lable at ScienceDirect

Tetrahedron 70 (2014) 6607e6612

Contents lists avai

Tetrahedron

journal homepage: www.elsevier .com/locate/ tet

Uncatalyzed, green aza-Michael addition of amines to dimethylmaleate

Giovanna Bosica *, Anthony John DebonoDepartment of Chemistry, University of Malta, Msida MSD 2080, Malta

a r t i c l e i n f o

Article history:Received 15 March 2014Received in revised form 17 June 2014Accepted 30 June 2014Available online 4 July 2014

Keywords:Dimethyl maleateaza-Michael reactionMono-adductSolvent-freeCatalyst-free

* Corresponding author. E-mail address: giovanna.b

http://dx.doi.org/10.1016/j.tet.2014.06.1240040-4020/� 2014 Elsevier Ltd. All rights reserved.

a b s t r a c t

Dimethyl maleate was found to be a very reactive and selective acceptor for the aza-Michael addition incomparison to other commonly used electron-deficient alkenes. It reacts efficiently with a variety ofaliphatic amines in complete absence of any catalyst and solvent at room temperature. Under theseenvironmentally-friendly conditions, high yields of selectively mono-adducts were obtained within shortreaction times.

� 2014 Elsevier Ltd. All rights reserved.

1. Introduction

In recent years significant attention has been given to the de-velopment of efficient and operationally simple protocols for car-bonecarbon and carboneheteroatom bonds formation, aimed atthe construction of valuable molecules. Elimination of volatile andharmful organic solvents is an important target of green chemistryto prevent solvent wastes, hazards and toxicity and to make syn-theses simpler, saving energy.1 Uncatalyzed reactions can offera step forward in this direction being interesting ways of carryingon more eco-sustainable synthetic methodologies.2 Thus, the de-velopment of efficient procedures for useful chemical trans-formations without any solvent and any catalyst is highlyappreciated.

The aza-Michael reaction is considered a very efficient andversatile method of creating new CeN bond3 and one of theshortest routes to b-amino carbonyl derivatives, which have be-come increasingly important to the natural product and pharma-ceutical areas. In fact, it is one of the most widely used reactions inmodern organic synthesis of biologically active compounds andbeing a conjugate addition it benefits from good atom economy.4

Moreover aza-Michael addition is of remarkable significance inasymmetric synthesis as documented by the various asymmetricaza-Michael protocols available to perform this reaction in highly

osica@um.edu.mt (G. Bosica).

stereoselective manner as well as applied to the total synthesis ofnatural products.4g,5

Typical procedures for aza-Michael reactions require strong acidor base catalysts, which are harmful to the environment and pro-duce undesirable by-products.6 Much work has been carried out onthe aza-Michael addition and a variety of novel catalytic systemsand conditions have been reported in the literature, mainly aimingat further improving the green credentials of this reaction class.7

Such innovations include, among others, the use of lanthanidederivatives,8 silica-supported acids,9 resins,10 clay-supported Lewisacids,11 organic polymers,12 task-specific ionic liquids,13 and re-actions in water14 or solvent-free.15 Although some improvements,many of the above procedures still require harsh reaction condi-tions, expensive catalysts, long reaction times, use of hazardousorganic solvents and excess amount of Michael acceptors, withpoor selectivity, all features, which are not desirable from a greenchemistry point of view. Most of the reported methods have fo-cussed on the addition of secondary aliphatic amines or, at times,aromatic amines and the few non-catalytic aza-Michael reactionsare restricted to electron-poor acceptors with terminal doublebonds or very active double bonds, or else highly nucleophilic ali-phatic amines.16,3a

Dimethyl maleate (2) is a high versatile Michael acceptor, havingtwo electronwithdrawing groups in a- and b-position, which easilyallow to access multi-functionalized final adducts.17 To the best ofour knowledge only a very limited number of aza-Michael addi-tions using dimethyl maleate have previously been reported,which, whereas has previously been shown to be suitable acceptor

G. Bosica, A.J. Debono / Tetrahedron 70 (2014) 6607e66126608

for Michael addition with nitro compounds, under different basiccatalysts.18 Among the few examples of aza-Michael additions withdimethyl maleate, and mainly different alkyl fumarates, there areprocedures, which require the prior preparation of an ionic liquidcatalyst using harsh chemicals and an excess of Michael acceptor,19

or organic solvents like ethanol at 0 �C and pyridine and triethyl-amine at 100 �C, to overcome the insolubility in organic solvents ofmethylamine hydrochloride, used as nucleophile in excess;20 whileneat conditions for 24 h at room temperature or for 10 h underrefluxing are reported with a few amines only.21 Whereas someother procedures refer to regioselective additions to unsymmetricalalkyl fumarates under high temperatures and with long reactiontimes22 or require an additional inert atmosphere.23 Overall mostlyof these have a finite scope of substrates since their main target isthe synthesis of specific compounds like aminoacids, poly-carboxylates with surfactant proprieties and unsaturated polyesterresins.20,23

Following our previous studies on solvent-free and uncatalyzedaza-Michael additions,24,16c herein we report a green aza-Michaelreaction between dimethyl maleate and different amines (1aep)under neat conditions, without any catalyst and solvent, at roomtemperature (Scheme 1).

RNR1H

+ OMeOMeO

O

OMeOMeO

ONRR1

1a-p 2 3a-p

Scheme 1. aza-Michael addition of amines to dimethyl maleate.

