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DOI: 10.1055/s-2007-977445
Novel and Efficient Synthesis of 2- and 4-N-Substituted Pyridine N-Oxides under Solvent-Free Conditions
Publikationsverlauf
Publikationsdatum:
18. April 2007 (online)
Abstract
Displacement of 2-or 4-chloropyridine N-oxides, with nitrogen nucleophiles, under solvent-free conditions offers a simple route to scarce N-substituted pyridine N-oxides.
Key words
chloropyridine N-oxides - nucleophilic substitution - amination - solvent-free conditions
- 1
Ranganathan S.Rao ChC.Vudayagiri SD.Rajesh YBRD.Jagadeesh B. J. Chem. Sci. 2004, 116: 169 -
2a
Katritzky AR. J. Chem. Soc. 1956, 2404 -
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Katritzky AR. J. Chem. Soc. 1957, 191 -
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Katritzky AR.Randall EW.Sutton LE. J. Chem. Soc. 1957, 1769 -
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Gardner JN.Katritzky AR. J. Chem. Soc. 1957, 4375 -
2e
Jones RA.Katritzky AR. J. Chem. Soc. 1960, 2937 - 3
Ochiai E. J. Org. Chem. 1953, 18: 534 - For similar procedures, see:
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4a
Essery JM.Schofield K. J. Chem. Soc. 1960, 4953 -
4b
Taylor EC.Driscoll JS. J. Am. Chem. Soc. 1960, 82: 3141 -
4c
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Coppens G.Declerck F.Gillet C.Nasielski J. Bull. Soc. Chim. Belg. 1961, 70: 480 - 7
Kato T.Niitsuma T.Kusaka N. Yakugaku Zasshi 1964, 84: 432 ; Chem. Abstr. 1964, 61, 4171d - The chemistry and applications of pyridine N-oxides is receiving increasing attention due to their usefulness as synthetic intermediates in biologically important compounds, protecting groups, auxiliary agents, oxidizing agents, templates for metal complexation and in the design of catalysts. See:
-
8a
Youssif S. ARKIVOC 2001, (i): 242 -
8b
Albini A.Pietra S. Heterocyclic N-Oxides CRC Press; Boca Raton: 1991. -
8c
Katritzky AR.Lagowski JM. Chemistry of the Heterocyclic N-Oxides Academic Press; New York: 1971. - 11
Ranganthan D.Singh GP.Ranganathan S. J. Am. Chem. Soc. 1989, 111: 1144
References and Notes
Chloropyridine N-oxides on treatment with KNH2/NH3 can undergo either elimination to pyridyne N-oxides (dehydropyridine N-oxides) or direct substitution. In the former case, elements of ammonia can be accepted at either of the locations to give a mixture of amino pyridine N-oxides.
9As predicted by the order of reactivity (cf. ref. 5) nucleophilic displacement was very efficient with
2-chloropyridine N-oxides. On the other hand those with 4-chloropyridine N-oxides was sluggish and failed in some cases.
Karle, I. L.; Rajesh, Y. B. R. D.; Ranganathan, S. unpublished results.
12The effect of all the compounds reported on the enhancement of the solubility of silica in water will be examined.
13
General Procedure for the Preparation of 2- and 4-N-Substituted Pyridine
N
-Oxides
A mixture of 2- or 4-chloro pyridine N-oxide (3 mmol) and amine (3.6 mmol) was heated at 80 °C for the 2-chloro compounds, and at 100 °C for the 4-chloro compounds for time periods indicated in Table
[1]
and Table
[2]
. Pure products were secured by chromatography on a column of silica gel and elution with CHCl3-MeOH.
Most compounds reported are novel and the remaining lack modern data. Therefore data for their characterization are presented below.
Spectral Data
Compound 1: mp 120-124 °C (dark brown plates). IR (KBr): 1242, 773 cm-1. 1H NMR (300 MHz, CDCl3): δ = 1.61-1.68 (m, 2 H), 1.75-1.82 (m, 4 H), 3.30-3.34 (m, 4 H), 6.79-6.86 (m, 2 H), 7.18 (app t, 1 H, J = 8.5 Hz), 8.19 (d, 1 H, J = 7.7 Hz). 13C NMR (75.47 MHz, CDCl3): δ = 24.0, 25.2, 48.7, 114.8, 117.0, 126.8, 140.3, 155.0. MS (EI): m/z = 178 [M+]. HRMS: m/z calcd for C10H14N2O: 178.1106; found: 178.1026.
