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M. W. Bundesmann et al. / Tetrahedron Letters 51 (2010) 3879–3882
10. The amidation of esters using MgCl2/NHR1R2 in THF has been reported: Guo, Z.;
Dowdy, E. D.; Li, W.-S.; Polniaszek, R.; Delaney, E. Tetrahedron Lett. 2001, 42,
1843–1845.
11. We believe that the aqueous solubility of these products is increased by the
magnesium or calcium salts present.
12. The 2.1 M solution of Mg(OCH3)2 was used in these experiments.
13. Ley and coworkers noted (Ref. 6b) that the reaction proceeded uneventfully for
a large number of esters, but that upon investigation of furan and indole esters
explosions occurred despite measures to control the exothermic reaction of
Mg3N2 with MeOH.
14. Amide 12 was prepared in 81% yield on a 24 mmol scale by linear scale up of
these conditions.
15. A reaction time of 6 days was required to attain 90% conversion of 1 to 2 under
the conditions of Table 2 in the absence of Mg(OCH3)2.
16. Treatment of 1 with 1 equiv BnNH2 under the conditions of Table 2 returned a
<10% yield of N-benzyl 4-chlorobenzamide, suggesting that an excess of amine
is required to secure complete consumption of the ester.
Mg(OCH3)2 or CaCl2 is autocatalytic, as any amide that is formed
spontaneously from the ester and NH3 can undergo reaction with
additional ester to form imide, which may then undergo aminoly-
sis to form additional amide.
O
O
N
H
NH
HN
Cl
Cl
36
The formation of a precipitate in all reactions employing
Mg(OCH3)2/NH3, particularly reactions such as with ester 1, in
which all reactants and products are completely soluble in the
hot reaction mixture, provides evidence that residual water has
been consumed by reaction with Mg(OCH3)2 with the formation
of insoluble Mg(OH)2.
In summary, we present a method for the amidation of esters by
ammonia and amines, or their hydrochloride salts that uses inex-
pensive commercial reagents.27 The method affords good yields
with the convenient reaction times associated with Mg3N2 but
without the safety liability inherent in the use of Mg3N2.
17. This corresponds to about 1.7 bar or about 25 psig.
18. Commercially available from Sigma–Aldrich and Alfa/Aesar. These solutions
typically contain about 0.6 M Mg(OCH3)2 as determined by quenching with
1.00 M H2SO4 and back-titration with 1.00 M NaOH to a phenolphthalein
endpoint.
19. Baumgarten, H. E.; Petersen, J. M. Org. Synth. 1961, 41, 82–90. We have typically
used about 4 g of Mg turnings per 100 mL of MeOH; this affords a solution that
is approximately 2.1 M Mg(OCH3)2..
20. Ammonia concentrations were determined by titration with 1.00 M H2SO4 to a
methyl red endpoint.
21. Amine HCl salts are preferred because the by-product MgCl2 is soluble in the
reaction mixture at 80 °C.
22. Substitution of CaO or MgO for Mg(OCH3)2 in amidations of 1 with NH4Cl
returned 2 significantly contaminated by 4-chlorobenzoic acid.
23. The authors of Ref. 2 attempted to use Mg(OCH3)2 with ammonia in methanol
with low yield (23%). It is unclear to us why this attempt was not more
successful. See Ref. 2, footnote 12.
Acknowledgments
The authors wish to thank colleagues Robert Maguire, David
Hepworth, John Humphrey, and Joel Hawkins for their support
and valuable discussions.
24. A modification of these conditions was subsequently published, see: Allred, E.
L.; Hurwitz, M. D. J. Org. Chem. 1965, 30, 2376–2381; Jagdmann, G. E., Jr.;
Munsun, H. R., Jr.; Gero, T. W. Synth. Commun. 1990, 20, 1203–1208.
25. In this case, the relatively low solubility of the reactants and products in the
reaction mixture may have facilitated the recovery of the imide 36 from this
experiment.
