Facile Procedure for the Synthesis of N-Aryl-N-hydroxy Carbamates

Abstract

An efficient one-pot procedure for the zinc-mediated reduction of nitroarenes in the presence of chloroformates leading to the corresponding N,O-bisprotected hydroxylamine is described. Reactions proceed smoothly under ambient conditions in THF-­water mixtures in good to excellent yield (34-81%). Solvolysis of the bisprotected hydroxylamines with sodium methoxide at room temperature provides access to synthetically versatile N-aryl-N-­hydroxy carbamates in excellent yields (89-97%).

Key words

hydroxylamine - carbamate - zinc-mediated reduction

References and Notes

• 1 Schmidt A. Science of Synthesis   Vol. 31b:  Ramsden CA. Thieme; Stuttgart: 2007.  p.1739 
• 2 For the preparation of indoles, see: Blechert S. Tetrahedron Lett.  1984,  25:  1547 
• 3 For the preparation of isoxazolidines, see: Imran M. Khan SA. Siddiqui N. Ind. J. Pharm. Sci.  2004,  66:  377 
• 4 For the preparation of oxadiazolidinones, see: Gopalsamy A. Kincaid SL. Ellingboe JW. Groeling TM. Antrilli TM. Krishnamurthy G. Aulaugh A. Friedrichs GS. Crandall DL. Bioorg. Med. Chem. Lett.  2004,  14:  3477 
• 5 For the preparation of aziridines, see: Murugan E. Siva A. Synthesis  2005,  2022 
• For the preparation of nitrones, see:
• 6a Evans DA. Song H.-J. Fandrick KR. Org. Lett.  2006,  8:  3351 
• 6b Chatterjee A. Bhattacharya PK. J. Org. Chem.  2006,  71:  345 
• 6c Young IS. Williams JL. Kerr MA. Org. Lett.  2005,  7:  953 
• For applications in [3,3]-sigmatropic rearrangements, see:
• 7a Porzelle A. Woodrow MD. Tomkinson NCO. Eur. J. Org. Chem.  2008,  5135 
• 7b Lobo AM. Prabhakar S. Pure Appl. Chem.  1997,  69:  547 
• 8 Srivastava RS. Khan MA. Nicholas KM. J. Am. Chem. Soc.  2005,  127:  7278 
• 9 For the preparation of β-amino acids, see: Fuller AA. Chen B. Minter AR. Mapp AK. J. Am. Chem. Soc.  2005,  127:  5376 
• 10 For the preparation of β-amino alcohols, see: Aschwanden P. Kværnø L. Geisser RW. Kleinbeck F. Carreira EM. Org. Lett.  2005,  7:  5741 ; and references cited therein
• 11 Johansson W. Parkinson GN. Denny WA. Neidel S. J. Med. Chem.  2003,  46:  4009 
• 12a Beshara CS. Hall A. Jenkins RL. Jones KL. Jones TC. Killeen NM. Taylor PH. Thomas SP. Tomkinson NCO. Org. Lett.  2005,  7:  5729 
• 12b Beshara CS. Hall A. Jenkins RL. Jones TC. Parry RT. Thomas SP. Tomkinson NCO. Chem. Commun.  2005,  1478 
• 12c Hall A. Jones KL. Jones TC. Killeen NM. Porzig R. Taylor PH. Yau SC. Tomkinson NCO. Synlett  2006,  3435 
• 12d Hall A. Huguet EP. Jones KL. Jones TC. Killeen NM. Yau SC. Tomkinson NCO. Synlett  2007,  293 
• 12e Jones TC. Tomkinson NCO. Org. Synth.  2007,  84:  233 
• 12f Knowles DA. Mathews CJ. Tomkinson NCO. Synlett  2008,  2769 
• 13 Jones KL. Porzelle A. Hall A. Woodrow MD. Tomkinson NCO. Org. Lett.  2008,  10:  797 
• 14 Porzelle A. Woodrow MD. Tomkinson NCO. Org. Lett.  2009,  11:  233 
• 15 Kamm O. Org. Synth., Coll. Vol. I  1941,  445 
• 16a Ayyanger NR. Brahme KC. Kalkote UR. Srinivasan KV. Synthesis  1984,  938 
• 16b Entwistle ID. Gilkerson T. Johnstone RAW. Telford RP. Tetrahedron  1978,  34:  213 
• 16c Rondestvedt CS. Johnson TA. Synthesis  1977,  850 
• For example:
• 17a Ren P.-D. Pan X.-W. Jin Q.-H. Yao Z.-P. Synth. Commun.  1997,  27:  3497 
• 17b Ren P.-D. Dong T. Wu S. Synth. Commun.  1997,  27:  1547 
• 17c Bartra M. Romea P. Urpí F. Vilarrasa J. Tetrahedron  1990,  46:  587 
• 17d Yanada K. Yamaguchi H. Meguri H. Uchida S. J. Chem. Soc., Chem. Commun.  1986,  1655 
• 17e Uchida S. Yanada K. Yamaguchi H. Meguri H. Chem. Lett.  1986,  1069 
• 18 Shi QX. Lu RW. Jin K. Zhang ZX. Zhao DF. Chem. Lett.  2006,  35:  226 
• 19 Kin BH. Cheong JW. Han R. Jun YM. Baik W. Lee BM. Synth. Commun.  2001,  31:  3577 
• 20 Kin BH. Jun YM. Suh SW. Baik W. Lee BM. J. Chem. Res., Synop.  1998,  46 

