Investigations of the halogen dance reaction on N-substituted 2-thiazolamines

Article abstract of DOI:10.1021/jo0484326

(Chemical Equation Presented) The halogen dance (HD) reaction on various 2-thiazolamine systems was investigated providing an easy access to a series of 5-substituted 4-bromo-2-thiazolamine derivatives. We could show that HD is a very favored process for

Full text of DOI:10.1021/jo0484326

Investigations of the Halogen Dance Reaction on N-Substituted
2-Thiazolamines§
Peter Stanetty,*,† Michael Schnu¨rch,† Kurt Mereiter,‡ and Marko D. Mihovilovic†
Vienna University of Technology, Institute of Applied Synthetic Chemistry and Institute for Chemical
Technology and Analytics, Getreidemarkt 9/163, A-1060 Vienna, Austria
peter.stanetty@tuwien.ac.at
Received September 7, 2004
The halogen dance (HD) reaction on various 2-thiazolamine systems was investigated providing
an easy access to a series of 5-substituted 4-bromo-2-thiazolamine derivatives. We could show that
HD is a very favored process for the investigated systems and that prevention of HD is only possible
when optimized reaction conditions and selected electrophiles are applied.
Introduction
Since the first observation of a halogen dance (HD)
reaction in 1953,3 intensive research on both aromatic
as well as heteroaromatic systems has been carried out.
The heteroaromatic systems included thiophene4 and
benzo[b]thiophene,5 furan,2c isothiazole,6 imidazole,7 pyra-
zole,8 pyridine,9 quinoline,10 and imidazo[1,2-a]pyridine,11
and very recently, Stangeland and Sammakia12 reported
the first HD on a thiazole derivative. This publication
Thiazoles bearing substituents in positions 4 and 5 are
an upcoming class of compounds with interesting biologi-
cal properties.1 In a search for a versatile and facile
method to prepare such compounds, the halogen dance
(HD)2 reaction promised to be a powerful strategy. HD
reactions can be induced by various bases, e.g., NaNH2,
anilides, alkoxides, BuLi, or LDA,2 and generalized in a
way depicted in Scheme 1.
In the literature, such reaction types have been re-
ferred to by different names such as halogen scrambling,
halogen migration, halogen isomerization, halogen dance
(HD), or base-catalyzed halogen dance (BCHD) reactions.
(3) Vaitekunas, A.; Nord, F. F. J. Am. Chem. Soc. 1953, 75, 1764.
(4) (a) Moses, P.; Gronowitz, S. Ark. Kemi 1961, 18, 119. (b)
Gronowitz, S. Adv. Heterocycl. Chem. 1963, 1, 75. (c) Gronowitz, S.;
Holm, B. Acta Chem. Scand. 1969, 23, 2207. (d) Reinecke, M. G.;
Adickes, H. W. J. Am. Chem. Soc. 1968, 90, 511. (e) Reinecke, M. G.;
Adickes, H. W.; Pyun, C. J. Org. Chem. 1971, 36, 2690. (f) Reinecke,
M. G.; Adickes, H. W.; Pyun, C. J. Org. Chem. 1971, 36, 3820. (g)
Lukevics, E.; Arsenyan, P.; Belyakov, S.; Popelis, J.; Pudova, O.
Tetrahedron Lett. 2001, 41, 2039. (h) Fro¨hlich, J. Bull. Soc. Chim. Belg.
1996, 105, 615. (i) Fro¨hlich, J.; Hametner, C.; Kalt, W. Monatsh. Chem.
1996, 127, 325. (j) Kano, S.; Yuasa, Y.; Yokomatsu, T.; Shibuya, S.
