Advertisement

Nitrilimine cycloadditions catalyzed by iron oxide nanoparticles

  • Giorgio Molteni
  • Anna M. Ferretti
  • Sara Mondini
  • Alessandro Ponti
Research Paper

Abstract

Nitrilimine cycloadditions to ethylenes, acetylenes, and activated nitriles have been exploited in the presence of catalytic amounts of oleic-acid-coated iron oxide nanoparticles (diameter = 11.9 ± 1.0 nm). The reactions were fully regioselective with monosubstituted ethylenes and ethyl cyanoformiate, while mixtures of cycloadducts were obtained in the presence of methyl propiolate. The intervention of iron oxide nanoparticles allowed carrying out the cycloadditions at milder conditions compared to the metal-free thermal processes. A labile intermediate has been proposed to explain this behavior.

Graphical abstract

Nitrilimine cycloadditions to ethylenes, acetylenes, and activated nitriles have been exploited in the presence of catalytic amounts of oleic-acid-coated iron oxide nanoparticles.

Keywords

Dipolar cycloadditions Nitrilimines Catalysis Magnetic nanoparticles Nanoparticle catalysis 

Introduction

Iron is an ubiquitous element. It is the fourth most abundant element in the Earth’s crust, of which it constitutes about 5% by weight; low iron concentrations are found in the soil as well as in groundwaters and oceans (Marshak 2005). The total amount of iron in human body is approximately 3–4 g (Kohgo et al. 2008).

Due to the relevance of biological oxygen carriers and metal-sulfide proteins, the role of iron in the field of bio-inorganic chemistry can be hardly overestimated (Bertini et al. 1994). Thus, it could be safe to say that iron-based processes would be economical as well as intrinsically benign for the environment. This paradigm has recently been extended by the development and understanding of magnetic nanoparticles (NPs) (Reddy et al. 2012) which can act as catalysts in heterocyclic synthesis (Elwahy and Shaaban 2017). In particular, iron oxide nanoparticles have shown interesting catalytic properties in a variety of organic transformations including the three-component aldehyde-alkyne-amine coupling (Zeng et al. 2010), the anti-Markovnikov addition of thiols to alkenes and alkynes (Movassagh and Yousefi 2015), the condensation of aldehydes, enolizable ketones, and esters (Movassagh and Talebsereshki 2013), and the cycloadditive synthesis of cyclic carbonates (Qu et al. 2012) and 1,2,3-triazoles (Kamal and Swapna 2013). The pyrazole ring arising from the nitrilimine cycloaddition onto an unsaturated dipolarophile represents a relevant synthetic target in both academia and industry due to the fact that it constitutes the core of a number of drugs (Elguero et al. 2002), including the widely prescribed Celebrex and Viagra (Penning et al. 1997). It is apparent that the regioselectivity control of the nitrilimine cycloaddition should be of interest in view of the mentioned synthetic relevance of the pyrazole ring (Wade 1992; Padwa 1992; Padwa 2002).

Following our interest in the catalysis of 1,3-dipolar cycloadditions by metal oxide NPs (Molteni et al. 2006; Ferretti et al. 2015), we exploited the first case of nitrilimine cycloaddition spurred by catalytic amounts of monodisperse iron oxide NPs coated with oleic acid.

Experimental section

Materials

Hydrazonoyl chlorides 1a (Broggini and Molteni 2000), 1b (Fusco and Romani 1946), and 1c (Cocco et al. 1985) were prepared according to literature procedures (Fig. 1).
Fig. 1

Hydrazonoyl chloride 1 to be submitted to nitrilimine cycloaddition

Reagents 35 were used as supplied from chemical sources as appropriate. Solvents were dried and stored over 4-Å molecular sieves prior to use. Reagent chemicals, as well as silica gel used for column chromatography, were purchased from Aldrich Chemical Company Ltd (Fig. 2).
Fig. 2

Dipolarophiles to be submitted to nitrilimine cycloaddition

Methods of investigation and equipment

Melting points were determined on a Büchi apparatus in open tubes and are uncorrected. FTIR spectra were recorded on a Thermo Nicolet NEXUS 670 FTIR or a Perkin Elmer 1725X spectrophotometer. Mass spectra were determined on a VG-70EQ apparatus. 1H NMR (300 MHz) and 13C NMR (75 MHz) spectra were taken with a Bruker F 300 instrument (in CDCl3 solutions at room temperature). Chemical shifts are given as parts per million from tetramethylsilane. Coupling constant (J) values are given in hertz and are quoted to ± 0.1 Hz consistently with NMR machine accuracy. Transmission electron microscopy (TEM) images were collected using a Zeiss LIBRA 200FE microscope. The TEM specimens were prepared by evaporating in air a drop of diluted NP dispersion on a carbon-coated copper grid. The size distribution of the NP was obtained analyzing TEM images by the software Pebbles (Mondini et al. 2012).

Synthesis of iron(III) oleate

Iron(III) oleate was obtained as described in the literature (Park et al. 2004), except for the use of potassium oleate instead of sodium oleate. The hexanic solution of iron(III) oleate was washed with water and then with brine (3×) before evaporating the solvent and drying the product under vacuum (50 °C overnight). A red-brown waxy solid was obtained. IR (KBr): 3007 (=C–H), 2952–2853 (C–H), 1582 and 1451 (COO), 583 (FeO) (cm−1).

