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Synlett 2009(6): 965-967  
DOI: 10.1055/s-0028-1088197
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

β-Nitroacrylates as Key Starting Materials for the Uncatalysed One-Pot Synthesis of Polyfunctionalized Dihydroquinoxalinone Derivatives, via an anti-Michael Reaction

Roberto Ballini*, Serena Gabrielli, Alessandro Palmieri
‘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 16 December 2008
Publication Date:
16 March 2009 (online)

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Abstract

The reaction of o-phenylenediamine with β-nitroacrylates allows the in situ preparation of dihydroquinoxalinones, via an anti-Michael reaction, under uncatalysed reaction conditions.

Key words

β-nitroacrylates - anti-Michael reaction - uncatalysed - quinoxalinones

Quinoxalinone derivatives represent an important class of nitrogen-containing heterocycles as they are useful intermediates in organic synthesis. [¹] They have received considerable interest from the pharmaceutical industry because they are useful templates for drug development due to their structural relationship to benzodiazepines. [²] In addition, quinoxalinones exhibit a wide variety of biological activity, including antidiabetic [³] and antiviral effects, in particular against retroviruses such as HIV. [4] They also are inhibitors of aldose reductase, [5] partial agonists of the γ-aminobutyric acid (GASBA)-benzodiazepine receptor complex, [6] and antagonists of the AMPA and angiotensis II receptors. [7] Related 3,4-dihydroquinoxalines also possess biological activity, for example, as inhibitors of cholesteryl ester transfer proteins. [8] Quinoxalinones have been identified as desirable scaffolds for diversity-oriented synthesis as they may be assembled in a modular fashion on solid-phase media. [9]

Despite the importance of these heterocycles, their synthetic routes are limited, and the main strategies are based on nucleophilic aromatic substitution of o-halonitrobenzene, followed by cyclization of the obtained o-nitro­amine, [¹0] or the reaction of o-phenylenediamines with different substrates such as acetylenedicraboxylates, [¹¹] α-bromoesters, [¹²] anisylidine pyruvic acid, [¹³] and 2,3-epoxyaldehydes. [¹4]

β-Nitroacrylates are an emerging class of functionalized electron-poor alkenes since they can be converted into other important intermediates [¹5] or employed as Michael acceptors with indoles, [¹6] amines, [¹7] and β-dicarbonyl derivatives. [¹8]

The synthetic utility of β-nitroacrylates is due to the simultaneous presence of two different electron-withdrawing groups, in α- and β-positions on a double bond.

During our studies devoted to explore the chemical potential of β-nitroacrylates we discovered an innovative ­procedure for the synthesis of polyfunctionalised dihydroquinoxalinone derivatives in one-pot under uncatalysed reaction conditions. Thus, the reaction of o-phenylenediamine (1) with β-nitroacrylates 2 allows the anti-Michael adducts 3 that, in situ, convert to the target dihydroquinoxalinones 4 (Scheme  [¹] ).

Scheme 1

In order to optimize the reaction conditions, we first examined, as a representative conversion, the preparation of compound 4c starting from the o-phenylenediamine with the β-nitroacrylate 2c. As reported in Table  [¹] , the best yield was obtained after two hours at room temperature, using 1.25 equivalents of diamine and ethyl acetate as solvent.

Table 1 Optimization of the Reaction

1 (equiv) Solvent Yield of 4c (%)a
1.0 EtOAc 59
1.25 EtOAc 84
1.5 EtOAc 78
1.25 CH2Cl2 68
1.25 toluene 60
a Yield of pure isolated product.

Use of an excess of diamine reduces the formation of byproducts. Use of one equivalent of diamine results in formation of the target dihydroquinoxalinone 4c accompanied by a moderate amount of the bisadduct 5 (Figure  [¹] ). Thus, the formation of 5 can be minimized by employing a slight excess of diamine.

Figure 1

Finally, with the intent to test the generality of our method, we examined a variety of β-nitroacrylates obtaining good to excellent yields (70-90%) of 4 (Table  [²] ).

