via a laborious three step sequence, namely ester hydrolysis,
formation of an activated ester and finally, aminolysis.7 The
use of magnesium nitride therefore represents a significant
simplification of exisiting procedures.
Table 3. Comparison of Commercially Available Ammonia in
Solution to Magnesium Nitride
We proceeded to test more challenging substrates including
conjugated ester 19 and lactone 21, both of which afforded
the desired amides 20 and 22 in good yield (entries 10 and
11). The only substrate in this study that presented any
difficulties was ꢀ-ketoester 23 (entry 12). In this case, a retro-
Claisen reaction was, not unexpectedly, observed in addition
to aminolysis, to cleanly yield acetamide and isobutyramide.
It is noteworthy that the reaction of esters 13, 15, and 17
likely proceed via transesterification to the corresponding
methyl ester, which is then able to undergo aminolysis. The
methyl ester of isopropyl myristate was isolated as a
byproduct of the reaction, which lends support to this
hypothesis. Furthermore, when 1 was subjected to magne-
sium nitride in ethanol, cyclohexane ethyl ester 27 was
isolated as the sole product (Scheme 1).
entrya
ammonia source
Mg3N2
commercial solution
Mg3N2
ammonia concn (M) yieldb (%)
1
2
3
1.3
2
50
20
85
3.1
a Reactions performed in methanol in a sealed tube at 80 °C for 24 h.
b Isolated yield of pure product.
In summary, we have described the first application of
magnesium nitride as a convenient source of ammonia to
effect the conversion of a range of ester substrates to primary
amides. Noteworthy features of this procedure include the
facile reaction setup as magnesium nitride is a bench-stable
solid, the ease of reaction workup,13 and the excellent yields
observed in the majority of cases. It is anticipated that
magnesium nitride will find further application within the
field of organic synthesis.
Scheme 1.
Treatment of 1 with Magnesium Nitride in Ethanola
aReaction performed in a sealed tube at 80 °C for 24 h.
Acknowledgment. We gratefully acknowledge the EPSRC
for funding (G.E.V. and K.L.B.) and Pfizer Global Research
and Development (Sandwich) for additional support (S.V.L.).
We were interested to see how a commercially available
solution of ammonia in methanol would compare to mag-
nesium nitride. Accordingly, 1 was treated with a 2 M
solution of ammonia in methanol11 which afforded amide 2
in poor yield (table 3, entry 2). This suggests that other
factors play a role in assisting the reaction pathway with
magnesium nitride as the experiments performed in this paper
gave higher yields at both lower (entry 1) and higher (entry
3) concentrations.12
Supporting Information Available: Experimental pro-
cedures and spectral data for all compounds. This material
OL801398Z
(12) In an attempt to recreate the reaction medium generated with
magnesium nitride, cyclohexane methyl ester 1 was treated with 2 M
ammonia in methanol and additional magnesium methoxide. However, the
desired amide 2 was still isolated in low yield (23%). Further studies are
currently underway to ascertain the precise mechanism of action of this
reagent.
(10) Hellberg, M. R.; Conrow, R. E.; Sharif, N. A.; McLaughlin, M. A.;
Bishop, J. E.; Crider, J. Y.; Dean, W. D.; DeWolf, K. A.; Pierce, D. R.;
Sallee, V. L.; Selliah, R. D.; Severns, B. S.; Sproull, S. J.; Williams, G. W.;
Zinke, P. W.; Klimko, P. G. Bioorg. Med. Chem. 2002, 10, 2031–2049.
(11) Sigma-Aldrich catalog no. 341428.
(13) See the Supporting Information for full experimental details.
Org. Lett., Vol. 10, No. 16, 2008
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