Nitroethane in Polyphosphoric Acid: A New Reagent for Acetamidation and Amination of Aromatic Compounds

Abstract

A new method of acetamidation of aromatic compounds based on their reaction with nitroethane in polyphosphoric acid has been developed. Upon the hydrolysis of acetamides during the reaction mixture workup, the corresponding amines can be obtained.

aromatic compounds - nitroethane - polyphosphoric ­acid - acetamidation - amination

References and Notes

1a Zhang Z. Yin A. Kadow JF. Meanwell NA. Wang TJ. J. Org. Chem.  2004,  69:  1360 

1b Lidocaine, In Merck Index   12th ed., Vol. 5505:  Budavari S. Merck; Rahway NJ: 1996.  p.936 

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2a Beckwith ALJ. The Chemistry of Amides   Zabicky J. Interscience; London: 1970.  p.73 

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4 PPA containing 86% P₂O₅ have been used; preparation according to: Uhlig F. Angew. Chem.  1954,  66:  435 

5

Preparation of Compounds 3a-k: General Procedure Corresponding aromatic compound 1a-j (1 mmol) and nitroethane (2a) or nitrobutane (2b, 1.1 mmol) in PPA (3-4 g) was stirred at 105-110 ˚C for 3-5 h (Table  [¹] , Scheme  [³] ). [9] Reaction mixture was poured in cold H₂O (10 mL) with intense stirring. The resulting mixture was extracted by CH₂Cl₂ (10 × 30 mL). The solution was evaporated under vacuum, and compounds 3a-i,k were purified by recrystallization. Compound 5j was purified by flash chromatography on silica gel, eluting with toluene-EtOAc.
N -(4-Hydroxyphenyl)acetamide (3a)
Mp 168-170 ˚C (H₂O); lit. [¹0] mp 168-169.5 ˚C. ^¹H NMR (300 DMSO-d ₆): δ = 1.97 (3 H, s, COMe), 6.67 (2 H, d, J = 8.7 Hz, H-3/5), 7.32 (2 H, d, J = 8.7 Hz, H-2/6), 9.15 (1 H, br s, OH), 9.66 (1 H, br s, NH). IR (KBr): ν_max = 3376, 3185 (OH, NH), 1664 (CONH), 1596 (CONH) cm^-¹. Anal. Calcd (%) for C₈H₉NO₂: C, 63.57; H, 6.00; N, 9.27. Found: C, 63.76; H, 5.92; N, 9.21.
N -(4-Methoxyphenyl)acetamide (3b)
Mp 130-132 ˚C (H₂O); lit. [²d] mp 130-132 ˚C. ^¹H NMR (300 MHz, DMSO-d ₆): δ = 2.00 (3 H, s, COMe), 3.70 (3 H, s, OMe), 6.85 (2 H, d, J = 9.0 Hz, H-3/5), 7.47 (2 H, d, J = 9.0 Hz, H-2/6), 9.79 (1 H, br s, NH). IR (KBr): ν_max = 3240 (NH), 1644 (CONH), 1606 (CONH) cm^-¹. Anal. Calcd (%) for C₉H₁₁NO₂: C, 65.44; H, 6.71; N, 8.48. Found: C, 65.56; H, 6.68; N, 8.42.
N -(2,5-Dimethoxyphenyl)acetamide (3c)
Mp 91-92 ˚C (H₂O); lit. [¹¹] mp 91. ^¹H NMR (300 MHz, acetone-d ₆): δ = 2.11 (3 H, s, COMe), 3.78 (3 H, s, OMe), 3.82 (3 H, s, OMe), 6.48 (1 H, dd, J = 8.2, 3.6 Hz, H-4), 6.84 (1 H, d, J = 8.2 Hz, H-3), 7.99 (1 H, d, J = 3.6 Hz, H-6), 8.89 (1 H, br s, NH). IR (KBr): ν_max = 3284 (NH), 1658 (CONH), 1604 (CONH) cm^-¹. Anal. Calcd (%) for C₁₀H₁₃NO₃: C, 61.53; H, 6.71; N, 7.17. Found: C, 61.69; H, 6.61; N, 7.03.
N -(3,4-Dimethoxyphenyl)acetamide (3d)
