Aminolysis of esters or lactones promoted by NaHMDS-A general and efficient method for the preparation of N-aryl amides

Article abstract of DOI:10.1055/s-2001-16798

An efficient method for the preparation of N-aryl amides from anilines, esters or lactones promoted by NaHMDS is described. Advantages of this new method include high yields and mild reaction conditions which tolerate functional groups such as ketones and halides.

Full text of DOI:10.1055/s-2001-16798

LETTER
1485
Aminolysis of Esters or Lactones Promoted by NaHMDS-A General and
Efficient Method for the Preparation of N-Aryl Amides
Jianji Wang,* Miguel Rosingana, Robert P. Discordia, Nachimuthu Soundararajan, Richard Polniaszek
Process Research & Development Department, Pharmaceutical Research Institute, Bristol-Myers Squibb Co., New Brunswick, NJ 08903,
USA
Fax (732) 519-3240; E-mail: jianji.wang@bms.com
Received 3 April 2001
ester or lactone as shown in the Scheme, to give the corre-
Abstract: An efficient method for the preparation of N-aryl amides
sponding N-aryl amides in 88-99% yields (Table 1). In all
cases, complete conversion to the amide was observed by
from anilines, esters or lactones promoted by NaHMDS is de-
scribed. Advantages of this new method include high yields and
HPLC analysis. Good to excellent yields have been
achieved including reactions involving sterically hindered
esters (Entries 3, 6, 7, and 8). In these cases, no diminution
of the reaction rate was observed. Moreover, this new
method can be applied to the preparation of N-aryl amides
containing functional groups which are incompatible with
strongly nucleophilic bases, e.g. n-BuLi (Entries 1, 2, 4,
and 5).
mild reaction conditions which tolerate functional groups such as
ketones and halides.
Key words: aminolysis, amides, anilines, esters, halides
The most common method for the preparation of N-aryl
amides is by reaction of anilines with carboxylic acids, an-
hydrides and acyl halides.1 Although esters and lactones
are stable and easily handled, preparation of N-aryl
amides via aminolysis has not been widely employed be-
cause of the poor nucleophilicity of N-aryl amines and,
subsequently, their poor reaction rates. Over the past 40
years, a variety of metal amides such as LiNR2,2,3
The presence of NaHMDS is required for this reaction. In
two control experiments corresponding to entries 1 and 2
in Table 1, no products were produced in the absence of
NaHMDS, even under forcing conditions. We also found
that the reaction worked equally well regardless of the or-
der of addition. For example, mixing an appropriate
aniline with NaHMDS and adding the corresponding ester
gave the same result as when NaHMDS was added to a
premixed aniline/ester solution (Entries 1 and 7).
NaNR2,4-7 XMgNR2,8 R3SnNR2,9,10 R2AlNR2,11-14 and
15,16
Ti(NR2)4
have been used to enhance the reactivity of
anilines. More recently, Marnoka and coworkers17 report-
ed the preparation of aromatic sec-amides from esters and
lactones using bislithium amides generated by treatment
of a primary aniline with 2 equivalents of n-BuLi. How-
ever, these conditions often preclude using this method in
the presence of halides or carbonyl functionalities. In the
course of our research, we needed to access N-aryl amides
from the corresponding anilines and esters or lactones.
Activation methods using Al, Sn, and Ti were not desir-
able for large scale processes due to environmental con-
cerns. We therefore evaluated activation methods using
Li, Na, and Mg based reagents. These methods failed to
give satisfactory yields for our substrates; thus, we fo-
cused on the development of a new method that would be
amenable to large scale production of N-aryl amides.
We briefly examined application of this method for the
preparation of N-alkyl amides. Although complete con-
sumption of the esters was observed, the reactions were
not as efficient. In the cases examined, lower yields were
obtained because of the production of undesired by-prod-
ucts (Table 2).
The observed difference between anilines and alkyl
amines in the reaction with esters or lactones promoted by
NaHMDS can be attributed to difference in the N-H acid-
ity. NaHMDS (pKa 30)18 would totally deprotonate
anilines (pKa 25).18 However, alkyl amines (pKa 35)18 can
not be deprotonated by NaHMDS to their corresponding
salts. Since the alkali salts are generally more nucleophilic
than neutral alkyl amines, the reaction of anilines with es-
ters or lactones is more efficient.
Encouraged by the results obtained in the case of entry 3
in Table 1, a series of anilines were treated with 1.5 to 2.0
equivalents of NaHMDS and reacted with the appropriate
R2
R2
N
R2
N
R3
NH
R3COOR4
NaHMDS
R1
R1
Na
R1
O
0 °C to r.t
1
2
3
R1 = H, F,Br, I, OMe, CF3, PhCO; R2 = H, Me; R3 = H, alkyl, aryl; R4 = Me, Et, t-Bu
Scheme
Synlett 2001, No. 9, 1485–1487 ISSN 0936-5214 © Thieme Stuttgart · New York

