Efficient synthesis of aromatic sec-amides from esters: Synthetic utility of bislithium amides

Article abstract of DOI:10.1055/s-1999-2731

Convenient, efficient preparation of aromatic sec-amides from esters has been accomplished using dilithium amides which are easily prepared by treatment of aromatic amines with 2 equiv of BuLi in THF. This new method allows a facile formation of amide bond even with sterically hindered esters.

Full text of DOI:10.1055/s-1999-2731

LETTER
729
Efficient Synthesis of Aromatic sec-Amides from Esters: Synthetic Utility of
Bislithium Amides
Takashi Ooi, Eiji Tayama, Masao Yamada, Keiji Maruoka*
Department of Chemistry, Graduate School of Science, Hokkaido University, Sapporo 060-0810, Japan
Fax +81 (11) 7462557; E-mail: maruoka@sci.hokudai.ac.jp
Received 1 March 1999
methyl methacrylate can be readily converted to the cor-
Abstract: Convenient, efficient preparation of aromatic sec-amides
responding aminolysis products (entry 7), and lactone was
from esters has been accomplished using dilithium amides which
also found to be a good substrate for the present amide for-
mation process, producing the hydroxy amide in high
yield (entry 8).
are easily prepared by treatment of aromatic amines with 2 equiv of
BuLi in THF. This new method allows a facile formation of amide
bond even with sterically hindered esters.
Key words: aminolysis, esters, aromatic amines, dilithium amides,
aromatic sec-amides
A typical experimental procedure follows (entry 1 in Ta-
ble 1): To a solution of aniline (100 mL, 1.1 mmol) in THF
(5 mL) was added a 1.52 M hexane solution of BuLi (1.45
mL, 2.2 mmol) at 0 °C and the mixture was stirred at room
temperature for 1 h. After cooling to -78 °C, ethyl pro-
pionate (115 mL, 1.0 mmol) was added dropwise and the
stirring was continued at this temperature for an additional
1 h. The reaction was quenched with saturated NH4Cl and
extractive workup was performed with ethyl acetate. The
organic extracts were dried over Na2SO4 and concentrat-
ed. Purification of the residue by column chromatography
on silica gel (hexane/ethyl acetate = 2:1 as eluant) gave N-
phenyl propionamide (141 mg, 0.95 mmol; 95% yield) as
a white crystal.
Aminolysis of esters is an important synthetic transforma-
tion and a variety of metal amides have been elaborated to
enhance reactivity and selectivity.1 Despite the ease of
preparation and versatility, lithium amides have not found
much application for this purpose since the first introduc-
tion as an aminolysis agent in 1970 because of relatively
poor nucleophilicity,2 particularly in the case of aromatic
amides.3 In contrast to previously utilized monolithium
amides, we here wish to report that dilithium amides of
type A, simply prepared from aromatic amines and 2
equiv of BuLi in THF, exhibit high reactivity and enable
the facile aminolysis of esters under very mild conditions
as illustrated in Scheme 1.
Acknowledgement
This work was partially supported by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Science, Sports and Cul-
ture, Japan.
O
Li
Li
RCO2R'
-78 °C
BuLi
Ar
ArNH2
Ar
N
R
N
THF
0 °C~r.t.
H
References and Notes
A
80~98%
Scheme 1
(1) Na: Huebner, C. F.; Lucas, R.; MacPhillamy, H. B.; Troxell,
H. A. J. Am. Chem. Soc. 1955, 77, 469. Singh, B. Tetrahedron
Lett. 1971, 321. Mg: Bassett, H. L.; Thomas, C. R. J. Chem.
Soc. 1954, 1188. Houghton, R. P.; Williams, C. S.
Tetrahedron Lett. 1967, 3929. Williams, J. M.; Jobson, R. B.;
Yasuda, N.; Marchesini, G. Tetrahedron Lett. 1995, 36, 5461.
Al: Basha, A.; Lipton, M.; Weinreb, S. M. Tetrahedron Lett.
1977, 4171. Rao, V. B.; George, C. F.; Wolff, S.; Agosta, W.
C. J. Am. Chem. Soc. 1985, 107, 5732. Hart, D. J.; Hong, W.-
P.; Hsu, L.-Y. J. Org. Chem. 1987, 52, 4665. Shimizu, T.;
Osako, K.; Nakata, T. Tetrahedron Lett. 1997, 38, 2685. Ti:
Weingarten, H.; White, W. A. J. Am. Chem. Soc. 1966, 88,
850. Weingarten, H.; Miles, M. G. J. Org. Chem. 1968, 33,
1506. Chandra, G.; George, T. A.; Lappert, M. F. J. Chem.
Soc. (C) 1969, 2565. Sn: George, T. A.; Lappert, M. F. J.
Chem. Soc. (A) 1969, 992. Ricci, A.; Romanelli, M. N.;
Taddei, M. Synthesis 1983, 319.
Treatment of aniline in THF with 2 equiv of BuLi at
0 °C~room temperature for 1 h4 and subsequent reaction
with ethyl propionate at -78 °C for 1 h gave rise to N-phe-
nylpropionamide cleanly in 95% isolated yield (entry 1,
Table 1).5 It should be noted that none of the condensation
and alkylation products such as ethyl 2-methyl-3-oxopen-
tanoate, 3-heptanone or 5-ethyl-5-nonanol were obtained.
Other selected examples summarized in Table 1 clearly
demonstrate the usefullness of this new method for the
facile preparation of a variety of aromatic sec-amides.
Neither electron donating nor withdrawing properties of
the aromatic substituents of aniline affect the efficiency of
the aminolysis (entries 2, 3 and 4). Sterically hindered 1-
adamantanecarboxylic acid methyl ester, on reaction with
dilithium anilide at 0 °C, afforded the corresponding sec-
amide in 91% yield (entry 6), revealing the characteristic
feature of dilithium amide. a,b-Unsaturated esters such as
(2) Yang, K.-W.; Cannon, J. G.; Rose, J. G. Tetrahedron Lett.
1970, 1791.
(3) For the application, see: Ruggeri, R. B.; Heathcock, C. H. J.
Org. Chem. 1987, 52, 5745.
Synlett 1999, No. 6, 729–730 ISSN 0936-5214 © Thieme Stuttgart · New York

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T. Ooi et al.
LETTER
(4) Treatment of 4-fluoroaniline with BuLi (2 equiv) in THF-d8
at 0 °C~room temperature for 1 h and the resulting solution
was directly subjected to 1H NMR analysis, which showed
total disappearance of the amine proton signal. This result,
together with the fact that none of the butylation products were
obtained, could confirm the complete generation of dilithium
amides under the conditions.
(5) N-phenylpropionamide was obtained in 47% yield with
monolithium amide under the otherwise identical conditions.
Article Identifier:
1437-2096,E;1999,0,06,0729,0730,ftx,en;Y04599ST.pdf
Synlett 1999, No. 6, 729–730 ISSN 0936-5214 © Thieme Stuttgart · New York