Efficient procedure for the preparation of amides using polymer-bound reagents

Article abstract of DOI:10.1081/SCC-100103528

An effective method for the conversion of acids into amides is presented. The two-step procedure includes the preparation of acid chloride intermediates using Pol-Ph₃P and subsequent treatment of these intermediates with amines and polymer-bound base. The amides were accessible in high yields and purities without further purification.

Full text of DOI:10.1081/SCC-100103528

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EFFICIENT PROCEDURE FOR
THE PREPARATION OF AMIDES
USING POLYMER-BOUND
REAGENTS
Hans-Peter Buchstaller a , Heike M. Ebert a & Uwe
Anlauf a
a Medicinal Chemistry Research Laboratories ,
Merck KGaA, Frankfurter Str. 250, Darmstadt,
D-64271, Germany
Published online: 09 Nov 2006.
To cite this article: Hans-Peter Buchstaller , Heike M. Ebert & Uwe Anlauf
(2001) EFFICIENT PROCEDURE FOR THE PREPARATION OF AMIDES USING POLYMER-
BOUND REAGENTS, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 31:7, 1001-1005, DOI: 10.1081/
SCC-100103528
To link to this article: http://dx.doi.org/10.1081/SCC-100103528
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SYNTHETIC COMMUNICATIONS, 31(7), 1001–1005(2001)
EFFICIENT PROCEDURE FOR THE
PREPARATION OF AMIDES USING
POLYMER-BOUND REAGENTS
Hans-Peter Buchstaller,* Heike M. Ebert, and Uwe Anlauf
Merck KGaA, Medicinal Chemistry Research
Laboratories, Frankfurter Str. 250, D-64271 Darmstadt,
Germany
ABSTRACT
An effective method for the conversion of acids into
amides is presented. The two-step procedure includes the
preparation of acid chloride intermediates using Pol-Ph3P
and subsequent treatment of these intermediates with amines
and polymer-bound base. The amides were accessible in high
yields and purities without further purification.
Over the last decade, in context with combinatorial chemistry, differ-
ent strategies have been developed that enable compound libraries to be
produced in a rapid and efficient manner. Among these methods, the use
of reagents attached to polymers is of growing interest, since more and more
of these reagents become available. Recently, it has been shown that even
multi-step synthesis is feasible by combination of different polymer-
supported reagents.1–4
Several polymer-bound reagents, such as Pol-HOBt and Pol-EDC,
have been used for the conversion of acids into amides, but they have
* Corresponding author.
1001
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

1002
BUCHSTALLER, EBERT, AND ANLAUF
some disadvantages. Activation of acids with Pol-HOBt and PyBrOP
requires a double-coupling procedure and a three-fold excess of acid for
each activation step.5 Thus, the unreacted acid has to be recovered, espe-
cially if the acid is a valuable starting material. For the formation of an acid
anhydride intermediate with Pol-EDC, an excess of acid has to be applied as
well, and the addition of scavanger-resins is necessary to remove all by-
products. In addition, long reaction times at elevated temperatures were
essential for the complete reaction with aromatic amines.6 Harrison and
co-workers reported the application of Pol-Ph3P and carbon tetrachloride
for amide synthesis. However, the use of this combination requires reflux
temperature and an excess of the amine component, which subsequently had
to be removed by aqueous extraction.7
In this paper, we report an efficient, polymer-assisted, two-step pro-
cedure for the conversion of carboxylic acids to amides without any addi-
tional purification step. Phenylacetic acid and n-butylamine were chosen as
model compounds to determine suitable reaction conditions. When phenyl-
acetic acid was treated with polymer-bound Ph3P8 (3 equiv.) and trichloro-
acetonitrile (5equiv.) in dichloromethane (DCM) at room temperature for
3 h and the thus-formed acyl chloride intermediate was treated with n-butyl-
amine (1 equiv.) and polymer-bound morpholine9 (3 equiv.), the desired
amide was obtained in 38% purity along with one major by-product.
LC/MS-analysis revealed that this by-product was formed by reaction of
the amine with the excess trichloroacetonitrile. Thus, we systematically
decreased the amount of trichloroacetonitrile to optimize the amount,
which efficiently converts the acid into the acyl chloride, but also reduces
the formation of the observed by-product. It is interesting to note that the
best results were obtained by application of 1.2 equiv. of trichloroaceto-
nitrile, which is not the optimum in solution.10 Under these conditions, the
final amide was isolated as essentially pure compound by simple filtration
and evaporation (Table 1, entry 4). In addition, the reaction tolerates vari-
ous common solvents (entry 5–8). THF or toluene, for example, are possible
alternatives to dichloromethane, especially if one of the components is
poorly soluble in dichloromethane.
Further, we selected a set of different acids and amines to examine the
scope and limitations of this procedure. The QuestTM 210 synthesizer, which
allowed us to transfer the acyl chloride intermediates from one bank of
10 reaction vessels to the other under inert conditions, was used for this
purpose. The results are summarized in Table 2. All compounds, with the
exception of 6D, were obtained in good to excellent yields. Moreover, inves-
tigation by HPLC/MS revealed that all amides were obtained as essentially
pure compounds without any additional purification step. These results
emphasize the versatility of the described procedure and demonstrate

