N-Alkoxymethylation of Carboxamides Catalyzed by Brønsted Acids

Abstract

The reaction of carboxamides and dialkoxymethanes can be affected by sulfonic acids (methanesulfonic acid, p-toluenesulfonic acid, and Nafion-H SAC-13 silica nanocomposite) to yield N-alkoxymethylcarboxamides. Various types of N-alkyl- and N-aryl-substituted acetamides can be reacted in a one-step procedure to give the products in moderate to good yields.

Key words

acetals - amides - carbocations - catalysis - protecting groups

References

• 1 The Pesticide Manual   11th Ed.:  Tomlin CDS. British Crop Protection Council; Farnham: 1997. 
• 2 Olin JF. inventors; U.S. Patent  3442945. 
• 3 Vogel C, and Aebi R. inventors; German Patent  2328340.  ; Chem. Abstr. 1974, 80, 82440
• 4 Vértesi E, Huszák Gy, Pelyva J, Kovács M, Damján J, Kolonics Z, Kulcsár L, Sümegi E, Gy rfi B, Vass A, Lendvai L, Tömördi E, Szabó LJ, Nagy B, Nádasdy M, Haas A, and Hung . inventors; Patent  177876. 
• 5 Venkov AP. Minkov MM. Lukanov LK. Synth. Commun.  1989,  19:  2133 
• 6 Danikiewicz W. Szmigielski R. Synth. Commun.  2001,  31:  3047 
• 7 Dardoize F. Gaudemar M. Goasdoue N. Synthesis  1977,  567 
• 8 Lukyanov OA. Pokhvisneva GV. Ternikova TV. Izv. Akad. Nauk SSSR Ser. Khim.  1994,  1452 
• 9 Alzeer J. Nock N. Wassner G. Masciadri R. Tetrahedron Lett.  1996,  37:  6857 
• 10 Szmigielski R. Danikiewicz W. Synlett  2003,  372 
• 11 Bicking JB. Kwong SF. Fisher MH. Nicholson WH. J. Med. Chem.  1965,  8:  95 
• 12 Cauliez P. Rigo B. Fasseur D. Coutuier D. J. Heterocycl. Chem.  1991,  28:  1143 
• 13 Horsley LH. Adv. Chem. Ser.  1952,  6:  64 
• 16a Ogata Y. Kawasaki A. In The Chemistry of the Carbonyl Group   Zabicky J. Interscience; London: 1970.  p.20 
• 16b Olah GA. Prakash GKS. Sommer J. Superacids   Wiley-Interscience; New York: 1985.  p.116 
• 17 Stewart WE. Siddal TH. Chem. Rev.  1970,  70:  517 

14

General Procedure: A mixture of the secondary amide
(7 mmol) and the dialkoxymethane (105 mmol) was refluxed in the presence of p-toluenesulfonic acid (1.4 mmol) under magnetic stirring for 5 h and the azeotrope of the corresponding alcohol formed and the original acetal was distilled off to shift the equilibrium for the formation of the N-alkoxy-methylated products (in the case of diethoxymethane, a 20-cm column with glass Fenske packing was used). After cooling the reaction mixture was neutralized with saturated aq NaHCO₃, washed with NaCl solution and dried (Na₂SO₄). The unreacted acetal still present in the organic layer was removed by distillation at atmospheric pressure (in the case of diethoxymethane) or under reduced pressure (in the case of diisopropoxymethane and dibutoxymethane). The product was purified by column chromatography on silica gel using hexane-EtOAc mixture as the eluent.

