A convenient aminolysis of esters catalyzed by 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) under solvent-free conditions

Article abstract of DOI:10.1016/j.tetlet.2007.03.146

Aminolysis of esters by using the organocatalyst 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) is reported. Secondary and tertiary amides were synthesized from alkyl or aryl esters with a variety of primary and secondary amines in good to excellent yields (60-94%) under solvent-free conditions (SFC).

Full text of DOI:10.1016/j.tetlet.2007.03.146

Tetrahedron Letters 48 (2007) 3863–3866
A convenient aminolysis of esters catalyzed by 1,5,7-
triazabicyclo[4.4.0]dec-5-ene (TBD) under solvent-free conditions
*
´
Cyrille Sabot, Kanduluru Ananda Kumar, Stephane Meunier and Charles Mioskowski
`
´
Laboratoire de Synthese Bio-Organique, UMR 7175/LC1-CNRS, Universite Louis Pasteur de Strasbourg,
74 Route du Rhin, B.P 60024, 67401 Illkirch Graffenstaden cedex, France
Received 7 March 2007; revised 21 March 2007; accepted 26 March 2007
Available online 30 March 2007
Abstract—Aminolysis of esters by using the organocatalyst 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) is reported. Secondary and ter-
tiary amides were synthesized from alkyl or aryl esters with a variety of primary and secondary amines in good to excellent yields
(60–94%) under solvent-free conditions (SFC).
Ó 2007 Elsevier Ltd. All rights reserved.
The amide bond is among the most common chemical
function present in natural or synthetic organic mole-
cules.1 Few protocols are reported for the direct amino-
lysis of alkyl and aryl esters. Most of them involve harsh
conditions such as the use of strong basic reagents
(sodium/potassium hydrides, alkoxides and alkyl-
lithium),2–4 or metallic reagents.5–7 More recently,
DMF), only THF afforded a similar TBD reactivity.
The recent and successful use of solvent-free conditions
(SFC) for ester aminolysis encouraged us to consider
our optimized protocol under such conditions.4 Indeed
the solvent-free aminolysis in the presence of 30 mol %
of TBD afforded amide 3 after 12 h at room temperature
(75%) as well as at 75 °C (93%) (Scheme 1). Stereochem-
istry was conserved during the reaction (ee > 99%, deter-
mined by chiral HPLC).
´
Woodward and Joullie reported the amide bond forma-
tion from esters using AlMe3ÆDABCO complex8 and
bislithium amides,9 respectively.
The screening of a collection of oxygen and nitrogen
containing bases indicated that only TBD was efficient
under the solvent-free conditions at room temperature
for the synthesis of 3 (Table 1). Potassium tert-butoxide
and the bifunctional organocatalyst 2-hydroxypyridine
gave the amide product in low yield (entries 1–2).15
Nitrogen-containing bases other than TBD did not
afford the expected amide product (entries 3–8) after
12 h at room temperature.
Guanidines are widely used in organic synthesis as acid
scavengers and homogeneous base catalysts.10,11 Bicy-
clic guanidines such as the commercially available
TBD and its N-methyl derivative MTBD were shown
to catalyze a variety of reactions such as Michael addi-
tions,12 Henry reactions13 and transesterifications.14
In the course of our studies on the applications of gua-
nidine based catalysts, we decided to explore the use of
TBD for aminolysis. Initially, the aminolysis of methyl
phenylacetate 1 (1 equiv) by (S)-1-phenylethylamine 2
(1.2 equiv) was investigated. In toluene at 80 °C no
product formation was observed, whereas the use of
TBD (30 mol %) led to the expected amide 3 in 80%
yield. A larger quantity of TBD did not improve the
yield. The transformation was less efficient when more
polar solvents were used (CH2Cl2, CHCl3, CH3OH,
The optimized protocol was applied to various esters
and amines (Scheme 2).16
In the presence of a catalytic amount of TBD (0.3 equiv)
at 75 °C benzylamine reacted efficiently with methyl
O
O
TBD (30 mol%)
Ph
Ph
+ Ph
NH2
OMe
N
Ph
SFC, rt or 75 °C, 12 h
H
2
3
1
(75% or 93%)
Keywords: Aminolysis; TBD; Organocatalyst; Solvent-free conditions.
*
Scheme 1. Aminolysis of 1 catalyzed by TBD under solvent-free
Corresponding author. Tel.: +33 (0)3 90 24 42 97; fax: +33 (0)3 90 24
conditions.
43 06; e-mail: mioskow@aspirine.u-strasbg.fr
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.03.146

