A single vessel protocol for the efficient formation of amide bonds from esters and lactones

Article abstract of DOI:10.1016/S0040-4039(02)01657-X

A single vessel solution phase protocol for the formation of amide bonds from esters or lactones has been developed. The process involves hydrolysis of the ester or lactone followed by amide bond formation utilizing resin-bound carbodiimide. Excess reagen

Full text of DOI:10.1016/S0040-4039(02)01657-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 7221–7223
A single vessel protocol for the efficient formation of amide
bonds from esters and lactones
Noriyuki H. Kawahata, Jeseca Brookes and Gergely M. Makara*
NeoGenesis Pharmaceuticals, Inc., 840 Memorial Drive, Cambridge, MA 02139, USA
Received 1 July 2002; accepted 7 August 2002
Abstract—A single vessel solution phase protocol for the formation of amide bonds from esters or lactones has been developed.
The process involves hydrolysis of the ester or lactone followed by amide bond formation utilizing resin-bound carbodiimide.
Excess reagents and reactants are sequestered using polymer-supported scavengers to yield the desired products in high yields and
purities without the need for extraction or chromatography. © 2002 Elsevier Science Ltd. All rights reserved.
The recent development of a variety of reagents
attached to solid supports has brought about the
expansion of the synthetic methodologies that can be
used to populate compound collections.1 The applica-
tion of solution phase synthetic techniques towards
combinatorial chemistry has allowed for the rapid
development of combinatorial libraries possessing sev-
eral advantages over those synthesized using solid
phase techniques.2 During development, these reactions
can be easily monitored and do not require cleavage for
unambiguous characterization of intermediates. A more
efficient use of reactants is realized in solution phase
chemistry as solid phase reactions often rely on excess
reagents to drive the reaction to completion. Addition-
ally, the diversity of the reactants in solution phase
combinatorial chemistry is not limited by the cleavage
conditions required to release the desired product from
the solid support.
efficient and provides the desired products in high
yields, the use of DIBAL limits the diversity of the
functional groups that can exist on either the amine or
the carboxylic acid components. The conversion of
2,2,2-trihaloethyl esters to amides using phospho-
rous(III) reagents was also accomplished in one-pot.5
However, for this procedure to be effective, the 2,2,2-
trihaloethyl ester would have to be synthesized due to
the lack of a diverse set of commercially available
trihaloesters. It is important to note that both of the
above procedures utilize a chromatographic step to
achieve high purities. Therefore, a flexible method that
can be readily applied to the efficient syntheses of a
large number of compounds in parallel without need
for chromatographic purification was sought.
The use of esters as a starting point necessitated a
hydrolysis protocol that would allow for an efficient
sequestration of the by-products and excess reactants.
Tetraalkylammonium hydroxides have previously been
shown to affect the hydrolysis of esters.6 Gratifyingly, it
was found that both aliphatic and aromatic esters were
readily hydrolyzed in THF at 50°C (Scheme 1). Treat-
ment of the crude reaction mixture with polymer-bound
A large number of methodologies and reagents have
been developed for the formation of amide bonds on
solid phase.3 The number and functional diversity of
carboxylic acids and amines often make amide bond
formation a diversification step of choice for the expan-
sion and diversity of combinatorial libraries. The incor-
poration of amides in the middle of a synthetic scheme
typically requires a carboxylic acid that is often pro-
tected as an ester. A recent report described the conver-
sion of an ester or lactone to an amide using
DIBAL–amine complexes.4 Although this method is
Keywords: polymer-supported; scavenger; parallel; ester; amide.
* Corresponding author. Fax: 617-868-1515; e-mail: gregm@
neogenesis.com
Scheme 1. One-pot formation of amide bonds utilizing poly-
mer bound reagents and scavenging agents.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01657-X