POLYMER-BOUND REAGENTS
Table 1. Optimization of the Reaction Conditions
1003
Purity
Entry Eq. Cl3CCN Eq. Pol-Ph3P Solvent Eq. amine Eq. Pol-base (%)*
1
2
3
4
51.2
6
7
53
3
2
1.2
DCM
1
3
38
3
3
DCM
DCM
DCM
1
Dioxane
Toluene
ACN
1
1
1
3
3
72
79
3
THF
3
3
3
3
100
3
3
97
3
3
1.2
1.2
1.2
1
1
1
86
95
81
8
3
*Reversed-phase HPLC at 220 nm.
Table 2. Synthesis of Various Amides on the Quest 210
A
B
C
D
E
99/75*
98/73
99/82
94/93
95/89
1
88/86
95/86
100/77
98/86
93/73
92/86
96/96
94/99
100/95
93/97
2
3
96/83
98/89
98/86
98/99
97/87
97/98
98/99
4
5
6
100/73
100/71
100/83
98/66
97/70
100/76
96/42
—y/71
*Purity (%)/yield (%); yThe product showed no significant absorption at 220 nm.

1004
BUCHSTALLER, EBERT, AND ANLAUF
that there are no major restrictions regarding the reactivity of the amine
component.
In summary, the presented two-step procedure using polymer-bound
reagents is an effective method for the conversion of acids into amides.
Equimolar amounts of acids and amines were transformed into the corre-
sponding amides under neutral conditions at ambient temperature. The
products were accessible in high yields and purities by simple filtration
and evaporation without any additional purification step.
EXPERIMENTAL
PS-Ph3P resin (184 mg, 3 mmol/g, 0.55 mmol) was loaded into a reac-
tion vessel on bank A of the Quest 210 and the vessel purged with argon for
1 min. Dichloromethane (0.5mL) was added and the mixture was agitated
for 10 min. Phenylacetic acid (25mg, 0.18 mmol), dissolved in dichloro-
methane (1.5mL) and trichloroacetonitrile (22 mL, 0.22 mmol) were added
and the mixture was agitated for 3 h at room temperature. On bank B of the
Quest 210, Morpholinomethyl polystyrene HL (157 mg, 3.5 mmol/g,
0.55 mmol) was loaded into a reaction vessel, purged with argon, and the
resin treated with dichloromethane (1 mL) and butylamine (18 mL,
0.18 mmol). The acid chloride intermediate of bank A was transferred to
the respective vessel of bank B via transfer cannula using argon gas. The
resin of bank A was rinsed once with dichloromethane and the solution
transferred as well. After agitation of the reaction mixture at room tempera-
ture overnight, the vessel was drained, washed with dichloromethane (2ꢀ),
and the combined solutions evaporated to dryness to give N-butyl-2-phenyl-
acetamide (33.3 mg, 95%).
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POLYMER-BOUND REAGENTS
1005
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