Table 2 Preparation of Dihydroquinoxalinones 4a-j

Entry R Yield of 4 (%)a drb
 1 Me 83 65:35
 2 Et 79 73:27
 3 Pr 84 70:30
 4 MeO(O)C(CH2)4 80 50:50
 5 BnCH2 82 65:35
 6 Me(OCH2CH2O)CCH2 85 75:25
 7 CH2=CH(CH2)8 70 50:50
 8 NºC(CH2)4 90 70:30
 9 Me(CH2)6 71 65:35
10 Me2CHCH2CH2 82 60:40
a Yield of pure isolated product.
b The dr was evaluated by ¹H NMR spectroscopy.

A particular behaviour was observed with β-nitroacrylate 2k (R = Ph), since the crude product 4k (obtained after 1 h, Scheme  [²] ) was unstable during the purification step (chromatography), giving the quinoxalin-2(1H)-one 7 (confirmed by NMR spectroscopy). The probable mechanism (Scheme  [²] ) consists of an intramolecular deprotonation of 4k and simultaneous cleavage of C-C bond in 4- and 3-positions, respectively, affording 6 and the nitronic acid 7 (stabilized by the high conjugation with the aromatic system), that tautomerises into the more stable phenyl­nitromethane 8 (detected by GC and TLC).

Scheme 2

In conclusion, we have discovered an novel procedure for the synthesis compounds 4, that can be considered as a new important class of dihydroquinoxalinone derivative due to the presence of other important functionalities, such as ether, nitrile, ketal, and nitro, that can be preserved under the mild reaction conditions. Of particular interest is the presence of a valuable functionality such as the secondary nitro group that can be converted into an array of other functionalities, [¹9] or can be employed to stabilise a carbanion for the generation of new C-C bonds. [¹9c] [²0]

Acknowledgment

The authors thank the University of Camerino and MIUR-Italy ­(National Project ‘Sintesi organiche ecosostenibili da nuovi sistemi catalitici‘) for financial support.