Table 2aza-Michael addition of various amines (1bep) to dimethyl maleate (2)

Entry R1 R2 Time (h) Yieldb 3 (%)

1 n-C3H7 (1b) H 4 972 (CH3)2CH (1c) H 6 523 n-C4H9 (1d) H 5 87

2. Results and discussion

A series of screening reactions using 1-pentylamine (1a), as thenucleophile, and 2, as the Michael acceptor, were used in order todetermine the most efficient conditions for reaction. All reactionswere performed on a 0.01 mol scale of the reagents in stoichio-metric ratio. A variety of catalysts were tested with both acetoni-trile and THF as solvent. All of the reactions resulted in excellentyield of mono-adduct (3a) within a relatively short reaction time(Table 1). It is also of note that the reaction was, in all cases,

Table 1Model reaction between 1-pentylamine (1a) and dimethyl maleate (2)

Entry Catalyst Solvent Temp Time(h)

Yieldb

3a (%)

1 DBU (1 equiv) Acetonitrile rt 5 952 DBU (1 equiv) THF rt 5 963 DBU (0.1 equiv) Acetonitrile rt 5 954 K2CO3 (1 equiv) Acetonitrile rt 6 905 K2CO3 (0.1 equiv) Acetonitrile rt 6 886 [DBU][Ac] (1 equiv) / rt 7 727 [DBU][Ac] (0.1 equiv) / rt 7 758 Al2O3 (acidic, 1 equiv) THF rt 8 809 Al2O3 (weakly acidic, 1 equiv) THF rt 10 8310 Amberlyst A-21 (1 equiv) THF rt 6 9711 Amberlyst 15 (1 equiv) THF rt 6 9612 / / rt 4 9613a / / rt 4 9514 / / 50 �C 4 9715 / THF rt 6 8816 / Acetonitrile rt 5.5 92

a Ratio of amine:acceptor was 1.2:1.b Yield of pure isolated product.

selective towards the mono-adduct, with no bis-adduct detectedunder any of the conditions. Much to our surprise, the neat reactioncarried out in absence of both catalyst and solvent at room tem-perature also resulted in an excellent yield of 96%, within 4 h (entry12, Table 1).

One notable observationwas that when the reactionwas carriedout in absence of solvent and catalyst, the isomeric dimethyl fu-marate precipitated out of the reaction after a few minutes. How-ever it was not found to hinder the aza-Michael addition in any waysince the reaction between dimethyl fumarate and the amineproceeds efficiently to result in the same mono-adduct.

On recognising that such mild conditions resulted in high yieldsof solely mono-adduct, we decided to explore whether they wouldhave been suitable for other amines, and a variety of differentamines (1bep) were reacted with 2 (Table 2). Other linear aliphaticprimary amines gave similar results, with yields ranging from 87%to 97% (entries 1, 3, 10, Table 2), as well as the secondary aliphaticamine tested, dibutylamine (entry 7, Table 2), with 72% yield within7 h of reaction. The cyclic (entries 9 and 11, Table 2) and branched(entries 2, 4, 5, 6 and 8, Table 2) aliphatic primary amines alsoresulted in good yields within relatively short reaction times. Oneanomalywas the low yield obtained using isopropyl amine (entry 2,Table 2)dthis was probably due to the volatility of the amine. Noreaction was observed with the aromatic amines (entries 13e15,Table 2) used, after 24 h of stirring at room temperature in absenceof solvent and catalyst. Although the reaction with aniline (entry13, Table 2) was warmed to 50 �C for two extra hours and latermixed with 1 equiv of DBU in acetonitrile, none of these conditionselicited any observable reaction.

4 C2H5CH(CH3) (1e) H 5 855 (CH3)2CHCH2 (1f) H 6 686 (CH3)3C (1g) H 7 657 n-C4H9 (1h) n-C4H9 7 728 (CH3)2CHC2H4 (1i) H 4 709 c-C5H9 (1j) H 5.5 6710 n-C6H13 (1k) H 4 9411 cy-C6H11 (1l) H 5 7812 C6H5CH2 (1m) H 6 6213a C6H5 (1n) H 24 NR14 C6H5 (1o) CH3 24 NR15 p-(C2H5)C6H4 (1p) H 24 NR

NR¼‘no reaction’.a After 24 h, the reaction was heated to 50 �C for 2 h and then 1 equiv of DBU in

acetonitrile was added.b Yield of pure isolated product.

Under the same neat reaction conditions other typical Michaelacceptors (4) were then tested with hexylamine (1k), to comparethe results with those obtained using dimethyl maleate. As can beseen in Table 3, they performed very differently to dimethyl mal-eate and the results were highly dependent on the structure of theacceptor. Methyl acrylate (4a) and acrylonitrile (4b) resulted ina high percentage conversion of starting material with a muchlonger reaction time (20 h). In both cases, the result was a mixtureof both mono- (5) and bis-adduct (6). Other acceptors tested weremuch less reactive: trans-methyl crotonate (4c) gave a yield of 60%

Table 3Reaction between 1-hexylamine (1k) and various Michael acceptors (4)

Entry Acceptor (4) Time (h) Yielda 5 (%) Yielda 6 (%)

1 4a 20 70 12

2 4b 20 80 8

3 4c 96 60 NR

4 4d 96 NR NR

5 4e 96 NR NR

6 4f 96 NR NR

7 4g 96 NR NR

G. Bosica, A.J. Debono / Tetrahedron 70 (2014) 6607e6612 6609

mono-adduct after 96 h while trans-4-phenyl buten-2-one (4d),2-cyclopentenone (4e), 2-cyclohexenone (4f) and trans-2-hexenal(4g) resulted in no observable reaction, under these conditions.

Michael acceptors with terminal double bonds are typicallymore reactive than those with non-terminal double bonds.3a Thiswould explain the higher reactivity of methyl acrylate and acrylo-nitrile compared to the other acceptors tested. It would also explainthe non-selectivity of these acceptors, which leads to the formationof some bis-adduct.24 However, dimethyl maleate is clearly an ex-ception to this rule. The presence of two electron-withdrawinggroups alpha to the double bond make it highly electron-deficient, thus a very reactive acceptor despite possessing a non-terminal double bond. The fact that the double bond is non-terminal and so sterically hindered may be the reason behind theselectivity towards a mono-adduct when compared to methyl ac-rylate and acrylonitrile.

