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

Subramania Ranganathan; Y. B. R. D. Rajesh; Isabella L. Karle

doi:10.1055/s-2007-977445

LETTER

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

Subramania Ranganathan*^a, Y. B. R. D. Rajesh^a, 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;

Abstract

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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

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References

References and Notes

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

2b Katritzky AR. J. Chem. Soc. 1957, 191

2c Katritzky AR. Randall EW. Sutton LE. J. Chem. Soc. 1957, 1769

2d 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:

4a Essery JM. Schofield K. J. Chem. Soc. 1960, 4953

4b Taylor EC. Driscoll JS. J. Am. Chem. Soc. 1960, 82: 3141

4c Badger GM. Rao RP. Aust. J. Chem. 1964, 17: 1399

5 Coppens G. Declerck F. Gillet C. Nasielski J. Bull. Soc. Chim. Belg. 1961, 70: 480

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.

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.

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.

11 Ranganthan D. Singh GP. Ranganathan S. J. Am. Chem. Soc. 1989, 111: 1144

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.