Synthesis of 5-aminothiazoles as building blocks for library synthesis

Article abstract of DOI:10.1016/j.tetlet.2006.02.004

A convenient route to 4-phenyl-5-aminothiazoles is described, which offers control over substitution at the 2-position. 2-N-Acylglycinamides were dithionated and a subsequent TFAA-mediated cyclisation step was followed by removal of the 5-N-trifluoroacety

Full text of DOI:10.1016/j.tetlet.2006.02.004

Tetrahedron Letters 47 (2006) 2361–2364
Synthesis of 5-aminothiazoles as building blocks
for library synthesis
Mark J. Thompson, William Heal and Beining Chen*
Department of Chemistry, University of Sheffield, Brook Hill, Sheffield S3 7HF, UK
Received 30 November 2005; revised 20 January 2006; accepted 1 February 2006
Available online 17 February 2006
Abstract—A convenient route to 4-phenyl-5-aminothiazoles is described, which offers control over substitution at the 2-position.
2-N-Acylglycinamides were dithionated and a subsequent TFAA-mediated cyclisation step was followed by removal of the 5-N-tri-
fluoroacetyl group providing the free amines. Though applicable generally the method was found to be most effective when intro-
ducing aromatic substituents at the 2-position, whereupon moderate overall yields of the 5-amino compounds were obtained.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Thiazoles are amongst the most frequently encountered
heterocycles in compounds of biological interest, along
with many other applications. Whilst syntheses of thia-
zoles and 2-aminothiazoles have been studied exten-
sively, the preparation of 5-aminothiazoles has not
been so widely reported. This class of compounds has
received attention in a range of applications from antibi-
otics1 to photosensitisers;2 however, searching the litera-
ture for a general approach allowing structural variation
and based on readily available starting materials gave
limited results. Known routes3–5 to 5-aminothiazoles
are narrow in scope with regard to substituents at the
2- and 4-positions, sometimes involving many synthetic
steps.
Ph
N
R
NH2
S
1
Figure 1. General structure of 2-substituted-4-phenyl-5-aminothia-
zoles 1.
yields upon treatment with neat TFAA. However, in
our hands, the analogous reaction of 2-phenyl-2-(thio-
benzoylamino)acetamide 2—not a substrate investigated
by Barrett—was found to result in the formation of an
approximately equal mixture of thiazole 3 and oxazole
4 (Scheme 1). This problem of mixed product formation
was overcome by reaction of 2 with Lawesson’s reagent
prior to treatment with TFAA, resulting in exclusive
formation of the desired thiazole product 3.
We were looking for a convenient route to a series of
differently 2-substituted 4-phenyl-5-aminothiazoles 1
(Fig. 1), and since we required access to moderate quan-
tities of compounds of this type for subsequent library
synthesis, the development of a more flexible approach
to such structures was therefore investigated. This letter
reports a convenient route to synthesise this class of
compounds.
Based upon these observations, a general route to 5-(tri-
fluoroacetylamino)thiazoles 8 was devised (Scheme 2).
2-N-Acylglycinamides 6a–e, prepared by reaction of D-
(À)-phenylglycinamide 5 with various acid chlorides
(R = alkyl, aryl) in the presence of N-ethylmorpholine
(NEM), were dithionated to provide bis(thioamide)
intermediates of type 7. These compounds were not suf-
ficiently stable to allow their isolation and were conse-
quently treated with TFAA directly to give products
8a–e via a two-step, one-pot procedure.
Our initial approach was based on the results of Barrett,6
who reported conversion of 2-N-(thiobenzoyl)acet-
amides into 5-(trifluoroacetylamino)thiazoles in good
Keywords: Thiazoles; Thionation reactions; Lawesson’s reagent; Bel-
leau’s reagent; Cyclisation reactions.
*
As a modification of Barrett’s procedure, use of DCM
as a co-solvent in the cyclisation reactions was found
Corresponding author. Fax: +44 (0)114 222 9346; e-mail: b.chen@
shef.ac.uk
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.02.004

