Efficient access to 5-substituted thiazoles by a novel metallotropic rearrangement

Article abstract of DOI:10.1016/j.tetlet.2007.11.029

A novel rearrangement process involving the migration of trimethylstannanyl or trimethylsilanyl groups around the thiazole ring provides access to either 2- or 5-metallated thiazoles by tuning the reaction conditions. The proposed mechanism, based on expe

Full text of DOI:10.1016/j.tetlet.2007.11.029

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 66–69
Efficient access to 5-substituted thiazoles by a novel
metallotropic rearrangement
Alfonso Zambon,* Giuseppe Borsato, Stefania Brussolo, Pietrogiulio Frascella
and Vittorio Lucchini
`
Department of Environmental Sciences, Universita Ca’ Foscari, S. Marta 2137, Venice, Italy
Received 23 September 2007; revised 28 October 2007; accepted 2 November 2007
Available online 7 November 2007
Abstract—A novel rearrangement process involving the migration of trimethylstannanyl or trimethylsilanyl groups around the
thiazole ring provides access to either 2- or 5-metallated thiazoles by tuning the reaction conditions. The proposed mechanism,
based on experimental evidence, is characterized by the catalytic role of thiazole bisadducts as metal-transfer agents.
Ó 2007 Elsevier Ltd. All rights reserved.
Thiazoles are a prominent class of heterocycles with a
wide range of biological properties,1 as well as being
investigated for other applications such as liquid crys-
tals2 and molecular diodes.3 The interest in substituted
thiazoles with reactive functionalities resides also in
their synthetic potential as building blocks for natural
product synthesis4 and/or as masked aldehydes,5 thanks
to the ready conversion of the thiazole ring into the
formyl group. Furthermore, synthetic thiazoles offer
the opportunity to increase the structural diversity of
natural thiazole substrates.
as building blocks. The regioselectivity of both the
silanylation and stannanylation reactions is normally
regulated by the recognized acidity of thiazole protons,
H2 > H5 ꢀ H4: the insertion of functional groups at
the 2-position (generation of 2-trimethylsilanyl-thiazole
2a or 2-trimethylstannanyl-thiazole 2b) is then accom-
plished by the addition of 1 equiv of strong base and
1 equiv of chlorosilane or chlorostannane.9 On the other
hand, the generation of 5-trimethylsilanyl- 3a or 5-tri-
methylstannanyl-thiazole 3b requires either the metal–
halogen exchange reactions of synthetically more
demanding monohalogenated thiazoles7b or the use of
a protecting group on the more reactive 2-position.8 In
the case of silanylation to 4a, the protection can be
accomplished by the same functional group, so that
2 equiv of strong base and 2 equiv of chlorosilane are
required. The silanyl group can then be selectively
removed from the more labile 2-position by treatment
with acid (Scheme 1, i–iii).8
Although the Hantzsch process,6 in which an a-halo
ketone is condensed with a thioamide, has been for
decades the method of choice for the synthesis of thi-
azoles, great attention has been recently dedicated to
more flexible and rapid procedures, and particularly to
that of carbon–carbon bond formation at the thiazole
ring.7 Among the literature methods, the functionali-
zation of the desired positions with silicon or tin
allows the direct insertion of the thiazole ring into
greater molecular systems, via Stille coupling or substi-
tution of the silanyl or stannanyl group by carbon
electrophiles.8 According to these considerations, our
approach to the synthesis of substituted thiazoles was
based on the use of 5- and 2-trimethylstannanyl-thiazole
During the metallation of thiazole 1 we observed an
unreported rearrangement that raised the opportunity
to obtain 5-stannanyl- or 5-silanyl-thiazole 3a,b from
unbrominated starting materials and without protecting
groups.10 In fact, when the reactions were run with an
excess of base and up to 2 equiv of metal chloride, the
2-substituted products 2a,b were still obtained at low
temperature and within short reaction times (Scheme
1, i), but started to interconvert to their 5-substituted
analogues when longer reaction times and higher tem-
peratures were applied (Scheme 1, iii). After overnight
stirring, a 10% excess of base and chloride was sufficient
Keywords: Base-catalyzed halogen dance; Substituted thiazoles;
Metallotropic rearrangement.
*
Corresponding author. Tel.: +39 041 234 8537; fax: +39 041 234
8584; e-mail: azambon@unive.it
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.11.029