Compound 2: mp 143-146 °C (colorless crystals). IR (KBr): 2867, 2819, 1599, 1491, 1240, 1110, 767 cm-1. 1H NMR (300 MHz, CDCl3): δ = 3.40-3.43 (m, 4 H), 3.91-3.95 (m, 4 H), 6.83-6.93 (m, 2 H), 7.21-7.26 (m, 1 H), 8.20 (d, 1 H, J = 7.7 Hz). 13C NMR (50 MHz, CDCl3): δ = 48.0, 66.6, 114.5, 118.2, 127.4, 140.6, 154.1. MS (EI): m/z = 180 [M+]. HRMS: m/z calcd for C9H12N2O2: 180.0899; found: 180.0877.
Compound 3: thick brown liquid. IR (Neat): 3348, 2932, 1627, 1195 cm-1. 1H NMR (300 MHz, CDCl3): δ = 3.38-3.43 (m, 2 H), 3.90-3.93 (m, 2 H), 6.55-6.63 (m, 2 H), 7.21-7.27 (m, 1 H), 7.57 (br, 1 H), 8.05 (d, 1 H, J = 7.7 Hz). 13C NMR (50 MHz, CDCl3): δ = 45.5, 60.5, 106.7, 111.3, 130.2, 137.3, 150.6. MS (EI): m/z = 154 [M+]. HRMS: m/z calcd for C7H10N2O2: 154.0742; found: 154.0744.
Compound 4: pale brown liquid. IR (neat): 3365, 1506, 1202 cm-1. 1H NMR (200 MHz, CDCl3): δ = 3.60-3.65 (m, 4 H), 3.71-3.75 (m, 4 H), 6.88 (app t, 1 H, J = 7.0 Hz), 7.10 (d, 1 H, J = 10.1 Hz), 7.31 (app t, 1 H, J = 8.5 Hz), 8.14 (d, 1 H, J = 7.9 Hz). 13C NMR (75.47 MHz, CDCl3): δ = 52.0, 58.5, 116.7, 117.5, 129.5, 139.7, 152.8. MS (EI): m/z = 198 [M+]. HRMS: m/z calcd for C9H14N2O3: 198.1004; found: 198.1104.
Compound 5: quasi-crystalline brown thick liquid. IR (neat): 2926, 2855, 1241 cm-1. 1H NMR (300 MHz, CDCl3,): δ = 0.84-0.88 (m, 6 H), 1.24 (br, 20 H), 1.52 (br, 4 H), 3.38-3.43 (m, 4 H), 6.74-6.84 (m, 2 H), 7.14 (app t, 1 H, J = 8.7 Hz), 8.14 (d, 1 H, J = 7.8 Hz). 13C NMR (75.47 MHz, CDCl3): δ = 14.0, 22.4, 26.8, 27.5, 29.0, 29.2, 31.7, 50.5, 116.2, 116.3, 127.8, 140.9, 153.6. MS (EI): m/z = 334 [M+]. HRMS: m/z calcd for C21H38N2O: 334.2984; found: 334.2969.
Compound 6: pale yellow liquid. IR (neat): 2931, 2854, 1622, 1571, 1525, 1196, 750 cm-1. 1H NMR (300 MHz, CDCl3): δ = 1.21-1.45 (m, 6 H), 1.76-1.83 (m, 2 H), 2.00-2.04 (m, 2 H), 3.27-3.38 (m, 1 H), 6.47-6.60 (m, 2 H), 6.80 (br, 1 H), 7.20 (app t, 1 H, J = 8.3 Hz), 8.11 (d, 1 H, J = 7.4 Hz). 13C NMR (50 MHz, CDCl3): δ = 24.6, 25.2, 32.6, 50.5, 105.9, 110.5, 128.2, 137.2, 149.3. MS (EI): m/z = 193 [M+ + 1]. HRMS: m/z calcd for C11H16N2O: 192.1263; found: 192.1164.
Compound 7: mp 180-182 °C (dark brown plates). IR (KBr): 3423, 3234, 1628, 1575, 1198 cm-1. 1H NMR (200 MHz, D2O): δ = 3.23-3.29 (m, 2 H), 3.68-3.74 (m, 2 H), 6.81 (app t, 1 H, J = 6.8 Hz), 6.95 (d, 1 H, J = 8.6 Hz), 7.55 (app t, 1 H, J = 7.8 Hz), 8.02 (d, 1 H, J = 6.6 Hz). 13C NMR (75.47 MHz, D2O): δ = 38.3, 39.0, 108.1, 113.3, 133.7, 137.6, 149.7. MS (EI): m/z = 153 [M+]. HRMS: m/z calcd for C7H11N3O: 153.0902; found: 153.0899.
