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Solid [NH4][H2PO4] was allowed to settle and the supernatant
Trimethylorthovalerate 3b. GC/MS (relative intensity, 70 eV)
clear solution was transferred, by means of a needle, to a m/z: 131 ([M − OCH3]+, 87%), 105 (100), 101 ([M − 2OCH3]+,
500 mL flask containing a 0.5 M aqueous solution of Na2CO3 36), 85 ([CH3(CH2)3CO]+, 9), 61 (13), 59 (35), 57 (69).
(200 mL). The white solid NH4Cl was extracted with an
Trimethylorthobenzoate 3c. GC/MS (relative intensity, 70
additional 2 × 10 mL of ethyl acetate. The aqueous phase was eV) m/z: 151 ([M − OCH3]+, 100%), 105 ([C6H5CO]+, 64), 91
then discharged and extracted with 2 × 10 mL of ethyl acetate. (18), 77 (42), 59 (12), 51 (20).
The extracts were collected, dried on Na2SO4 and the solvent
Methylpropionate 4a. GC/MS (relative intensity, 70 eV) m/z:
was removed by rotary evaporation. The pale yellow liquid thus 88 ([M]+, 20%), 59 (27), 57 (86), 29 (100), 28 ([M − ?]+, 19), 27
obtained was purified by distillation at reduced pressure (42). Database Wiley: Ref 3808, match quality 94%.
(80 °C at 5 torr), yielding trimethylorthobenzoate in 65.0%
yield (22.0 g, 121 mmol).
Methylvalerate 4b. GC/MS (relative intensity, 70 eV) m/z: 101
(1%), 87 (29), 85 (31), 74 (100), 59 (26), 57 (42), 55 (22), 43 (56),
Scale up of the synthesis of trimethylorthobenzoate. TMOB 42 (14), 41 (47), 39 (21). Database Wiley: Ref 12 990, match
was also prepared on a larger (6 times higher) scale. Benzo- quality 95%.
imidate hydrochloride 2c·HCl was obtained starting from
Methylbenzoate 4c. GC/MS (relative intensity, 70 eV) m/z:
1.17 mol of benzonitrile (120 g) and methanol (150 mL, 136 ([M]+, 32%), 105 ([C6H5CO]+, 100), 77 ([C6H5]+, 73). Data-
3.70 mol). The mixture was placed in a 250 mL flask and base Wiley: Ref 24 271, match quality 97%.
cooled to 5 °C. Once the temperature was stable, gaseous HCl
Benzamide 5c. GC/MS (relative intensity, 70 eV) m/z: 121
(127.0 g, 3.50 mmol) was slowly added keeping the temp- ([M]+, 32%), 105 ([C6H5CO]+, 100), 77 ([C6H5]+, 98). Database
erature below 10 °C. After 20 hours at 5–10 °C, 2c·HCl was Wiley: Ref 15 171, match quality 91%.
obtained as a white solid in a 92.1% yield (184 g, 1.07 mol).
The salt was slowly added over a mixture of ethyl acetate
(500 mL) and a 1.8 M aqueous solution of K2CO3 (1.5 L). The
aqueous phase was discharged and extracted with 2 × 50 mL of
ethyl acetate. The resulting methyl benzoimidate 2c dissolved
Notes and references
in ethyl acetate was treated with anhydrous H3PO4 (109 g,
1.11 mol) dissolved in MeOH (50 mL) at 5 °C, for 60 minutes.
A white, microcrystalline solid of O-methyl benzoimidate di-
hydrogenphosphate [2c·H3PO4: 240 g; 1.03 mol; 96.3%] was
isolated. This compound was set to react with MeOH (900 mL,
22.2 mol) at the reflux temperature (65 °C) with stirring, for
8 hours. The mixture was then treated as in the previous prepa-
ration, increasing all the quantities by a factor equal to 6, yield-
ing trimethylorthobenzoate in 62.9% yield (118 g, 648 mmol).
1 (a) P. Wipf, T. Tsuchimoto and H. Takahashi, Pure Appl.