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C. Sabot et al. / Tetrahedron Letters 48 (2007) 3863–3866
Table 1. Bases screening for the synthesis of 3 from ester 1a
phenylacetate, methyl benzoate as well as with methyl
pentanoate affording the corresponding amides in very
good yields (Table 2, entries 1–3). The use of a more hin-
dered ester did not reduce the yield for the synthesis of
N-benzyl phenylacetamide (entry 4). Aniline as well as
bulky primary amines reacted with methyl phenylacetate
or benzyl benzoate in the presence of TBD leading to the
corresponding amides in yields above 75% (entries 5–8).
Secondary amines are well tolerated as shown by entries
9–11. Although primary amines are more reactive under
the studied procedure. Indeed the reaction of N-methyl-
ethylenediamine on methyl phenylacetate affords exclu-
sively the primary amide (entry 12). Ethanolamine
under our conditions led to the aminolysis reaction
affording N-(2-hydroxyethyl) phenylacetamide in 66%
yield (entry 13). Finally reaction of benzylamine with
c-butyrolactone led to the expected opening of the lac-
tone and amide formation in a good yield (entry 14).17
Entry
Catalyst
Yieldb (%)
1
2
3
4
5
6
7
8
9
t-BuOK
2-Hydroxypyridine
TEA
DMAP
DBN
Imidazole
TMG
MTBD
21
<2
0c
0c
0c
0c
0c
0c
TBD
75
a 1.0 equiv of ester, 30 mol % of catalyst and 1.2 equiv of amine, rt,
12 h.
b Crude yield on the basis of 1H NMR.
c Starting material was recovered.
O
O
TBD (30 mol%)
R3R4NH
R1 OR2
R1 NR3R4
SFC, 75 °C, 12 h
A mechanism for the reaction can be proposed by anal-
ogy with the work of Waymouth and Hedrick, who
studied the TBD catalyzed polymerization of cyclic
Scheme 2. Aminolysis reactions catalyzed by 30 mol % of TBD under
solvent-free conditions.
Table 2. Amides syntheses catalyzed by 30 mol % of TBD under solvent-free conditionsa
Entry
Ester
Amine
Productb
Yieldc (%)
94
O
O
Ph
Ph
NH2
NH2
1
Ph
N
H
Ph
OMe
O
O
2
83
Ph
Ph
N
H
Ph
Ph
OMe
O
O
3
4
93
92
Ph
Ph
NH2
NH2
N
Ph
OMe
H
O
O
O
O
O
Ph
Ph
Ph
Ph
Ph
N
H
Ph
OiPr
O
O
5
6
Ph–NH2
Ph
75
94
Ph
Ph
N
H
OMe
NH2
N
H
OMe
O
7
8
93 (ee > 99d)
Ph
N
H
Ph
Ph
NH2
NH2
OMe
Ph
O
O
94
Ph
N
H
Ph
Ph
Ph
Ph
Ph
Ph
O
O
O
N
H
9
89
94
Ph
Ph
N
N
Ph
OMe
OMe
O
O
10
NH

C. Sabot et al. / Tetrahedron Letters 48 (2007) 3863–3866
3865
Table 2 (continued)
Entry
Ester
Amine
Productb
Yieldc (%)
92e
O
O
Ph
HN
NH
11
N
Ph
OMe
N
Ph
O
O
O
O
H
N
H
N
12
13
14
Ph
78
66
60
Ph
Ph
N
H
NH2
OMe
OMe
O
HO
Ph
OH
NH2
N
H
O
O
O
HO
Ph
NH2
N
H
Ph
a All reactions were carried out with 1.0 equiv of ester (except entry 11), 30 mol % of catalyst and 1.2 equiv of amine, at 75 °C for 12 h.
b All the products were characterized by 1H, 13C NMR and mass spectroscopy.
c The yield refers to isolated products.
d Enantiomeric excess (ee) determined by chiral HPLC analysis using a chiral phase column (Chiralcel OD-H, n-hexane/EtOH (97:3), 1 mL/min
(tr1 = 21.83 min and tr2 = 28.51 min)).
e Reaction carried out with 2.0 equiv of ester, 30 mol % of catalyst and 1.0 equiv of diamine.
esters.18 This analogy is supported by the observation
of the inefficiency of MTBD for the catalysis of amino-
lysis despite a similar basicity than TBD (pKa values of
conjugate acid are 25.7 and 26.2, respectively). The pro-
posed mechanism is based on TBD acting as a bifunc-
tional nucleophilic organocatalyst. In a first step, TBD
reacts on the ester leading to intermediate I (Scheme
3) where the protonated nitrogen allows an easy proton
transfer affording the TBD amide II and liberating the
alcohol. Finally hydrogen bond activation of the amine
facilitates the amide formation and the regeneration of
TBD.
compared to other bases could be ascribed to its nucleo-
philicity and to a bifunctional nucleophilic mechanism.
Acknowledgments
The author would like to thank Rhodia and the CNRS
for financial support to C.S.
References and notes
1. (a) Hudson, D. J. Org. Chem. 1988, 53, 617; (b) Beckwith,
A. L. J. In The Chemistry of Amides: Synthesis of Amides;
Zabicky, J., Ed.; Interscience: New York, 1970; p 96; (c)
Trost, B. M.; Fleming, I. In Comprehensive Organic
Synthesis; Winterfeld, E., Ed.; Pergamon: Oxford, 1991;
Vol. 6.
2. Barrow, R. A.; Hemscheidt, T.; Liang, J.; Paik, S.; Moore,
R. E.; Tius, M. E. J. Am. Chem. Soc. 1995, 117, 2479.
3. Smith, M. B.; March, J. Advanced Organic Reactions:
Reactions, Mechanisms and Structure, 5th ed.; J. Wiley &
Sons: New York, 2001, p 510.
In summary, we have established that TBD, an inexpen-
sive and non toxic commercially available compound, is
an efficient organocatalyst for the aminolysis of a range
of esters in the presence of various amines under
solvent-free conditions. The superior activity of TBD
O
O
4. Perreux, L.; Loupy, A.; Delmotte, M. Tetrahedron 2003,
59, 2185, and references cited wherein.
N
R1 OR2
R1 NHR3
N
N
5. Riviere-Baudet, M.; Morere, A.; Dias, M. Tetrahedron
Lett. 1992, 33, 6453.
H
6. Weinreb, S. M.; Anderson, G. T.; Nylund, C. S. In
Encyclopedia of Reagents for Organic Synthesis; Paquette,
L. A., Ed.; Wiley: Chichester, 1995; Vol. 3, p 1997.
7. Houghton, R. P.; Williams, C. S. Tetrahedron Lett. 1967,
8, 3929.
R3NH2
N
N
N
-O
R1
N
N
N
8. Novak, A.; Humphreys, L. D.; Walker, M. D.; Wood-
ward, S. Tetrahedron Lett. 2006, 47, 5767.
H
O
O
R1
R2
´
9. Faler, C. A.; Joullie, M. M. Tetrahedron Lett. 2006, 47,
II
I
7229.
-R2OH
´
´
10. Kovacˇevic, B.; Maksic, Z. B. Org. Lett. 2001, 3, 1523.
11. Ballini, R.; Fiorini, D.; Maggi, R.; Righi, P.; Sartori, G.;
Sartorio, R. Green Chem. 2003, 5, 396.
Scheme 3. Mechanism proposed for the aminolysis of esters catalyzed
by TBD.

