Versatile assembly of 5-aminothiazoles based on the Ugi four-component coupling

Article abstract of DOI:10.1016/j.tetlet.2008.06.067

A flexible route to novel 5-aminothiazoles has been developed based on cyclisation of diamide adducts, prepared using the Ugi reaction, in the presence of Lawesson's reagent. The Walborsky reagent (1,1,3,3-tetramethylbutyl isocyanide) was used as the isonitrile component, facilitating subsequent deprotection of the N-alkyl group to yield free 5-aminothiazoles, which were prepared with a variety of substituents at the 2- and 4-positions.

Full text of DOI:10.1016/j.tetlet.2008.06.067

Tetrahedron Letters 49 (2008) 5324–5327
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Versatile assembly of 5-aminothiazoles based
on the Ugi four-component coupling
*
Mark J. Thompson, Beining Chen
Department of Chemistry, University of Sheffield, Brook Hill, Sheffield S3 7HF, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
A flexible route to novel 5-aminothiazoles has been developed based on cyclisation of diamide adducts,
prepared using the Ugi reaction, in the presence of Lawesson’s reagent. The Walborsky reagent (1,1,3,3-
tetramethylbutyl isocyanide) was used as the isonitrile component, facilitating subsequent deprotection
of the N-alkyl group to yield free 5-aminothiazoles, which were prepared with a variety of substituents at
the 2- and 4-positions.
Received 12 May 2008
Revised 13 June 2008
Accepted 16 June 2008
Available online 20 June 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Thiazole
Ugi reaction
Multicomponent reaction
Lawesson’s reagent
1. Introduction
S
N
Ph
O
NH
N
The thiazole ring occurs widely in structures of pharmaceutical
interest together with many natural products.1 Of the amino-
substituted derivatives, 2-aminothiazoles have been extensively
studied due to their ease of synthesis, whereas the related 5-amino
compounds remain comparatively unexplored.
NH
O
N
S
R
Ph
NH
O
S
R
1
2
Aside from our recent discovery of 2,4-diphenylthiazolyl-5-
amides 1 as antiprion agents2 (Fig. 1), only a handful of other
libraries containing the 5-aminothiazole substructure have been
reported. Compounds of type 2 displayed potential as novel anti-
bacterial and antifungal agents through inhibition of methionine
aminopeptidases,3 and those of type 3 were investigated as thymi-
dylate synthase inhibitors possessing antitumour activity.4 Other
than these small libraries, only a handful of other examples are
to be found as members of wider-ranging screening sets. In order
to progress our SAR studies with second-generation analogues of
active compounds 1, a synthetic route was required which would
permit easy variation of the 2- and 4-substituents using readily
available starting materials.
R
N
H
N
HO2C
N
S
N
HO2C
O
NH
O
3
Figure 1. Biologically active 5-aminothiazoles.
(i) Lawesson's
reagent, PhMe,
100 ºC
Ph
O
Ph
N
NH2
R1
N
H
NH
O
R1
S
CF3
(ii) TFAA—DCM
O
Our reported route5 (Scheme 1) to 4-phenyl-5-aminothiazoles 6,
from N-acylated glycinamides 4 via trifluoroacetamides 5, meets
this requirement in terms of variation at the 2-position but is rather
inflexible with regard to the 4-position, since differently substi-
tuted glycinamides are not easily available as building blocks.
To address this deficiency, we assumed that precursors to gen-
eral 5-aminothiazoles 7 (Scheme 2) could readily be accessed via
5 (21—47%)
Ph
4
3 M NaOH
70 ºC, 3 days
N
NH2
R1
S
6 (30—83%)
* Corresponding author. Tel.: +44 114 2229467; fax: +44 114 2229346.
E-mail address: b.chen@sheffield.ac.uk (B. Chen).
