ORGANIC
LETTERS
2000
Vol. 2, No. 1
11-13
Direct Synthesis of â-Aminoketones
from Amides via Novel Sequential
Nucleophilic Substitution/Michael
Reaction†
Arthur Gomtsyan
Abbott Laboratories, Neurological and Urological Diseases Research,
Abbott Park, Illinois 60064
Received October 1, 1999
ABSTRACT
The synthesis of â-aminoketones from amides can be achieved in a process consisting of sequential nucleophilic substitution at the carbonyl
group by vinylmagnesium bromide followed by Michael reaction after quench of the first reaction by water.
Sequential transformations in organic chemistry have both
theoretical and practical importance.1 The pathways available
for molecules once they are activated under certain conditions
widen the arsenal of new reactions and lead to a better
understanding of the mechanistic aspects of organic reactions.
The utilization and optimization of self-controlled consecu-
tive processes can offer advantages over the stepwise
transformations by increasing synthetic efficiency, as well
as by saving time, reagents, and waste.
It is well known that amides react with organometallic
reagents to give ketones2,3 by nucleophile substitution of the
amine functionality. However, we wish to report that
reactions of amides and vinylmagnesium bromide followed
by quenching with water afforded â-aminoketones.4 An
illustrative case is shown in Scheme 1 for the conversion of
Weinreb amide 1 to the phenyl â-aminoethylketone 2.
vinylmagnesiun bromide followed by water quench as
summarized in Table 1.5 The Weinreb amides of aromatic
and heteroaromatic carboxylic acids provided corresponding
phenylaminoketone (entry 1) and pyridylaminokeones (en-
tries 2 and 3) in good yields. The electronic nature of the
aromatic ring does not seem to be of critical importance for
the outcome of the reaction as pyridinecarboxamides with
electron-withdrawing (entry 2) and electron-donating (entry
3) groups gave the corresponding â-aminoketones in com-
parable yields. We have also shown that the Weinreb amide
(1) For a discussion of sequential transformations in organic chemistry,
see: (a) Tietze, L. F. Chem. ReV. 1996, 96, 115. (b) Bunce, R. A.
Tetrahedron 1995, 48, 13103. (c) Tietze, L. F.; Beifuss, U. Angew. Chem.,
Int. Ed. Engl. 1993, 32, 131. (d) Posner, G. H. Chem ReV. 1986, 86, 831.
(2) For selected examples, see: (a) Nahm, S.; Weinreb, S. M. Tetrahe-
dron Lett. 1981, 22, 3815. (b) Olah, G. A.; Prakash, S, G. K. S.; Arvanaghi,
M. Synthesis 1984, 228.
(3) For a review on the chemistry of the Weinreb amides, see: Sibi, M.
P. Org. Prep. Proced. Intl. 1993, 25, 15.
(4) Presented at the ACS National Meeting in New Orleans, LA, August
22-26, 1999; Abstract 513 ORG.
Scheme 1
(5) General Procedure for the Sequential Transformation of Amides
to â-Aminoketones: To a solution of amide 1 (2.18 g, 13.2 mmol) in dry
THF (20 mL) at 0 °C was added a 1 M solution of vinylmagnesium bromide
(14.5 mL, 14.5 mmol) in THF within 1 min. After 10 min the mixture was
allowed to attain ambient temperature and was stirred for 1 h. The mixture
was quenched with water (15 mL) and after 15 min diluted with ethyl acetate
and washed twice with water. Organic layer was separated, concentrated,
and chromatographed on SiO2 (20% EtOAc-hexanes) to afford 2 (2.0 g,
77%) as a yellow oil: 1H NMR (300 MHz, CDCl3) δ 8.00 (m, 2H), 7.58-
7.40 (m, 2H), 3.50 (s, 3H), 3.28 (t, 2H, J ) 4.2 Hz), 3.10 (t, 2H, J ) 4.2
Hz), 2.65 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 198.6, 136.7, 132.7, 128.2,
127.7, 59.6, 55.2, 44.8, 35.9; HRMS calcd for C11H16NO2 194.1181, found
194.1183.
In a preliminary assessment of the generality of this
reaction, we tested several amides in the reaction with
† Dedicated to Professor Stephen Hanessian on the occasion of his 65th
birthday.
10.1021/ol9911122 CCC: $19.00 © 2000 American Chemical Society
Published on Web 11/25/1999