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Synlett 2003(3): 0372-0376
DOI: 10.1055/s-2003-37116
LETTER
© Georg Thieme Verlag Stuttgart · New York

N-Alkoxymethylation of Secondary Amides, Sulfonamides and Phosphamides Using Dialkoxymethanes in the Presence of Lewis Acids

Rafa Szmigielski, Witold Danikiewicz*
Institute of Organic Chemistry, Polish Academy of Sciences ul, Kasprzaka 44/52, 01-224 Warszawa 42 POB 58, Poland
Fax: +48(22)6326681; e-Mail: witold@icho.edu.pl;
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Publication History

Received 20 November 2002
Publication Date:
07 February 2003 (online)

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Abstract

A convenient and efficient one-pot synthesis of N-alkoxymethyl derivatives of secondary amides, sulfonamides and phosphamides in reaction with the appropriate dialkoxymethanes in the presence of a Lewis acid is described. In this method the use of toxic and carcinogenic chloromethyl alkyl ethers was eliminated.

Key words

acetals - amides - heterocycles - protecting groups - sulf­onamides

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Alkoxymethylation of Secondary Amides, Sulfonamides or Phosphamides - Representative Example: To a solution of 1-chloro-N-phenylmethanesulfonamide (1.03 g, 5 mmol) in dialkoxymethane (24 mL, 0.27 mol) boron trifluoride etherate (0.76 mL, 6 mmol) was added and the mixture was refluxed during 5 h under argon atmosphere. After cooling to r.t. the reaction mixture was treated with 3 mL of the sat. aq K2CO3 and the aq solution extracted with EtOAc (3 × 20 mL). The combined organic layers were dried with Na2SO4 and the solvent evaporated under reduced pressure. The crude product was purified by crystallization from hexane/EtOAc yielding 1.14 g (91% yield, mp 65-66 °C, lit. [17] mp 67-68 °C) of 1-chloro-N-(methoxymethyl)-N-phenylmethanesulfonamide (12) as white crystals.