Compound 8: mp 242-244 °C (pale brown rods). IR (KBr): 3337, 1626, 1578, 1528, 1188, 767 cm-1. 1H NMR (300 MHz, D2O): δ = 3.73 (s, 4 H), 6.73 (app t, 2 H, J = 7.2 Hz), 6.97 (d, 2 H, J = 7.2 Hz), 7.45 (app t, 2 H, J = 8.4 Hz), 8.02 (d, 2 H, J = 6.6 Hz). 13C NMR (75.47 MHz, D2O): δ = 41.2, 107.9, 112.3, 133.2, 137.3, 150.0. MS (EI): m/z = 246 [M+]. HRMS: m/z calcd for C12H14N4O2: 246.1116; found: 246.1105.
Compound 9: pale brown liquid. IR (neat): 3420, 1365 cm-1. 1H NMR (200 MHz, CDCl3): δ = 2.79-2.84 (m, 3 H), 3.07 (s, 3 H), 3.33-3.40 (m, 2 H), 3.61-3.67 (m, 2 H), 6.96-7.05 (m, 2 H), 7.42 (app t, 1 H, J = 8.7 Hz), 8.11 (d, 1 H, J = 7.6 Hz). 13C NMR (75.47 MHz, CDCl3): δ = 34.4, 37.9, 46.3, 47.9, 115.7, 117.9, 130.3, 139.7, 153.5. MS (EI): m/z = 181 [M+]. HRMS: m/z calcd for C9H15N3O: 181.1215; found: 181.1215.
Compound 10: mp 192-194 °C (pale brown rods). IR (KBr): 3369, 3257, 1615, 1516, 1186, 777 cm-1. 1H NMR (300 MHz, CDCl3): δ = 3.04 (s, 6 H), 3.89 (s, 4 H), 6.76 (app t, 2 H, J = 6.8 Hz), 6.82 (d, 2 H, J = 8.5 Hz), 7.16 (app t, 2 H, J = 8.7 Hz), 8.09 (d, 2 H, J = 7.7 Hz). 13C NMR (50 MHz, CDCl3): δ = 39.2, 49.9, 114.6, 116.3, 127.4, 140.3, 154.4. MS (EI): m/z = 274 [M+]. HRMS: m/z calcd for C14H18N4O2: 274.1429; found: 274.1419.
Compound 11: pale brown liquid. IR (neat): 2947, 1637 cm-1. 1H NMR (200 MHz, CDCl3): δ = 1.70-1.73 (m, 6 H), 3.47-3.50 (m, 4 H), 6.82 (d, 2 H, J = 7.8 Hz), 8.09 (d, 2 H, J = 8.0 Hz). 13C NMR (75.47 MHz, CDCl3): δ = 23.9, 25.0, 47.7, 108.9, 139.3, 150.7. MS (ESI): m/z = 179 [M+ + 1]. HRMS: m/z calcd for C10H14N2O: 178.1106; found: 178.1091.
Compound 12: thick brown liquid. IR (neat): 3278, 1642, 1539, 1061 cm-1. 1H NMR (300 MHz, D2O): δ = 3.36-3.40 (m, 2 H), 3.75-3.81 (m, 2 H), 6.74 (d, 2 H, J = 7.4 Hz), 7.87 (d, 2 H, J = 7.4 Hz). 13C NMR (75.47 MHz, D2O): δ = 44.7, 59.6, 108.4, 139.0, 152.5. MS (EI): m/z = 155 [M+ + 1]. HRMS: m/z calcd for C7H10N2O2: 154.0742; found: 154.0644.
Compound 13: quasi-crystalline thick brown liquid. IR (neat): 2927, 2855, 1466 cm-1. 1H NMR (200 MHz, CDCl3): δ = 0.87-0.92 (m, 6 H), 1.29 (br, 20 H), 1.52 (br, 4 H), 2.57-2.64 (m, 4 H), 7.27 (d, 2 H, J = 7.9 Hz), 8.15 (d, 2 H, J = 7.9 Hz). 13C NMR (50 MHz, CDCl3): δ = 14.2, 22.5, 25.9, 26.8, 29.0, 29.1, 31.6, 47.7, 126.7, 140.3, 157.6. MS (ESI): m/z = 335 [M+ + 1]. HRMS: m/z calcd for C21H38N2O: 334.2984; found: 334.2964.
Compound 14: pale brown liquid. IR (neat): 3401, 3047, 1643, 1551, 1339, 1218, 815 cm-1. 1H NMR (200 MHz, D2O): δ = 2.78 (br, 3 H), 3.24 (s, 3 H), 3.33-3.49 (m, 2 H), 3.91-4.01 (m, 2 H), 7.03 (d, 2 H, J = 7.3 Hz), 8.15 (d, 2 H, J = 7.3 Hz). 13C NMR (50 MHz, D2O): δ = 35.8, 40.8, 47.8, 50.3, 109.9, 141.6, 160.2. MS (ESI): m/z = 182 [M+ + 1]. HRMS: m/z calcd for C9H15N3O: 181.1215; found: 181.1225.