Aminolysis of allyl esters with bislithium aryl amides

Article abstract of DOI:10.1016/j.tetlet.2006.07.136

The aminolysis of allyl esters with bislithium amides is reported. Tertiary aryl amides were synthesized in a one-pot reaction with bislithium amides and a suitable electrophile in good yields. The scope of this reaction was demonstrated with a variety of anilines and aminopyridines and applied to the synthesis of triphenylmethylacetamides.

Full text of DOI:10.1016/j.tetlet.2006.07.136

Tetrahedron Letters 47 (2006) 7229–7231
Aminolysis of allyl esters with bislithium aryl amides
*
´
Catherine A. Faler and Madeleine M. Joullie
Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104-6323, USA
Received 17 April 2006; revised 20 July 2006; accepted 26 July 2006
Available online 22 August 2006
Abstract—The aminolysis of allyl esters with bislithium amides is reported. Tertiary aryl amides were synthesized in a one-pot reac-
tion with bislithium amides and a suitable electrophile in good yields. The scope of this reaction was demonstrated with a variety of
anilines and aminopyridines and applied to the synthesis of triphenylmethylacetamides.
Ó 2006 Elsevier Ltd. All rights reserved.
OCH3
Several reactions are known for the aminolysis of simple
O
alkyl esters.1 Due to their stability, alkyl esters are not
N
commonly used in the synthesis of amides and extreme
conditions are often required to convert unactivated
esters directly to amides.2 A convenient and mild
synthesis of sec-amides from methyl and ethyl esters
using dilithium amides has been reported by Maruoka
and co-workers.3
Li NC H OCH
3
THF, -78 C, 78%
2
6
4
H
N
o
Bn
2
O
NaH, MeI
THF, 98%
OCH3
N
Bn
1
OCH3
O
We have used the method employed by Maruoka on
amino acid derivatives en route to bicyclic cyclopropyl-
amines.4 In our synthesis, a tertiary amide (3) was
required and prepared by reaction of the secondary
amide (2) with sodium hydride and methyl iodide.
(Fig. 1) We discovered that quenching the aminolysis
reaction with methyl iodide provided N,N-4-methoxy-
phenyl methyl amide (3a) directly from the methyl ester
in good yield. In a similar fashion, N,N-4-methoxyphen-
yl benzyl amide (3b) was also prepared. This one-pot
reaction gives the tertiary amide in comparable yields
as the two-step protocol.
o
Li NC H OCH , THF, -78 C;
2
6
4
3
o
N
R
MeI, 20 C, 75%
BnBr, 20 C, 73%
o
N
Bn
3a: R = Me
3b: R = Bn
Figure 1. Tertiary amide synthesis.
steps in our synthesis. Application of the conditions
reported by Maruoka to N,N-diallyl phenylalanine allyl
ester (4) resulted in aminolysis of the ester in poor yield,
but with recovery of starting material. When the temper-
ature was raised from À78 °C to 20 °C over several
hours, the sec-amide product (5) was isolated in 79%
yield (Fig. 2). Similarly to the phenylalanine methyl
ester, the tert-amide (6) could be obtained in one step
in comparable yield.
The robust allyl ester is often used as a protecting group
in peptide synthesis because it can be removed mildly
and selectively with a Pd(0) catalyst.5 The resulting acid
is then free to undergo further modification. There are
very few examples, however, of direct aminolysis of allyl
esters, the exception being the Staudinger ligation.6 We
attempted to convert an allyl ester directly to an aro-
matic amide as this procedure would eliminate several
We confirmed the scope of this reaction with various
anilines (Table 1).17 The reaction is unaffected by the
electronic properties of the anilines, but yields decrease
when the substituents are incompatible with butyl lith-
ium (entry 5). Additionally, benzyl benzoate (entry 18)
underwent facile aminolysis with anisidine and we
predict that benzyl esters will react with a variety of
aromatic amines with the same success.
Keywords: Aromatic amide; Allyl ester aminolysis; Triphenylmethyl
amide.
*
Corresponding author. Tel.: +1 215 898 3158; fax: +1 215 573
9711; e-mail: mjoullie@sas.upenn.edu
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.07.136