Synthesis of iron oxide nanoparticles

Iron oxide NPs were synthesized by the solvothermal decomposition of Fe(CO)5 in a solution of oleic acid in octadec-1-ene at 320 °C. The synthesis resulted in spherical NPs (Fig. 1) with median diameter <d> = 11.9 nm and diameter standard deviation σ d  = 1.0 nm (dispersion σ d /<d> = 9%). The electron diffraction pattern of the NPs corresponds to the spinel structure of cubic ferrites. The poor resolution of the diffraction pattern, due to the nanometer size of the crystallites, prevented us from distinguishing between magnetite (Fe3O4) and maghemite (γ-Fe2O3), so we non-committally refer to them as iron oxide (FeOx) NPs (Fig. 3).
Fig. 3

Morphology and crystal structure of iron oxide nanoparticles. a TEM image. b Histogram of the nanoparticle diameter. c Electron diffraction pattern indexed as to the cubic ferrite (spinel) structure

Iron oxide nanoparticles coated with oleic acid were obtained by a modification of a published procedure (Calcagnile et al. 2012) carried out on medium scale. A solution of oleic acid (60.8 mmol, 0.314 M) in octadec-1-ene (194 mL) was heated under Ar to 105 °C (heating rate 3.3 °C/min) under magnetic stirring. The reaction mixture was degassed by several vacuum/Ar cycles, and Fe(CO)5 (30.4 mmol, 0.157 M) was afterwards injected. The reaction mixture was held at 105 °C for 40 min and then heated to 320 °C (heating rate 15 °C/min) and aged for 3 h. The nanoparticles were precipitated by adding ethanol, collected by centrifugation, and redispersed in hexane. This procedure was repeated four times. The nanoparticles were finally dispersed in toluene at a concentration corresponding to CFe = 1.17 g/L (Fig. 3).

Nitrilimine cycloadditions

Uncatalyzed cycloaddition between hydrazonoyl chloride 1a and methyl acrylate: general procedure

A solution of hydrazonoyl chloride 1a (200 mg, 0.94 mmol), methyl acrylate (90 mg, 1.05 mmol), and triethylamine (0.19 g, 1.88 mmol) in dry solvent (4.5 mL) was stirred for the time and at the temperature indicated in Table 1 (vide infra). Solvent (10 mL) was added, and the mixture was washed with water (10 × 3 mL) and dried over sodium sulfate. Evaporation of the solvent gave a residue.
Table 1

Reaction between hydrazonoyl chloride 1a and methyl acrylate 3aa

Entry

Solvent

Catalyst (equiv.)

Base (equiv.)

T (°C)

Time (h)

6aa (%)

1

Toluene

Et3N (2.0)

20

24

6b

2

Toluene

Et3N (2.0)

20

120

62b

3

Toluene

Et3N (2.0)

70

4

83

4

Chloroform

Et3N (2.0)

61

5

78

5

Toluene

HgO (2)

20

24

8b

6

1,4-Dioxane

Ag2O (2)

20

24

18b

7

1,4-Dioxane

Ag2O (2)

70

5

47c

8

Toluene

Fe2O3 (2)

20

24

5b

9

Toluene

Fe2O3 (2)

Et3N (2.0)

20

24

10b

10

Toluene

Fe2O3 (0.2)

Et3N (2.0)

70

3

85

11

Toluene

Ol3Fe (0.2)

20

24

b

12

Toluene

Ol3Fe (0.2)

Et3N (2.0)

20

24

7b

13

Toluene

FeOx NPsd

Et3N (2.0)

20

3

85

a5:6 Mixture of reactants

b Significant amounts of unreacted 1a were recovered

cSome amounts of tarry materials were formed

d0.042 eq. with respect to Fe

In the case of entries 1 and 2, the residue was chromatographed on a silica gel column with hexane-ethyl acetate 3:1 affording unchanged 1a (158 mg, 79%, entry 1, and 52 mg 26%, entry 2) and the pyrazoline 6aa (15 mg, 6%, entry 1, and 153 mg, 62%, entry 2).

In the case of entries 3 and 4, the residue was crystallized with diisopropyl ether giving the pyrazoline 6aa (205 mg, 83%, entry 3, and 193 mg, 78%, entry 4).

Cycloaddition between hydrazonoyl chloride 1a and methyl acrylate in the presence of bulk metal oxides: general procedure

A solution of hydrazonoyl chloride 1a (210 mg, 0.99 mmol) and methyl acrylate (0.10 g, 1.16 mmol) in dry solvent (5.0 mL) was added to metal oxide (2.0 mmol) and stirred (in the dark in the case of entries 5 and 6) for the time and at the temperature indicated in Table 1. The reaction crude was filtered over a celite pad which was washed with solvent (2 × 5 mL). Evaporation of the solvent gave a residue which was chromatographed on a silica gel column with hexane-ethyl acetate 3:1.

In the case of entries 4, 5, and 7, unchanged 1a was eluted first (153 mg, 73%; 147 mg, 70%; and 155 mg, 74%, respectively), followed by the pyrazoline 6aa (21 mg, 8%; 47 mg, 18%; and 13 mg, 5%, respectively).

In the case of entry 6, the crude pyrazoline was crystallized with diisopropyl ether giving 122 mg, 47% of 6aa.

Cycloaddition between hydrazonoyl chloride 1a and methyl acrylate in the presence of bulk Fe2O3 and triethylamine: general procedure

A solution of hydrazonoyl chloride 1a (210 mg, 0.99 mmol), methyl acrylate (0.10 g, 1.16 mmol), and triethylamine (0.20 g, 1.98 mmol) in dry toluene (5.0 mL) was added with Fe2O3 (see Table 1) and stirred for the time and at the temperature indicated in Table 1. The reaction crude was filtered over a celite pad which was washed with toluene (2 × 5 mL) and the solvent was evaporated under reduced pressure.