References and notes
1. (a) Larock, R.C. Comprehensive Organic Transformations A Guide to Functional
Group Preparations, 2nd ed., John Wiley& Sons, Inc., New York, NY, 1999.; In
particular, the use of dialkylaluminum amides described by Weinreb has gained
popularity, see: (b) Basha, A.; Lipton, M.; Weinreb, S. M. Tetrahedron Lett. 1977,
18, 4171–4174; (c) Levin, J. I.; Turos, E.; Weinreb, S. M. Synth. Commun. 1982, 12,
989–993; A modification of this procedure uses DABCOÁMe3Al complex, see: (d)
Novak, A.; Humphreys, L. D.; Walker, M. D.; Woodward, S. Tetrahedron Lett. 2006,
47, 5767–5769; It should be noted that the DABCOÁMe3Al complex is not
commercially available and may be pyrophoric in air if not prepared and isolated
properly, see; (e) Biswas, K.; Prieto, O.; Goldsmith, P. J.; Woodward, S. Angew.
Chem., Int. Ed. 2005, 44, 2232–2234.
2. Veitch, G. E.; Bridgwood, K. L.; Ley, S. V. Org. Lett. 2008, 10, 3623–3625.
3. See Table 3 in Ref. 2.
4. The reaction of Mg3N2with water or methanol is highly exothermic, estimated
at 165 kcal/mol. If uncontrolled, this may be sufficient to raise the pressure of
the mixture to between 30 and 60 atmospheres. See: Buske, G. Chem. Eng. News
2009, 87, 2.
26. Characterization of 36: 1H NMR (400 MHz, DMSO-d6) d ppm 7.29 (dd, J = 8.78,
2.15 Hz, 2H) 7.50 (d, J = 8.97 Hz, 2H) 7.56 (d, J = 1.37 Hz, 2H) 7.80 (d,
J = 1.95 Hz, 2H) 11.17 (s, 1H) 12.12 (s, 2H). 13C NMR (100 MHz, DMSO-d6) d
ppm 106.97, 114.22, 121.27, 124.71, 125.01, 127.62, 131.54, 135.88, 159.79. IR
(film): 3304, 2955, 1725, 1673 cmÀ1. API MS 372, 374, 376 (MH+, 2Cl isotope
pattern). Mp 293–296 °C (decomposes). Anal. Calcd for
C18H11Cl2N3O2: C,
58.09; H, 2.98. Found: C, 58.21; H, 2.90.
27. Representative procedure: To the reaction vessel28 equipped with a magnetic
stir bar under N2 are added the substrate ester (3 mmol), Mg(OCH3)2 in MeOH
(6–10%, about 0.6 M, 4.5 mL, about 3 mmol),29 and 7 N NH3 in MeOH (4.5 mL,
about 30 mmol). The reaction vessel is sealed and heated at 80 °C for 24 h.
Workup may be accomplished using either of the two methods. (a) For reaction
products that may be expected to be solids, the reaction mixture is
concentrated and the residue is treated with saturated NH4Cl solution (1 mL
per mmol substrate) and H2O (3 mL per mmol substrate). The resulting
mixture is adjusted to pH 5 with HCl, and the mixture is stirred for 20 min to
dissolve Mg or Ca salts, after which the precipitated amide is filtered, washed
with H2O, and dried. (b) For small scale reactions, or for amide products that
are not solids, the reaction mixture is concentrated and the residue is treated
with saturated NH4Cl solution as described above. The mixture is then
extracted with a suitable solvent. If the reaction product is not soluble in
dilute acid, the residue may be treated with dilute HCl instead of NH4Cl, which
permits a more rapid removal of Mg or Ca salts from the product.
5. The nature and extent of the exotherm were not elaborated upon in the Letter
or Supplementary data and some subsequent workers may have been unaware
of the need to control it.
6. (a) Crane, S. Chem. Eng. News 2009, 87, 2; (b) Ley, S. V. Chem. Eng. News 2009, 87, 4.
These accidents may have resulted either from failure to control the exotherm, or
from attempts to use the reagent on a larger scale than first reported.
7. The reactions described in Ref. 2 were carried out on 0.7 mmol scale.
8. Kobayashi, S.; Busujima, T.; Nagayama, S. Chem. Eur. J. 2000, 6, 3491–3494.
9. Preparative yields were generally slightly higher than screening yields, except
in the cases of CeCl3 and ZnCl2, presumably due to losses of NH3 in screening
due to multiple septum punctures during sampling of screening reactions.
28. Both 15 mL heavy walled pressure tubes (Chemglass CG-1880-01) and 20 mL
Biotage microwave vials are satisfactory.
29. When CaCl2 was used, the Mg(OMe)2 solution was replaced with anhydrous
CaCl2 (3 mmol) and 4.5 mL of MeOH.