Scheme 1. Synthesis of 4-phenyl-5-aminothiazoles from N-acylated phenylglycin-
amide derivatives.5
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.06.067

M. J. Thompson, B. Chen / Tetrahedron Letters 49 (2008) 5324–5327
5325
R1 CO2H
R2 CHO
CN
O
R2
(i) MeOH
H
N
R1
N
H
NH2
OMe
(ii) 20% TFA—DCM
O
MeO
8
R2
R2
Lawesson's reagent
reflux, 20—180 min
1:1 TFA—DCM
20 min
N
R1
NH
N
R1
NH2
S
S
9
7
Scheme 2. Synthesis of 2,4-disubstituted 5-aminothiazoles from Ugi adducts 8.5
the Ugi four-component coupling6–8 (Ugi 4-CC) given a suitable
protection strategy. The Walborsky reagent (1,1,3,3-tetramethyl-
butyl isocyanide) was chosen as the isonitrile component since
the N-alkyl group is easily removable from the penultimate prod-
uct, as demonstrated by the successful application of this reagent
Table 2
Isolated yields obtained for the three-step synthesis shown in Scheme 2 with differing
substituents R1 and R2
R2
7a–m
N
R1
NH2
S
in
[1,2-a]pyridines.9–11 It was also used as a cleavable isonitrile in
the synthesis of
-aminomethyl tetrazoles.12 Since an ammonia
a related multicomponent synthesis of 3-aminoimidazo-
R1
R2
8, %
9, % (t, h)
7, %
50
a
equivalent was also required,13 2,4-dimethoxybenzylamine was
employed for this purpose.14 In this case the 2,4-dimethoxybenzyl
(DMB) group is straightforward to remove after the Ugi 4-CC by
treatment with TFA. Thus, a one-pot route to diamide intermedi-
ates 8 with considerable scope for variation of substitution was
realised.
S
a
45
75
59 (3)
55 (1)
b
32 (3)
46
MeO
F
Cyclisation to N-protected 5-aminothiazoles
9 was then
addressed. Optimisation reactions were carried out using 8a as
substrate (R1 = Ph; R2 = thiophen-2-yl, Table 1). Refluxing with
Lawesson’s reagent in toluene resulted in efficient thionation but
little formation of the thiazole. In line with Lawesson’s brief initial
studies on glycine derivatives,15 we found that a higher tempera-
ture reflux in m-xylene was required to drive the cyclisation,
conversion to 9a being essentially complete in 1 h.
S
c
40
57
76
54 (3)
42
30
69
d
e
28b (1)
O
21 (3)
32 (1)
Me
As in our earlier work, we found that incorporation of an aque-
ous work-up prior to column chromatography markedly improved
the isolated yield. Extending the reaction time offered little advan-
tage. Finally, we observed that using a larger excess of Lawesson’s
reagent had a negative effect upon the yield. Thus, the optimum
protocol for conversion of 8a to 9a was established as a one hour
reflux in m-xylene, using 1.2 equiv of Lawesson’s reagent and
incorporating an aqueous workup before purification by column
chromatography.
f
74
69
48 (3)
30 (3)
36
51
F
g
MeO
S
h
i
89
31 (3)
36 (3)
41
55
40c
Deprotection of the N-(1,1,3,3-tetramethylbutyl) group pro-
ceeded rapidly in the presence of TFA to give the desired 5-amino-
29a
45
S
S
N
S
Table 1
j
72 (3)
15 (1)
Optimisation results for cyclisation of diamide 8a (R1 = Ph, R2 = thiophen-2-yl) to
thiazole 9a
N
Solventa
t, min
Aqueous work-upc
Thiazole 9a, %
Thioamide, %
Cl
Cl
k
44
36 (3)
15 (1)
47
Toluene
20
20
60
N
N
N
Y
N
Y
8
70
29
6
n.d.
n.d.
n.d.
n.d.
MeO
m-Xylene
m-Xylene
m-Xylene
m-Xylene
m-Xylene
m-Xyleneb
39
37
52
55
59
49
60
Cl
Cl
l
74
41
32 (3)
38 (1)
46
30
180
180
180
Y
S
m
a
All reactions carried out with 1 mmol 8a and 1.2 mmol Lawesson’s reagent at
reflux, under N2, in the solvent stated (20 mL).
a
b
Synthesised using PMB protection.
No aqueous work-up, as hydrolysis of the furan was observed in this case.
52% yield based on recovered starting material (incomplete conversion).
1.6 mmol Lawesson’s reagent used.
Refers to partitioning of crude product between DCM and satd NaHCO3
b
c
c
followed by separation and drying of organic extract.

5326
M. J. Thompson, B. Chen / Tetrahedron Letters 49 (2008) 5324–5327
thiazole 7a. A range of aromatic and aliphatic substituents at the R1
and R2 positions were then investigated in order to evaluate the
scope of our synthetic procedure (Table 2).
additional methanol (2 mL) was added followed by 4-fluorobenz-
oic acid (700 mg, 5 mmol) and finally 1,1,3,3-tetramethylbutyl iso-
cyanide (877 lL, 696 mg, 5 mmol). The reaction mixture was
Ugi 4-CC products 8a–m were produced smoothly in moderate
to good isolated yields, mostly being recovered without the need
for chromatography. Compound 8i was not directly accessible by
this method, however, as it was isolated still in DMB-protected
form. The presence of the 3-pyridyl substituent arrested the TFA-
mediated deprotection in this case, and neither could removal of
the DMB group be achieved using buffered potassium persulfate
in aqueous media.16 Instead, the Ugi 4-CC was repeated with
4-methoxybenzylamine and the PMB protecting group was cleaved
successfully using CAN to afford 8i in 29% overall yield.
stirred at room temperature overnight, then evaporated to dryness.