In the case of entry 8 after evaporation, the residue was chromatographed on a silica gel column with hexane-ethyl acetate 3:1. Unchanged 1a was eluted first (141 mg, 67%), followed by the pyrazoline 6aa (26 mg, 10%).

In the case of entry 9, the residue was crystallized with diisopropyl ether giving the pyrazoline 6aa (220 mg, 85%).

Cycloaddition between hydrazonoyl chloride 1a and methyl acrylate in the presence of iron(III) oleate and triethylamine

A solution of hydrazonoyl chloride 1a (210 mg, 0.99 mmol), methyl acrylate (120 mg, 1.40 mmol), triethylamine (0.20 g, 1.98 mmol), and iron(III) oleate (360 mg, 0.2 mmol) in dry toluene (5.0 mL) was stirred at 20 °C for 24 h. Toluene (15 mL) was added, and the mixture was washed with aqueous 0.1 N hydrochloric acid (5 mL), water (5 mL), 5% aqueous sodium hydrogen carbonate (5 mL), and water (2 × 5 mL). The organic layer was dried over sodium sulfate and evaporated. The residue was chromatographed on a silica gel column with hexane-ethyl acetate 3:1. Unchanged 1a was eluted first (151 mg, 72%), followed by the pyrazoline 6aa (18 mg, 7%).

FeOx NPs catalyzed cycloadditions between hydrazonoyl chloride 1 and dipolarophiles (3 or 5): general procedure

A solution of hydrazonoyl chloride 1 (1.0 mmol) and dipolarophile (3 or 5) (1.2 mmol) in dry toluene (5.0 mL) was added with FeOx NPs (2.34 mg, 42 μmol of Fe) dissolved in toluene (2.0 mL) and triethylamine (0.20 g, 1.98 mmol). The mixture was stirred at 20 °C for the time indicated in the appropriate table. The reaction crude was filtered over a celite pad which was washed with toluene (2 × 5 mL) and the solvent was removed under reduced pressure. The crude was crystallized with diisopropyl ether giving the corresponding cycloadduct 6 or 9aa.

1-(4-Chlorophenyl)-3-methoxycarbonyl-5-cyano-4,5-dihydropyrazole (6cb) (228 mg, 87%). Pale yellow powder, mp 126–129 °C; IR (Nujol): 2225 (-C≡N), 1735 (-COOMe), (cm−1); 1H-NMR: 3.60 (2H, d, J = 9.3, -CH2-), 3.92 (3H, s, CH3O-), 5.08 (1H, t, J = 9.3, >CH-N<), 7.19–7.37 (4H, m, aromatics); 13C-NMR: 37.8 (t, pyrazoline -CH2-), 50.4 (q, CH3O-), 52.6 (d, >CH-N<), 115.7 (s, aromatic), 116.1 (d, aromatic), 128.4 (s, aromatic), 129.5 (d, aromatic), 139.9 (s, -C≡N), 140.1 (s, >C=N-), 161.4 (s, >C=O); MS: 263 m/z (M+). Anal. Calcd for C12H10ClN3O2: C, 54.66; H, 3.82; N, 15.94. Found: C, 54.72; H, 3.78; N, 16.02.

1-(4-Chlorophenyl)-3-methoxycarbonyl-5-butyl-4,5-dihydro pyrazole (6cc) (229 mg, 78%). Pale yellow oil; IR (Nujol): 1736 (-COOMe), (cm−1); 1H-NMR: 0.90 (3H, t, J = 6.5, -CH3), 1.26–1.73 (6H, m, -CH2CH2CH2-), 2.96 (1H, dd, J = 17.8, 5.2, pyrazoline -CH2-), 3.31 (1H, dd, J = 17.8, 12.1, pyrazoline -CH2-), 3.89 (3H, s, CH3O-), 4..46–4.55 (1H, m, >CH-N<), 7.11–7.28 (4H, m, aromatics); 13C-NMR: 13.9 (q, CH3-), 22.4 (t, -CH2-), 26.4 (t, -CH2-), 31.4 (t, -CH2-), 36.8 (t, pyrazoline -CH2-), 52.1 (q, CH3O-), 61.1 (d, >CH-N<), 115.8 (d, aromatic), 126.2 (s, aromatic), 129.1 (d, aromatic), 138.7 (s, aromatic), 140.7 (s, >C=N-), 163.2 (s, >C=O); MS: 294 m/z (M+).

FeOx NPs catalyzed cycloaddition between hydrazonoyl chloride 1 and acetylene 4: general procedure

A solution of hydrazonoyl chloride 1a (210 mg, 0.99 mmol) and dipolarophile 4 (1.2 mmol) in dry toluene (5.0 mL) was added with FeOx NPs (1.17 mg, 21 μmol of Fe) dissolved in toluene (5.0 mL) and triethylamine (0.20 g, 1.98 mmol). The mixture was stirred at 20 °C for 5 (4a) or 3 h (4b). The reaction crude was filtered over a celite pad which was washed with toluene (2 × 5 mL) and the solvent was removed under reduced pressure.

In the case of methyl propiolate 4a, the residue was chromatographed on a silica gel column with hexane-ethyl acetate 2:1 obtaining a mixture of pyrazoles 7aa and 8aa in the ratio 7aa:8aa = 16:84 as deduced by 1H NMR (173 mg, 67% overall yield).