Heterocycles 1983, 20, 2035.
* To whom correspondence should be addressed. Fax: +43-1-58801-
15494.
§ Dedicated to the memory of Prof. Roland Schmid.
† Institute of Applied Synthetic Chemistry.
‡ Institute for Chemical Technology and Analytics.
(5) Reinecke, M. G.; Hollingworth, T. A. J. Org. Chem. 1972, 37,
4257.
(1) (a) Rivkin, A.; Cho, Y. S.; Gabarda, A. E.; Yoshimura, F.;
Danishefsky, S. J. J. Nat. Prod. 2004, 67, 139. (b) He, L.; Orr, G. A.;
Horwitz, S. B. Drug Discovery Today 2001, 6, 1153. (c) Nicolaou, K.
C.; Roschangar, F.; Vourloumis, D. Angew. Chem., Int. Ed. 1998, 37,
2014. (d) Bach, T.; Heuser, S. Angew. Chem., Int. Ed. 2001, 40, 3184.
(e) Plazzi, P. V.; Bordi, F.; Silva, C.; Morini, G.; Caretta, A.; Barocelli,
E.; Vitali, T. Eur. J. Med. Chem. 1995, 30, 881.
(6) Bie, D. A. d.; Plas, H. C. v. d. Tetrahedron Lett. 1968, 36, 3905.
(7) Bie, D. A. d.; Plas, H. C. v. d. Recl. Trav. Chim. Pays-Bas 1969,
88, 1246.
(8) Bie, D. A. d.; Plas, H. C. v. d.; Geurtsen, G.; Nijdam, K. Recl.
Trav. Chim. Pays-Bas 1973, 92, 245.
(9) (a) Mallet, M.; Queguiner, G. Tetrahedron 1979, 35, 1625. (b)
Mallet, M.; Queguiner, J. G. Tetrahedron 1982, 38, 3035. (c) Cochenec,
C.; Rocca, P.; Marsais, F.; Godard, A.; Queguiner, G. Synthesis 1995,
3, 321. (d) Sammakia, T.; Stangeland, E. L.; Whitcomb, M. C. Org.
Lett. 2002, 4, 2385. (e) Saitton, S.; Kihlberg, J.; Luthman, K. Tetra-
hedron 2004, 60, 6113.
(2) For reviews of the halogen dance reaction, see: (a) Bunnett, J.
F. Acc. Chem. Res. 1972, 5, 139. (b) Fro¨hlich, J. Bull. Soc. Chim. Belg.
1996, 105, 615. (c) Fro¨hlich, J. In Progress in Heterocyclic Chemistry;
Suschitzky, H., Scriven, E. F. V., Eds.; Oxford: New York, 1994; Vol.
6, pp 1-35. (d) Marzi, E.; Bigi, A.; Schlosser, M. Eur. J. Org. Chem.
2001, 1371. (e) Tre´court, F.; Gervais, B.; Mallet, M.; Queguiner, G. J.
Org. Chem. 1996, 61, 1673. (f) Comins, D. L.; Saha, J. K. Tetrahedron
Lett. 1995, 36, 7995. (g) Tre´court, F.; Mallet, M.; Mongin, O.; Que-
guiner, G. J. Org. Chem. 1994, 59, 6173. (h) Guillier, F.; Nivoliers, F.;
Godard, A.; Marsais, F.; Queguiner, G. Tetrahedron Lett. 1994, 35,
6489. (i) Rocca, P.; Cochenec, C.; Marsais, F.; Thomas-dit-Dumont, L.;
Mallet, M.; Godard, A.; Queguiner, G. J. Org. Chem. 1993, 58, 7832.
(j) Marsais, F.; Pineau, P.; Nivolliers, F.; Mallet, M.; Truck, A.; Godard,
A.; Queguiner, G. J. Org. Chem. 1992, 57, 565.
(10) (a) Hertog, H. J.; Buurman, D. J. Recl. Trav. Chim. Pays-Bas
1973, 92, 304. (b) Arzel, E.; Rocca, P.; Marsais, F.; Godard, A.;
Queguiner, G. Tetrahedron Lett. 1998, 39, 6465. (c) Arzel, E.; Rocca,
P.; Marsais, F.; Godard, A.; Queguiner, G. Heterocycles 1999, 50, 215.
(d) Arzel, E.; Rocca, P.; Marsais, F.; Godard, A.; Queguiner, G.
Tetrahedron 1999, 50, 12149.
(11) Guildford, A. J.; Tometzki, M. A.; Turner, R. W. Synthesis 1983,
987.
(12) Stangeland, E. L.; Sammakia, T. J. Org. Chem. 2004, 69, 2381.
10.1021/jo0484326 CCC: $30.25 © 2005 American Chemical Society
Published on Web 12/23/2004
J. Org. Chem. 2005, 70, 567-574
567

