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

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.

acetals - amides - heterocycles - protecting groups - sulf­onamides

References

<A NAME="RG31802ST-1">1</A> Greene TW. Wuts PGM. Protective Groups in Organic Synthesis   Wiley; New York: 1991. 

<A NAME="RG31802ST-2">2</A> Vogl C, and Aebi R. inventors; German Patent  2328340.  ; Chem. Abstr. 1974, 80, 82440

<A NAME="RG31802ST-3">3</A> Vogl C, and Aebi R. inventors; Swiss Patent  576945.  ; Chem. Abstr. 1976, 85, 142866

<A NAME="RG31802ST-4">4</A> Vogl C, and Aebi R. inventors; Swiss Patent  581607.  ; Chem. Abstr. 1977, 86, 72242

<A NAME="RG31802ST-5">5</A> Vogl C, and Aebi R. inventors; U.S. Patent  4160660.  ; Chem. Abstr. 1979, 91, 118677

<A NAME="RG31802ST-6">6</A> Kolpin DW. Nations BK. Goolsby DA. Thurman EM. Environ. Sci. Technol.  1996,  30:  1459 

<A NAME="RG31802ST-7">7</A> Venkov AP. Minkov MM. Lukanov LK. Synth. Commun.  1989,  19:  2133 

<A NAME="RG31802ST-8">8</A> Jacobsen NE. Sanders M. Toia RF. Casida JE. J. Agric. Food Chem.  1991,  39:  1342 

<A NAME="RG31802ST-9">9</A> Olah GA. Laali KK. Wang Q. Surya Prakash GK. Onium Ions   Wiley; New York: 1998. 

<A NAME="RG31802ST-10">10</A> Zupancic BG. Sobcic M. Synthesis  1982,  942 

<A NAME="RG31802ST-11">11</A> Danikiewicz W. Szmigielski R. Synth. Commun.  2001,  31:  3047 

<A NAME="RG31802ST-12">12</A> Blair A. Kazerouni N. Cancer Causes Control  1997,  8:  473 

<A NAME="RG31802ST-13">13</A> Bicking JB. Kwong SF. Fisher MH. Nicholson WH. J. Med. Chem.  1965,  8:  95 

<A NAME="RG31802ST-14">14</A> Cauliez P. Rigo B. Fasseur D. Couturier D. J. Heterocycl. Chem.  1991,  28:  1143 

<A NAME="RG31802ST-15">15</A>

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.

<A NAME="RG31802ST-16">16</A>

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.

<A NAME="RG31802ST-17">17</A> Danikiewicz W. Wojciechowski K. Rapid Commun. Mass Spectrom.  1996,  10:  36