3866
C. Sabot et al. / Tetrahedron Letters 48 (2007) 3863–3866
12. Ye, W.; Xu, J.; Tan, C. T.; Tan, C. H. Tetrahedron Lett.
2005, 46, 6875.
13. Ma, D.; Pan, Q.; Han, F. Tetrahedron Lett. 2002, 43, 9401.
14. Schuchardt, U. L. F.; Vargas, R. M.; Gelbard, G. J. Mol.
Catal. A 1995, 99, 65.
10H), 6.27 (s, 1H), 4.38 (d, J = 4.5 Hz, 2H), 3.57 (s, 2H).
13C NMR (75 MHz, CDCl3): d 171.5, 138.7, 135.4, 129.8,
129.4, 129.0, 127.9, 127.8, 127.7, 44.1, 43.9. MS (m/z) =
226.12 (M+Å).
1
17. All new compounds were characterized by H, 13C NMR
15. Openshaw, H. T.; Whittaker, N. J. J. Chem. Soc. (C)
1969, 89.
and mass spectroscopy. N-(2-Hydroxyethyl)-2-phenylace-
tamide (Table 2, entry 13): 1H NMR (CDCl3, 300 MHz): d
7.23–7.33 (m, 5H), 6.27 (bs, 1H), 3.54–3.62 (m, 5H), 3.30–
3.35 (m, 2H). 13C NMR (CDCl3, 75 MHz): d 172.8, 135.0,
129.6, 129.2, 127.6, 62.0, 43.7, 42.8. MS (m/z) = 180.10
(M+Å). N-Benzyl-4-hydroxybutanamide (entry 14, Table
2): 1H NMR (CDCl3, 300 MHz): d 7.19–7.28 (m, 5H), 6.89
(b, 1H), 4.32 (d, J = 5.6 Hz, 2H), 4.02 (bs, 1H), 3.54–3.58
(m, 2H), 2.27–2.31 (m, 2H), 1.77–1.83 (m, 2H). 13C NMR
(CDCl3, 75 MHz): d 174.0, 138.5, 128.9, 127.9, 127.6, 62.0,
43.8, 33.7, 28.5. MS (m/z) = 194.10 (M+Å).
16. Representative procedure for the aminolysis reaction (Table
2, entry 1): To a stirred solution of methyl phenylacetate
(100 lL, 0.71 mmol) was added TBD (29.6 mg, 30 mol %)
followed by benzylamine (93 lL, 0.85 mmol) under nitro-
gen atmosphere. The reaction mixture was slowly warmed
to 75 °C and stirred for 12 h, allowed to cool to ambient
temperature and concentrated in vacuo. The residue
obtained was chromatographed on silica gel using 20%
ethyl acetate/cyclohexane as eluent to afford N-benzyl
phenylacetamide as a solid (453 mg, 94%), mp 119 °C. IR
(transmission, film KRS-5): 3291, 3084, 3032, 1643, 1552,
18. Pratt, R. C.; Lohmeijer, B. G. G.; Long, D. A.;
Waymouth, R. M.; Hedrick, J. L. J. Am. Chem. Soc.
2006, 128, 4556.
1
1454 cmÀ1; H NMR (CDCl3, 300 MHz): d 7.20–7.30 (m,