21

Spectroscopic Data for New CompoundsBenzyl N-Phenyl-N-(benzoxycarbonyloxy) Carbamate
^¹H NMR (400 MHz, CDCl₃): δ = 7.47-7.45 (m, 2 H), 7.40-7.26 (m, 13 H), 5.26 (s, 2 H), 5.22 (s, 2 H). ^¹³C NMR (62.5 MHz, CDCl₃): δ = 154.2, 153.4, 139.4, 135.4, 134.1, 129.1, 129.0, 128.8, 128.7, 128.6, 128.5, 128.4, 128.0, 127.7, 124.0, 71.6, 68.6. HRMS: m/z calcd for [M + H]⁺ C₂₂H₁₉NO₅Na: 400.1161; found: 400.1167.
Benzyl N-4-Tolyl-N-(benzoxycarbonyloxy) Carbamate
^¹H NMR (400 MHz, CDCl₃): δ = 7.40-7.29 (m, 12 H), 7.18 (d, 2 H, J = 8.0 Hz), 5.27 (s, 2 H), 5.24 (s, 2 H), 2.25 (s, 3 H). ^¹³C NMR (62.5 MHz, CDCl₃): δ = 154.7, 153.0, 140.7, 136.0, 135.5, 134.5, 129.7, 129.0, 128.8, 128.7, 128.6, 128.4, 122.0, 70.9, 67.2, 20.9. HRMS: m/z calcd for [M + H]⁺ C₂₃H₂₂NO₅: 392.1498; found: 392.1497.
Benzyl N-4-Cyano-N-(benzoxycarbonyloxy) Carbamate
^¹H NMR (400 MHz, CDCl₃): δ = 7.65-7.58 (m, 4 H), 7.39-7.31 (m, 10 H), 5.28 (s, 2 H), 5.27 (s, 2 H). ^¹³C NMR (62.5 MHz, CDCl₃): δ = 153.6, 151.9, 143.0, 134.7, 133.7, 133.0, 129.3, 128.8, 128.7, 128.6, 128.2, 120.1, 118.4, 109.1, 72.3, 69.2. HRMS: m/z calcd for [M + NH₄]⁺ C₂₃H₂₂N₃O₅: 420.1559; found: 420.1570.
Benzyl N-3-Trifluoromethylphenyl-N-(benzoxycarbonyl-oxy) Carbamate
^¹H NMR (400 MHz, CDCl₃): δ = 7.74 (br s, 1 H), 7.66-7.64 (m, 1 H), 7.50-7.49 (m, 2 H), 7.39-7.30 (m, 10 H), 5.27 (s, 2 H), 5.26 (s, 2 H). ^¹³C NMR (62.5 MHz, CDCl₃): δ = 153.9, 152.7, 140.0, 135.0, 133.9, 131.8 (q, CF₃, J = 42 Hz), 129.6, 129.1, 128.8, 128.7, 128.6, 128.5, 128.1, 125.6, 123.6, 123.6, 119.5, 72.0, 69.0. HRMS: m/z calcd for [M + NH₄]⁺ C₂₃H₂₂F₃N₂O₅: 463.1481; found: 463.1472.
Methyl N-2-Tolyl-N-(methoxycarbonyloxy) Carbamate
^¹H NMR (400 MHz, CDCl₃): δ = 7.44 (d, 1 H, J = 7.8 Hz), 7.29-7.24 (m, 3 H), 3.88 (s, 3 H), 3.82 (s, 3 H), 2.37 (s, 3 H). ^¹³C NMR (62.5 MHz, CDCl₃): δ = 154.8, 154.8, 137.8, 137.4, 131.1, 129.5, 128.5, 126.7, 56.2, 54.0, 17.16. HRMS: m/z calcd for [M + H]⁺ C₁₁H₁₄NO₅: 240.0872; found: 240.0867.