3. Conclusions

It has been shown that the use of catalysts, solvents and heatingare not necessary for the efficient addition of 1-pentylamine todimethyl maleate. The reaction proceeds efficiently resulting inhigh yields of solelymono-adduct after 4 h of reaction time. The useof DBU, potassium carbonate, alumina, Amberlyst resins and ionicliquid [DBU][Ac] did not improve the yield or reaction time whenscreened as catalysts.

Several novel aza-Michael mono-adducts were prepared in ab-sence of catalyst and solvent, under ambient conditions by usingdimethyl maleate as acceptor. It can thus be concluded that the aza-Michael addition of linear, cyclic and branched aliphatic primaryand secondary amines to dimethyl maleate can be carried out ef-fectively with remarkable advantages, such as the simple experi-mental procedure, mild reaction conditions, short reactiontime and high product yields, and more importantly avoidinghazardous organic solvents and any excess of reagents, so with100% of atom economy.

It was found that in comparison to other common Michael ac-ceptors, dimethyl maleate is quite particular. It is more reactivethan acceptors with terminal double bonds, such as methyl acrylateand acrylonitrile, which are considered to be some of the mostreactive Michael acceptors. Furthermore, dimethyl maleate is alsohighly selective towards the mono-adduct in contrast to theseacceptors.

4. Experimental

4.1. General

All commercially available chemicals and reagents were pur-chased from Aldrich and used without further purification. Acidic(Scharlau, grain size: 0.05e0.2 mm, 70e290 mesh ASTM, pH 4.5,activity degree 1), weakly acidic (SigmaeAldrich, w150 mesh,pHw6.0) alumina were used without any activation. IR spectrawere recorded on a Shimadzu IRAffinity-1 FTIR Spectrometer,calibrated against a 1602 cm�1 polystyrene absorbance spectrum.Samples were either analysed as a thin film or in a Nujol� mull,between sodium chloride discs. The 1H and 13C NMR spectra wererecorded on Bruker AM250 NMR spectrometer fitted with a dualprobe at frequencies of 250 MHz and 62.9 MHz for 1H and 13C NMR,respectively. An Aspect 3000 computer using 16 K complex pointsfor 1H NMR and 64 K complex points for 13C NMR was used forprocessing. Samples were dissolved in deuterated chloroform (withTMS); 5 mg in 0.8 mL CDCl3 for 1H NMR and between 35 mg and50mg in 0.8mL CDCl3 for 13C NMR.Mass spectra (EI) were recordedwith a Thermo Finnigan Trace DSQ quadropole mass spectrometertogether with a Thermo Finnigan Trace GC Ultra equipped witha 25 m by 0.22 mm BP1 (100% dimethlypolysiloxane stationaryphase) column. Microanalyses were performed with a CHNS-Oanalyzer Model EA 1108 from Fisons Instruments. Reaction moni-toring was done by TLC and GC analysis. Ready-purchased silica onPET sheets with fluorescent indicator, 254 nm, were used as sta-tionary phase for TLC. Gas chromatography was carried out on

G. Bosica, A.J. Debono / Tetrahedron 70 (2014) 6607e66126610

a Shimadzu GC-2010 plus gas chromatograph equipped witha flame ionisation detector and HiCap 5 GC column with di-mensions of 0.32 mm (internal diameter)�30 m (length)�0.25 mm(film thickness), using nitrogen as carrier gas. Many of the syn-thesised compounds are known and their spectroscopic data are inagreement with those reported in the literature.

4.2. Procedure A: general procedure followed for the prepa-ration of 3a during screening reactions (Table 1)

To a stirred solution of dimethyl maleate (2) (10 mmol) in thechosen solvent (10 mL), 1-pentylamine (1a) (10 mmol) was added,followed by the chosen catalyst (10 mmol) (see Table 1). The re-action was left stirring and monitored by TLC and GC. Theresulting diester (3a) was purified by gravity column chromatog-raphy on silica gel (using mixtures of n-hexane and ethyl acetate)and dried by rotary evaporation. The yield was obtained and theproduct was then analysed by NMR and IR spectroscopy. When nocatalyst and solvent were used the same procedure was followedexcept that the reactants were mixed together immediately. Whensolid catalysts were used the crude mixture was filtered througha filter paper and the catalyst rinsed with diethyl ether, then thefiltrate was concentrated by rotary evaporation before purification.When the reaction was not carried out at room temperature an oilbath and a reflux condenser were used. In some cases the quan-tities of reagents or catalyst were varied from the general pro-cedure, as indicated in table. When [DBU][Ac] was used as reactionmedium (Table 1, entries 6 and 7) the reaction components wereextracted from the mixture using three 5 mL portions of diethylether.

4.3. Procedure B: general procedure followed for the prepa-ration of adducts 3, 5 and 6

Amine (1) (10 mmol) was added to dimethyl maleate (2)(10 mmol), under stirring in a round bottomed flask equipped witha magnetic bar. The reaction was left stirring at ambient conditionsandmonitored by TLC and GC analysis. The resulting adduct (3) waspurified by gravity column chromatography on silica gel, usingmixtures of n-hexane and ethyl acetate, and dried by rotary evap-oration. The yield was obtained and the product was then analysedby IR and NMR spectroscopy. For adducts 5 and 6 Procedure B wasfollowed with the difference being that the Michael acceptor 4wasused instead of 2 together with 1-hexylamine (1k), while keepingall of the other conditions the same.

4.4. Preparation of ionic liquid [DBU][Ac]

The ionic liquid [DBU][Ac], used during the initial screeningreactions, was prepared, as described in the literature,13c by care-fully mixing equimolar portions of DBU and glacial acetic acid ina round-bottomed flask at room temperature and stirring for 6 h.The resulting mixture was then dried by rotary-evaporation for 6 h.