Chem., 1999, 71, 415–421; (b) E. J. Corey and N. Raju, Tetra-
hedron Lett., 1983, 24, 5571–5574; (c) S. M. McElvain and
M. J. Curry, J. Am. Chem. Soc., 1948, 70, 3781–3786.
2 A. Ercoli and R. Gardi, US Pat. 3147249, 1964.
3 (a) J. G. Erickson, J. Org. Chem., 1955, 20, 1573–1576;
(b) S. M. McElvain and D. Kundiger, J. Am. Chem. Soc.,
1942, 64, 254–259; (c) S. M. McElvain and J. T. Venerable,
J. Am. Chem. Soc., 1950, 72, 1661–1669; (d) K.-H.
G. Brinkhaus, E. Steckhan and D. Degner, Tetrahedron,
1986, 42, 553–560; (e) W. M. Kantlehner, Thomas, Kapassa-
kalidis and J. Joannis, Synthesis, 1981, 1981, 380–381.
4 (a) A. Pinner and F. Klein, Ber. Dtsch. Chem. Ges., 1877, 10,
1889–1897; (b) A. Pinner and F. Klein, Ber. Dtsch. Chem.
Ges., 1878, 11, 1475–1487; (c) A. Pinner, Ber. Dtsch. Chem.
Ges., 1883, 16, 1643–1655.
Characterisation data
All the compounds were characterised by GC/MS and 1H NMR.
Spectroscopic properties were in agreement with those
reported in the literature.
Methylpropioimidate 2a.16 GC/MS (relative intensity, 70 eV)
m/z: 87 ([M+], 41%), 86 (47), 58 (70), 57 ([M − CH3 − NH]+, 41),
56 ([M − OCH3]+, 100), 54 (14), 44 (20); 1H NMR (CDCl3) δ 3.71
(s, 3H), 2.26 (q, J = 7.6 Hz, 2H), 1.12 (t, J = 7.6 Hz, 3H).
Methylvaleroimidate 2b.17 GC/MS (relative intensity, 70 eV)
m/z: 101 ([M − CH2], 98%), 59 (11), 55 ([C4H7]+, 100), 41 16), 39
(11); 1H NMR (CDCl3) δ 3.69 (s, 1H), 2.28–2.17 (m, 1H), 1.53
(qui, J = 7.4 Hz, 1H), 1.34 (sex, J = 7.3 Hz, 1H), 0.91 (t, J = 7.3
Hz, 1H).
5 A. J. Hill and I. Rabinowitz, J. Am. Chem. Soc., 1926, 48,
732–737.
6 P. P. T. Sah, J. Am. Chem. Soc., 1928, 50, 516–518.
7 R. Roger and D. G. Neilson, Chem. Rev., 1961, 61, 179–211.
8 S. M. McElvain and B. E. Tate, J. Am. Chem. Soc., 1951, 73,
2233–2238.
9 Die Imidoaether und ihre Derivate, ed. A. Pinner, Oppen-
heim, 1892.
Methylbenzoimidate 2c.18 GC/MS (relative intensity, 70 eV)
m/z: 135 ([M]+, 10%), 134 ([M − H]+, 35), 140 ([M − CH3]+, 31), 10 The alcoholysis reaction proceeds to the desired tri-
105 ([C6H5CO]+, 19), 104 ([C6H5CNH]+, 100), 103 (23), 91 (10),
methylorthobenzoate in very low yield (20%), after a very
long reaction time (six weeks). See for details:
L. G. S. Brooker and F. L. White, J. Am. Chem. Soc., 1935,
57, 2480–2488.
1
77 (49), 76 (16), 51 (34,) 50 (18); H NMR (CDCl3) δ 8.32–8.27
(m, 2H), 7.68–7.60 (m, 1H), 7.56–7.46 (m, 2H), 4.47 (s, J = 2.1
Hz, 3H).
Trimethylorthopropionate 3a. GC/MS (relative intensity, 70 11 J. Mack and S. Muthukrishnan, in Green Techniques for
eV) m/z: 105 ([M − OCH3]+, 56%), 103 ([M − OCH3]+, 100), 59
Organic Synthesis and Medicinal Chemistry, John Wiley &
Sons, Ltd, 2012, pp. 297–323.
(16), 57 ([CH3CH2CO]+, 48), 45 (7).
Green Chem.
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