21

Typical Procedure for the Conjugate Addition of Active Methylene 5 to β-Nitroacrylates 1 β-Nitroacrylate 2 (1 mmol) and o-phenylenediamine 1 (1.25 mmol) were dissolved in EtOAc (2 mL) and mixed at r.t., with magnetic stirring, for 2 h. Then, acetone (2 mL, in order to increase the solubility of 4) and 0.8 g of SiO2 (Silica Gel 60, 0,040-0,063 mm, 230-400 mesh ASTM, Merck), were added and the mixture was stirred for 5 min. Finally, the solvent was removed under vacuum and the crude product (adsorbed on SiO2) was charged onto a chromatography column (cyclohexane-EtOAc) allowing the pure products 4. Spectroscopic Data for Representative Compounds
Compound 4b (diastereomeric mixture): yellow solid. IR (KBr): ν = 1362, 1546, 1686, 3049, 3414 cm-¹. ¹H NMR (400 MHz, acetone): δ = 0.95 (t, 3 H, J = 7.3 Hz), 1.88-2.02 (m, 1 H), 2.07-2.25 (m, 1 H), 4.39 (dd, 0.27 H, J = 3.4, 6.8 Hz), 4.62 (dd, 0.73 H, J = 2.6, 4.3 Hz), 4.76-4.84 (m, 0.27 H), 4.88-4.97 (m, 0.73 H), 5.68 (br s, 0.73 H), 5.81 (br s, 0.27 H), 6.66-6.76 (m, 1 H), 6.79-6.92 (m, 3 H), 9.65 (br s, 1 H). ¹³C NMR (100 MHz, acetone): δ = 10.6, 10.8, 23.1, 24.1, 59.4, 59.8, 90.3, 91.5, 114.9, 115.6, 116.0, 116.1, 119.8, 119.9, 124.4, 124.5, 126.0, 126.3, 132.7, 133.4, 163.6, 164.2. API-ES: m/z = 258.2 [M + Na+]. Anal. Calcd for C1 1H13N3O3 (235.24): C, 56.16; H, 5.57; N, 17.86. Found: C, 56.44; H, 5.71; N, 17.71.
Compound 4d (diastereomeric mixture): yellow solid. IR (KBr): ν = 1363, 1544, 1677, 1735, 3067, 3397 cm-¹. ¹H NMR (400 MHz, acetone): δ = 1.26-1.48 (m, 2 H), 1.51-1.70 (m, 2 H), 1.86-2.02 (m, 1 H), 2.07-2.25 (m, 1 H), 2.26-2.35 (m, 2 H), 3.58 (s, 1.5 H), 3.59 (s, 1.5 H), 4.41 (dd, 0.5 H, J = 3.0, 6.8 Hz), 4.64 (dd, 0.5 H, J = 2.6, 4.3 Hz), 4.85-4.93 (m, 0.5 H), 4.99-5.06 (m, 0.5 H), 5.67 (br s, 0.5 H), 5.82 (br s, 0.5 H), 6.67-6.74 (m, 1 H), 6.78-6.91 (m, 3 H), 9.64 (br s, 1 H). ¹³C NMR (100 MHz, acetone): δ = 24.9, 25.0, 26.0, 26.1, 29.4, 30.3, 33.8, 33.9, 51.6, 59.4, 59.9, 88.7, 89.7, 114.9, 115.5, 116.0, 116.1, 119.8, 119.9, 124.3, 124.4, 126.0, 126.2, 132.6, 133.4, 163.7, 164.1, 173.8, 173.9.
API-ES: m/z = 344.4 [M + Na+]. Anal. Calcd for C15H19N3O5 (321.33): C, 56.07; H, 5.96; N, 13.08. Found: C, 56.38; H, 6.18; N, 12.81.
Compound 4e (diastereomeric mixture): yellow solid. IR (KBr): ν = 1361, 1544, 1679, 3059, 3397 cm-¹. ¹H NMR (400 MHz, acetone): δ = 2.18-2.32 (m, 1 H), 2.40-2.55 (m, 1 H), 2.59-2.74 (m, 2 H), 4.49 (dd, 0.35 H, J = 3.0, 6.8 Hz), 4.66 (dd, 0.65 H, J = 2.6, 4.3 Hz), 4.91-4.98 (m, 0.35 H), 4.99-5.05 (m, 0.65 H), 5.74 (br s, 0.65 H), 5.86 (br s, 0.35 H), 6.65-6.73 (m, 1 H), 6.78-6.90 (m, 3 H), 7.11-7.32 (m, 5 H), 9.67 (br s, 1 H). ¹³C NMR (100 MHz, acetone): δ = 31.6, 32.5, 32.6, 32.7, 59.6, 60.0, 88.1, 89.5, 114.9, 115.4, 116.0, 116.1, 119.8, 119.9, 124.4, 124.5, 125.9, 126.1, 127.1, 129.2, 129.3, 129.4, 129.5, 132.6, 133.2, 141.1, 141.3, 163.7, 164.0. API-ES: m/z = 334.4 [M + Na+]. Anal. Calcd for C17H17N3O3 (311.34): C, 65.58; H, 5.50; N, 13.50. Found: C, 65.84; H, 5.73; N, 13.23.
Compound 4f (diastereomeric mixture): yellow solid. IR (KBr): ν = 1040, 1376, 1553, 1683, 3051, 3389 cm-¹. ¹H NMR (400 MHz, acetone): δ = 1.21-1.26 (m, 3 H), 2.21 (dd, 0.75 H, J = 1.7, 15.4 Hz), 2.38 (dd, 0.25 H, J = 2.6, 15.4 Hz), 2.64-2.79 (m, 1 H), 3.71-3.96 (m, 4 H), 4.33 (dd, 0.25 H, J = 3.0, 7.3 Hz), 4.50 (dd, 0.75 H, J = 2.6, 4.3 Hz), 4.89-4.96 (m, 0.25 H), 5.06-5.13 (m, 0.75 H), 5.66 (br s, 0.75 H), 5.82 (br s, 0.25 H), 6.67-6.76 (m, 1 H), 6.79-6.91 (m, 3 H), 9.67 (br s, 1 H). ¹³C NMR (100 MHz, acetone): δ = 24.3, 24.4, 38.4, 39.0, 60.1, 60.3, 65.4, 65.5, 84.1, 85.7, 108.5, 114.9, 115.7, 115.9, 116.0, 116.1, 119.8, 119.9, 124.4, 124.5, 125.9, 126.0, 132.4, 132.9, 163.4, 163.5. API-ES: m/z = 330.4 [M + Na+ ]. Anal. Calcd for C14H17N3O5 (307.30): C, 54.72; H, 5.58; N, 13.67. Found: C, 54.36; H, 5.31; N, 13.83.