7230
C. A. Faler, M. M. Joullie´ / Tetrahedron Letters 47 (2006) 7229–7231
OCH3
O
HO
O
O
i) BuLi, THF
N
Li2NC6H4OCH3
THF, 79%
H
O
N
H
N
ii) Allyl benzoate
67%
7
8
5
O
O
O
H2N
i) LDA, THF
NaH, MeI
THF, 98%
N
ii) Allyl benzoate
N
H
OCH3
4
O
58% (42% recovered SM)
i) Li2NC6H4OCH3
THF
ii) MeI, 71%
N
Figure 3. Aminolysis in the presence of a ketone.
N
Me
6
Figure 2. Synthesis of an amide from phenylalanine allyl ester.
H
N
n
OCH3
O
In the presence of a ketone moiety, insertion of a butyl
group occurs (entries 11 and 12).18 When a less nucleo-
philic lithium base is used, aminolysis proceeds with
retention of the ketone (Fig. 3). Use of lithium diisopro-
pyl amine results in 58% yield and recovery of the start-
ing ester.
9: n = 0 (69%)
10: n = 1 (59%)
H
H
N
N
N
n
n
N
O
We also found, in agreement with Maruoka’s results,
that aminolysis of allyl benzoate with a monolithium
amide gave a low yield (19%).
O
13: n = 0 (50%)
14: n = 1 (89%)
11: n = 0 (26%)
12: n = 1 (71%)
Aminopyridines, which are poor nucleophiles, also
afforded good yields (entries 13–17). We were concerned
that the aminopyridine product could undergo ortho-
lithiation.7 Though we did not see evidence of side
reactions, we attempted to trap any possible lithiated
intermediate to confirm our assumption that pyridyl
benzamide was not reacting further. When the aminoly-
sis was complete, as shown by TLC, chlorotrimethyl-
silane was added to the reaction, but no silylated
product was isolated. We are, therefore, confident that
no unwanted lithiation occurs.
Figure 4. Triphenylmethylamides (yield from methyl ester).
This reaction was applied to methyl and allyl esters of
triphenylacetic acid and triphenylpropionic acid. Figure
4 shows some of the synthesized compounds. Amides 9,
10, and 11 were first made by Hergenrother and
co-workers as part of a library of compounds targeted
to induce apoptosis in melanoma cells.19 Although
conversion of the triphenylacetic and propionic acid
Table 1. Products of aminolysis
Entry Ester
Amine
Product
Yield Mp (lit.) °C
(%)
1
2
3a
4
Allyl benzoate
Aniline
Anisidine
Anisidine
3,5-Dimethoxyaniline
4-Nitroaniline
4-Aminophenol
3-Aminophenol
2-Aminophenol
4-Fluoroaniline
2,4-Dichloroaniline
2-Aminobenzophenone
4-Aminobenzophenone
4-Aminopyridine
3-Aminopyridine
2-Aminopyridine
N-Phenylbenzamide
93
93
92
65
21
62
71
58
71
74
79
162–164 (163)8
N-(4-Methoxyphenyl)benzamide
N-(4-Methoxyphenyl)-N-methylbenzamide
N-(3,5-Dimethoxyphenyl)benzamide
N-(4-Nitrophenyl)benzamide
N-(4-Hydroxyphenyl)benzamide
N-(3-Hydroxyphenyl)benzamide
N-(2-Hydroxyphenyl)benzamide
N-(4-Fluorophenyl)benzamide
N-(2,4-Dichlorophenyl) benzamide
N-[2-(1-Hydroxy-1-phenylpentyl)phenyl]-benzamide
N-[4-(1-Hydroxy-1-phenylpentyl)-phenyl]-benzamide (7) 67
N-Pyridin-4-ylbenzamide
N-Pyridin-3-ylbenzamide
N-Pyridin-2-ylbenzamide
134–135 (153–155)9
89–90 (143–145)10
175–179 (197–198)11
214–216 (216)12
167–169 (173)8
168–169 (168)
175–177 (184–185)13
111–113 (115)14
142–145
5
6b
7b
8b
9
10
11
12
13
14
15
16
17
18
110–112
86
70
84
69
43
77
205–207 (210–211)7
113–115 (118)15
81–83 (82–84)7
122–123
2-Amino-5-chloropyridine N-(4-Chloropyridin-2-yl)benzamide
3-Amino-2-chloropyridine N-(2-Chloropyridin-3-yl)benzamide
82–83 (89–90)16
Benzyl benzoate Anisidine
N-(4-Methoxyphenyl)benzamide
a 3 Equiv of methyl iodide were added and the reaction stirred for 3 h at room temperature.
b Additional equivalents (3.3) of butyl lithium were used.