4.5. Product identification

4.5.1. Dimethyl 2-(pentylamino)succinate (3a). Clear, colourless oil.IR (neat, cm�1): n¼3335, 2955, 2930, 2858, 1730, 1456, 1437, 1364.1H NMR (250 MHz, CDCl3): d 3.75 (3H, s, OMe), 3.70 (3H, s, OMe),3.65 (1H, t, J¼6.4 Hz, CHN), 2.80e2.55 (2H, m, CH2N), 2.70e2.45(2H, m, CH2CO), 1.80 (1H, s, NH), 1.55e1.40 (3H, m), 1.40e1.20 (3H,m), 0.90 (3H, t, J¼6.8 Hz, Me). 13C NMR (62.9 MHz, CDCl3): d 174.0,171.5, 58.0, 57.8, 52.0, 48.0, 38.0, 30.0, 29.9, 22.5, 15.0. MS (EI): m/z(%)¼231 (5) [M]þ, 216 (3), 200 (4), 172 (100), 158 (15), 114 (25), 98

(14), 71 (16), 43 (12). Anal. Calcd for C11H21NO4 (231.289): C, 57.12;H, 9.15; N, 6.06; O, 27.67. Found: C, 57.35; H, 9.31; N, 6.21; O, 27.50.

4.5.2. Dimethyl 2-(propylamino)succinate (3b).21 Clear, colourlessoil. IR (neat, cm�1): n¼3325, 2961, 2872, 1732, 1437, 1370. 1H NMR(250 MHz, CDCl3): d 3.75 (3H, s), 3.70 (3H, s), 3.65 (1H, t, J¼6.5 Hz),2.80e2.55 (2H, m), 2.70e2.40 (2H, m), 1.65 (1H, s), 1.55e1.40 (2H,m), 0.90 (3H, t, J¼7.3 Hz). 13C NMR (62.9 MHz, CDCl3): d 174.5, 172.0,58.0, 52.2, 51.8, 50.0, 38.0, 23.2, 11.6.

4.5.3. Dimethyl 2-(iso-propylamino)succinate (3c).21 Clear, colour-less oil. IR (neat, cm�1): n¼3325, 2963, 2873, 2845,1734,1436,1370.1H NMR (250 MHz, CDCl3): d 3.75 (3H, s), 3.70 (3H, s), 3.75e3.70(1H, m), 2.90e2.70 (1H, sep, J¼6.1 Hz), 2.75e2.60 (2H, m), 1.75 (1H,s),1.05 (6H, m). 13C NMR (62.9MHz, CDCl3): d 174.8,171.3, 55.5, 52.1,51.8, 47.2, 38.7, 23.6, 22.2.

4.5.4. Dimethyl 2-(butylamino)succinate (3d). Clear, colourless oil.IR (neat, cm�1): n¼3328, 2954, 2932, 2862,1730,1436,1366. 1H NMR(250 MHz, CDCl3): d 3.75 (3H, s, OMe), 3.70 (3H, s, OMe), 3.65 (1H, t,J¼6.4 Hz, CHN), 2.80e2.55 (2H,m, CH2N), 2.60e2.45 (2H,m, CH2CO),1.70 (1H, s, NH),1.55e1.20 (4H,m), 0.90 (3H, t, J¼7.3Hz,Me). 13CNMR(62.9MHz, CDCl3): d 174.3,171.4, 57.9, 52.3, 52.1, 47.8, 37.9, 32.2, 20.3,13.9. MS (EI):m/z (%)¼217 (5) [M]þ, 174 (18), 158 (100), 144 (15), 114(22), 84 (16), 57 (12). Anal. Calcd for C10H19NO4 (217.262): C, 55.28;H,8.81; N, 6.45; O, 29.46. Found: C, 55.39; H, 9.01; N, 6.28; O, 29.53.

4.5.5. Dimethyl 2-(sec-butylamino)succinate (3e). Clear, colourlessoil. IR (neat, cm�1): n¼3332, 2960, 2936, 2878, 1748, 1732, 1435,1373. 1H NMR (250 MHz, CDCl3): d 3.75 (3H, s, OMe), 3.70 (3H, s,OMe), 3.75e3.65 (1H, m, CHN), 2.80e2.60 (1H, m, CHN), 2.60e2.45(2H, m, CH2CO), 1.75 (1H, s, NH), 1.55e1.20 (2H, m), 1.00 (3H, m,Me), 0.85 (3H, m, Me). 13C NMR (62.9 MHz, CDCl3): d 174.9, 174.8,171.4, 171.1, 55.7, 55.3, 53.2, 53.1, 52.1, 52.0, 51.8, 38.8, 38.76, 30.3,29.0, 20.3, 19.5, 10.3, 9.8. MS (EI):m/z (%)¼217 (5) [M]þ, 202 (8), 188(87), 158 (100), 144 (25), 128 (59), 102 (30), 70 (19). Anal. Calcd forC10H19NO4 (217.262): C, 55.28; H, 8.81; N, 6.45; O, 29.46. Found: C,55.40; H, 8.95; N, 6.29; O, 29.50.

4.5.6. Dimethyl 2-(iso-butylamino)succinate (3f).25 Clear, colourlessoil. IR (neat, cm�1): n¼3332, 2954, 2872, 1745, 1732, 1437, 1366. 1HNMR (250 MHz, CDCl3): d 3.75 (3H, s), 3.70 (3H, s), 3.65 (1H, t,J¼6.1 Hz), 2.70 (2H, m), 2.50e2.25 (2H, m),1.65 (2H, m), 0.90 (6H, d,J¼6.7 Hz). 13C NMR (62.9 MHz, CDCl3) d 174.4, 171.5, 58.1, 56.1, 52.1,51.9, 38.0, 28.7, 20.6, 20.5.