The crude intermediate so obtained was stirred in TFA/DCM (1:4,
10 mL) for 1 h, then evaporated, and the sticky residue was tritu-
rated with satd aq NaHCO3. A small amount of ether (approxi-
mately 5 mL) was added to the mixture and trituration continued
until the initially sticky gum had precipitated as a solid, which
was collected by filtration and washed successively with satd aq
NaHCO3 (Â3), water (Â2), then ether (2 Â 10 mL). Pure product
was isolated by washing through the sinter slowly with chloroform
(4 Â 30 mL) and drying the solution over MgSO4, then evaporating
to afford 8c18 as an off-white solid (0.78 g, 40%).
The cyclisation step appears to be quite general, though further
investigation of optimum heating time with other examples (9j–k)
revealed the longer 3 h reflux to be advantageous. The exception to
this was when the product bore an aliphatic substituent (9e), pre-
sumably due to thermal instability of this particular compound
under extended heating. Indeed, no obvious trend was identifiable
in the isolated yields with respect to electron donating or with-
drawing characteristics of the 2- and 4-substituents (R1 and R2)
being introduced. It is thus probable that the cyclisation yields
are primarily dictated by the thermal stability of each individual
compound at the high temperature necessary to drive the reaction.
Deprotection of cyclised products 9a–m to the corresponding
free 5-aminothiazoles 7a–m was achieved using a short (20 min)
treatment with 50% TFA in DCM, resulting in acceptable yields in
most cases. One notable exception was 7d, isolated in low yield
as might be expected given the acid sensitivity of the 2-furyl group.
Though both aliphatic and aromatic substituents are well-tolerated
at the 2-position (R1), only aryl groups may be reliably introduced
at the 4-position (R2). When we tried to incorporate an aliphatic
group at this position (R2 = cyclohexyl or 2-phenylethyl), deprotec-
tion of intermediates 9 gave very low crude yields (<20%) of
impure 5-amino compounds 7, and any further attempted purifica-
tion resulted in decomposition. We therefore concluded that free
5-aminothiazoles 7 bearing an aliphatic substituent at the 4-posi-
tion (R2) are unstable, even though their N-protected counterparts
9 may be isolated successfully.
2.2. Representative cyclisation procedure
The diamide starting material 8c (0.75 g, 1.92 mmol) was sus-
pended in anhydrous m-xylene (40 mL) under N2, together with
Lawesson’s reagent (0.93 g, 2.30 mmol). The mixture was heated
at reflux for 3 h, then the solvent was removed by rotary evapora-
tion and the residue taken up in DCM, washed with satd aq NaH-
CO3, dried over MgSO4 and evaporated once more. The crude
product was purified by flash column chromatography on silica
gel, eluted with 2% then 4% ethyl acetate–hexane, yielding thiazole
9c19 as a thick, bright yellow oil (0.40 g, 54%) which slowly crystal-
lised on standing to give a pale yellow solid.
2.3. Representative deprotection procedure
The N-(1,1,3,3-tetramethylbutyl)amine 9c (0.38 g, 0.98 mmol)
was dissolved in 1:1 TFA/DCM (8 mL) and stirred for 20 min at
room temperature, then the reaction mixture was evaporated.
The residue was taken up in DCM and washed with satd aq NaH-
CO3, then the organic layer was dried over MgSO4 and evaporated.
Following column chromatography on basic alumina, eluted with
20% then 33% then 50% ethyl acetate–hexane, free amine 7c20
was isolated as a pale brown powder (114 mg, 42%).
Nonetheless, despite modest yields in most cases, we found that
this new synthetic method offered a viable route to a range of
novel 2,4-disubstituted 5-aminothiazoles in sufficient quantities
to be carried forward as building blocks in parallel library
synthesis. By way of example, scale-up of the preparation of 7a
and 7e proved quite practicable.
Acknowledgement
This work was supported by a grant from BBSRC (Grant No. BB/
E014119/1).