Stanetty et al.
SCHEME 1. General Scheme of a HD
SCHEME 2. Product Distribution in the Initial Lithiation Experimenta
a Key: (a) (1) 1 added to LDA at -80 °C, 30 min at -20 °C; (2) 1,2-dibromoethane added at -40 °C.
TABLE 1. General Guidelines to Control HD Reactions
increased. For the same reason, less than a stoichiometric
amount of base should be used to enhance the HD
reaction. The order of addition of substrates and reagents
has also an influence on the course of the reaction as well
as the solvent and the selected electrophile. THF as
solvent, addition of base to the starting material, and
slowly reacting electrophiles proved to favor HD reac-
tions. Tetrahydropyran (THP) on the contrary often helps
to prevent HD reactions since the initial lithiation is
faster in this solvent compared to THF due to the
increased reactivity of lithium organyls in THP (Table
1).2c
HD
HD prevention
low temperatures
no excess of base
addition of base to the halide
THF
slow reacting electrophile
high temperatures
excess of base
addition of halide to the base
THP
fast reacting electrophile
prompted us to report our results in this research field.
In 2-substituted thiazoles, halogens can be transferred
via HD from the 5-position into the by far less accessible
4-position of the thiazole moiety. While creating a new
reactive center in the 4-position this approach offers the
possibility to introduce also various electrophiles into the
5-position by quenching the intermediate. The bromine
in the 4-position can be then also used for subsequent
transformations, e.g., metal-halogen exchange followed
by reaction with electrophiles as well as cross-coupling
reactions leading finally to a variety of 2,4,5-trisubsti-
tuted thiazoles.
To obtain complete HD it is crucial that unlithiated
starting material and already lithiated intermediates are
present simultaneously in the reaction mixture in order
to start a cascade of metal-halogen exchanges. Since
these exchange reactions are equilibria, the product
distribution found after quenching the reaction reflects
the reaction progress at the moment of the quench. If
one intermediate is considerably more stable than the
others, one product can be formed predominantly or even
exclusively. Extensive research has been carried out on
various systems and general procedures have been
developed to achieve complete HD or complete HD
prevention which must of course be adapted and opti-
mized for any particular synthetic problem.2c Some
general guidelines providing useful hints for initial
experiments are summarized in Table 1. Low tempera-
tures favor HD since in that case the initial lithiation is
slowed and the possibility of having unlithiated starting
material together with an already lithiated species is
Results and Discussion
We first observed a HD during attempts to obtain
N-(4,5-dibromothiazol-2-yl)-2,2-dimethylpropanamide (2)
from N-(5-bromothiazol-2-yl)-2,2-dimethylpropanamide
(1). Since direct bromination using various general
methods13 was not successful, we tried to introduce the
bromine via lithiation with LDA (2.1 equiv) and subse-
quent quenching with 1,2-dibromoethane. After workup,
a mixture of dibrominated, monobrominated, and non-
brominated products was isolated and separated (Scheme
2).
The desired product 2 was obtained in only 9% yield,
and three other compounds were isolated. Besides the
starting material 1 (8%), debrominated N-(thiazol-2-yl)-
2,2-dimethylpropanamide (4) (36%) and N-(4-bromothia-
zol-2-yl)-2,2-dimethylpropanamide (3) (47%) as the major
product were isolated. A hypothesis to explain the forma-
tion of all compounds would be a HD mechanism as
depicted in Scheme 3. The first step in this reaction
sequence is of course the lithiation of the starting
material 1 to form the organometal species 1a. Interme-
diate 1a can by itself act as a lithiating agent and reacts
with starting material 1 to give a metal-halogen ex-
(13) Applied bromination conditions: Br2 in CHCl3 at rt and reflux,
Br2 in AcOH at rt and reflux, Br2 in AcOH/AcONa at rt and reflux.
568 J. Org. Chem., Vol. 70, No. 2, 2005