A. Zambon et al. / Tetrahedron Letters 49 (2008) 66–69
67
S
N
2a,b
tion,12 in which a halogen substituent moves to a new
position on an aromatic ring system under basic condi-
tions. In BCHD the driving force of the rearrangement
is the formation of a more stable organolithium; on
heterocycles, as, for example, in the rearrangement of
2,3-dibromothiophene to 2,4-dibromothiophene,13 the
driving force is related to the different site acidities.
Recently, the stannanylation of the 4- and 5-positions
of the thiazole ring has been achieved by the application
of the BCHD reaction to halothiazoles.14 Following the
acidity order of the thiazole protons, the migration of
the halogen atom occurs from the 2-position to the
thermodynamically favoured 5- or 4-positions, and is
followed by the generation of the corresponding tin
compounds by metal–halogen exchange and quenching
with organic chlorostannane.
X
(ii)
(i)
X
S
S
N
3a,b
N
1
(iii)
a: X = Si
b: X = Sn
Scheme 1. Access routes to 2-functionalized (2a,b) and 5-functional-
ized (3a,b) thiazoles. Reagents and conditions: (i) n-BuLi and Me3XCl
(1 equiv), ꢁ78 °C, THF; (ii) n-BuLi (0.1 equiv) and Me3XCl
(0.1 equiv), ꢁ40 °C, THF; (iii) n-BuLi (1.1 equiv) and Me3XCl
(1.1 equiv), ꢁ40 °C, THF.
to reach a total conversion of the initial 2-substituted
compounds 2a,b to their 5-substituted analogues 3a,b.
The catalytic role of the base and the conversion
towards the conjugated bases of the stronger acids bring
evident similarities of this new rearrangement with
BCHD. Interestingly, also in BCHD the nucleophilic
attack of an aryl anion on a hyperbrominated interme-
diate is the proposed key step.12a The apparent inconsis-
tency of having a metal cation instead of a halogen as
the migrating group is not surprising, when it is consid-
ered that BCHD occurs by the transfer of a positive
halogen fragment from one carbon to another and the
release of an aryl anion as leaving group.12
It is worth noticing that the rearrangement took place
only if slight excesses of both base and electrophile were
present, while no change in the initial product pattern
was observed if any of these two reagents was less than
stoichiometric. The same phenomenon was observed
when a clean sample of 2-substituted thiazole was trea-
ted for 5 h at ꢁ40 °C with a catalytic amount (10%) of
both electrophile and base (Scheme 1, ii).
Besides the synthetic advantages, the reaction presents
some intriguing mechanistic aspects. On the basis of
our experimental data, we propose for this rearrange-
ment the mechanism illustrated in Scheme 2. The key
step is the nucleophilic attack of the 2-metallated thi-
azole-5-anions 20a,b on the 2,5-difunctionalized thiazoles
4a,b, which in turn generate the corresponding 5-metal-
lated thiazole-2-anions 30a,b; difunctionalized thiazoles
are then both consumed and created by the same nucle-
ophilic attack. The essential thiazole bisadducts 4a,b are
probably formed in small amount during the metallation
of thiazole, while steps i and iii of Scheme 2 are acid–
base reactions. Given the catalytic amount of strong
base required, it is likely that the thiazole-5-anions are
also generated by deprotonation of 2a,b by the thiazole
2-anions 30a,b. Such an acid/base equilibrium is possible
due to the close pKa values of H2 and H5 in thiazole.11
To test this hypothesis, a 5% molar of 2,5-bis-trimethyl-
silanyl-thiazole 4a8a was added to a solution of 2-stann-
anylated 2b in the presence of 10% molar excess of base.
The resulting rearrangement rate was much faster than
the one measured running the reaction under the same
conditions without any added silanyl adduct, thus con-
firming the role of difunctionalized species in the reac-
tion. Scheme 3 illustrates how disilylated 4a may
promote the rearrangement, reacting with two molecules
of 2-trimethylstannanyl-thiazole-5-anion 20b to give the
catalytic 2,5-bis-trimethylstannanyl-thiazole 4b and
two molecules of 5-trimethylsilanyl-thiazole-2-anion 30a.
The key steps in Schemes 2 and 3 are the nucleophilic
attacks on silicon or tin by the thiazole-5-anion, which
occurs selectively on the 2-position of the bisadduct; this
selectivity can be explained by the already mentioned
lability of the bond between the metal and the elec-
tron-poor C2 carbon, which is far more reactive than
C5 and C4.8
The proposed mechanism presents many similarities
with the base-catalyzed halogen dance (BCHD) reac-
n-BuLi,
S
X
-40 oC
S
a: X = Si
b: X = Sn
X
N
overnight
N
Me3Si
Me3Si
Me3Si
Me3Si
SnMe3
S
N
2a,b
S
N
S
N
S
N
3a,b
SnMe3
SnMe3
SiMe3
3'a,b
2'a,b
(i)
(iii)
Me3Sn
Me3Si
SnMe3
3a,b
S
N
S
N
S
N
S
N
2a,b
SnMe3
X
S
N
X
S
(ii)
S
N
X
S
X
X
Me3Si
Me3Sn
Me3Si
SnMe3
S
N
X
S
S
S
N
SnMe3
SiMe3
2
N
2
N
N
N
3'a
4a,b
2'a,b
3'a,b
4a,b
4a
2'b
4b
Scheme 2. Proposed mechanism for the interconversion of 2-substi-
tuted thiazoles 2a,b into 5-substituted 3a,b.
Scheme 3. Catalytic effect of disilanylated species 4a on the rearrange-
ment of 2-trimethylstannanyl-thiazole 2b.