Supplementary data
Though a one-pot, multicomponent-based assembly of thiazole
libraries was previously developed by Dömling,17 this approach
focused upon varying the substituent at the 2-position only. Thus,
the strategy reported herein builds upon previously documented
multicomponent approaches to the thiazole ring by allowing a
novel entry to 5-aminothiazoles with full control over substitution
at the 2- and 4-positions. The substituents introduced at these
positions are derived from simple and widely variable building
blocks. Though yields are modest, the route offers access to a large
number of diverse new compounds, based around this pharmaceu-
tically relevant substructure, which would otherwise be consider-
ably more difficult to prepare by alternative routes.
Supplementary data associated with this article (full experi-
mental details, together with characterisation data and NMR spec-
tra for all compounds) can be found, in the online version, at
doi:10.1016/j.tetlet.2008.06.067.
References and notes
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5327
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13. On the suggestion of a reviewer, we attempted direct synthesis of 8a by an Ugi
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obtained in a modest 36% yield, but this single step method did not prove
general. Attempted preparation of 8e and 8k by the same procedure resulted in
the formation of product mixtures, necessitating separation by column
chromatography. After purification, 8e and 8k were isolated only in rather
low yields (26% and 16%, respectively). For example uses of ammonia in the Ugi
reaction, see: (a) Pick, R.; Bauer, M.; Kazmaier, U.; Hebach, C. Synlett 2005, 757–
760; (b) Banfi, L.; Basso, A.; Damonte, G.; De Pellegrini, F.; Galatini, A.; Guanti,
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18. 1H NMR (400 MHz, CDCl3) 7.90–7.83 (m, 2H), 7.61 (d, 1H, J = 6.5 Hz), 7.29–7.27
(m, 1H), 7.18 (d, 1H, J = 3.0 Hz), 7.12 (t, 2H, J = 8.6 Hz), 6.98 (dd, 1H, J = 3.5 Hz,
5.0 Hz), 5.96 (s, 1H), 5.86 (d, 1H, J = 6.5 Hz), 1.79–1.60 (m, 2H), 1.43–1.41 (m,
6H), 0.91 (s, 9H). 13C NMR (100 MHz, CDCl3) 167.5, 165.5, 165.0 (d, J = 251 Hz),
141.0, 129.9, 129.6, 129.5, 126.9, 126.6, 125.9, 115.6 (d, J = 22.0 Hz), 56.1, 53.4,
52.2, 31.5, 31.2, 28.9, 28.4. mmax (solid)/cmÀ1 3280, 2957, 1632, 1547, 1502,
1226, 848, 693. m/z (ES), 397 ([M+H]+); HRMS, found 391.1864 (C21H28FN2O2S,
[M+H]+, requires 391.1856).
19. 1H NMR (400 MHz, CDCl3) 7.94–7.89 (m, 2 H), 7.51 (d, 1H, J = 3.5 Hz), 7.31–7.28
(m, 1H), 7.16–7.09 (m, 3H), 3.96 (s, 1H), 1.76 (s, 2H), 1.45 (s, 6H), 1.08 (s, 9H).
13C NMR (100 MHz, CDCl3) 163.3 (d, J = 248 Hz), 154.5, 140.2, 138.0, 135.5,
130.4, 127.5, 127.4, 127.2, 123.9, 123.8, 115.8 (d, J = 22.0 Hz), 57.3, 53.1, 31.7,
31.6, 29.5. mmax (solid)/cmÀ1 3293, 2952, 1226, 1150, 831, 698. m/z (ES),
389 ([M+H]+); HRMS, found 389.1510 (C21H26N2FS2, [M+H]+, requires
389.1521).
20. 1H NMR (250 MHz, CDCl3) 7.88–7.79 (m, 2H), 7.38 (dd, 1H, J = 1.5 Hz, 4.0 Hz),
7.31 (dd, 1H, J = 1.5 Hz, 5.5 Hz), 7.17–7.05 (m, 3H), 3.76 (s, 2H). 13C NMR
(62.8 MHz, CDCl3) 163.4 (d, J = 249 Hz), 152.6, 140.3, 137.7, 132.4, 130.1, 128.4,
127.6, 127.5, 124.1, 123.3, 115.9 (d, J = 22.0 Hz). mmax (solid)/cmÀ1 3276, 1605,
1502, 1434, 1224, 972, 834, 694. m/z (ES), 277 ([M+H]+); HRMS, found
277.0272 (C13H10FN2S2, [M+H]+, requires 277.0269).
16. Shiozaki, M.; Ishida, N.; Hiraoka, T.; Maruyama, H. Tetrahedron 1984, 40, 1795–
1802.
17. (a) Heck, S.; Dömling, A. Synlett 2000, 424–426; (b) Kolb, J.; Beck, B.;
Almstetter, M.; Heck, S.; Herdtweck, E.; Dömling, A. Mol. Div. 2003, 6, 297–