Methyl N-3-Tolyl-N-(methoxycarbonyloxy) Carbamate
^¹H NMR (500 MHz, CDCl₃): δ = 7.31-7.28 (m, 3 H), 7.15 (d, 1 H, J = 7.0 Hz), 3.94 (s, 3 H), 3.87 (s, 3 H), 2.39 (s, 3 H). ^¹³C NMR (125 MHz, CDCl₃): δ = 154.7, 154.1, 139.2, 139.1, 128.9, 128.8, 125.1, 121.5, 56.4, 54.0, 21.5. HRMS: m/z calcd for [M + H]⁺ C₁₁H₁₄NO₅: 240.0872; found: 240.0863.
Methyl N-4-Tolyl-N-(methoxycarbonyloxy) Carbamate
^¹H NMR (400 MHz, CDCl₃): δ = 7.34 (d, 2 H, J = 8.1 Hz), 7.19 (d, 2 H, J = 8.1 Hz), 3.90 (s, 3 H), 3.83 (s, 3 H), 2.36 (s, 3 H). ^¹³C NMR (62.5 MHz, CDCl₃): δ = 154.8, 154.3, 138.4, 136.8, 129.7, 125.1, 56.3, 53.9, 21.1. HRMS: m/z calcd for [M + H]⁺ C₁₁H₁₁NO₅: 240.0866; found: 240.0868.
Methyl N-3-Trifluoromethylphenyl-N-(methoxycar-bonyloxy) Carbamate
^¹H NMR (400 MHz, CDCl₃): δ = 7.75 (s, 1 H), 7.68-7.66 (m, 1 H), 7.54-7.52 (m, 2 H), 3.96 (s, 3 H), 3.89 (s, 3 H). ^¹³C NMR (62.5 MHz, CDCl₃): δ = 154.4, 153.4, 139.9, 131.4 (q, CF₃, J = 32 Hz), 129.5, 125.9, 123.8, 121.4, 119.6, 56.7, 54.2. HRMS: m/z calcd for [M + H]⁺ C₁₁H₁₁NO₅F₃: 294.0589; found: 294.0589.
Methyl N-4-Iodophenyl-N-(methoxycarbonyloxy) Carbamate
^¹H NMR (400 MHz, CDCl₃): δ = 7.63 (d, 2 H, J = 4.8 Hz), 7.14 (d, 2 H, J = 4.8 Hz), 3.84 (s, 3 H), 3.77 (s, 3 H). ^¹³C NMR (62.5 MHz, CDCl₃): δ = 154.5, 153.5, 139.1, 138.1, 125.2, 92.3, 56.6, 54.2. HRMS: m/z calcd for [M + H]⁺ C₁₀H₁₁NO₅ ^¹²7I: 351.9682; found: 351.9675.
Methyl N-4-Cyanophenyl-N-(methoxycarbonyloxy) Carbamate
^¹H NMR (400 MHz, CDCl₃): δ = 7.63 (d, 2 H, J = 8.1 Hz), 7.58 (d, 2 H, J = 7.0 Hz), 3.94 (s, 3 H), 3.88 (s, 3 H). ^¹³C NMR (62.5 MHz, CDCl₃): δ = 154.1, 152.5, 143.0, 133.0, 120.3, 118.3, 109.2, 57.0, 54.4. HRMS: m/z calcd for [M + NH₄]⁺ C₁₁H₁₄N₃O₅: 268.0928; found: 268.0931.

