Microwave-assisted solvent-free parallel synthesis of thioamides

Article abstract of DOI:10.1016/S0040-4039(00)01360-5

Rapid parallel synthesis of thioamides is described. A library of amides, synthesised by mixing acyl chlorides and diamines, was transformed into the corresponding thioamides utilising Lawesson's reagent as the oxygen/sulphur exchange reagent. Purification by solid-phase extraction afforded the library members in adequate purities and yields. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01360-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 7947–7950
Microwave-assisted solvent-free parallel synthesis of
thioamides
Roger Olsson,* Henrik C. Hansen and Carl-Magnus Andersson
Synthetic Chemistry, ACADIA Pharmaceuticals A/S, Fabriksparken 58, DK-2600 Glostrup, Denmark
Received 6 July 2000; accepted 10 August 2000
Abstract
Rapid parallel synthesis of thioamides is described. A library of amides, synthesised by mixing acyl
chlorides and diamines, was transformed into the corresponding thioamides utilising Lawesson’s reagent
as the oxygen/sulphur exchange reagent. Purification by solid-phase extraction afforded the library
members in adequate purities and yields. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: microwave; parallel synthesis; thioamide.
By analysing a large virtual library of a million compounds constructed from frameworks
frequently found in drug molecules it was concluded that amides incorporating a basic amine
moiety would constitute an interesting family of potentially CNS-active molecules amenable to
combinatorial chemistry.1 However, the therapeutic utility of amides is limited due to consider-
able degradation in plasma. One approach to increase the half-life of peptides is to substitute
one or more amide linkage(s) by thioamide linkage(s), a modification leading to improved
resistance to enzyme degradation.2 Furthermore, the larger and less electronegative sulphur
atom, relative to oxygen, might alter the hydrogen-bonding ability and/or induce conforma-
tional changes in the modified molecule. As a result, the substitution of thioamides for amides
might be productive in the search for novel CNS-active drugs.3
Although the synthesis of thioamides has been well documented,4 to our knowledge, no
examples have been reported on the direct conversion of a hydrochloride salt of an amide
incorporating a basic amine function into the corresponding thioamide using an oxygen/sulphur
exchange reagent. In this communication, our synthetic strategy, an extension of a procedure
recently published by Varma and Kumar,5 is exemplified by the rapid synthesis of a representa-
tive 25-membered library of thioamides.
The synthetic route to the thioamide library is illustrated in Scheme 1. Generally, in
synthesising a library of compounds for high-throughput biological screening (HTS) it is
important not only to generate products with adequate purities, but also to minimise the
* Corresponding author. E-mail: roger@acadia-pharm.com
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01360-5

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occurrence of assay-interfering byproducts, in our case the amides used as precursors. A
multivariate screening analysis of variables influencing the oxygen/sulphur exchange reaction on
a model substrate revealed two important variables—the procedure for mixing the solids and the
irradiation time. The major obstacle to achieve completion of the reaction was to obtain a
homogeneous mixture, at 0.05 mmol scale, of the solid reactants. Several methods were
evaluated. The most practical one that gave optimal mixing was to add three small stirring bars
and subsequently stir and grind for 10–15 min. Furthermore, an excess of Lawesson’s reagent
(1.0–1.5 equiv.) was required. Fewer equivalents gave incomplete reactions while larger excess
produced thioamides of low purities. Irradiation for 6–7 min at 900 W in a domestic microwave
oven led to a 96:4 mixture of the thioamide and the corresponding amide. No byproducts were
detected. Shorter irradiation time, 5 min, drastically lowered the thioamide/amide ratio (36:64).
Although considerable decomposition of the product occurred at longer irradiation times, e.g. 8
min gave 90% purity of the thioamide in the crude product mixture, 8 min irradiation time was
selected for the library synthesis due to a nearly complete consumption of the starting amide;
less than 2% remained.
Scheme 1. Representative reaction for the synthesis of thioamides, illustrating the model substrate used to optimise
the oxygen/sulphur exchange reaction
The intermediate amide library was synthesised by assembling the building blocks depicted in
Fig. 1. Amide synthesis and subsequent oxygen/sulphur exchange reaction produced the
thioamides according to the following protocol: the diamine was added to an ethereal solution
of an acyl chloride in a Teflon-capped vial.6 Salt precipitation was instant.† The solvent was
Figure 1. Building blocks for the amide library synthesis
† CH2Cl2 was used as solvent in cases where the acyl chlorides had low solubility in ether. After completion of the
reaction the salt was precipitated by addition of ether.

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removed by filtration, where the Teflon cap served as the filter. Lawesson’s reagent (1.0–1.5
equiv.) was added to the salt and the resulting mixture of solids was mixed thoroughly and
thereafter irradiated for 8 min in a domestic microwave oven (900 W, Whirlpool M401).
Solid-phase extraction (SPE) afforded the thioamides in adequate purities and yields (Table 1).
Table 1
Puritiesa and yieldsb for the amide and thioamide libraries
Comp.
Purity%
(yield%)
Comp.
Purity%
(yield%)
Comp.
Purity%
(yield%)
Comp.
Purity%
(yield%)
Comp.
Purity%
(yield%)
A1B1
100
A2B1
100
A3B1
100
A4B1
100
A5B1
75
A1B1S
A1B2
100 (89)
99
A2B1S
A2B2
96 (81)
93
A3B1S
A3B2
98 (91)
81
A4B1S
A4B2
100 (47)
90
A5B1S
A5B2
85 (61)
89
A1B2S
A1B3
A1B3S
A1B4
A1B4S
A1B5
92 (71)
76
A2B2S
A2B3
A2B3S
A2B4
A2B4S
A2B5
93 (79)
70
A3B2S
A3B3
A3B3S
A3B4
A3B4S
A3B5
97 (87)
68
A4B2S
A4B3
A4B3S
A4B4
A4B4S
A4B5
95 (43)
97
91 (39)
79
90 (56)
99
A5B2S
A5B3
A5B3S
A5B4
A5B4S
A5B5
81 (65)
82
85 (63)
100
38 (61)c
68
44 (69)c
96
80 (71)
95
35 (71)c
98
62 (56)c
64
77 (56)
99
51 (60)c
58
A1B5S
96 (67)
A2B5S
85 (73)
A3B5S
80 (73)
A4B5S
96 (38)
A5B5S
81 (65)
a Purities were measured on a HP1100 LC–MS using DAD. Eluent: 8 mM ammonium acetate in CH3CN/water.
UV-data were measured at UVmax. Matrix characterisation by NMR, performed on one fifth of the products,
confirmed LC.
b Yields of the crude product mixture after SPE purification using ISOLUTE SCX ion-exchange cartridges.
c Discarded compounds.
A correlation can be seen between the purities in the intermediate amide library and the
thioamide library. In the amide library, 68% of the members had +80% purity and the average
purity was 87%. Corresponding values for the thioamide library were that 76% of the library
members had a purity +80% and the average was 81%. All thioamides with a purity below
80 3% and/or with an amide impurity above 3% were discarded. The remaining 80% of the
library was considered to be of adequate quality for HTS utilising the R-SAT™ technology.7
In conclusion, we have developed a rapid and practical method for parallel synthesis of
thioamides incorporating a basic amine moiety, delivering products of adequate quality for
high-throughput biological screening.
Acknowledgements
We thank Tina Jensen and Monica Jørgensen for HPLC analyses.
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7950
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