n-butyl-amine and cyclohexylamine reacted with a,b-unsaturatedesters to give only the mono-alkylated adduct. No sideproduct was observed by using excess of the reactants.When aromatic amines, such as aniline, were added to ana,b-unsaturated ester or a nitrile (entry 8h, Table 2 and entry7gg, Table 3), the conjugate adduct was formed in only lowyield. The difference in the reactivity of aromatic aminesshows the chemoselectivity of conjugate addition ofaliphatic amines in this method. Thus, when a mixture ofaniline and piperidine were exposed to excess methylacryl-ate in the presence of ZrOCl2$8H2O/montmorillonite K10,the piperidine adduct was obtained as the sole product(Scheme 2).

This method also works well for a,b-unsaturated nitriles,amides and ketones. Thus, the conjugate addition ofaliphatic amines to these a,b-unsaturated compounds inthe presence of ZrOCl2$8H2O/montmorillonite K10 gavethe corresponding conjugate adducts in high yield and in ashort time. The results are summarized in Table 3. On theother hand, in the case of a,b-unsaturated aldehydes such asacrolein, the reaction suffers from regiochemical restrictioncaused by competing 1,2- versus 1,4-addition (Scheme 3).As is well know, iminium salts generally react faster and

morillonite K10

. X

R1R

2N

R'

R

COOMe, CN, COMe, CONH2

under different conditions

ntmorillonite K10 (g) Time (min) Yield (%)a

0.1 60 340.1 35 850.1 35 830.1 45 520.1 45 560.1 45 620.1 30 84, 80, 79, 80b

0.1 30 650.1 30 870 60 57

0.1 60 480 60 23

Table 2. Conjugate addition of amines to a,b-unsaturated esters catalyses by ZrOCl2$8H2O/montmorillonite K10 under solvent-free conditions

Entry Amines Ester Product Yield (%)a (time, min)b

1aNH COOMe

NCOOMe

84 (30)4f

2bNH COOMe

NCOOMe

96 (30)4f

3cO NH COOMe

NCOOMe

O

76 (35)20

4dNH COOMe

NCOOMe

82 (30)4f

5e Ph NH2 COOMeCOOMe

HNPh 86 (30)27

6fNH2

COOMeHN

COOMe 87 (30)21

7g n-BuNH2COOMe

COOMe

HN

n-Bu89 (30)27

8h PhNH2COOMe

COOMe

HN

Ph 29 (180)27

9i

NH COOEtPh

COOEtN

Ph

79 (30)4f

10j

O NH COOEtPh

COOEtN

Ph

O

88 (35)4f

11k

NH COOEtPh

COOEtN

Ph

74 (30)4f

12lPh NH2 COOEt

Ph

COOEt

HN

Ph

Ph80 (35)22

13mNH2 COOEt

Ph

COOEt

HN

Ph85 (40)23

14n n-BuNH2

COOEtPh

COOEt

HN

Ph

n-Bu 86 (35)26

15oNH

COOMe COOMeN 82 (35)27

16pNH

COOMe COOMeN 88 (30)27

17qO NH

COOMe COOMeN

O

84 (30)20

18rNH

COOMe COOMeN 73 (35)27

19sPh NH2

COOMeCOOMe

HNPh 80 (30)27

20tn-BuNH2

COOMeCOOMe

HN

n-Bu 82 (35)27

21uNH COOEt

COOEtN 84 (25)4f

22vO NH COOEt

COOEtN

O

89 (30)20

23wNH COOEt

COOEtN 57 (35)4f

a Isolated yields.b References.