C. A. Faler, M. M. Joullie´ / Tetrahedron Letters 47 (2006) 7229–7231
7231
J. Org. Chem. 1991, 56, 1713; (d) Kalivretenos’st, A.;
Nakanishi, K. J. Org. Chem. 1993, 58, 6596; (e) Roe, E.;
Scanlan, J.; Swern, D. J. Am. Chem. Soc. 1949, 71, 2215.
2. Chakrabarti, J.; Hotten, T.; Pullar, I.; Tye, N. J. Med.
Chem. 1989, 32, 2573.
chlorides to the triphenylmethyl amides worked well in
most cases, it failed with several aminopyridines (12–
14). The bislithium amide of 3-amino- and 4-aminopyri-
dine succeeded in preparing these triphenylmethyl
amides in good yield. Accordingly, tertiary amides were
also produced (approx. 35% yield). The ease of synthesis
of these amides illustrates the value of this methodology.
3. Ooi, T.; Tayama, E.; Yamada, M.; Maruoka, K. Synlett
1999, 6, 729.
´
4. Faler, C.; Joullie, M. Heterocycles 2006, 67, 519.
5. (a) Kocienski, P. In Protecting Groups; Georg Thieme:
Stuttgart, 2004; pp 417–424; (b) Kunz, H.; Waldmann, H.
Angew. Chem., Int. Ed. Engl. 1984, 23, 71; (c) Friedrich-
Bochnitschek, S.; Waldmann, H.; Kunz, H. J. Org. Chem.
1989, 54, 751.
In conclusion, the synthetic utility of bislithium amides
was extended to include the aminolysis of allyl and benz-
yl esters. We have also demonstrated a facile, one-pot
synthesis of tertiary aromatic amides from unactivated
esters.
6. Restituyo, J.; Comstock, L.; Petersen, S.; Stringfellow, T.;
Rajski, S. Org. Lett. 2003, 5, 4357.
7. Jozwiak, A.; Brzezinski, J.; Plotka, M.; Szczesniak, A.;
Malinowski, Z.; Epsztajn, J. Eur. J. Org. Chem. 2004,
3254.
Acknowledgements
8. (a) Haridazan, V.; Ajayaghosh, A.; Pillai, V. J. Org. Chem.
1987, 52, 2662; (b) Ghiaci, M.; Bakhtiari, K. Synth.
Commun. 2001, 31, 1803.
9. Lai, Y.; Huang, L.; Lee, K.; Xiao, Z.; Bastow, K.;
Yamori, T.; Kuo, S. Bioorg. Med. Chem. 2005, 13, 265.
10. Hadjeri, M.; Mariotte, A.; Boumendjel, A. Chem. Pharm.
Bull. 2001, 49, 1352.
We thank the NSF (CHEM-1030958), Wyeth and the
University of Pennsylvania for financial support. Addi-
tionally, a fellowship provided by the NSF (DGE-
0231923 005) aided this work. We are also grateful to
Dr. George Furst, Dr. Patrick Carroll, and Dr. Rakesh
Kohli for technical assistance.
11. Babu, V.; Vasanthakumar, G.; Tantry, S. Tetrahedron
Lett. 2005, 46, 4099.
12. Hey, D.; Leonard, J.; Rees, C. J. Chem. Soc. 1963, 5251.
13. Ikenoya, S.; Masui, M.; Ohmori, H.; Sayo, H. J. Chem.
Soc., Perkin Trans. 2 1974, 571.
14. Chattaway, F.; Orton, K.; Hurtly, W. Chem. Ber. 1899,
32, 3637.
Supplementary data
Experimental procedures and spectroscopic data for all
compounds are available. The supplementary data asso-
ciated with this article are available online in Science
Direct, at doi:10.1016/j.tetlet.2006.07.136.
15. Pentimalli, L. Tetrahedron 1960, 9, 194.
16. Couture, A.; Grandclaudon, P. Synthesis 1985, 533.
17. Compounds were purified by recrystallization or column
chromatography and isolated yields are reported. Ethyl
acetate/petroleum ether (40:60) and acetone/hexanes
(50:50) were typical solvent systems.
References and notes
1. For some examples, see: (a) Barrow, R.; Hemscheidt, T.;
Liang, J.; Paik, S.; Moore, R.; Tiu, M. J. Am. Chem. Soc.
1995, 117, 2479; (b) Fellincer, L.; Audrieth, L. J. Am.
Chem. Soc. 1938, 60, 579; (c) Witzeman, J.; Nottingham, W.
18. The regiochemistry of the butyl group insertion was
confirmed by X-Ray crystallography.
19. Dothager, R.; Putt, K.; Allen, B.; Leslie, B.; Nesterenko,
V.; Hergenrother, P. J. Am. Chem. Soc. 2005, 127, 8686.