In the case of DMAD 4b, the residue was chromatographed on a silica gel column with dichloromethane obtaining 7ab (246 mg, 78%).

Magnetic recovery of the FeOx NP catalyst from the reaction between hydrazonoyl chloride 1a and methyl acrylate 3a

First run

In a 100-mL cylindric reaction funnel, hydrazonoyl chloride 1a (1.06 g, 5.0 mmol) and methyl acrylate 3a (0.52 g, 6.0 mmol) were dissolved in dry toluene (25 mL). FeOx NPs (11.7 mg, 0.21 mmol of Fe) dissolved in toluene (10 mL) and triethylamine (1.00 g, 0.99 mmol) were added dropwise in 4 min. The mixture was submitted to vigorous mechanical shaking for 3 h at 20 °C.

The undissolved material was recovered with an external magnet and dried with a rotative pump (0.04 mmHg) for 1 h obtaining 10.4 mg (89%) of Fe NPs as black residue A.

The mother solution was washed with water (3 × 25 mL), dried over sodium sulfate, and evaporated under reduced pressure. The crude was crystallized with diisopropyl ether giving 6aa (1.10 g, 84%).

Second run

The residue A was dissolved in dry toluene (25 mL) and an amount of the reagents was added as above. After 3 h, magnetic recovering of the undissolved material and subsequent solvent evaporation gave 8.8 mg (85%) of residue of Fe NPs as black residue B. The treatment of the mother solution as above gave 1.05 g of 6aa (80%).

Results and discussion

Nitrilimines are 1,3-dipolar species which belong to the class of nitrilium betaines (Huisgen 1963; Huisgen 1984). Except for a few examples (Sircard et al. 1988; Fauré et al. 1997), these are labile intermediates (Bégué et al. 2012) which can be generated in situ bydehydrohalogenation of hydrazonoyl halides with an excess of organic base in warm or refluxing solvent (Shimizu et al. 1984). Other effective methods were then developed including the use of silver(I) salts (Molteni 2007) or weak inorganic bases in aqueous medium (Molteni et al. 2002; Molteni and Del Buttero 2005; Dadiboyena and Hamme II 2013). Although these methods allow the formation of the cycloadducts at room temperature, it should be highlighted that more than stoichiometric amounts of the metallic salts were needed.

Since hydrazonoyl chlorides 1 are often used as the precursors of the corresponding nitrilimines 2 (Caramella and Grünanger 1984) (Fig. 4), they have been submitted to the above variety of reaction conditions (Bégué et al. 2012; Shimizu et al. 1984; Molteni 2007; Molteni et al. 2002; Molteni and Del Buttero 2005; Dadiboyena and Hamme II 2013).
Fig. 4

Hydrazonoyl chlorides 1 as precursors of nitrilimines 2 which have been submitted to dipolar cycloaddition in the presence of FeOx NPs as the catalyst

For the sake of clarity, the results obtained with FeOx NPs will be presented according to the nature of the dipolarophile, namely ethylenes, acetylenes, and nitriles (Fig. 2). In order to set the appropriate reaction conditions, we first investigated the behavior of the hydrazonoyl chloride 1a towards methyl acrylate 3a. As can be inferred from Table 1, the metal-free reaction at room temperature (entries 1and 2) gave a poor to moderate yield of the 4,5-dihydropyrazole 6aa (see Scheme 1).
Scheme 1

Cycloaddition between nitrilimine 2 and ethylene 3 catalyzed by FeOx NPs at 20 °C

According to the thermal nature of the nitrilimine cycloadditions (Kamal and Swapna 2013; Bégué et al. 2012), a significant amount of unreacted 1a was recovered in the case of entry 1. Heterogeneous mixtures containing stoichiometric or catalytic amounts of bulk metal oxides at room temperature showed roughly the same behavior (entries 5, 6, 8, and 9). A disappointing product yield was also experienced in a homogeneous iron(III) oleate solution, entries 11 and 12. Much better results were obviously achieved at higher temperatures and no significant solvent effects were detected, as expected for a concerted process (entries 3, 4, 7, and 10). In the latter case, however, any catalytic activity of iron(III) oxide can be hardly revealed. From these data, it is apparent that heterogeneous reaction mixtures in the presence of bulk Fe2O3 did not affect the usual metal-free outcome of nitrilimine cycloaddition. This behavior was similar to that observed with other bulk metal oxides, namely HgO and Ag2O. In this latter case, the slightly better yields are due to the known ability of the silver ion to promote the heterolysis of the carbon-halogen bond (Molteni 2007; Molteni and Garanti 2001; De La Mare and Swedlund 1973). Homogeneous solutions of iron (III) oleate (Ol3Fe) were also ineffective, probably due to the hexacoordinated nature of the iron atom. It can be argued that the three carboxylate groups as well as the three oleyl chains are able to efficiently hide the iron ion from the reagents.

The above picture changes very favorably in the presence of catalytic amounts of FeOx NPs, entry 13. Furthermore, the undissolved material was magnetically recovered and reused one time without significant loss of catalytic activity (80% yield of 6aa and 85% recovery efficiency of the catalyst; see “Experimental section”).

