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Synlett 2009(2): 268-270  
DOI: 10.1055/s-0028-1087515
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Solvent-Free, anti-Michael Addition of Active Methylene Derivatives to β-Nitroacrylates: Eco-Friendly, Chemoselective Synthesis of Polyfunctionalized Nitroalkanes

Roberto Ballini*, Giovanna Bosica, Alessandro Palmieri, Khadijeh Bakhtiari
‘Green Chemistry Group’, Dipartimento di Scienze Chimiche dell’Università di Camerino, Via S. Agostino 1, 62032 Camerino, Italy
Fax: +39(0737)402297; e-Mail: Roberto.ballini@unicam.it;

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Publication History

Received 23 October 2008
Publication Date:
15 January 2009 (online)

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Abstract

The chemoselective, anti-Michael addition of active ­methylene derivatives to β-nitroacrylates can be easily performed at room temperature, under solvent-free conditions, using a catalytic amount of potassium carbonate as heterogeneous catalyst.

Key words

anti-Michael addition - solvent-free - eco-friendly synthesis - chemoselective - polyfunctionalized nitroalkanes

Catalytic technologies have played a vital role in the economic development of the chemical industry in the 20th century. In the 21st century, we can expect the drive toward cleaner technologies [¹] and, in this context, heterogeneous systems show great potential since the use of toxic solvent is drastically reduced, the chemoselectivity and the atom-efficiency are often improved, the product isolation is simplified, and the volume of waste is significantly reduced. [²]

Aliphatic nitro compounds, an important class of starting material for the generation of new carbon-carbon bonds, demonstrate high sensitivity to the catalytic system employed, in terms of yields, waste production, chemoselectivity, and of atom-efficiency. [³] Thus, the right choice of the catalyst becomes crucial in the reaction of nitro derivatives.

β-Nitroacrylates are an emerging class of electron-poor alkenes since they can be converted into other important ‘fine chemicals’ [4] or employed as Michael acceptors with indoles, [5] amines, [6] and β-dicarbonyl derivatives. [7] The latter conjugate addition of active methylene derivatives 2 has been studied using a homogeneous solution of two equivalents of DBU as organic base, in acetonitrile, giving the in situ elimination of nitrous acid (Scheme  [¹] ) from the Michael adduct 3.

The nitrous acid elimination is induced both by the presence of (i) the electron-withdrawing group at the β-position to the nitro function in the intermediate 3 and (ii) a strong base like DBU. However, in spite of the great utility of the unsaturated systems 4 obtained, the elimination of the nitro group from the Michael adduct 3 represents an important loss in terms of atom economy and functionality, due to the easy conversion of the nitro group into a variety of other powerful functionalities. [8] In addition, the need for two equivalents of DBU and a toxic solvent like MeCN make this procedure of limited interest from the eco-sustainability point of view.

Scheme 1

During our studies into the application of heterogeneous catalysis, [³a] [9] we have now found that the reaction of 1 with active methylene compounds 5 can be easily performed under solvent-free conditions and in the presence of a catalytic amount (0.1 equiv) of potassium carbonate. Under these mild, solvent-free reaction conditions (Scheme  [²] ) a variety of polyfunctionalized nitro derivatives 6 is obtained in high yields (75-95%) via an anti-Michael reaction [¹0] and with complete chemoselectivity since no elimination of nitrous acid is observed from the adduct 6. [¹¹]

Scheme 2

The reaction works well at room temperature and under very short reaction times (1-2 h) and seems to be independent of the bulk of the reactants since hindered nucleophilic derivatives (6k-n) furnish comparable results to those obtained from simple active methylenes (6a-j, Table  [¹] ).

Table 1 Synthesis of Compounds 6 [¹²]
Entry R R³ R4 EWG
 Yield (%)a of 6 (reaction time, h)
a Et Me H COMe
 75 (1.5)
b Me OEt H COOEt
 85 (1)
c n-Pr Ph H COPh
 80 (2)
d n-Pr OEt H COMe
 83 (1.5)
e n-Pr OEt H CN
 95 (1)
f n-C5H11 OEt H CN
 87 (1)
g MeOCO(CH2)4 OEt H CN
 83 (1)
h Et OEt H CN
 92 (1)
i Ph OEt H CN
 84 (2)
j Ph(CH2)2 OEt H CN
 94 (1)
k n-Bu OEt n-C5H11 CN
 84 (1)
l Ph(CH2)2 OEt n-C5H11 CN
 95 (1)
m Et OEt Me2CHCH2 CN
 95 (1)
n n-C5H11 OEt Me2CHCH2 CN
 86 (1)
a Yield of pure isolated product.