Mp 129-131 ˚C (H₂O); lit. [¹²] mp 130-131 ˚C. ^¹H NMR (300 MHz, CDCl₃): δ = 2.15 (3 H, s, COMe), 3.84 (3 H, s, OMe), 3.86 (3 H, s, OMe), 6.77 (1 H, d, J = 8.6 Hz, H-5), 6.89 (1 H, dd, J = 8.6, 2.4 Hz, H-6), 7.30 (1 H, d, J = 2.4 Hz, H-2), 7.55 (1 H, br s, NH). IR (KBr): ν_max = 3276 (NH), 1653 (CONH), 1606 (CONH) cm^-¹. Anal. Calcd (%) for C₁₀H₁₃NO₃: C, 61.53; H, 6.71; N, 7.17. Found: C, 61.65; H, 6.64; N, 7.09.
N -Phenylacetamide (3e)
Mp 113-115 ˚C (H₂O); lit. [¹¹] mp 113.5-114.5 ˚C. ^¹H NMR (300 MHz, DMSO-d ₆): δ = 2.04 (3 H, s, COMe), 7.01 (1 H, dt, J = 7.5, 1.2 Hz, H-4), 7.28 (2 H, dd, J = 8.4, 7.5 Hz, H-3/5), 7.58 (2 H, dd, J = 8.4, 1.2 Hz, H-2/6), 9.94 (1 H, br s, NH). IR (KBr): ν_max = 3296 (NH), 1662 (CONH), 1600 (CONH) cm^-¹. Anal. Calcd (%) for C₈H₉NO: C, 71.09; H, 6.71; N, 10.36. Found: C, 71.26; H, 6.63; N, 10.28.
N -(4-Methylphenyl)acetamide (3f)
Mp 147-148 ˚C (H₂O); lit. [¹¹] mp 147-148.5 ˚C. ^¹H NMR (300 MHz, DMSO-d ₆): δ = 2.01 (3 H, s, COMe), 2.23 (3 H, s, Me), 7.08 (2 H, d, J = 8.1 Hz, H-3/5), 7.45 (2 H, d, J = 8.1 Hz, H-2/6), 9.84 (1 H, br s, NH). IR (KBr): ν_max = 3300 (NH), 1664 (CONH), 1604 (CONH) cm^-¹. Anal. Calcd (%) for C₉H₁₁NO: C, 72.46; H, 7.43; N, 9.39. Found: C, 72.65; H, 7.37; N, 9.31.
N -(3,4-Dimethylphenyl)acetamide (3g)
Mp 94-96 ˚C (H₂O); lit. [¹³] mp 94-95 ˚C. ^¹H NMR (300 MHz, DMSO-d ₆): δ = 2.05 (3 H, s, COMe), 2.26 (6 H, s, Me), 6.97 (1 H, dd, J = 8.1, 2.0 Hz, H-6), 7.04 (1 H, d, J = 2.0 Hz, H-2), 7.21 (1 H, d, J = 8.1 Hz, H-5), 9.73 (1 H, br s, NH). IR (KBr): ν_max = 3300 (NH), 1660 (CONH), 1601 (CONH) cm^-¹. Anal. Calcd (%) for C₁₀H₁₃NO: C, 73.59; H, 8.03; N, 8.58. Found: C, 73.72; H, 7.96; N, 8.49.
N -(4-Methoxyphenyl)butyramide (3h)
Mp 88-90 ˚C (EtOH). ^¹H NMR (300 MHz, DMSO-d ₆): δ = 0.84 (3 H, t, J = 7.5 Hz, Me), 1.61 (2 H, m, CH₂), 2.08 (2 H, t, J = 6.7 Hz, CH₂), 3.72 (3 H, s, OMe), 6.82 (2 H, d, J = 8.9 Hz, H-3/5), 7.46 (2 H, d, J = 8.9 Hz, H-2/6), 9.72 (1 H, br s, NH). IR (KBr): ν_max = 3265 (NH), 1656 (CONH), 1604 (CONH) cm^-¹. Anal. Calcd (%) for C₁₁H₁₅NO₂: C, 68.37; H, 7.82; N, 7.25. Found: C, 68.52; H, 7.77; N, 7.18.
N -(9-Anthracenyl)acetamide (3i)
Mp 276-278 ˚C (EtOH); lit. [¹4] mp 277 ˚C. For spectral data, see ref. 15.
N -(3-Indolyl)acetamide (3j)
Mp 162-163 ˚C (EtOH-H₂O); lit. [¹5] mp 162-163 ˚C. ^¹H NMR (300 MHz, acetone-d ₆): δ = 2.17 (3 H, s, COMe), 7.01 (1 H, m, ArH), 7.12 (1 H, m, ArH), 7.38 (1 H, d, J = 8.3 Hz, ArH), 7.74 (1 H, d, J = 8.1 Hz, ArH), 7.89 (1 H, d, J = 2.4 Hz, ArH), 9.32 (1 H, br s, NH), 10.06 (1 H, br s, NH). IR (KBr): ν_max = 3306 (NH), 1661 (CONH), 1603 (CONH) cm^-¹. Anal. Calcd (%) for C₁₀H₁₀N₂O: C, 68.95; H, 5.79; N, 16.08. Found: C, 69.12; H, 5.71; N, 15.99.
6 (7)-Acetoaminoperimidine (3k)
Mp 225-226 ˚C (EtOAc); lit. [¹6] mp 225-226 ˚C. For spectral data, see ref. 17.