1486
J. Wang et al.
LETTER
Table 1 Preparation of Aryl Amides by Aminolysis of Lactones or Esters Mediated by NaHMDSa
Entry
1
Aryl Amines
Esters (eq)
NaHMDS (eq)b
1.5
Products
I
Isolated Yield (%)
F3C
I
F3C
O
PhCOOMe (1.1)
94
NH2
N
H
Ph
H
N
NH2
OH
O
O
O
O
(1.5)
O
2
3
2.0
1.5
88
96
F3C
F3C
F3C
O
Me3COOMe (1.2)
EtOAc (1.5)
NH2
N
H
F3C
I
I
O
4
5
1.5
1.5
99
95
NH2
N
H
Me
F
F
Br
F
F
Br
O
HCOOEt (1.5)
O
NH2
NH2
N
H
H
F
F
F
F
O
6
(1.1)
1.5
90
O
N
H
F3C
OMe
Cl
O
OMe
Cl
F3C
EtOOC
N
(1.1)
7
8
1.5
1.5
92
89
H
NH2
MeO
MeO
O
Me3COOMe (1.5)
NH
Me
N
Me
a) All reactions were carried out in THF for 2 h from 0 °C to r.t.
b) NaHMDS (1 M in THF) was from Aldrich.
In conclusion, this new method has considerable utility
for the preparation of aryl amides, especially where one
requires mild reaction conditions and high yielding trans-
formations.
and allowed to warm to r.t. over a period of 20 min. After stirring at
room temperature for 2 h, the reaction was quenched by the addition
of saturated aqueous NH4Cl (50 mL). The mixture was partitioned
between EtOAc (300 mL) and water (200 mL). The aqueous layer
was extracted with EtOAc (2 100 mL). The combined organic so-
lution was washed with brine (200 mL), dried over anhydrous
Na2SO4, filtered and concentrated in vacuo to give N-[4-(trifluo-
romethyl)phenyl]-trimethylacetamide (43.7 g, 96% yield, HPLC
Experimental
Preparation of N-[4-(trifluoromethyl)phenyl]-trimethylaceta-
mide (Entry 3)
1
AP 99) as a white solid. MS: (M+H)+ 246; H NMR (400 MHz,
CDCl3): 7.64 (d, J = 8.8, 2H), 7.54 (s, br, 1H, N-H), 7.53 (d,
J = 8.8, 2H), 1.30 (s, 9H); 13C NMR (100 MHz, CDCl3): 176.6(CO),
140.8, 125.6, 125.9 (2C), 123.7 (J = 275, CF3), 119.5(2C), 40.5,
28.2.
NaHMDS in THF (1.0 M, 279 mL, 0.279 mmol) was added over 30
min to a solution of 4-trifluoromethylaniline (30 g, 0.186 mol) and
methyl trimethylacetate (25.9 g, 0.223 mol) in THF (150 mL) at
0 °C. The resulting brown solution was stirred at 0 °C for 10 min
Synlett 2001, No. 9, 1485–1487 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Aminolysis of Esters or Lactones
1487
Table 2 Preparation of Alkyl Amides by Aminolysis of Lactones or Esters Mediated by NaHMDSa
Entry
Esters (eq)
COOMe
Alkyl Amines (eq)
PhCH2NH2 (1.1)
NaHMDS (eq)b
(1.5)
Products
Isolated Yield (%)
76
1
CONHCH2Ph
t-BuNH2 (1.1)
(1.5)
(1.5)
26
56
2
COOMe
OMe
CONH-t-Bu
OMe
O
H
N
Cl
(2.0)
3
N
Cl
COOMe
a) All reactions were carried out in THF for 2 h from 0 °C to r.t.
b) NaHMDS (1 M in THF) was from Aldrich.
(11) Basha, A.; Lipton, M.; Weinreb, S. M. Tetrahedron Lett.
References and Notes
1977, 4171.
(12) Dole, R. E.; Nicolau, K. C. J. Am. Chem. Soc. 1985, 107,
(1) Klausner, Y. S; Bodansky, M. Synthesis 1972, 453.
(2) Yang K.-W.; Gannon, J. G.; Rose, J. G. Tetrahedron Lett.
1970, 21, 1791.
(3) Ruggeri, R. B.; Heathcock, C. H. J. Org. Chem. 1987, 52,
5745.
(4) De Feo, R. J.; Strickler, P. D. J.Org. Chem. 1963, 28, 2915.
(5) Huebner, C. F.; Lucas, R.; MacPhilamy, B.; Troxell, H. A. J.
Am. Chem. Soc. 1955, 77, 469.
1695.
(13) Hart, D. J.; Hong, W.-P.; Hsu, L.-Y. J. Org. Chem. 1987, 52,
4665.
(14) Sim, T. B.; Yoon, N. M. Synlett 1994, 10, 827.
(15) Wang, W. B.; Roskamp, E. J. J. Org. Chem. 1992, 57, 6101.
(16) Smith, L. A.; Wang, W. B.; Burnell, C. C.; Roskamp, E. J.
Synlett 1993, 850.
(17) Ooi, T.; Tayama, E.; Yamada, M.; Maruoka, K. Synlett 1999,
6, 729.
(6) Singh, B. Tetrahedron Lett. 1971, 321.
(7) Williams, J.M.; Jobson, R. B.; Yasuda, N.; Marchesini, G.;
Dolling, U. H.; Grabowski, E. J. Tetrahedron Lett. 1995, 36,
5461.
(18) March, J. "Advanced Organic Chemistry", 4th Ed., pp 250-
252.
(8) Bassett, H. L.; Thomas, C. R. J. Chem. Soc. 1954, 1188.
(9) George, T. A.; Lappert, M. F. J. Chem. Soc. (A) 1969, 992.
(10) Chandra, G.; George, T. A.; Lappert, M. F J. Chem. Soc.
Chem. Commun. 1969, 2565.
Article Identifier:
1437-2096,E;2001,0,09,1485,1487,ftx,en;S03401ST.pdf
Synlett 2001, No. 9, 1485–1487 ISSN 0936-5214 © Thieme Stuttgart · New York