Pyrolytic Methods in Organic Synthesis: Novel Routes for the Synthesis of 3-Oxoalkanenitriles, 2-Acyl Anilines, and 2-Aroyl Anilines

Abstract

3-Oxoalkanenitriles 1a-d were obtained in high yield by treating enaminones 6a-d with hydroxylamine hydrochloride and stirring the resulting oxime with diethyl oxalate. The formed 3-oxoalkanenitriles 1a,b readily undergo self-condensation to yield 2-aroylanilines 3a,b on heating in pyridine for eight hours or by irradiation in microwave for 1.5 minutes. In contrast, 1c-e were recovered unreacted under similar conditions. Pyrolysis of 3-aminocrotononitrile 14 produced a mixture of the aminopyridine 16, 19, and aminobenzene 22. Heating 14 in aqueous media has resulted in formation of the pyridine 20, while heating the same compound in acetic acid has afforded pyridone 20 and acetyl pyridine 24.

microwave heating - aminoacetophenone derivative - HMBC ¹⁵N NMR

References and Notes

1

Al-Awadi, N.; Abdelhamid, I. A.; Al-Etaibi, A.; Elnagdi, M. H. Synlett, accepted for publication.

2 Al-Awadi NA. George BJ. Dib HH. Ibrahim MR. Ibrahim YA. El-Dusouqui OM. Tetrahedron  2005,  61:  8257 

3 Al-Awadi H. Ibrahim MR. Dib HH. Al-Awadi NA. Ibrahim AI. Tetrahedron  2005,  61:  10507 

4 Al-Awadi NA. Elnagdi MH. Ibrahim YA. Kaul K. Kumar A. Tetrahedron  2001,  57:  1609 

5 Al-Awadi SA. Abdallah MR. Dib HH. Ibrahim MR. Al-Awadi NA. El-Dusouqui OME. Tetrahedron  2005,  61:  5769 

6 El-Dusouqui OME. Abdelkhalik MM. Al-Awadi NA. Dib HH. George BJ. Elnagdi MH. J. Chem. Res.  2006,  295 

7 Al-Awadi NA. Ibrahim YA. Patel M. George BJ. Al-Etiabi AM. Int. J. Chem. Kinet.  2007,  39:  59 

8 Al-Awadi NA. Ibrahim Y. Kaul K. Dib H. J. Phys. Org. Chem.  2001,  14:  521 

9 Elgemeie GEH. Elfahham HA. Elnagdi MH. Heterocycles  1985,  23:  1999 

10 Al-Omran F. El-Khair AA. Elnagdi MH. Org. Prep. Proced. Int.  1998,  30:  211 

11 Abdelrazek FM. Michael FA. J. Heterocycl. Chem.  2006,  43:  7 

12

Microwave heating was carried out with a single-mode cavity explorer microwave synthesizer, CEM Corporation, NC, USA.

13 Microwaves in Organic Synthesis   Loupy A. Wiley-VCH; Weinheim: 2002. 

14a Kappe CO. Angew. Chem.  2004,  116:  6408 

14b Kappe CO. Angew. Chem.  2004,  43:  6250 

15

NMR spectra were measured using a Bruker DPX 400 MHz superconducting spectrometer, ¹HMBC-¹⁵N and NOE spectra were measured using Bruker Avance II 600 MHz superconducting spectrometer, and FT-IR measurements were performed with a Perkin Elmer 2000 FT-IR system. Mass spectrometric analysis was carried out on a VG-Autospec-Q high performance tri-sector GC/MS/MS.

16

General Method for Preparation of Compounds 3a,bMethod A: Arylacetonitrile (10 mmol) was refluxed in pyridine (20 mL) for 8 h. The solvent was evaporated under vacuum, and the solid product was collected by filtration and crystallized from DMF-EtOH.
Method B: Arylacetonitrile 1a in pyridine (2 mL) was heated alone for 1.5 min in a microwave oven, the reaction mixture was then poured on cold H₂O. The so-formed solid product was collected by filtration and crystallized from EtOH-DMF.
5′-Amino-6′-benzoyl-[1,1′;3′,1′′]terphenyl-2′,4′-dicarbonitrile (3a)
Yield 78%; mp 295 °C. MS: m/z (%) = 399(40). IR: 3437 and 3175 (NH₂), 2224 and 2199 (2 CN), 1654 (CO) cm^-1. ¹H NMR (400 MHz, DMSO): δ = 7.52-7.83 (m, 15 H, PhH), 8.01 (br s, 2 H, NH₂). ¹³C NMR (100 MHz, DMSO): δ = 80.0, 100.7, 116.5, 118.2, 119.5, 128.5, 128.6, 128.9, 129, 129.2, 129.6, 130.7, 131.8, 132.0, 133.4,135.9, 137.6, 155.3, 155.8, 157.0, 186.7.