4.5.7. Dimethyl 2-(tert-butylamino)succinate (3g).26 Clear, colour-less oil. IR (neat, cm�1): n¼3333, 2959, 2870, 1735, 1645, 1635, 1437,1390. 1H NMR (250 MHz, CDCl3): d 3.80 (1H, m), 3.75 (3H, s), 3.70(3H, s), 2.60 (2H, m), 1.05 (9H, s). 13C NMR (62.9 MHz, CDCl3):d 176.1, 171.3, 52.4, 52.3, 51.7, 50.7, 40.6, 29.2.

4.5.8. Dimethyl 2-(dibutylamino)succinate (3h). Clear, colourless oil.IR (neat, cm�1): n¼3325, 2958, 2928, 2871, 1734, 1437, 1368. 1H NMR(250MHz, CDCl3): d 3.90 (1H, m, CHN), 3.72 (3H, s, OMe), 3.68 (3H, s,OMe), 2.90e2.65 (2H,m, CH2CO), 2.60e2.45 (4H,m, CH2N),1.50e1.20(8H,m), 0.90 (6H, t, J¼7.2Hz,Me).13CNMR (62.9MHz,CDCl3): d172.7,172.1, 59.8, 51.6, 51.3, 35.0, 31.0, 29.7, 20.3,14.0. MS (EI):m/z (%)¼273(5) [M]þ, 230 (32), 214 (100), 200 (18),158 (16),114 (14), 84 (6), 57 (6),32 (10).Anal. Calcd for C14H27NO4 (273.369): C, 61.51;H, 9.96;N, 5.12;O, 23.41. Found: C, 61.39; H, 9.81; N, 5.26; O, 23.49.

4.5.9. Dimethyl 2-(iso-pentylamino)succinate (3i). Clear, colourlessoil. IR (neat, cm�1): n¼3336, 2955, 2928, 2870, 1740, 1466, 1437,1366. 1H NMR (250 MHz, CDCl3): d 3.75 (3H, s, OMe), 3.70 (3H, s,OMe), 3.65 (1H, t, J¼6.7 Hz, CHN), 2.80e2.60 (2H, m, CH2N),

G. Bosica, A.J. Debono / Tetrahedron 70 (2014) 6607e6612 6611

2.60e2.45 (2H, m, CH2CO), 1.70e1.55 (2H, m, CH2), 1.65 (1H, s, NH),1.40e1.25 (1H, m, CH), 0.90 (6H, d, J¼6.5 Hz, Me). 13C NMR(62.9 MHz, CDCl3): d 174.3, 171.4, 57.9, 52.1, 51.8, 46.3, 39.1, 37.9,25.9, 22.7, 22.5. MS (EI): m/z (%)¼231 (5) [M]þ, 216 (3), 200 (4), 172(100), 158 (15), 116 (55), 114 (16), 84 (18), 43 (20). Anal. Calcd forC11H21NO4 (231.289): C, 57.12; H, 9.15; N, 6.06; O, 27.67. Found: C,57.30; H, 9.26; N, 6.11; O, 27.49.

4.5.10. Dimethyl 2-(cyclopentylamino)succinate (3j). Clear, colour-less oil. IR (neat, cm�1): n¼3325, 2953, 2868, 1748, 1435, 1360. 1HNMR (250 MHz, CDCl3): d 3.75 (3H, s, OMe), 3.70 (3H, s, OMe),3.70e3.65 (1H, t, J¼6.7Hz CHN), 3.10e3.00 (1H, quin, J¼6.1Hz, CHN),2.80e2.60 (2H, m, CH2CO), 1.90e1.30 (9H, m). 13C NMR (62.9 MHz,CDCl3): d 174.8, 171.3, 58.1, 56.6, 52.1, 51.8, 38.5, 33.7, 32.6, 23.9, 23.9.MS (EI): m/z (%)¼229 (5) [M]þ, 214 (3), 200 (6), 170 (100), 156 (13),102 (25), 70 (8). Anal. Calcd for C11H19NO4 (229.273): C, 57.62; H,8.35; N, 6.11; O, 27.91. Found: C, 57.73; H, 8.16; N, 6.34; O, 27.76.

4.5.11. Dimethyl 2-(hexylamino)succinate (3k). Clear, colourless oil.IR (neat, cm�1): n¼3335, 2993, 2953, 2927, 2856, 1747, 1732, 1435,1362. 1H NMR (250 MHz, CDCl3): d 3.75 (3H, s, OMe), 3.70 (3H, s,OMe), 3.65 (1H, t, J¼6.7 Hz, CHN), 2.80e2.60 (2H, m, CH2N),2.70e2.40 (2H, m, CH2CO), 1.60 (1H, s, NH), 1.55e1.40 (2H, m, CH2),1.35e1.20 (6H, m, CH2), 0.90 (3H, t, J¼6.7 Hz, Me). 13C NMR(62.9MHz, CDCl3): d 174.3,171.4, 57.8, 52.1, 51.8, 48.2, 37.9, 31.7, 30.1,26.9, 22.6, 14.0. MS (EI): m/z (%)¼245 (6) [M]þ, 230 (3), 213 (4), 186(100), 172 (16), 114 (14), 85 (9), 43 (8). Anal. Calcd for C12H23NO4(245.315): C, 58.75; H, 9.45; N, 5.71; O, 26.09. Found: C, 58.69; H,9.40; N, 5.56; O, 26.19.