2362
M. J. Thompson et al. / Tetrahedron Letters 47 (2006) 2361–2364
Ph
Ph
S
Ph
TFAA
O
O
N
N
NH2
+
Ph
N
Ph
Ph
H
N
CF3
N
CF3
S
O
O
H
H
2
3
4
Scheme 1. No regioselectivity was seen in the TFAA-mediated cyclisation of 2.
Ph
O
Ph
RCOCl
NH2
NH2
H2N
R
N
H
py, NEM
O
O
5
6a–e
Ph
S
Ph
9 or 10
TFAA
DCM
O
N
NH2
R
N
R
H
N
CF3
S
S
H
7a–e
8a–e
Scheme 2. Preparation of 5-(trifluoroacetylamino)thiazoles 8a–e based on an initial thionation step ensuring formation of a single cyclisation
product.
Table 1. Comparative yields of differently 2-substituted 4-phenyl-5-
(trifluoroacetylamino)thiazoles 8a–e prepared as outlined in Scheme 2
to improve the efficiency of these steps by ensuring dis-
solution of the otherwise sparingly soluble material.
Furthermore, in contrast to the limited accessibility of
thioamides of type 2, use of intermediates of general
structure 6 as a starting point in thiazole formation
permits a wide variety of substituents derived from com-
mercially available acid chlorides to be introduced at the
2-position.
Entry
R
Product Yield, %
Yield, %
(Method A) (Method B)
1
2
3
8a
8b
8c
47
41
46
40
33
The thionation step was explored using both Lawesson’s
reagent 9 and Belleau’s reagent7,8 10 (Fig. 2) to establish
whether any advantage could be gained from the milder
conditions offered in utilising the latter. Reactions of the
2-N-acylglycinamide intermediates 6 were thus carried
out both with Lawesson’s reagent 9 in toluene at
100 ꢁC for 35–60 min (Method A, with the duration of
heating dependent upon the solubility of the starting
material), and with Belleau’s reagent 10 in THF at
50 ꢁC overnight (Method B)—although thionation of
the primary amide group of 6 was complete in 1–2 h
at room temperature, extended reaction times with heat-
ing were found to be necessary to effect any significant
conversion of the less reactive secondary amide func-
tion. In each case, the crude thionated product 7 was
subsequently treated with TFAA for 45 min to afford
the corresponding trifluoroacetamide 8, which was iso-
lated by column chromatography.
MeO
S
28a
4
5
8d
8e
21
30
22
35
Reactions were performed on a 2 mmol scale.
a Reaction was carried out on a 1 mmol scale. A 20% yield of the
oxazole product was isolated in addition to the thiazole.
The results so obtained, summarised in Table 1, show
that where aryl groups were introduced at the 2-position
(entries 1–3), moderate overall yields of 8a–c were
obtained for the two-step procedure. Where an alkyl
group was introduced, however, notably lower yields
were obtained (8d–e; entries 4–5). It is thought that
the limiting factor in the yields obtained by this route
is the stability of the bis(thioamide) intermediates 7, and
that the presence of an aryl group (i.e., R = Ar) confers
additional stability upon these intermediates leading to
the higher yields observed.
S
R'O
P
S
S
P
S
OR'
9
R' = Me
10 R' = Ph
Unexpectedly, the use of Belleau’s reagent under milder
conditions offered no discernable advantage in the pres-
Figure 2. Structures of the thionating reagents used: Lawesson’s
reagent 9 and Belleau’s reagent 10.