The FeOx NP-catalyzed cycloadditions between nitrilimine 2 and monosubstituted ethylene 3 at 20 °C were fully regioselective giving rise to known 5-substituted-4,5-dihydropyrazole 6 (Molteni et al. 2002, compounds 6aa, 6ab, 6ac; Corsico Coda et al. 1987, compound 6ad; Molteni et al. 2000, compound 6ba; De Benassuti et al. 2007, compound 6ca) with good yields (Scheme 1, Table 2).
Table 2

Cycloaddition between nitrilimine 2 and ethylene 3 catalyzed by FeOx NPs at 20 °C

Entry

R1

R2

R3

Product

Time (h)

Yields (%)a

1

H

COOMe

H

6aa

3

85

2

H

CN

H

6ab

3

80

3

H

nBu

H

6ac

4

83

4

H

COOMe

COOMe

6ad

4

92

5

Me

COOMe

COOMe

6bd

4

90

6

Cl

COOMe

H

6ca

5

85

7

Cl

CN

H

6cb

5

87

8

Cl

nBu

H

6cc

4

78

aIsolation yields

This preference towards the 4-unsubstituted isomer seems to be scarcely dependent by the electronic features of the reagents according to their frontier molecular orbital (FMO) analysis (Shimizu et al. 1984; Caramella and Houk 1976). The example of cycloaddition to a 1,2-disubstituted ethylene, namely diethyl fumarate 3d (Table 2, entries 4 and 5), gave very good yields. This result is significant considering that very small amounts of FeOx NPs were used (9.4–11.0 ‰ in weight of Fe with respect to 1).

The behavior of methyl propiolate 4a towards nitrilimine 2a in the presence of FeOx NPs as the catalyst at 20 °C (Scheme 2) recalls that observed in the usual thermal conditions (Ponti and Molteni 2001), since mixtures of the known regioisomeric pyrazoles 7aa and 8aa (Cvetovich et al. 2003, compound 7aa; Díaz-Ortiz et al. 2006, compound 8aa) were obtained with moderate yield (67%). However, it should be emphasized that FeOx NPs allowed milder reaction conditions compared to the metal-free thermal processes. In terms of yield, better results were experienced with dimethylacetylene dicarboxylate 4b as a representative of 1,2-disubstituted alkynes to give the corresponding pyrazole 7ab (Alemagna et al. 1981, compound 7ab) with 78% yield (Scheme 2).
Scheme 2

Pyrazoles arising from the cycloaddition between nitrilimine 2a and acetylene 4 catalyzed by FeOx NPs at 20 °C

The activated nitrile group of ethyl cyanoformiate 5a reacted satisfactorily with nitrilimine 2a at 20 °C in the presence of FeOx NPs giving the known 1,2,4-triazole 9aa (Dadiboyena and Hamme II 2013) with good yields (Scheme 3, Table 3). In these cases, the harsh conditions of the metal-free cycloadditions (Huisgen et al. 1962) were avoided. Unactivated benzonitrile 5b and p-tolunitrile 5c failed to react with nitrilimine 2a as can be expected by the known poor reactivity of unactivated nitriles as dipolarophiles (Meyers and Sircar 1970).
Scheme 3

Cycloaddition between nitrilimine 2 and nitrile 5 catalyzed by FeOx NPs at 20 °C

Table 3

Cycloaddition between nitrilimine 2 and nitrile 5 catalyzed by FeOx NPs at 20 °C

Entry

R1

R6

Product

Time (h)

Yield (%)a

1

H

COOEt

9aa

8

72

2

H

Ph

24

3

H

4-Me-C6H4

24

aIsolation yields

The above results clearly show that the nitrilimine cycloaddition rate increase at 20 °C is due to the FeOx NPs, since neither bulk iron oxide nor molecular Fe(III) oleate had a significant effect on the reaction rate. The catalytic effect of the FeOx NPs is such to increase the reaction rate without altering the regioselectivity output (Shimizu et al. 1984; Ponti and Molteni 2001). In fact, fully regioselective cycloadditions occurred to ethylene 3 while mixtures of isomeric pyrazoles were found in the presence of methyl propiolate 4a. This suggests that the effectiveness of FeOx NPs to promote nitrilimine cycloadditions may be related to their capability to catalyze the formation of nitrilimine 2 from the corresponding hydrazonoyl chloride 1. In the light of the known complexation of hydrazones with iron(III) ions in homogeneous solution (Reddy et al. 2000), it was envisaged the intermediacy of complex 10, following the diffusion of 1 through the oleic acid coating. Such labile complex could result from the interaction between hydrazonoyl chloride 1 and an undercoordinated iron(III) ion at the NP surface (Fig. 5).
Fig. 5

Proposed catalytic cycle of nitrilimine cycloaddition in the presence of FeOx NPs. For the sake of clarity, alkene 3 and pyrazole 6 are depicted in the cycle. However, it can be extended to the remaining dipolarophiles 4 and 5 and products 79

Dehydrohalogenation of 10 by Et3N would generate reactive nitrilimine 2 whose back diffusion in the bulk solution was responsible for the reaction with the dipolarophile. Due to the unchanged regioselectivity, it seems unlikely that the cycloaddition occurs between dipolarophile and a NP-complexed nitrilimine. To account for the observed reaction rate increase, the formation of nitrilimine 2 by the proposed pathway has to be faster than the dehydrohalogenation occurring in the solvent bulk. Due to the enhanced acidity of the NH moiety of metal-complexed hydrazones (Su and Aprahamian 2014), labile complex 10 is likely to react with Et3N more promptly than 1. However, the increased production of 2 is not such to cause appreciable degradation or side reactions.