4.5.12. Dimethyl 2-(cyclohexylamino)succinate (3l). Clear, colour-less oil. IR (neat, cm�1): n¼3327, 2928, 2853, 1730, 1437, 1368. 1HNMR (250 MHz, CDCl3): d 3.80 (1H, m, CHN), 3.75 (3H, s, OMe), 3.70(3H, s, OMe), 2.80e2.55 (2H,m, CH2CO), 2.40 (1H,m, CHN),1.90e1.60(5H, m), 1.30e0.90 (6H, m). 13C NMR (62.9 MHz, CDCl3): d 174.8,171.2, 55.1, 54.9, 52.0, 51.7, 38.7, 33.8, 32.8, 25.9, 24.8, 24.5. MS (EI):m/z (%)¼243 (6) [M]þ, 200 (17),184 (100),170 (15),140 (11),102 (21),70 (6), 55 (8). Anal. Calcd for C12H21NO4 (243.299): C, 59.24; H, 8.70;N, 5.76; O, 26.30. Found: C, 59.36; H, 8.59; N, 5.68; O, 26.19.

4.5.13. Dimethyl 2-(benzylamino)succinate (3m).27 Clear, colourlessoil. IR (neat, cm�1): n¼3337, 3028, 3001, 2953, 2845, 1728, 1494. 1HNMR (250 MHz, CDCl3): d 7.30e7.25 (5H, m), 3.92e3.81 (2H, m),3.75 (3H, s), 3.70e3.64 (1H, m), 3.68 (3H, s), 2.70 (2H, m), 2.0 (1H, s).13C NMR (62.9 MHz, CDCl3): d 174.1, 171.3, 139.6, 128.4, 128.3, 127.2,57.0, 52.1, 52.0, 51.8, 38.0.

4.5.14. Methyl 3-(hexylamino)propanoate (5a).28,24 Clear, yellowoil. IR (neat, cm�1): n¼3320, 2957, 2937, 2857, 1746, 1663, 1558,1437, 1364. 1H NMR (250 MHz, CDCl3): d 3.70 (3H, s), 2.90 (2H, t,J¼6.7 Hz), 2.60 (2H, t, J¼7.3 Hz), 2.50 (2H, t, J¼6.30 Hz), 1.70 (1H, s),1.55e1.40 (2H, m),1.35e1.20 (6H, m), 0.90 (3H, t, J¼6.7 Hz). 13C NMR(62.9 MHz, CDCl3): d 173.3, 51.6, 49.8, 45.1, 34.5, 31.8, 30.0, 27.0,22.6, 14.1.

4.5.15. 3-(Hexylamino)propanenitrile (5b).29 Clear, yellow oil. IR(neat): n¼3313, 2953, 2940, 2913, 2855, 2247, 1468, 1422, 1377,1341, 1128 cm�1. 1H NMR (250 MHz, CDCl3): d 2.93 (2H, t, J¼6.7 Hz),2.62 (2H, t, J¼7.3 Hz), 2.52 (2H, t, J¼6.1 Hz), 1.55e1.40 (3H, m),1.40e1.22 (6H, m), 0.87 (3H, t, J¼6.7 Hz). 13C NMR (62.9 MHz,CDCl3): d 118.8, 49.3, 45.1, 31.7, 29.9, 26.9, 22.6, 18.7, 14.0.

4.5.16. Methyl 3-(hexylamino)butanoate (5c). Brown solid: IR(Nujol mull, cm�1): n¼2963, 2944, 2893, 2862, 2847, 1717, 1456,1377. 1H NMR (250MHz, CDCl3): d 3.70 (3H, s, OMe), 3.40e3.20 (1H,m, CHN), 3.10e2.95 (2H, m, CH2N), 2.85e2.60 (2H, m, CH2CO),

2.55e2.40 (2H, m), 1.80e1.55 (2H, m), 1.5e1.20 (8H, m), 0.90 (3H, t,J¼6.7 Hz, Me). 13C NMR (62.9 MHz, CDCl3): d 172.0, 52.0, 50.6, 45.5,38.0, 31.3, 26.7, 26.6, 22.5, 17.1, 14.0. MS (EI): m/z (%)¼201 (8) [M]þ,186 (16), 172 (3), 130 (100), 128 (84), 98 (50), 56 (28), 43 (12). Anal.Calcd for C11H23NO2 (201.306): C, 65.63; H, 11.52; N, 6.96; O, 15.90.Found: C, 65.79; H, 11.41; N, 6.78; O, 15.79.

4.5.17. Methyl 3-[hexyl(3-methoxy-3-oxopropyl)amino]propanoate(6a).4d,24 Clear, yellow oil. IR (neat, cm�1): n¼2954, 2930, 2857,1740, 1456, 1437, 1356. 1H NMR (250 MHz, CDCl3): d 3.65 (6H, s),2.75 (4H, t, J¼7.3 Hz), 2.50e2.35 (6H, m), 1.50e1.35 (2H, m),1.30e1.20 (6H, m), 0.85 (3H, t, J¼6.7 Hz). 13C NMR (62.9 MHz,CDCl3): d 173.1, 53.9, 51.5, 49.4, 32.6, 31.8, 27.2, 27.1, 22.7, 14.1.

4.5.18. 3-[(2-Cyanoethyl)(hexyl)amino]propanenitrile (6b).30 Clear,yellow oil. IR (neat, cm�1): n¼2955, 2932, 2857, 2255, 1732, 1456,1437, 1201, 1177. 1H NMR (250 MHz, CDCl3): d 2.75 (4H, t, J¼6.7 Hz),2.45 (4H, t, J¼7.3 Hz), 2.40 (2H, t, J¼7.9 Hz), 1.50e1.35 (2H, m),1.30e1.20 (6H, m), 0.87 (3H, t, J¼6.7 Hz). 13C NMR (62.9 MHz,CDCl3): d 118.6, 53.6, 49.8, 31.7, 27.4, 26.8, 22.6, 17.0, 14.03.

Acknowledgements

The authors thank the University of Malta and the StrategicEducational Pathways ScholarshipdMalta (European Social Fund(ESF) under Operational Programme IIdCohesion Policy2007e2013, ‘Empowering People for More Jobs and a Better QualityOf Life’) for financial support.