22

Phenyl N-Phenyl-N-hydroxy Carbamate
^¹H NMR (400 MHz, CDCl₃): δ = 7.85 (br s, 1 H), 7.54 (d, 2 H, J = 7.8 Hz), 7.40-7.35 (m, 4 H), 7.26-7.22 (m, 2 H), 7.14 (d, 2 H, J = 7.8 Hz). ^¹³C NMR (62.5 MHz, CDCl₃): δ = 153.7, 150.7, 140.2, 129.5, 128.8, 126.5, 126.0, 122.5, 121.5. HRMS: m/z calcd for [M + H]⁺ C₁₃H₁₂NO₃: 230.0812; found: 230.0812.
Phenyl N-4-Tolyl-N-hydroxy Carbamate
^¹H NMR (400 MHz, CDCl₃): δ = 7.88 (br s, 1 H), 7.41-7.33 (m, 4 H), 7.25-7.21 (m, 1 H), 7.19-7.11 (m, 4 H), 2.36 (s, 3 H). ^¹³C NMR (62.5 MHz, CDCl₃): δ = 153.8, 150.8, 137.7, 136.7, 129.5, 129.4, 125.9, 123.0, 121.5, 21.0. HRMS: m/z calcd for [M + NH₄]⁺ C₁₄H₁₇N₂O₃: 261.1239; found: 261.1230.
Benzyl N-4-Tolyl-N-hydroxy Carbamate
^¹H NMR (400 MHz, CDCl₃): δ = 7.37-7.30 (m, 7 H), 7.15 (d, 2 H, J = 8.2 Hz), 5.21 (s, 2 H), 2.23 (s, 3 H). ^¹³C NMR (62.5 MHz, CDCl₃): δ = 155.6, 140.8, 138.4, 135.8, 129.2, 128.6, 128.1, 127.1, 122.7, 68.3, 21.0. HRMS: m/z calcd for [M + H]⁺ C₁₅H₁₆NO₃: 258.1125; found: 258.1126. Benzyl N-4-Cyano-N-hydroxy Carbamate
^¹H NMR (400 MHz, CDCl₃): δ = 7.70 (d, 2 H, J = 9.0 Hz), 7.58 (d, 2 H, J = 9.0 Hz), 7.43-7.33 (m, 5 H), 5.30 (s, 2 H). ^¹³C NMR (62.5 MHz, CDCl₃): δ = 154.2, 144.7, 134.9, 132.7, 128.98, 128.4, 119.4, 118.8, 107.0 69.1. HRMS: m/z calcd for [M + NH₄]⁺ C₁₅H₁₆N₃O₃: 286.1192; found: 286.1194. Benzyl N-3-Trifluoromethylphenyl-N-hydroxy Carbamate
^¹H NMR (400 MHz, CDCl₃): δ = 7.68 (br s, 1 H), 7.56-7.55 (m, 1 H), 7.31-7.29 (m, 2 H), 7.21-7.13 (m, 5 H), 5.10 (s, 2 H). ^¹³C NMR (62.5 MHz, CDCl₃): δ = 155.0, 141.4, 135.0, 131.0 (q, J = 32 Hz, CF₃), 129.1, 128.7, 128.7, 128.2, 127.8, 127.1, 124.2, 118.1, 69.0. HRMS: m/z calcd for [M + NH₄]⁺ C₁₅H₁₆FN₂O₃: 329.1108; found: 329.1110. Methyl N-2-Tolyl-N-hydroxy Carbamate