M. M. Hashemi et al. / Tetrahedron 62 (2006) 672–677674

Table 3. Conjugate addition of amines to a,b-unsaturated nitriles, amides and ketones catalyses by ZrOCl2$8H2O/montmorillonite K10 under solvent-freecondition

Entry Amine Ethylenic compound Product Yield (%)a (time, min)b

1aaNH CN

NCN

94 (15)4b

2bbNH CN

NCN

98 (30)4b

3ccO NH CN

NCN

O

98 (20)21b

4ddNH CN

NCN

O

75 (10)27

5ee Ph NH2 CNHN

CNPh 89 (15)27

6ffn-BuNH2 CN

HN

CNn-Bu93 (15)27

7ggPhNH2 CN

HN

CNPh 32 (120)26

8hhNH

NH2

O CONH2

N 87 (30)28

9iiO NH

NH2

O

N

O

CONH2

90 (35)24

10jjPh NH2

NH2

O

CONH2

HNPh

83 (35)26

11kk

n-BuNH2 NH2

O

CONH2

HN

n-Bu 86 (35)26

12ll

NH

ON

O

72 (25)4b

13mm

O NH

ON

O

O

86 (30)4a

14nn

NH

ON

O

73 (25)25

15oo PhNH2 O

HN

Ph

O

94 (75)27

a Isolated yields.b References.

COOMe

HN

Ph

NCOOMe

+ PhNH2 +

3 mmol 3 mmol 2 mmol

ZrOCl2 / Montmorillonite K10

r.t, 30 min

100%

0%

1a

NH COOMe

8h

Scheme 2.

NHH

O

H

N

N

N

ZrOCl2 / Montmorillonite K10

r.t

iminium salt

+

Scheme 3.

M. M. Hashemi et al. / Tetrahedron 62 (2006) 672–677 675

M. M. Hashemi et al. / Tetrahedron 62 (2006) 672–677676

more regioselectively than the corresponding carbonylcompounds.19 Thus, in the a,b-unsaturated iminium salt,the hard electrophilic character of the N-linked carbon atomis enhanced, that 1,2-attack by a second molecule of aminetakes place almost exclusively.

3. Conclusion

In conclusion, we have developed a new simple method foraccelerating the conjugate reaction of amines with a,b-unsaturated olefins by using the ZrOCl2$8H2O/montmor-illonite K10. Due to the stability of the catalyst under thereaction conditions, it is possible to recover it by simplefiltration and use it again after reactivating it by heating invacuum at 80 8C. The present procedure provides anefficient and general methodology for the preparation ofb-amino esters, nitriles, amides and ketones.

4. Experimental

4.1. General

NMR spectra were recorded on a Bruker ACF 500.IR spectra were measured using a Perkin Elmer 781spectrometer. Column chromatography was performed onsilica gel, Merck grade 60. CH2Cl2 was distilled before use.ZrOCl2$8H2O and other chemicals were purchased fromFluka or Merck.

4.2. Procedure for preparation of catalyst

ZrOCl2$8H2O (3.35 g) was added to deionized water(20 mL) and the mixture was stirred for 5 min untilcomplete dissolution of the zirconium oxychloride. Mont-morillonite K10 (6.65 g) was then added. The resultingsuspension was refluxed and stirred vigorously for 2 h. Thesolvent was evaporated and then the dry solid was placed inoven at 80 8C for 3 h. 0.15 g of catalyst contains 0.05 gZrOCl2$8H2O (0.15 mmol).

4.3. General procedure for the conjugate reaction ofamines with a,b-unsaturated alkenes by using theZrOCl2$8H2O/montmorillonite K10

To a mixture of methylacrylate (2 mmol) and catalyst(0.15 g) was added piperidine (3 mmol) and stirred at roomtemperature for 30 min. After completion of the reaction,CH2Cl2 (10 mL) was added, and catalyst was removed byfiltration. The solvent was evaporated and the product wasisolated in almost pure form. Further purification wascarried out by short column chromatography on silica geleluting with ethyl acetate/petroleum ether. All compoundswere characterized by their spectroscopic data (IR, NMR)by comparison with those reported in the literature.

4.4. Reactivation of catalyst

The catalyst from the reaction mixture was recovered byfiltration and reactivated by washing with dichloromethane(3!5 mL) and heated in vacuum at 80 8C for 3 h.Reactivated catalyst was used for reaction of piperidine

with methylacrylate for four times (entry 7, Table 1) and nodecrease in the yield was observed.

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