21

Typical Procedure for the Conjugate Addition of Active Methylene 5 to β-Nitroacrylates 1 β-Nitroacrylate 2 (1 mmol) and o-phenylenediamine 1 (1.25 mmol) were dissolved in EtOAc (2 mL) and mixed at r.t., with magnetic stirring, for 2 h. Then, acetone (2 mL, in order to increase the solubility of 4) and 0.8 g of SiO2 (Silica Gel 60, 0,040-0,063 mm, 230-400 mesh ASTM, Merck), were added and the mixture was stirred for 5 min. Finally, the solvent was removed under vacuum and the crude product (adsorbed on SiO2) was charged onto a chromatography column (cyclohexane-EtOAc) allowing the pure products 4. Spectroscopic Data for Representative Compounds
Compound 4b (diastereomeric mixture): yellow solid. IR (KBr): ν = 1362, 1546, 1686, 3049, 3414 cm-¹. ¹H NMR (400 MHz, acetone): δ = 0.95 (t, 3 H, J = 7.3 Hz), 1.88-2.02 (m, 1 H), 2.07-2.25 (m, 1 H), 4.39 (dd, 0.27 H, J = 3.4, 6.8 Hz), 4.62 (dd, 0.73 H, J = 2.6, 4.3 Hz), 4.76-4.84 (m, 0.27 H), 4.88-4.97 (m, 0.73 H), 5.68 (br s, 0.73 H), 5.81 (br s, 0.27 H), 6.66-6.76 (m, 1 H), 6.79-6.92 (m, 3 H), 9.65 (br s, 1 H). ¹³C NMR (100 MHz, acetone): δ = 10.6, 10.8, 23.1, 24.1, 59.4, 59.8, 90.3, 91.5, 114.9, 115.6, 116.0, 116.1, 119.8, 119.9, 124.4, 124.5, 126.0, 126.3, 132.7, 133.4, 163.6, 164.2. API-ES: m/z = 258.2 [M + Na+]. Anal. Calcd for C1 1H13N3O3 (235.24): C, 56.16; H, 5.57; N, 17.86. Found: C, 56.44; H, 5.71; N, 17.71.
Compound 4d (diastereomeric mixture): yellow solid. IR (KBr): ν = 1363, 1544, 1677, 1735, 3067, 3397 cm-¹. ¹H NMR (400 MHz, acetone): δ = 1.26-1.48 (m, 2 H), 1.51-1.70 (m, 2 H), 1.86-2.02 (m, 1 H), 2.07-2.25 (m, 1 H), 2.26-2.35 (m, 2 H), 3.58 (s, 1.5 H), 3.59 (s, 1.5 H), 4.41 (dd, 0.5 H, J = 3.0, 6.8 Hz), 4.64 (dd, 0.5 H, J = 2.6, 4.3 Hz), 4.85-4.93 (m, 0.5 H), 4.99-5.06 (m, 0.5 H), 5.67 (br s, 0.5 H), 5.82 (br s, 0.5 H), 6.67-6.74 (m, 1 H), 6.78-6.91 (m, 3 H), 9.64 (br s, 1 H). ¹³C NMR (100 MHz, acetone): δ = 24.9, 25.0, 26.0, 26.1, 29.4, 30.3, 33.8, 33.9, 51.6, 59.4, 59.9, 88.7, 89.7, 114.9, 115.5, 116.0, 116.1, 119.8, 119.9, 124.3, 124.4, 126.0, 126.2, 132.6, 133.4, 163.7, 164.1, 173.8, 173.9.