^¹H NMR (400 MHz, CDCl₃): δ = 9.0 (br s, 1 H), 7.36-7.33 (m, 1 H), 7.28-7.22 (m, 3 H), 3.75 (s, 3 H), 2.34 (s, 3 H). ^¹³C NMR (62.5 MHz, CDCl₃): δ = 157.5, 139.5, 136.2, 130.9, 128.9, 127.5, 126.6, 53.8, 17.6. HRMS: m/z calcd for [M + Na]⁺ C₉H₁₁NO₃Na: 204.0631; found: 204.0634.
Methyl N-3-Tolyl-N-hydroxy Carbamate
^¹H NMR (400 MHz, CDCl₃): δ = 8.2 (br s, 1 H), 7.33-7.28 (m, 3 H), 7.06 (d, 2 H, J = 6.6 Hz), 3.84 (s, 3 H), 2.40 (s, 3 H). ^¹³C NMR (62.5 MHz, CDCl₃): δ = 156.4, 140.9, 138.5, 128.4, 126.9, 123.1, 119.7, 53.7, 21.5. HRMS: m/z calcd for [M]⁺ C₉H₁₁NO₃: 181.0739; found: 181.0735.
Methyl N-4-Tolyl-N-hydroxy Carbamate
^¹H NMR (400 MHz, CDCl₃): δ = 2.34 (s, 3 H), 3.77 (s, 3 H), 7.15 (d, 2 H, J = 8.2 Hz), 7.33 (d, 2 H, J = 8.2 Hz), 8.55 (br s, 1 H). ^¹³C NMR (62.5 MHz, CDCl₃): δ = 156.4, 138.4, 136.2, 129.2, 122.8, 53.7, 21.0. HRMS: m/z calcd for [M + Na]⁺ C₉H₁₁NO₃Na: 204.0631; found: 204.0629.
Methyl N-3-Trifluoromethylphenyl-N-hydroxy Carbamate
^¹H NMR (400 MHz, CDCl₃): δ = 7.80 (s, 1 H), 7.71 (d, 1 H, J = 8.0 Hz), 7.49-7.41 (m, 2 H), 7.20 (br s, 1 H), 3.89 (s, 3 H). ^¹³C NMR (62.5 MHz, CDCl₃): δ = 155.7, 141.3, 131.1 (q, CF₃, J = 32 Hz), 129.1, 129.1, 124.1, 122.0, 117.9, 54.0. HRMS: m/z calcd for [M]⁺ C₉H₈F₃NO₃: 235.0456; found: 235.0453.
Methyl N-4-Iodophenyl-N-hydroxy Carbamate
^¹H NMR (400 MHz, MeOD): δ = 7.65 (d, 2 H, J = 7.0 Hz), 7.25 (d, 2 H, J = 7.0 Hz), 3.83 (s, 3 H). ^¹³C NMR (62.5 MHz, MeOD): δ = 156.9, 143.5, 138.6, 123.6, 89.0, 53.8. HRMS: m/z calcd for [M + H]⁺ C₈H₈INO₃: 292.9549; found: 292.9550.
Methyl N-4-Cyanophenyl-N-hydroxy Carbamate
^¹H NMR (400 MHz, CDCl₃): δ = 7.69 (d, 2 H, J = 7.0 Hz), 7.60 (d, 2 H, J = 7.0 Hz), 3.90 (s, 3 H). ^¹³C NMR (62.5 MHz, CDCl₃): δ = 154.6, 144.3, 132.8, 119.3, 118.7, 107.3, 54.3. HRMS: m/z calcd for [M + Na]⁺ C₉H₈N₂O₃Na: 215.0427; found: 215.0427.