By our procedure a new class of useful, polyfunctionalized nitro derivatives can be easily prepared in high yields, at room temperature, and under very short reaction times with the minimum consumption of energy.

In addition, several other ecological advantages are offered since the amount of catalyst is 0.1 equivalents, and all the reactions can be performed in the absence of any solvent and with 100% of atom economy.

Finally, any workup can be avoided because the crude products can be directly charged onto a chromatographic column. [¹²]

Thus, our method represents an important step in the synthesis of polyfunctionalized nitroalkanes under eco-friendly reaction conditions.

Acknowledgment

The authors thank the University of Camerino and MUR-Italy (PRIN 2006, project: Sintesi Organiche Ecosostenibili Mediate da Nuovi Sistemi Catalitici) for financial support.

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Spectroscopic Data for Representative Compounds
Compound 6a: oil. IR (neat): 1732, 1555, 1369 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 0.98 (t, 3 H, J = 7.2 Hz), 1.24 (t, 3 H, J = 7.2 Hz), 1.90-2.00 (m, 1 H), 2.12-2.22 (m, 1 H), 2.34 (s, 3 H), 2.42 (s, 3 H), 3.75 (dd, 0.6 H, J = 3.4, 11.0 Hz), 3.82 (dd, 0.4 H, J = 5.8, 8.9 Hz), 3.92 (d, 0.6 H, J = 11.0 Hz), 4.02 (d, 0.4 H, J = 8.9 Hz), 4.11-4.22 (m, 2 H), 4.48-4.53 (m, 0.4 H), 4.96-5.09 (m, 0.6 H). ¹³C NMR (100 MHz, CDCl3): δ = 10.8, 14.0, 24.5, 31.0, 46.6, 47.3, 62.3, 62.4, 66.9, 88.5, 89.9, 169.2, 169.6, 200.2, 200.6. Anal. Calcd for C12H19NO6 (273.283): C, 52.74; H, 7.01; N, 5.13. Found: C, 52.01; H, 6.81; N, 4.98.
Compound 6b: oil. IR (neat): 1738, 1557, 1370 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 1.20-1.30 (m, 9 H), 1.55 (d, 1.35 H, J = 6.8 Hz), 1.65 (d, 1.65 H, J = 6.8 Hz), 3.69 (d, 0.45 H, J = 9.4 Hz), 3.76 (dd, 0.55 H, J = 5.1, 8.1 Hz). 3.88 (d, 0.55 H, J = 7.7 Hz), 3.96 (dd, 0.45 H, J = 5.5, 9.4 Hz), 4.12-4.28 (m, 6 H), 4.74-4.81 (m, 0.45 H), 4.89-4.96 (m, 0.55 H). ¹³C NMR (100 MHz, CDCl3): δ = 14.0, 14.1, 15.2, 17.5, 41.8, 47.8, 51.0, 51.5, 62.2, 62.4, 62.5, 81.0, 81.3, 167.0, 167.4, 169.1. Anal. Calcd for C13H21NO8 (319.308): C, 48.90; H, 6.63; N, 4.39. Found: C, 49.01; H, 6.61; N, 4.27.
Compound 6c: waxy solid. IR (neat): 1732, 1554, 1370 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 0.87 (t, 3 H, J = 7.3 Hz), 1.11-1.41 (m, 5 H), 1.61-2.40 (m, 2 H), 4.05-4.13 (m, 2 H), 4.18-4.30 (m, 1 H), 4.58-4.79 (m, 0.4 H), 4.81-4.87 (m, 0.6 H), 5.8 (d, 0.6 H, J = 8.7 Hz), 6.16 (d, 0.4 H, J = 10.6 Hz), 7.37-7.60 (m, 6 H), 7.85-8.00 (m, 4 H). ¹³C NMR (100 MHz, CDCl3): δ = 13.4, 13.6, 13.9, 14.0, 19.6, 19.8, 33.3, 34.0, 49.0, 49.2, 56.0, 56.4, 62.2, 62.3, 87.1, 88.0, 128.9, 129.1, 133.6, 134, 3, 136.0, 136.5, 169.2, 169.9, 193.5, 193.6, 193.7, 194.0. Anal. Calcd for C23H25NO6 (411.451): C, 67.14; H, 6.12; N, 3.40. Found: C, 67.81; H, 7.11; N, 3.87.