68
A. Zambon et al. / Tetrahedron Letters 49 (2008) 66–69
Table 1. Absolute energies of the lithiated structures 20, 200, 30 and 50,
optimized at the B3LYP/DGDZVP level and with bulk solvent (THF)
effect (CPCM method)
neutral ones. We have then optimized the lithium salts
of the 2-, 5- and 4-substituted thiazoles 20a,b-Li, 30a,b-
Li and 50a,b-Li in the presence of the THF solvent, using
the conductor-like polarizable continuum model
(CPCM).16 As 2-substituted thiazoles we also consid-
ered structures 200a,b-Li, lithiated on the 4 position.
The results are collected in Table 1, and are similar for
the silanyl and for the stannanyl derivatives.
S
N
Li
S
N
S
N
X
Li
S
N
X
X
Li
X
Li
2''a,b-Li
kcal molꢁ1
2'a,b-Li
5'a,b-Li
3'a,b-Li
Hartree
Compound
20a-Li
300a-Li
5 a-Li
200a-Li
ꢁ984.68969811
ꢁ984.69204261
ꢁ984.68669349
ꢁ984.67278407
ꢁ6719.93771004
ꢁ6719.93947337
ꢁ6719.93421201
ꢁ6719.92201711
1.47
0.00
3.36
It can be appreciated that the 5-functionalized 30a,b-Li
structures are more stable than the 2-functionalized
20a,b-Li structures. Also, of the two sets of 2-functionali-
zed structures, 20a,b-Li and 200a,b-Li, the former one
remains the more stable. This finding supports the
proposed mechanism (Scheme 2), which postulates
nucleophiles 20a,b as intermediates. On the other hand,
the 4-functionalized 50a,b-Li structures are less stable
than both the 2- and 5-functionalized isomers, and do
not appear anywhere along the reaction paths.
12.09
20b-Li
30b-Li
50b-Li
200b-Li
1.11
0.00
3.30
10.96
Table 2. Stille coupling of stannanyl thiazoles 2b and 3b
Ar
SnMe3
Indeed, these computational findings explain why all our
attempts to induce a migration of the silanyl or stanna-
nyl moiety from the 2- or 5- to the 4- position were
unsuccessful. In one experiment, 5-trimethylstannanyl-
2-triisopropylsilanylthiazole was reacted under the same
condition utilized for 3a,b. We expected a rearrange-
ment from the 5- to the 4-position, as the 2-position is
ruled out by the steric hindrance of the TIPS group as
mentioned before. We could only recover unrearranged
starting material.
Pd(PPh3)4 5%
Toluene, reflux, 12 h
S
N
S
Ar-X
N
Thiazole
Halide
Product
Yield (%)
60
S
1
2b
Br
Br
Br
F
N
N
S
N
2
3
4
5
6
7
8
2b
2b
2b
3b
3b
3b
3b
75
60
70
60
67
50
65
Br
N
S
Br
Br
F
N
To explore the synthetic potential of the stannanyl sub-
strates as building blocks, we tested their reactivity in
Stille coupling reactions under standard conditions.
The results are reported in Table 2. Both 2-trimethyl-
stannanyl- and 5-trimethylstannanyl-thiazole reacted
smoothly with both electron-poor and electron-rich aryl
halides, with no appreciable difference in reactivity.
S
O
O
O
O
N
H
H
S
Br
Br
F
Br
F
N
N
N
N
S
S
Br
In summary, the two protocols, labelled i and iii in
Scheme 1, allow the selective and quantitative functional-
ization of either the 2- or the 5-position of the non-substi-
tuted and non-protected thiazole ring. The proposed
mechanism, based on experimental evidences, is
characterized by the nucleophilic attack of the thiazole
anion on the catalytic bismetallated species. Studies
aimed at the extension of this reaction to other hetero
cycles are presently underway in our laboratories.
Br
Br
N
N
S
O
H
O
H
O
O
The influence of the steric hindrance of the metal
migrating group on the rearrangement can be regarded
as a further proof of the nucleophilic character of the
reaction. In fact, no reaction was observed when we
tried to perform the rearrangement with TIPS (triiso-
propylsilanyl) rather than with TMS (trimethylsilanyl)
as leaving group on the 2-position, probably because
the bulky isopropyl groups prevent the approach of
the thiazole anion to the metal centre.
Acknowledgement
This work was co-funded by MIUR (Rome) within the
national PRIN project ‘Caratterizzazione strutturale e
funzionale di protein chinasi con potenziale oncogenico:
Sintesi chimica degli inibitori’.
The exchange involves the two more acid protons of thia-
zole, namely H2 and H5, while H4 is unaffected. To get
some insight on the regioselectivity of the rearrange-
ment, we optimized the relevant structures at the
B3LYP/DGDZVP level.15 Since the key step of the reac-
tion is the nucleophilic attack of the 2-anions on the bis-
metallated thiazoles, the computational studies were
performed on the charged species rather than on the
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2007.11.029.

A. Zambon et al. / Tetrahedron Letters 49 (2008) 66–69
69
10. A similar rearrangement, however, occurring on a thiazole
ring functionalized with bromine, has been reported in:
Kelly, T. R.; Lang, F. Tetrahedron Lett. 1995, 36, 9293–
9296.
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