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Synlett 2007(8): 1215-1218  
DOI: 10.1055/s-2007-977445
LETTER
© Georg Thieme Verlag Stuttgart · New York

Novel and Efficient Synthesis of 2- and 4-N-Substituted Pyridine N-Oxides under Solvent-Free Conditions

Subramania Ranganathan*a, Y. B. R. D. Rajesha, Isabella L. Karle*b
a Discovery Laboratory, Organic III, Indian Institute of Chemical Technology, Hyderabad 500 007, India
b Laboratory for the Structure of Matter, Naval Research Laboratory, Washington, DC 20375-5341, USA
Fax: +91(40)27160757; e-Mail: ranga@iict.res.in;
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Publication History

Received 28 December 2006
Publication Date:
18 April 2007 (online)

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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

    References and Notes

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6

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.

9

As 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.

10

Karle, I. L.; Rajesh, Y. B. R. D.; Ranganathan, S. unpublished results.

12

The 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.