References and notes

1. (a) Tanaka, K. Solvent-free Organic Synthesis; Wiley-VCH: Weinheim, Germany,2003; (b) Tanaka, K.; Toda, F. Chem. Rev. 2000, 100, 1025e1074; (c) Ranu, B. C.;Dey, S. S.; Hajra, A. ARKIVOC 2002, 7, 76e81.

2. (a) Chemistry of Waste Minimisation; Clark, J. H., Ed.; Chapman and Hall: Lon-don, UK, 1995; (b) Poliakoff, M.; Fitzpatrick, J. M.; Farren, T. R.; Anastas, P. T.Science 2002, 297, 807e810.

3. (a) Rulev, A. Y. Russ. Chem. Rev. 2011, 80, 197e218; (b) Jung, M. E. In Compre-hensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, UK,1991; Vol. 4, p 1; (c) Perlmutter, P. Conjugate Addition Reactions in OrganicSynthesis; Pergamon: Oxford, UK, 1992; p 114; (d) Harrison-Marchand, A.;Chataigner, I.; Maddaluno, J. In Science of Synthesis; Georg Thieme: New York,NY, 2005; Vol. 26, p 1225.

4. (a) Cardillo, G.; Tomassini, C. Chem. Soc. Rev. 1996, 25, 117e128; (b) Carey, J. S.;Laffan, D.; Thomson, C.; Williams, M. T. Org. Biomol. Chem. 2006, 4, 2337e2347;(c) Dugger, R. W.; Ragan, J. A.; Brown Ripin, D. H. Org. Process Res. Dev. 2005, 9,253e258; (d) Denmark, S. E.; Forbes, D. C.; Hays, D. S.; De Pue, J. S.; Wilde, R. G.J. Org. Chem.1995, 60, 1391e1407; (e) Rulev, A. Y.; Yenil, N.; Pesquet, A.; Oulyadi,H.; Maddaluno, J. Tetrahedron 2006, 62, 5411e5416; (f) Mather, B. D.; Viswa-nathan, K.; Miller, K. M.; Long, T. E. Prog. Polym. Sci. 2006, 31, 487e531; (g)Krishna, P. R.; Sreeshailam, A.; Srinivas, R. Tetrahedron 2009, 65, 9657e9672; (h)Pletsas, D.; Garelnabi, E. A. E.; Li, L.; Phillips, R. M.; Wheelhouse, R. T. J. Med.Chem. 2013, 56, 7120e7132; (i) Georgiev, N. I.; Bojinov, V. B. Dyes Pigm. 2010, 89,249e256.

5. For recent reviews see: (a) Amara, Z.; Caron, J.; Joseph, D. Nat. Prod. Rep. 2013,30, 1211e1225; (b) Reyes, E.; Fernandez, M.; Uria, U.; Vicario, J. L.; Badia, D.;Carillo, L. Curr. Org. Chem. 2012, 16, 521e546; (c) Moyano, A.; Rios, R. Chem. Rev.2011, 111, 4703e4832; (d) Enders, D.; Wang, C.; Liebich, J. X. Chem.dEur. J. 2009,15, 11058e11076; (e) Hamashima, Y. Chem. Pharm. Bull. 2006, 54, 1351e1364; (f)Xu, L.-W.; Xia, C.-G. Eur. J. Org. Chem. 2005, 4, 633e639; (g) Sibi, M. P.; Manyem,S. Tetrahedron 2000, 56, 8033e8061.

6. (a) Azizi, N.; Saidi, M. R. Tetrahedron 2004, 60, 383e387; (b) Chan, P. W. H.;Cottrel, I. F.; Moloney, M. G. Tetrahedron Lett. 1997, 38, 5891e5894; (c) Shaikh,N. S.; Deshpande, V. H.; Bedekar, A. V. Tetrahedron 2001, 57, 9045e9048; (d)Jenner, G. Tetrahedron Lett. 1995, 36, 233e236; (e) Kobayashi, S.; Karumoto, K.;Sugiura, M. Org. Lett. 2002, 4, 1319e1322; (f) Reboule, I.; Gil, R.; Collin, J. Tet-rahedron Lett. 2005, 46, 7761e7764.

7. (a) Hou, X.; Hemit, H.; Yong, J.; Nie, L.; Aisa, H. Synth. Commun. 2010, 40,973e979; (b) Wei, T.; Hua, M.; Shi, H.; Liu, Y.; Zhang, Y. J. Chem. Res. 2010,452e454; (c) Yadav, J. S.; Reddy, A. R.; Rao, Y. G.; Narsaiah, A. V.; Reddy, B. V. S.Synthesis 2007, 3447e3450; (d) Khan, A. T.; Parvin, T.; Gazi, S.; Choudhury, L.Tetrahedron Lett. 2007, 48, 3805e3808.

8. (a) Duan, Z.; Xuan, X.; Li, T.; Yang, C.; Wu, Y. Tetrahedron Lett. 2006, 47,5433e5436; (b) Varala, R.; Sreelatha, N.; Adapa, S. R. Synlett 2006, 1549e1553;(c) Bartoli, G.; Bartolacci, M.; Giuliani, A.; Marcantoni, E.; Massacesi, M.; Tor-regiani, E. J. Org. Chem. 2005, 70, 169e174.

G. Bosica, A.J. Debono / Tetrahedron 70 (2014) 6607e66126612

9. (a) Mukherjee, C.; Misra, A. Lett. Org. Chem. 2007, 4, 54e59; (b) Wang, Y.; Yuan,Y.-Q.; Guo, S.-R. Molecules 2009, 14, 4779e4789; (c) Saidi, M. R.; Pourshojaei, Y.;Aryanasab, F. Synth. Commun. 2009, 39, 1109e1119.

10. (a) Pal, R.; Sarkar, T.; Khasnobis, S. ARKIVOC 2012, i, 570e609; (b) Das, B.;Chowdhury, N. J. Mol. Catal. A Chem. 2007, 263, 212e215.