7222
N. H. Kawahata et al. / Tetrahedron Letters 43 (2002) 7221–7223
toluenesulfonic acid (MP-TsOH)7 followed by filtration
and concentration of the filtrate yielded the correspond-
ing carboxylic acids in high yields and purities (data not
shown).
Table 1. Synthesis of amides (3a–f, 3i,j) and lactams (3g,h)
from a series of esters
In an effort to eliminate the filtration, washing and
concentration steps prior to the amide-bond formation,
the subsequent reaction was carried out in the same
well by adding the amine, 1-hydroxybenzotriazole
(HOBt) and polymer-bound carbodiimide resin8,9 to the
mixture (Scheme 1). Although the amides were formed
with the carbodiimide resin alone, addition of HOBt
significantly increased the final product yields and puri-
ties. The reaction was allowed to stir overnight at
ambient temperature. The excess amine was scavenged
using more MP-TsOH. Macroporous polymer-bound
carbonate resin (MP-carbonate)10 was used to extract
HOBt11 and any remaining carboxylic acid. Fortu-
itously, THF was found to be an appropriate solvent
for both steps. Filtration and concentration yielded the
desired products in high yields and purities.
The scope of the hydrolysis step was examined by
treating a range of esters to the above conditions. The
reactions were monitored by TLC and HPLC–MS, and
the results are summarized in Table 1. Several of the
coupling reactions incorporated an aromatic amine
(3b,d,f,h) as well as a more reactive alkyl amine
(3a,c,e,g,i,j).12 Aryl esters, including the more hindered
tert-butyl ester (3a,b) were cleanly hydrolyzed at 50°C
in THF overnight and gave the subsequent amides at
ambient temperatures. The method was tolerant to the
presence of ketone and hydroxyl functional groups
(entries 3c–f). A butyrolactone (entry 3g,h) was opened
and reacted to give the corresponding lactams (as
opposed to acyclic amides) with primary amines or
anilines. Coupling chiral amines to acids derived from
the hydrolysis of aliphatic esters (entries 3i,j) at elevated
temperatures resulted in the formation of two
diastereomers (6.5:1). This is most likely the result of
epimerization of the asymmetric center adjacent to the
original ester as only one product was detected when an
achiral amine was coupled to the subsequent carboxylic
acid. Epimerization in the basic milieu was significantly
reduced (10:1 diastereomeric ratio) by lowering the
temperature of the hydrolysis step to 4°C. It is notewor-
thy that hydrolysis of aryl esters was incomplete at
ambient temperatures but no remaining ester was
detected with the more labile alkyl esters
a
Amine A: 4-methylbenzylamine, B: p-anisidine, C: a-methylbenzyl-
b
c
amine. Isolated yield after filtration and concentration. As deter-
mined by ELSD-HPLC of the desired ion. Product is the corre-
sponding lactam, no acyclic amide was detected. Hydrolysis was
performed at 4°C, 10:1 diastereomeric ratio (6.5:1 diastereomeric
ratio at room temperature) was obtained. Hydrolysis was performed
at ambient temperatures, diastereomeric ratio was not determined due
to poor resolution of isomers.
d
e
f
Table 2. Synthesis of amides (3) from a series of amines
(2) and methyl 4-bromobenzoate
A family of amines was also successfully incorporated
using this methodology as illustrated in Table 2. A
hindered amine (3k), secondary amines (3l,m), Boc-pro-
tected amine (3o), and an amine containing a hydroxy
group (3n) gave the desired amides in high yields and
purities. Importantly, amines bearing an ester function-
ality (3p) gave the desired product in good yields. Thus,
the quaternary ammonium hydroxide became com-
pletely deactivated by sequestration with MP-TsOH.
This finding opens the avenue to the potential produc-
tion of polyamides after a simple filtration. If the amine
contains an ester moiety, the THF filtrate can conceiv-
ably be subjected to the same procedure to lead to
a
b
Isolated yield after filtration and concentration. As determined by
c
ELSD-HPLC of the desired ion. An equivalent amount of DIPEA
was added for the coupling step and treated with twice the amount of
TsOH resin during the scavenging step. In this case, the excess
d
amine was sequestered using PS-NCO.