To support the above mechanistic hypothesis, we carried out a series of model calculations based on density functional theory (DFT) of small clusters modeling the adsorption of chlorohydrazones and nitrilimines on the NP surface. We used the OPBE functional, which was shown perform well with Fe(III) complexes (Swart 2008), the LANL2 pseudopotential, and the LANL2DZ basis set as implemented in the Gaussian09 Suite (Frisch et al. 2009). All geometries were fully optimized and harmonic analysis showed that they were true energy minima. As a simplistic model for the undercoordinated Fe sites at the NP surface, we used the Fe(OH)3 neutral cluster, which mimics both tetrahedral and octahedral iron ions at the (111) surface of spinel-structure iron oxide. As model adsorbates, we used the hydrazonoyl chloride H2N-N=C(Cl)-COOMe and the corresponding nitrilimine HN-N≡C-COOMe; the oleate anion was modeled as acetate anion. Of course, computational results of model structures are not expected to yield quantitative conclusions but they can give qualitative support to the preceding hypothesis.

DFT calculations showed that all complexes (Fig. 6) have a high-spin (S = 5/2) Fe ion. Chlorohydrazone is able to chelate the Fe ion whereas acetate and nitrilimine coordinate the Fe ion as a monodentate ligand. Nitrilimine can act as both O- and N-donor and chelation is prevented by the nearly linear structure of the HN-N≡C dipolar moiety (Cargnoni et al. 2006). The formation of the Fe(OH)3-chlorohydrazone complex involves electron donation from the organic moiety to the Fe(III) ion and reasonably increases the acidity of the NH2 group thus favoring the Et3N-induced dehydrochlorination leading to the nitrilimine. The adsorption energy of the Fe(OH)3-chlorohydrazone complex is about 25 kcal/mol smaller than that of the acetate complex, showing that chlorohydrazones can be adsorbed onto the NP surface only at Fe sites which are not coordinated by oleate anions, i.e., chlorohydrazones are not able to replace the hard oleate ligands from the hard Fe(III) ions. This is in agreement with the colloidal stability of the NPs during the reaction and the moderate rate of nitrilimine formation. The Fe(OH)3-chlorohydrazone adsorption energy is a few kilocalories per mole larger than that of Fe(OH)3-nitrilimine complexes (in particular, 2 and 5 kcal/mol with respect to the N-nitrilimine and O-nitrilimine complexes, respectively). This suggests that, as nitrilimine forms by dehydrochlorination, it can be replaced by a chlorohydrazone molecule and preferentially released from the NP to the bulk of the reaction mixture.
Fig. 6

Minimum energy structures of high-spin Fe(III) complexes [Fe(III)(OH)3X] calculated by DFT at the OPBE/LANL2/LANL2DZ level. a X = chlorohydrazone; b X = O-nitrilimine; c X = N-nitrilimine; d X = O-acetate. Color code is as follows: white, hydrogen; gray, carbon; blue, nitrogen; red, oxygen; green, chlorine; violet, iron

Conclusions

The reactivity of hydrazonoyl chloride 1 towards an array of dipolarophiles has been exploited in the presence of catalytic amounts of FeOx NPs. Good product yields were usually obtained, while cycloaddition regioselectivities resemble the usual nitrilimine-dipolarophile orientation. The main advantages of this approach compared to the metal-free nitrilimine cycloadditions rely upon simple experimental procedures using a cheap, magnetically recoverable nanocatalyst and involving mild reaction conditions which allowed avoiding the heating of reaction mixtures. This latter point may be of interest in the case of thermally labile reactants.

Notes

Acknowledgements

The authors are grateful to F. Cargnoni (ISTM-CNR, Milan) for useful suggestions about the DFT calculations.

Author contributions

G.M. and A.P. together conceived and planned the research, discussed the results, and wrote the manuscript. G.M. carried out all the cycloadditions. A.M.F. and S.M. synthesized the nanoparticles and A.M.F. characterized them. A.P. carried out the calculations. All the authors read and approved the final manuscript.

Funding

This study was funded by Regione Lombardia (RSPPTECH Project); the Italian MIUR under grant FIRB RBAP115AYN (oxides at the nanoscale: multifunctionality and applications) and the Department of Chemistry of UNIMI under grant PSR2015-1716FDEMA_09 (cycloaddition reactions catalyzed by metal oxide nanoparticles: NANOCAT).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

11051_2018_4184_MOESM1_ESM.pdf (432 kb)
ESM 1 (PDF 431 kb)