See references in:

6a Berrocal MV. Gil MV. Roman E. Serrano JA. Tetrahedron  2002,  58:  5327 

6b White EH. Considine WJ. J. Am. Chem. Soc.  1958,  80:  626 

6c Cherest M. Lusinchi X. Tetrahedron  1986,  42:  3825 

6d Rank W. Baer H. Can. J. Chem.  1971,  49:  3236 

7 Ohwada T. Yamagata N. Shudo K. J. Am. Chem. Soc.  1991,  113:  1364 

8

Preparation of Compounds 6a-d: General Procedure Corresponding aromatic compound 3a-d (1 mmol) and nitroethane (2a, 0.083 g, 1.1 mmol) in PPA (3-4 g) was stirred at 105-110 ˚C for 3-5 h (Table  [¹] ). Reaction mixture was poured in H₂O (30 mL) with intense stirring, then boiled under reflux for 2 h. The resulting mixture was extracted by CH₂Cl₂ (3 × 50 mL). The aqueous layer was made alkaline with ammonia to pH 8-9, the precipitate after cooling (crystals or oil) was extracted by CH₂Cl₂ (10 × 30 mL). The solution was evaporated under vacuum and purified by crystallization (compounds 6a,b were purified by their hydrochlorides’ crystallization from ethanol).
4-Aminophenol (6a)
Mp 188-190 ˚C (alcohol-H₂O); lit. [¹7] mp 187-190 ˚C. Anal. Calcd (%) for C₆H₇NO: C, 66.04; H, 6.47; N, 12.84. Found: C, 66.23; H, 6.44; N, 12.76 (HCl); mp 303-305 ˚C (alcohol; with sublimation). ^¹H NMR (300 MHz, DMSO-d ₆): δ = 6.87 (d, J = 8.9 Hz, 2 H, H-3/5), 7.21 (d, J = 8.9 Hz, 2 H, H-2/6), 9.88 (br s, 1 H, OH); 10.19 (br s, 3 H, NH₃).
4-Anisidine (6b)
Mp 57-59 ˚C; lit. [¹8] mp 56-59 ˚C. Anal. Calcd (%) for C₇H₉NO: C, 68.27; H, 7.37; N, 11.37. Found: C, 68.44; H, 7.30; N, 11.31 (HCl); mp 217-220 ˚C (alcohol; with sublimation). ^¹H NMR (300 MHz, DMSO-d ₆): δ = 3.71 (s, 3 H, Me), 7.0 (d, J = 8.8 Hz, 2 H, H-3/5), 7.35 (d, J = 8.8 Hz, 2 H, H-2/6), 10.44 (br s, 3 H, NH₃).
2,5-Dimethoxyaniline (6c)
Mp 80-81 ˚C (PE); lit. [¹9] mp 80 ˚C. ^¹H NMR (300 MHz, CDCl₃): δ = 3.71 (s, 3 H, OMe), 3.76 (br s, 2 H, NH₂), 3.78 (s, 3 H, OMe), 6.24 (dd, J = 8.7, 2.8 Hz, 1 H, H-4), 6.31 (d, J = 2.8 Hz, 1 H, H-6), 6.67 (d, J = 8.7 Hz, 1 H, H-3). Anal. Calcd (%) for C₈H₁₁NO₂: C, 62.73; H, 7.24; N, 9.14. Found: C, 62.90; H, 7.18; N, 9.05.
3,4-Dimethoxyaniline (6d)
Mp 85-87 ˚C (PE); lit. [²0] mp 86 ˚C. ^¹H NMR (300 MHz, CDCl₃): δ = 3.44 (br s, 2 H, NH₂), 3.79 (s, 3 H, OMe), 3.82 (s, 3 H, OMe), 6.15 (d, J = 2.1 Hz, 1 H, H-2), 6.31 (dd, J = 6.0, 2.1 Hz 1 H, H-6), 6.70 (d, J = 6.0 Hz, 1 H, H-5). Anal. Calcd (%) for C₈H₁₁NO₂: C, 62.73; H, 7.24; N, 9.14. Found: C, 62.86; H, 7.19; N, 9.02.

9

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