API-ES: m/z = 344.4 [M + Na+]. Anal. Calcd for C15H19N3O5 (321.33): C, 56.07; H, 5.96; N, 13.08. Found: C, 56.38; H, 6.18; N, 12.81.
Compound 4e (diastereomeric mixture): yellow solid. IR (KBr): ν = 1361, 1544, 1679, 3059, 3397 cm-¹. ¹H NMR (400 MHz, acetone): δ = 2.18-2.32 (m, 1 H), 2.40-2.55 (m, 1 H), 2.59-2.74 (m, 2 H), 4.49 (dd, 0.35 H, J = 3.0, 6.8 Hz), 4.66 (dd, 0.65 H, J = 2.6, 4.3 Hz), 4.91-4.98 (m, 0.35 H), 4.99-5.05 (m, 0.65 H), 5.74 (br s, 0.65 H), 5.86 (br s, 0.35 H), 6.65-6.73 (m, 1 H), 6.78-6.90 (m, 3 H), 7.11-7.32 (m, 5 H), 9.67 (br s, 1 H). ¹³C NMR (100 MHz, acetone): δ = 31.6, 32.5, 32.6, 32.7, 59.6, 60.0, 88.1, 89.5, 114.9, 115.4, 116.0, 116.1, 119.8, 119.9, 124.4, 124.5, 125.9, 126.1, 127.1, 129.2, 129.3, 129.4, 129.5, 132.6, 133.2, 141.1, 141.3, 163.7, 164.0. API-ES: m/z = 334.4 [M + Na+]. Anal. Calcd for C17H17N3O3 (311.34): C, 65.58; H, 5.50; N, 13.50. Found: C, 65.84; H, 5.73; N, 13.23.
Compound 4f (diastereomeric mixture): yellow solid. IR (KBr): ν = 1040, 1376, 1553, 1683, 3051, 3389 cm-¹. ¹H NMR (400 MHz, acetone): δ = 1.21-1.26 (m, 3 H), 2.21 (dd, 0.75 H, J = 1.7, 15.4 Hz), 2.38 (dd, 0.25 H, J = 2.6, 15.4 Hz), 2.64-2.79 (m, 1 H), 3.71-3.96 (m, 4 H), 4.33 (dd, 0.25 H, J = 3.0, 7.3 Hz), 4.50 (dd, 0.75 H, J = 2.6, 4.3 Hz), 4.89-4.96 (m, 0.25 H), 5.06-5.13 (m, 0.75 H), 5.66 (br s, 0.75 H), 5.82 (br s, 0.25 H), 6.67-6.76 (m, 1 H), 6.79-6.91 (m, 3 H), 9.67 (br s, 1 H). ¹³C NMR (100 MHz, acetone): δ = 24.3, 24.4, 38.4, 39.0, 60.1, 60.3, 65.4, 65.5, 84.1, 85.7, 108.5, 114.9, 115.7, 115.9, 116.0, 116.1, 119.8, 119.9, 124.4, 124.5, 125.9, 126.0, 132.4, 132.9, 163.4, 163.5. API-ES: m/z = 330.4 [M + Na+ ]. Anal. Calcd for C14H17N3O5 (307.30): C, 54.72; H, 5.58; N, 13.67. Found: C, 54.36; H, 5.31; N, 13.83.

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Scheme 1

Figure 1

Scheme 2