15

Properties are given for compounds 3b, 8a, 9b, and 10a as representative examples of new compounds.
The presence of isomers (rotamers), the major and minor components in the case of compound 3b, is due to the hindered rotation about the carbonyl C-N bond in carboxamides. [17] Because of the conjugation between the lone pair of electrons of nitrogen and the carbonyl π-bond an electron delocalization occurs resulting in a significant π character of the C-N bond.
N -Isobutyl- N -(isopropoxymethyl)acetamide (3b). ¹H NMR (500 MHz, CDCl₃): major component δ = 0.88 (d, ³ J = 6.6, 6 H, 2 × CH ₃), 1.18 (d, ³ J = 6.0, 6 H, 2 × CH ₃), 1.92-2.00 (m, 1 H, CH), 2.17 (s, 3 H, CH ₃), 3.24 (d, ³ J = 7.4, 2 H, CH ₂), 3.65 (m, 1 H, CH), 4.67 (s, 2 H, CH ₂); minor component δ = 0.93 (m, 6 H, 2 × CH ₃), 1.15 (m, 6 H, 2 × CH ₃), 1.92-2.00 (m, 1 H, CH), 2.12 (s, 3 H, CH ₃), 3.16 (d, ³ J = 7,6, 2 H, CH ₂), 3.70 (m, 1 H, CH), 4.89 (s, 2 H, CH ₂). ¹³C NMR (500 MHz, CDCl₃): major component δ = 171.5 (CO), 77.8 (NCH₂O), 68.8 (OCH), 53.4 (NCH₂), 27.3 (CH₂), 21.9 (CH₂), 21.2 (CH₃CO), 20.0 (2 × CH₃); minor component δ = 171.5 (CO), 72.2 (NCH₂O), 68.9 (OCH), 53.9 (NCH), 27.6 (CH₂), 22.1, (2 × CH₃), 21.7 (CH₃CO), 19.9 (2 × CH₃). Anal. Calcd for C₁₀H₂₁NO₂: C, 64.13; H, 11.30; N, 7.48. Found: C, 63.72; H, 11.15; N, 7.17.
N -(4-Isopropylphenyl)- N -(isopropoxymethyl)chloro-acetamide (8a). ¹H NMR (500 MHz, CDCl₃): δ = 1.21 (d, ³ J = 5.9, 6 H, 2 × CH ₃), 1.26 (d, ³ J = 6.9, 6 H, 2 × CH ₃), 2.92-2.97 (m, 1 H, CH), 3.87 (s, 2 H, CH ₂Cl), 3.90-3.94 (m, 1 H, CH), 5.11 (s, 2 H, CH ₂), 7.16 (d, ³ J = 8.1, 2 H, Ar-H), 7.28 (d, ³ J = 7.9, 2 H, Ar-H). ¹³C NMR (500 MHz, CDCl₃): δ = 167.2 (CO), 149.7 (CPh), 137.5 (NPh) 128.0 (Ph), 127.8 (Ph), 75.9 (NCH₂O), 69.8 (OCH), 42.2 (CH₂Cl), 33.7 (PhCH), 23.8 (2 × CH₃), 22.2 (2 × CH₃). Anal. Calcd for C₁₅H₂₂NO₂Cl: C, 63.48; H, 7.81; N, 4.94. Found: C, 63.38; H, 7.66; N, 4.53.
N -(4-Bbromophenyl)- N -(butoxymethyl)acetamide (9b). ¹H NMR (500 MHz, CDCl₃): δ = 0.92 (t, ³ J = 7.4. 3 H, CH ₃), 1.33-1.40 (m, 2 H, CH ₂), 1.54-1.58 (m, 2 H, CH ₂), 1.89 (s, 3 H, CH ₃), 3.56 (s, 2 H, CH ₂), 5.04 (s, 2 H, CH ₂), 7.11 (d, ³ J = 8.4, 2 H, Ar-H), 7.54 (d, ³ J = 8.1, 2 H, Ar-H). ¹³C NMR (500 MHz, CDCl₃): δ = 170.9 (CO), 141.3 (NPh), 132.6 (Ph), 129.7 (Ph), 122.0 (BrPh), 77.2 (NCH₂O), 68.6 (OCH₂), 31.6 (CH₂), 22.6 (CH₃CO), 19.2 (CH₂), 13.7 (CH₃). Anal. Calcd for C₁₃H₁₈NO₂Br: C, 52.01; H, 6.04; N, 4.67. Found: C, 51.88; H, 5.93; N, 5.10.
N -(4-Methoxylphenyl)- N -(ethoxymethyl)acetamide (10a). ¹H NMR (500 MHz, CDCl₃): δ = 1.21 (t, ³ J = 7.1, 3 H, CH ₃), 1.87 (s, 3 H, CH ₃), 3.64 (q, ³ J = 7.0, 2 H, CH ₂), 3.83 (s, 3 H, CH ₃), 5.05 (s, 2 H, CH ₂), 6.92 (d, ³ J = 8.7, 2 H, Ar-H), 7.12 (d, ³ J = 8.7, 2 H, Ar-H). ¹³C NMR (500 MHz, CDCl₃): δ = 171.7 (CO), 159.1 (CH₃OPh), 135.0 (NPh), 129.1 (Ph), 114.7 (Ph), 77.1 (NCH₂O), 64.0 (OCH₂), 55.3 (CH₃O), 22.7 (CH₃CO), 15.0 (CH₃). Anal. Calcd for C₁₂H₁₇NO₃: C, 64.55; H, 7.67; N, 6.27. Found: C, 64.96; H, 7.63; N, 6.22.