References

  1. Alemagna A, Del Buttero P, Licandro E et al (1981) Inter- and intra-molecular reactions of arylazomethylenetriphenylphosphoranes with unsaturated carbon-carbon bonds. Gazz Chim Ital 111:285–288Google Scholar
  2. Bégué D, GuangHua Qiao G, Wentrup C (2012) Nitrile imines: matrix isolation, IR spectra, structures, and rearrangement to carbodiimides. J Am Chem Soc 134:5339–5350CrossRefGoogle Scholar
  3. Bertini, I, Gray HB, Lippard S et al (1994) Bioinorganic chemistry, University Science Books: Mill Valley, 1994Google Scholar
  4. Broggini G, Molteni G (2000) Dipolarophilic behaviour of (arylsulfonyl)allenes towards nitrile imines. J Chem Soc Perkin Trans 1:1685–1689CrossRefGoogle Scholar
  5. Calcagnile P, Fragouli D, Bayer IS, Anyfantis GC, Martiradonna L, Cozzoli PD, Cingolani R, Athanassiou A (2012) Magnetically driven floating foams for the removal of oil contaminants from water. ACS Nano 6:5413–5419CrossRefGoogle Scholar
  6. Caramella P, Grünanger P (1984) 1,3-Dipolar Cycloaddition Chemistry,Wiley: New York, Vol. 1, Ch. 3Google Scholar
  7. Caramella P, Houk KN (1976) Geometries of nitrilium betaines. The clarification of apparently anomalous reactions of 1,3-dipoles. J Am Chem Soc 98:6397–6399CrossRefGoogle Scholar
  8. Cargnoni F, Molteni G, Cooper DL, Raimondi M, Ponti A (2006) The electronic structure of nitrilimine: absence of the carbenic form. Chem Commun:1030–1032Google Scholar
  9. Cocco MT, Maccioni A, Plumitallo A (1985) Phytotoxic activity in pyrazole derivatives II. Farmaco Sci 40:272–284Google Scholar
  10. Corsico Coda A, De Gaudenzi L, Desimoni G et al (1987) A new thermal decomposition of the isoxazole ring. Heterocycles 26:745–750CrossRefGoogle Scholar
  11. Cvetovich RJ, Pipik B, Hartner FW, Grabowski EJJ (2003) Rapid synthesis of tetrahydro-4H-pyrazolo[1,5-a]diazepine-2-carboxylate. Tetrahedron Lett 44:5867–5870CrossRefGoogle Scholar
  12. Dadiboyena S, Hamme AT II (2013) Environmentally benign Lewis acid promoted [2+3] dipolar cycloaddition reactions of nitrile imines with alkenes in water. Eur J Org Chem 2013:7567–7574CrossRefGoogle Scholar
  13. De Benassuti L, Recca T, Molteni G (2007) 15N NMR spectroscopy of partially unsaturated pyrazoles. Tetrahedron 63:3302–3305CrossRefGoogle Scholar
  14. De La Mare PBD, Swedlund BE (1973) The chemistry of the carbon-halogen bond, John Wiley & Sons: London, Part 1, Ch. 7, pp. 407–458Google Scholar
  15. Díaz-Ortiz A, de Cózar A, Prieto P, de la Hoz A, Moreno A (2006) Recyclable supported catalysts in microwave-assisted reactions: first Diels–Alder cycloaddition of a triazole ring. Tetrahedron Lett 47:8761–8764CrossRefGoogle Scholar
  16. Elguero J, Goya P, Jagerovic N et al (2002) Pyrazoles as drugs: facts and fantasies. Targets Heterocycl Syst 6:52–98Google Scholar
  17. Elwahy AHM, Shaaban MR (2017) Synthesis of heterocycles catalyzed by iron oxide nanoparticles. Heterocycles 94:595–655CrossRefGoogle Scholar
  18. Fauré JL, Réau R, Wong MW, Koch R, Wentrup C, Bertrand G (1997) Nitrilimines: evidence for the allenic structure in solution, experimental and ab initio studies of the barrier to racemization, and first diastereoselective [3 + 2]-cycloaddition. J Am Chem Soc 119:2819–2824CrossRefGoogle Scholar
  19. Ferretti AM, Ponti A, Molteni G (2015) Silver(I) oxide nanoparticles as a catalyst in the azide–alkyne cycloaddition. Tetrahedron Lett 56:5727–5730CrossRefGoogle Scholar
  20. Frisch MJ, Trucks GW, Schlegel HB et al (2009) Gaussian 09, Revision C.01, Gaussian Inc.: WallingfordGoogle Scholar
  21. Fusco R, Romani R (1946) Investigations of formazyls. I. The action of diazo compounds on chloro- and bromomalonic acids. Gazz Chim Ital 76:419–438Google Scholar
  22. Huisgen R (1963) 1,3-Dipolar cycloadditions. Past and future. Angew Chem Int Ed Engl 2:565–598CrossRefGoogle Scholar
  23. Huisgen R (1984) 1,3-Dipolar cycloaddition chemistry, Wiley: New York, Vol. 1, Ch. 1Google Scholar
  24. Huisgen R, Grashey R, Seidel M et al (1962) 1,3-Dipolar additions. II. Synthesis of 1,2,4-triazoles from nitrilimines and nitriles. Ann Chem 653:105–113CrossRefGoogle Scholar
  25. Kamal A, Swapna P (2013) An improved iron-mediated synthesis of N-2-aryl substituted 1,2,3-triazoles. RSC Adv 3:7419–7426CrossRefGoogle Scholar
  26. Kohgo Y, Ikuta K, Ohtake T, Torimoto Y, Kato J (2008) Body iron metabolism and pathophysiology of iron overload. Int J Hematol 88:7–15CrossRefGoogle Scholar
  27. Marshak S (2005) The earth: portrait of a planet. W.W. Norton & Co., New YorkGoogle Scholar
  28. Meyers AI, Sircar CJ (1970) The chemistry of the cyano group. Wiley-Interscience, London, Ch 8Google Scholar
  29. Molteni G (2007) Silver(I) salts as useful reagents in pyrazole synthesis. ARKIVOC (2):224–246Google Scholar
  30. Molteni G, Del Buttero P (2005) Nitrilimine cycloadditions to the cyano group in aqueous media. Heterocycles 65:1183–1188CrossRefGoogle Scholar