11. (a) Choudhary, V. R.; Dumbre, D. K.; Patil, S. K. RSC Adv. 2012, 2, 7061e7065; (b)Mao, X.-X.; Shen, Y.-M.; Wang, J.; Xia, Q.-H. Kinet. Catal. 2011, 52, 525e528; (c)Vijender, M.; Kishore, P.; Satyanarayana, B. Synth. Commun. 2007, 37, 589e592.

12. (a) Beletskaya, I. P.; Tarasenko, E. A.; Khokhlov, A. R.; Tyurin, V. S. Russ. J. Org.Chem. 2010, 46, 461e467; (b) Polshettiwar, V.; Varma, R. S. Tetrahedron Lett.2007, 48, 8735e8738; (c) Kumar, D.; Patel, G.; Mishra, B. G.; Varma, R. S. Tet-rahedron Lett. 2008, 49, 6974e6976.

13. (a) Xu, J.-M.; Wu, Q.; Zhang, Q.-Y.; Zhang, F.; Lin, X.-F. Eur. J. Org. Chem. 2007,1798e1802; (b) Ying, A.; Zheng, M.; Xu, H.; Qiu, F.; Ge, C. Res. Chem. Intermed.2011, 37, 883e890; (c) Ying, A.-G.; Wang, L.-M.; Deng, H.-X.; Chen, J.-H.; Chen,X.-Z.; Ye, W.-D. ARKIVOC 2009, xi, 288e298; (d) Chen, X.; Li, X.; Song, H.; Qian,Y.; Wang, F. Tetrahedron Lett. 2011, 52, 3588e3591.

14. (a) Ranu, B. C.; Banerjee, S. Tetrahedron Lett. 2007, 48, 141e143; (b) Labade, V. B.;Pawar, S. S.; Shingare, M. S.Monatsh. Chem. 2011, 142, 1055e1059; (c) Matveeva,E. V.; Petrovskii, P. V.; Klemenkova, Z. S.; Bondarenko, N. A.; Odinets, I. L. C. R.Chim. 2010, 13, 964e970.

15. (a) Saikia, M.; Kakati, D.; Joseph, M. S.; Sarma, J. C. Lett. Org. Chem. 2009, 6,654e658; (b) Ai, X.; Wang, X.; Liu, J.-M.; Ge, Z.-M.; Cheng, T.-M.; Li, R.-T. Tet-rahedron 2010, 66, 5373e5377; (c) Nath, J.; Chaudhuri, M. K. Catal. Lett. 2009,133, 388e393.

16. (a) Medina, F.; Michon, C.; Agbossou-Niedercorn, F. C. R. Chim. 2013, 16,311e317; (b) Ballini, R.; Gabrielli, S.; Palmieri, A. Curr. Org. Chem. 2010, 14,65e83; (c) Ballini, R.; Baz�an, N. A.; Bosica, G.; Plamieri, A. Tetrahedron Lett.2008, 49, 3865e3867.

17. See, for example: (a) Ballini, R.; Bosica, G. Liebigs Ann. Chem. 1996, 2087e2089;(b) Ballini, R.; Bosica, G.; Fiorini, D.; Righi, P. Synthesis 2002, 681e685; (c)Ballini, R.; Bosica, G.; Palmieri, A.; Petrini, M.; Pierantozzi, C. Tetrahedron 2003,59, 7283e7289; (d) Ballini, R.; Bosica, G.; Mas�e, A.; Petrini, M. Eur. J. Org. Chem.2000, 2927e2931.

18. (a) Ballini, R.; Bosica, G. Tetrahedron 1995, 51, 4213e4222; (b) Ballini, R.; Bosica,G.; Damiani, M.; Righi, P. Tetrahedron 1999, 55, 13451e13456; (c) Ballini, R.;Barboni, L.; Bosica, G.; Fiorini, D.; Palmieri, A. Pure Appl. Chem. 2006, 78,1857e1866; (d) Ballini, R.; Palmieri, A. Adv. Synth. Catal. 2006, 348, 1154e1156.

19. Liang, X.; Wang, Y.; Gong, G.; Yang, J. Catal. Commun. 2008, 10, 281e284.20. Boros, M.; K€ok€osi, J.; V�amos, J.; K€ovesdi, I.; Nosz�al, B. Amino Acids 2007, 33,

709e717.21. Pfau, M. Bull. Soc. Chim. Fr. 1967, 1117e1125.22. Zaderenko, P.; L�opez, M. C.; Ballesteros, P. J. Org. Chem. 1996, 61, 6825e6828.23. (a) Okada, Y.; Banno, T.; Toshima, K.; Matsumura, S. J. Oleo Sci. 2009, 58,

519e528; (b) Straub, T.; Koskinen, A. M. P. Polym. Prepr. 2005, 46, 687.24. Bosica, G.; Spiteri, J.; Borg, C. Tetrahedron 2014, 70, 2449e2454.25. Davis, J. W.; Furst, A. Anal. Chem. 1968, 40, 1910e1912.26. Faderl, C.; Kachkovskyi, G.; Reiser, O.; Kachkovskyi, G. Adv. Synth. Catal. 2013,

355, 2240e2248.27. Nakajima, Y.; Oda, J.; Inouye, Y. Agric. Biol. Chem. 1975, 39, 2065e2068.28. (a) Coutts, R. T.; Hubbard, J. W.; Midha, K. K.; Prasad, K. J. Pharm. Sci. 1971, 60,

28e33; (b) Yadav, J. S.; Reddy, B. V. S.; Basak, A. K.; Narsaiah, A. V. Chem. Lett.2003, 32, 988e989.

29. Gay, M. L.; Molton, P.; Ponnamperuma, C. Org. Mass Spectrom. 1974, 9,1124e1126.

30. Denton, T. T.; Joyce, A. S.; Kiely, D. E. J. Org. Chem. 2007, 72, 4997e5000.