N. H. Kawahata et al. / Tetrahedron Letters 43 (2002) 7221–7223
7223
Kates, S. A.; Albericio, F., Eds.; Marcel Dekker: New
York, 2000; pp. 275–330.
4. Huang, P.-Q.; Zheng, X.; Deng, X.-M. Tetrahedron Lett.
2001, 42, 9039.
5. Hans, J. J.; Driver, R. W.; Burke, S. D. J. Org. Chem.
1999, 64, 1430.
6. Kataky, R.; Nicholson, P. E.; Parker, D. J. Chem. Soc.,
Perkin Trans. 2 1990, 321.
7. Macroporous 30–60 mesh, Aldrich.
8. PS-Carbodiimide, 100–200 mesh, Argonaut Technologies.
9. Parlow, J. J.; Mischke, D. A.; Woodward, S. S. J. Org.
Chem. 1997, 62, 5908.
10. MP-Carbonate, 18–52 mesh, Argonaut Technologies.
11. Weidner, J. J.; Parlow, J. J.; Flynn, D. L. Tetrahedron
Lett. 1999, 40, 239–242.
12. Typical procedure (3k): Methyl 4-bromobenzoate (0.02
mmol) was dissolved in THF (1 mL) and benzyltrimethyl-
ammonium hydroxide (0.04 mmol, 20% in MeOH) was
added. The solution was heated (55°C) for 18 h. The
mixture was cooled to rt and MP-TsOH (0.05 mmol) was
added. The mixture was agitated at rt for 3 h. The
reaction was diluted with THF (0.5 mL) and a,a-
dimethyl-3-(p-F-phenyl)ethylamine (0.1 mmol) and 1-
hydroxybenzotriazole (0.04 mmol) were added.
PS-carbodiimide (0.08 mmol) was then added and the
mixture was agitated for 18 h at rt. MP-carbonate resin
(0.12 mmol) and MP-TsOH (0.12 mmol) resin were
added and the mixture was agitated for 8 h. The mixture
was filtered and the resin was washed with THF (1.5
mL). The filtrate was concentrated to give 3k (6.5 mg,
98%) in high purity (99% determined by ELSD-HPLC of
the desired ion).
diamides. Amine hydrochloride salts were incorporated
by the addition of an equivalent of DIPEA during the
coupling step and an equivalent amount of MP-TsOH
for the scavenging step. The application of amines with
basic groups (3q) is also tolerated by sequestering the
excess amine with polymer-bound isocyanate (PS-
NCO)13 resin rather than MP-TsOH. The electrophilic
sequestrant is required because the acidic resin would
also sequester the product.
In conclusion, a single vessel conversion of esters to
amides has been accomplished using polymer-supported
reagents and scavengers. Our method also demonstrates
how resin-bound reagents can be utilized to effectively
carry out processes ordinarily requiring more rigorous
purification.14 The lack of filtration between the hydrol-
ysis and amide bond-forming steps simplifies the appli-
cation of this sequence towards parallel synthetic
techniques. Development of hydrolysis conditions free
of racemization of amino acids is currently under inves-
tigation in our laboratories.
References
1. (a) Ley, S. V.; Baxendale, I. R.; Bream, R. N.; Jackson,
P. S.; Leach, A. G.; Longbottom, D. A.; Nesi, M.; Scott,
J. S.; Storer, R. I.; Taylor, S. J. J. Chem. Soc., Perkin
Trans. 1 2000, 3815; (b) Flynn, D. L.; Crich, J. Z.;
Devraj, R. V.; Hockerman, S. L.; Parlow, J. J.; South, M.
S. J. Am. Chem. Soc. 1997, 119, 4874–4881.
13. PS-Isocyanate, 100–200 mesh, Argonaut Technologies.
14. Parlow, J. J. Tetrahedron Lett. 1995, 36, 1395.
2. Flynn, D. L. Med. Res. Rev. 1999, 19, 408–432.
3. Albericio, F.; Kates, S. A. In Solid-Phase Synthesis;