  31. Molteni G, Garanti L (2001) Behavior of hydrazonoyl chlorides towards the C=N double bond of Δ2-pyrazolines. A study on 2-(4-nitrophenyl)-2,3,3a,4,5,6-hexahydro-6-oxofuro[3,4-c]zpyrazole. Heterocycles 55:1573–1580Google Scholar
  32. Molteni G, Orlandi M, Broggini G (2000) Nitrilimine cycloadditions in aqueous media. J Chem Soc Perkin Trans 1:3742–3745CrossRefGoogle Scholar
  33. Molteni G, Ponti A, Orlandi M (2002) Uncommon aqueous media for nitrilimine cycloadditions. I. Synthetic and mechanistic aspects in the formation of 1-aryl-5-substituted-4,5-dihydropyrazoles. New J Chem 26:1340–1345CrossRefGoogle Scholar
  34. Molteni G, Bianchi CL, Marinoni G, Santo N, Ponti A (2006) Core-shell Cu@Cu-oxide nanoparticles as catalyst in the click azide-alkyne cycloaddition. New J Chem 30:1137–1139CrossRefGoogle Scholar
  35. Mondini S, Ferretti AM, Puglisi A et al (2012) Pebbles and Pebblejuggler: software for accurate, unbiased, and fast measurement and analysis of nanoparticle morphology from transmission electron microscopy (TEM) micrographs. Nanoscale 4:5356–5372 Pebbles is freely available from the authors, http://pebbles.istm.cnr.it CrossRefGoogle Scholar
  36. Movassagh B, Talebsereshki F (2013) Efficient one-pot synthesis of β-acetamido carbonyl compounds using Fe3O4 nanoparticles. Helv Chim Acta 96:1943–1947CrossRefGoogle Scholar
  37. Movassagh B, Yousefi A (2015) Magnetic iron oxide nanoparticles as an efficient and recyclable catalyst for the solvent-free synthesis of sulfides, vinyl sulfides, thiol esters, and thia-Michael adducts. Monatsh Chem 146:135–142CrossRefGoogle Scholar
  38. Padwa A (1992) Comprehensive organic synthesis. Pergamon Press, New York, 1992, Vol. 4, Ch. 4–9, p 1069Google Scholar
  39. Padwa A (2002) Synthetic applications of 1,3- dipolar cycloaddition chemistry toward heterocycles and natural products. Wiley, New YorkCrossRefGoogle Scholar
  40. Park J, An K, Hwang Y, Park JG, Noh HJ, Kim JY, Park JH, Hwang NM, Hyeon T (2004) Ultra-large-scale syntheses of monodisperse nanocrystals. Nat Mater 3:891–895CrossRefGoogle Scholar
  41. Penning TD, Talley JJ, Bertenshaw SR, Carter JS, Collins PW, Docter S, Graneto MJ, Lee LF, Malecha JW, Miyashiro JM, Rogers RS, Rogier DJ, Yu SS, Anderson GD, Burton EG, Cogburn JN, Gregory SA, Koboldt CM, Perkins WE, Seibert K, Veenhuizen AW, Zhang YY, Isakson PC (1997) Synthesis and biological evaluation of the 1,5-diarylpyrazole class of cyclooxygenase-2 inhibitors: identification of 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzene sul fonamide (SC-58635, Celecoxib). J Med Chem 40:1347–1365CrossRefGoogle Scholar
  42. Ponti A, Molteni G (2001) DFT-based quantitative prediction of regioselectivity: cycloaddition of nitrilimines to methyl propiolate. J Org Chem 66:5252–5255CrossRefGoogle Scholar
  43. Qu J, Cao CY, Dou ZF et al (2012) You have full text access to this content) Synthesis of cyclic carbonates: catalysis by an iron-based composite and the role of hydrogen bonding at the solid/liquid interface. ChemSusChem 5:652–655CrossRefGoogle Scholar
  44. Reddy PM, Kumar KA, Raju KM et al (2000) Synthesis and characterization of iron (II, III) complexes of 3-hydroxy-benzaldehyde isonicotinic acid hydrazone. Indian J Chem 39A:1182–1186Google Scholar
  45. Reddy LH, Arias JL, Nicolas J, Couvreur P (2012) Magnetic nanoparticles: design and characterization, toxicity and biocompatibility, pharmaceutical and biomedical applications. Chem Rev 112:5818–5878CrossRefGoogle Scholar
  46. Shimizu T, Hayashi Y, Nishio T (1984) The reaction of N-aryl-C-ethoxycarbonylnitrilimine with olefins. Bull Chem Soc Jpn 57:787–790CrossRefGoogle Scholar
  47. Sircard G, Baceiredo A, Bertrand G (1988) Synthesis and reactivity of a stable nitrile imine. J Am Chem Soc 110:2663–2664CrossRefGoogle Scholar
  48. Su X, Aprahamian I (2014) Hydrazone-based switches, metallo-assemblies and sensors. Chem Soc Rev 43:1963–1981CrossRefGoogle Scholar
  49. Swart M (2008) Accurate spin-state energies for iron complexes. J Chem Theory Comput 4:2057–2066CrossRefGoogle Scholar
  50. Wade PA (1992) Comprehensive organic synthesis. Pergamon Press, New York, Vol. 4, Ch. 4–10, p 1111Google Scholar
  51. Zeng T, Chen WW, Cirtiu CM, Moores A, Song G, Li CJ (2010) Fe3O4 nanoparticles: a robust and magnetically recoverable catalyst for three-component coupling of aldehyde, alkyne and amine. Green Chem 12:570–573CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V., part of Springer Nature 2018

Authors and Affiliations

  • Giorgio Molteni
    • 1
  • Anna M. Ferretti
    • 2
  • Sara Mondini
    • 2
  • Alessandro Ponti
    • 2
  1. 1.Dipartimento di ChimicaUniversità degli Studi di MilanoMilanItaly
  2. 2.Laboratorio di Nanotecnologie, Istituto di Scienze e Tecnologie MolecolariConsiglio Nazionale delle RicercheMilanItaly

Personalised recommendations