M. J. Thompson et al. / Tetrahedron Letters 47 (2006) 2361–2364
2363
ent work. It seems the harsher conditions required for
the use of Lawesson’s reagent are necessary to drive
the dithionation step to completion. In particular, for-
mation of the 2-thienyl product 8c (entry 3) required
these more vigorous conditions: when Belleau’s reagent
was used, an almost equal amount of the corresponding
oxazole product was isolated, indicating particularly low
reactivity of the secondary amide in this case.
tion procedure proved to be especially valuable: com-
pound 8a was prepared from 6a in 65% yield on a
15 mmol scale.
The synthetic route we have detailed proved most effec-
tive for the preparation of products containing an aro-
matic group at the 2-position of the thiazole ring.
Introduction of an aliphatic group was found to be pos-
sible, but at the expense of substantially compromising
the overall yield.
Deprotection of trifluoroacetamides 8a–e to the desired
free amines of general structure 1 was achieved by
heating in 3 M NaOH9 (Scheme 3): such concentrated
hydroxide was required given the ready formation of
the trifluoroacetamide anion of these compounds.
Diversity at the 4-position could easily be achieved by
use of differently substituted glycinamides 5, either
commercially available or synthesised using a literature
procedure,10,11 as starting materials to prepare the
2-N-acylglycinamides prior to cyclisation. Full library
synthesis and biological activities of 2,4,5-substituted
thiazoles based on this work will be reported elsewhere.
The hydrolysis reliably reached completion at 70 ꢁC and
for 8a–c, containing two aromatic substituents (R =
Ar), provided the corresponding free amines in good
yields after a simple workup procedure (Table 2, entries
1–3). However, under these conditions the trifluoroacet-
amides containing an aliphatic substituent gave mixed
results (entries 4–5): whereas the 2-cyclohexyl com-
pound 1d was obtained in good yield, 2-isopropyl deriv-
ative 1e was only isolated in low yield. Hydrolysis of the
trifluoroacetyl group of 8e was explored using 3 M
Representative thionation–cyclisation procedure (Table 1,
entry 3, product 8c): D-2-Phenyl-2-(thiophene-2-carbon-
ylamino)acetamide (6c; R = 2-thienyl; 0.52 g, 2.0 mmol)
and Lawesson’s reagent (0.97 g, 2.4 mmol) were sus-
pended in toluene (50 mL) and the mixture heated to
100 ꢁC under N2. Once a homogeneous solution was ob-
tained (after ꢀ20 min), heating was continued for a fur-
ther 20 min followed by cooling to rt and evaporation of
the solvent. TFAA (10 mL) was added, followed by
DCM (10 mL) 3 min later to affect dissolution, thus
ensuring efficient mixing of the thick, sticky residue with
the anhydride. The resultant mixture was stirred at rt for
an additional 45 min and evaporated to dryness. The
residue was taken up in DCM (100 mL) and washed
with PBS buffer pH 7.4 (2 · 100 mL) and the organic
layer dried over MgSO4, filtered and evaporated. Flash
column chromatography on silica gel, eluted with
40–50–60% DCM–hexane, afforded 2-thienyl-4-phenyl-
5-(trifluoroacetylamino)thiazole 8c as a yellowish solid
(324 mg, 46%).12
i
NaOH in PrOH–H2O (1:1) to improve solubility in an
attempt to overcome this problem. Though a homo-
geneous reaction solution resulted, hydrolysis of the tri-
fluoroacetamide was found to be considerably slower in
this solvent mixture and no improvement in yield over
the original conditions could be achieved.
In conclusion, we have described a general synthesis of
4-phenyl-5-aminothiazoles of type 1, which offers a wide
range of diversity in 2-substitution using readily avail-
able acid chlorides. The fact that compounds of type 6
are much more accessible than those of type 2 offers
improvement over reported procedures and allows for
greater structural diversity in the 5-aminothiazole prod-
ucts 1. These themselves serve as versatile building
blocks through subsequent derivatisation of the 5-amino
group. Furthermore, scale-up of our thionation–cyclisa-
Representative deprotection procedure (product 1c):
Compound 8c (296 mg, 0.84 mmol) was stirred in 3 M
NaOH (15 mL) at 70 ꢁC for 3 d. The reaction mixture
was diluted with water then extracted into ethyl acetate
(2 · 30 mL) and the combined organic extracts washed
with brine, dried over MgSO4, filtered and evaporated
to dryness. 2-Thienyl-4-phenyl-5-aminothiazole 1c was
obtained as a brownish solid (174 mg, 81%).13
3 M NaOH
70 ˚C, 3 d
Ph
Ph
O
N
N
R
R
N
CF3
NH2
S
S
H
8a–e
1a–e
Acknowledgements
Scheme 3. Hydrolysis of the 5-trifluoroacetyl group provided the
desired free amines 1a–e (see Table
information).
2 for further structural
The authors would like to thank Dr. R. Mutter for use-
ful discussions regarding the content of this manuscript.
This work was funded by the Department of Health
(contract no. DH007/0102).
Table 2. Yields of free amines 1a–e prepared as illustrated in Scheme 3
Entry
Substrate
Amine
Yield (%)
1
2
3
4
5
8a
8b
8c
8d
8e
1a
1b
1c
1d
1e
83
77
81
76
30
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12. Analytical data for compound 8c: 1H NMR (250 MHz,
DMSO-d6): d 12.13 (br s, 1H), 7.82–7.69 (m, 4H), 7.54–7.37
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2
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1
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259.0364, obs. 259.0356.
´
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