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The GLC analyses were performed with an SE-54 fused silica capillary column (25 m, 0.32 mm internal diameter), FID detector, and nitrogen as carrier gas. β-Nitroacrylates were prepared by the standard procedure. [4] Typical Procedure for the Conjugate Addition of Active Methylene 5 to β-Nitroacrylates 1: Nitroacrylate 1 (1 mmol), active methylene derivatives 5 (1 mmol), and K2CO3 (13.8 mg, 0.1 mmol) were mixed by magnetical stirring for the appropriate time (Table  [¹] , monitored by TLC). Then, the mixture was directly charged onto a chromatographic column (cyclohexane-EtOAc) allowing the pure products 6.

11

Spectroscopic Data for Representative Compounds
Compound 6a: oil. IR (neat): 1732, 1555, 1369 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 0.98 (t, 3 H, J = 7.2 Hz), 1.24 (t, 3 H, J = 7.2 Hz), 1.90-2.00 (m, 1 H), 2.12-2.22 (m, 1 H), 2.34 (s, 3 H), 2.42 (s, 3 H), 3.75 (dd, 0.6 H, J = 3.4, 11.0 Hz), 3.82 (dd, 0.4 H, J = 5.8, 8.9 Hz), 3.92 (d, 0.6 H, J = 11.0 Hz), 4.02 (d, 0.4 H, J = 8.9 Hz), 4.11-4.22 (m, 2 H), 4.48-4.53 (m, 0.4 H), 4.96-5.09 (m, 0.6 H). ¹³C NMR (100 MHz, CDCl3): δ = 10.8, 14.0, 24.5, 31.0, 46.6, 47.3, 62.3, 62.4, 66.9, 88.5, 89.9, 169.2, 169.6, 200.2, 200.6. Anal. Calcd for C12H19NO6 (273.283): C, 52.74; H, 7.01; N, 5.13. Found: C, 52.01; H, 6.81; N, 4.98.
Compound 6b: oil. IR (neat): 1738, 1557, 1370 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 1.20-1.30 (m, 9 H), 1.55 (d, 1.35 H, J = 6.8 Hz), 1.65 (d, 1.65 H, J = 6.8 Hz), 3.69 (d, 0.45 H, J = 9.4 Hz), 3.76 (dd, 0.55 H, J = 5.1, 8.1 Hz). 3.88 (d, 0.55 H, J = 7.7 Hz), 3.96 (dd, 0.45 H, J = 5.5, 9.4 Hz), 4.12-4.28 (m, 6 H), 4.74-4.81 (m, 0.45 H), 4.89-4.96 (m, 0.55 H). ¹³C NMR (100 MHz, CDCl3): δ = 14.0, 14.1, 15.2, 17.5, 41.8, 47.8, 51.0, 51.5, 62.2, 62.4, 62.5, 81.0, 81.3, 167.0, 167.4, 169.1. Anal. Calcd for C13H21NO8 (319.308): C, 48.90; H, 6.63; N, 4.39. Found: C, 49.01; H, 6.61; N, 4.27.
Compound 6c: waxy solid. IR (neat): 1732, 1554, 1370 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 0.87 (t, 3 H, J = 7.3 Hz), 1.11-1.41 (m, 5 H), 1.61-2.40 (m, 2 H), 4.05-4.13 (m, 2 H), 4.18-4.30 (m, 1 H), 4.58-4.79 (m, 0.4 H), 4.81-4.87 (m, 0.6 H), 5.8 (d, 0.6 H, J = 8.7 Hz), 6.16 (d, 0.4 H, J = 10.6 Hz), 7.37-7.60 (m, 6 H), 7.85-8.00 (m, 4 H). ¹³C NMR (100 MHz, CDCl3): δ = 13.4, 13.6, 13.9, 14.0, 19.6, 19.8, 33.3, 34.0, 49.0, 49.2, 56.0, 56.4, 62.2, 62.3, 87.1, 88.0, 128.9, 129.1, 133.6, 134, 3, 136.0, 136.5, 169.2, 169.9, 193.5, 193.6, 193.7, 194.0. Anal. Calcd for C23H25NO6 (411.451): C, 67.14; H, 6.12; N, 3.40. Found: C, 67.81; H, 7.11; N, 3.87.

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The GLC analyses were performed with an SE-54 fused silica capillary column (25 m, 0.32 mm internal diameter), FID detector, and nitrogen as carrier gas. β-Nitroacrylates were prepared by the standard procedure. [4] Typical Procedure for the Conjugate Addition of Active Methylene 5 to β-Nitroacrylates 1: Nitroacrylate 1 (1 mmol), active methylene derivatives 5 (1 mmol), and K2CO3 (13.8 mg, 0.1 mmol) were mixed by magnetical stirring for the appropriate time (Table  [¹] , monitored by TLC). Then, the mixture was directly charged onto a chromatographic column (cyclohexane-EtOAc) allowing the pure products 6.

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Scheme 1

Scheme 2