17 Elnagdi MH. Elmoghayer MRH. Elgemeie GEH. Synthesis  1984,  1 

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20 Al-Omran F. Abdelkhalik MM. El-Khair AA. Elnagdi MH. Synthesis  91, 

21

General Method for Preparation of Compounds 7 A mixture of each of the enaminones 6 (10 mmol), NH₂OH·HCl (20 mmol), and NaOAc (20 mmol) was stirred in EtOH-H₂O mixture for 2 h at r.t. The reaction mixture was then poured on cold H₂O. The so-formed solid product was collected by filtration and crystallized from EtOH.
3-Oxo-3-thiophen-2-yl-propionaldehyde Oxime (7c) Yield 78%; mp 118-120 °C. MS: m/z 169. IR: 3197 (OH), 1653 (CO) cm^-1. ¹H NMR (400 MHz, DMSO): δ = 3.92 (d, 2 H, CH₂), 4.02 (d, 2 H, CH₂), 7.00 (t, 1 H, vinyl-H), 7.26 (dd, 1 H, thiophene H4), 7.50 (t, 1 H, vinyl-H), 8.03 (d, 1 H, thiophene-H3), 8.05 (d, 1 H, thiophene-H5). ¹³C NMR (100 MHz, DMSO): δ = 36.03, 36.2, 50.5, 52.3, 125.9, 127.02, 127.7, 129.7, 134.8, 135.1, 136.1, 136.2, 143.9, 144.02, 145.3, 148.7, 189.6, 190.5.

22

General Procedures for Preparation of 1a-d
A mixture of each of the oximes 7 (10 mmol), diethyloxalate (10 mmol), and NaH (20 mmol) in dioxane (5 mL) was stirred for 2 h at r.t. The reaction mixture was then evaporated and triturated with EtOH. The so-formed solid product was collected by filtration and crystallized from EtOH.

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24 Gilchrist TL. Heterocyclic Chemistry   3rd ed.:  Prentice Hall; New York: 1997.  p.205 

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27 Von Meyer E. J. Prakt. Chem.  1895,  52:  89 

28

General Method for Preparation of Compounds 14, 17, 18, and 20
3-Aminocrotononitrile (10 mmol) was refluxed in pyridine (20 mL) for 8 h. The solvent was evaporated under vacuum, and the solid product was collected by filtration. The mixture of the three compounds was separated by means of column chromatography on silica gel with EtOAc-PE (1:4) as eluent.
4-Amino-2,6-dimethylnicotinonitrile (14)
Yield 30%; mp 313 °C. MS: m/z = 148. IR: 3367, 3358 (NH₂), 2211 (CN) cm^-1. ¹H NMR (400 MHz, DMSO): δ = 2.42 (s, 3 H, CH₃), 2.60 (s, 3 H, CH₃), 7.65 (s, 1 H, vinyl-H), 10.62 (s, 2 H, NH₂). ¹³C NMR (100 MHz, DMSO): δ = 20.8, 23.6, 101.5, 110.5, 117.5, 152.4, 155.0, 161.2.
6-Amino-2,4-dimethylnicotinonitrile (17)
Yield 32%; mp 230 °C. MS: m/z = 148. IR: 3391, 3336 (NH₂), 2212 (CN) cm^-1. ¹H NMR (400 MHz, DMSO): δ = 2.23 (s, 3 H, CH₃), 2.38 (s, 3 H, CH₃), 6.20 (s, 1 H, vinyl-H), 6.82 (br, 2 H, NH₂). ¹³C NMR (100 MHz, DMSO): δ = 20.2, 23.5, 95.5, 105.8, 118.7, 150.5, 161.1, 162.1.
4-Amino-5-(1-iminoethyl)-2,6-dimethylisophthalonitrile (20)
Yield 27%; mp 302-304 °C. MS: m/z = 212. IR: 3391 (NH), 3330, 3148 (NH₂), 2211 (CN), 1662 (C=NH) cm^-1. ¹H NMR (400 MHz, DMSO): δ = 2.20 (s, 3 H, CH₃), 2.38 (s, 3 H, CH₃), 2.68 (s, 3 H, CH₃), 6.20 (s, 1 H, vinyl-H), 6.60-6.83 (br, 2 H, NH₂) 9.80 (s, 1 H, NH). ¹³C NMR (100 MHz, DMSO): δ = 20.8, 21.65, 24.2, 75.6, 102.1, 111.3, 117.7, 121, 152.0, 154.6, 156.3, 161.7.

29 Sato K. Ohashi M. Bull. Chem. Soc. Jpn.  1969,  42:  2319 

30

2,4-Dimethyl-6-oxo-1,6-dihydropyridine-3-carbonitrile (18)
Yield 42%; mp 295 °C. MS: m/z = 148: IR: 3090 (NH), 2217 (CN), 1659 (CO) cm^-1. ¹H NMR (400 MHz, DMSO): δ = 2.20 (s, 3 H, CH₃), 2.40 (s, 3 H, CH₃), 6.16 (s, 1 H, vinyl-H), 6.82 (br, 1 H, NH). ¹³C NMR (100 MHz, DMSO): δ = 18.2, 20.1, 90.9, 116.2, 149.5, 150.5, 154.8, 161.6.