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Properties of new compounds:
N -Benzyl- N -(methoxymethyl)acetamide(5). 1H NMR (400 MHz, CDCl3): δ = 2.24 (s, 3 H, CH 3CO), 3.28 (s, 3 H, CH 3O), 4.60 (s, 2 H, PhCH 2), 4.67 (s, 2 H, NCH 2O), 7.18-7.38 (s, 5 H, Ph). 13C NMR (400 MHz, CDCl3): δ = 21.3 (CH3CO), 48.0 (PhCH2), 55.3 (CH3O), 79.5 (NCH2O), 127.3 (Ph), 128.1 (Ph), 128.5 (Ph), 137.4 (Ph), 171.4 (CO). MS:
m/z (%) = 193 (1) [M+], 162 (12), 161 (71), 148 (6), 120 (31), 119 (48), 118 (30), 106 (100), 92 (8), 91 (93), 79 (10), 65 (13), 60 (14), 45 (23), 43 (48). HRMS calcd for C11H15NO2: 193.1102. Found: 193.1113.
2-[(Ethoxymethoxy)methyl]-1 H -isoindole-1,3-(2 H )-dione(8c). 1H NMR (400 MHz, CDCl3): δ = 1.08 (t, 3 H, 3 J = 7.1 Hz, CH 3CH2O), 3.56 (q, 2 H, 3 J = 7.1 Hz, CH3CH 2O), 4.76 (s, 2 H, OCH 2O), 5.18 (s, 2 H, NCH 2O), 7.65-7.89 (m, 4 H, ArH). 13C NMR (400 MHz, CDCl3): δ = 14.8 (CH3CH2O), 63.6 (CH3 CH2O), 64.5 (NCH2O), 94.3 (OCH2O), 123.5 (Ar), 131.8 (Ar), 134.2 (Ar), 167.5 (CO). LSIMS MS: m/z = 258 [M + Na+]. Anal. Calcd for C12H13NO4: C, 61.25; H, 5.57; N, 5.96. Found: C, 61.09; H, 5.49; N, 6.00. Mp: 61.5-62 °C (hexane/EtOAc).
2-(Methoxymethyl)-2 H -naphtho[1,8- cd ]isothiazole 1,1-dioxide(13a). 1H NMR (400 MHz, CDCl3): δ = 3.52 (s, 3 H, CH 3O), 5.26 (s, 2 H, NCH 2O), 6.96-8.14 (m, 6 H, ArH). 13C NMR (400 MHz, CDCl3): δ = 56.7 (CH3O), 74.4 (NCH2O), 104.6 (Ar), 119.0 (Ar), 119.1 (Ar), 119.9 (Ar), 128.1 (Ar), 129.4 (Ar), 130.1 (Ar), 130.6 (Ar), 131.3 (Ar), 135.5 (Ar). MS: m/z (%) = 249 (23) [M+], 219 (21), 218 (9), 188 (4), 154 (7), 127 (10), 77 (5), 75 (7), 74 (5), 61 (14), 45 (100), 33 (4). HRMS calcd for C12H11NO3S: 249.0439. Found: 249.0459. Mp: 90-91.5 °C (hexane/EtOAc).
2-(Ethoxymethyl)-2 H -naphtho[1,8- cd ]isothiazole 1,1-dioxide(13b). 1H NMR (400 MHz, CDCl3): δ = 1.24 (t, 3 H, 3 J = 6.8 Hz, CH 3CH2O), 3.75 (q, 2 H, 3 J = 6.8 Hz, CH3CH 2O), 5.30 (s, 2 H, NCH 2O), 7.07-8.14 (m, 6 H, ArH). 13C NMR (400 MHz, CDCl3): δ = 14.7 (CH3CH2O), 64.6 (CH3 CH2O), 72.8 (NCH2O), 104.6 (Ar), 118.9 (Ar), 119.0 (Ar), 119.8 (Ar), 128.0 (Ar), 129.4 (Ar), 130.1 (Ar), 130.6 (Ar), 131.3 (Ar), 135.6 (Ar). MS: m/z (%) = 263 (47) [M+], 233 (19), 219 (7), 218 (42), 205 (100), 172 (5), 141 (48), 140 (17), 128 (7), 127 (38), 115 (8), 114 (16), 113 (7), 77 (17), 63 (10), 59 (64), 43 (10). HRMS calcd for C13H13NO3S: 263.0616. Found: 263.0622. Mp: 130-131 °C (hexane/EtOAc).
3-(Methoxymethyl)-3 H -1,2,3-benzoxathiazole 2,2-dioxide(14). 1H NMR (500 MHz, acetone-d 6): δ = 3.49 (s, 3 H, CH 3O), 5.28 (s, 2 H, NCH 2O), 7.13-7.34 (m, 4 H, ArH). 13C NMR (500 MHz, acetone-d 6): δ = 57.0 (CH3O), 78.1 (NCH2O), 111.9 (Ar), 112.2 (Ar), 124.0 (Ar), 126.1 (Ar), 131.4 (Ar), 142.1 (Ar). MS: m/z (%) = 179 (37) [M+·], 164 (2), 149 (9), 148 (14), 135 (2), 134 (3), 120 (4), 78 (4), 77 (17), 65 (4), 52 (3), 51 (8), 45 (100), 39 (3). HRMS calcd for C9H9NO3: 179.0582. Found: 179.0575.
N -(Methoxymethyl)- N , P , P -triphenylphosphinic Amide(16). 1H NMR (400 MHz, DMSO-d 6): δ = 3.09 (s,
3 H, CH 3O), 4.62 (d, 2 H, 3 J = 13.2 Hz, NCH 2O), 6.94-7.90 (m, 15 H, Ph). 13C NMR (500 MHz, DMSO-d 6): δ = 54.7 (CH3O), 82.4 (d, 1 C, 2 J = 6.4 Hz, NCH2O), 124.9 (Ph), 125.6 (Ph), 125.7 (Ph), 128.4 (Ph), 128.5 (Ph), 128.7 (Ph), 130.8 (Ph), 131.8 (Ph), 131.9 (Ph), 132.2 (Ph), 132.3 (Ph), 134.8 (Ph), 143.3 (Ph) (Note: number of signals is higher than the number of carbon atoms due to the 13C - 31P coupling in the aromatic rings). MS: m/z (%) = 337 (1) [M+·], 307 (1), 306 (3), 291 (1), 232 (37), 231 (100), 220 (16), 219 (37), 213 (4), 202 (15), 201 (14), 200 (8), 199 (52), 155 (19), 153 (6), 152 (13), 136 (10), 134 (13), 125 (5), 109 (9), 106 (7), 92 (12), 91 (11), 78 (9), 77 (54), 62 (12), 51 (24), 47 (8), 45 (25), 43 (24). HRMS calcd for C20H20NO2P: 337.1231. Found: 337.1225.