Halogen Dance on Thiazoles
SCHEME 3. Suggested Mechanism for the Observed HD on 1
TABLE 2. Introduction of Electrophiles into the
change to form the intermediates 2a and 4a. This is the
beginning of a cascade, where all the intermediates can
interact with each other to form the species depicted in
Scheme 3. Quenching the reaction with water could in
general lead to all observed compounds since all the
reactions are equilibria. The addition of 1,2-dibromo-
ethane should further promote the HD since the 4,5-
dibromo compound 2 can act as a co-catalyst. Co-catalysts
in HD reactions are usually polyhalogenated species,
which act as electrophilic halogen donors.2c
5-Position
entry
E
electrophile
product yield (%)
1
2
3
4
5
6
7
8
9
CHO
DMF
5a
5b
2
92
73
93
20
76
86
74
99
46
C6H10(OH)
cyclohexanone
Br
Br2
Br
1,2-dibromoethane
2
I
I2
5c
5d
5e
3
PhCH(OH)
benzaldehyde
TMSCl
TMS
H
H2O
(C6H5)2COH (C6H5)2CO
5f
The reason a HD can occur on an aromatic system can
be explained by differences in the acidity of the various
positions which correlates with the different stability of
the formed lithiated species.14 In this particular case, the
5-position is more acidic than the 4-position, therefore
favoring lithiation at position 5 relative to the 4-position.
Besides the possibility of obtaining the desired com-
pound 2, this sequence would also give access to a range
of interesting 4-substituted and especially 4,5-disubsti-
tuted thiazoles which in particular are difficult to prepare
via other routes.6 Having this in mind, we tried to find
reaction conditions whereafter the initial lithiation of the
4-position either quantitative HD or complete prevention
of HD can be achieved.
via HD reaction as a model transformation in more detail
we changed to bromine as superior electrophile compared
to 1,2-dibromoethane (Table 2, entries 3 and 4).
To find optimized HD conditions, the reaction to the
4,5-dibromo compound 2 starting from the 5-bromo
compound 1 was investigated in more detail. Since we
had the 5-bromo compound 1 and the 4-bromo compound
3 already in hand, we could follow the conversion from 1
to 3 in our lithiation experiments by TLC before adding
bromine as electrophile. In our initial experiment, a
solution of compound 1 in dry THF was treated dropwise
with 2.1 equiv of LDA at -85 °C over a period of 15 min.
Quenching with bromine gave a conversion to 80% of HD
product 2 besides starting material 1. By using a greater
excess of base (3.3 equiv), full conversion to the HD
product was observed. The method was simplified when
we found that an “inverse” addition of base and low
reaction temperatures (-80 °C) are not necessary in this
case. Addition of the halide to the LDA solution at 0 °C
Halogen Dance Conditions. To obtain complete HD,
reaction conditions were applied, whichsaccording to the
literature2cspromote efficiently the rearrangement pro-
cess (Table 1). Investigating the introduction of bromine
(14) Eicher, T.; Hauptmann, S. In The Chemistry of Heterocycles;
Wiley-VCH: Weinheim, 2003; p 149.
J. Org. Chem, Vol. 70, No. 2, 2005 569

Stanetty et al.
SCHEME 4. Introduction of Electrophiles into the
5-Positiona
to HD products. This means that the initial lithiation
should be a fast process, which can be ensured in many
cases by using elevated temperatures and slow addition
of the halide to an excess of base (Table 1). The use of a
fast reacting electrophile also helps to obtain HD-preven-
tion products: for that purpose we chose TMSCl. Since
in dry THF the HD reaction took place also under
reaction conditions, which according to the literature,2c
should prevent the HD we switched to dry THP since it
is described as a solvent where HD-prevention is some-
times favored. Although various temperatures and
amounts of base (2.1-4.3 equiv) were applied, no HD-
prevention products were obtained. In all cases the halide
was added very slowly (up to 45 min/mL) to an excess of
base at temperatures ranging from -110 °C (THP/
hexane) to 0 °C (THP). Consequently, the HD-reaction
seems to take place immediately after the lithiation.
a Key: (a) (1) 3.3 equiv of LDA, 0 °C, 30 min, THF; (2) 3.3 equiv
of E+.
SCHEME 5. Characteristic 13C-Shifts of the C-4
and C-5 in Various 2-Thiazolamine Derivatives
Influence of the NH Proton. Since attempts to
prevent the HD were not successful so far, we investi-
gated if the NH proton has a significant influence on the
HD reaction. Slow deprotonation at this position would
favor HD reactions because already formed 4-lithio
species could be intermolecularly reprotonated. This leads
to mixtures of lithiated and unlithiated species, which
could be a reason HD prevention was not successful so
far. Therefore proton donation by the amide nitrogen
atom should be prevented and we had in mind to
methylate the amide nitrogen. We found that deproto-
nation with NaH or LDA (1.05-1.20 equiv) and subse-
quent quenching with MeI or DMS (2.0-14 equiv) led to
methylation of the ring nitrogen (compound 6) and not
to the desired methylation of the amide nitrogen (Scheme
6, optimized conditions). The structure of 6 was confirmed
by X-ray analysis (Supporting Information). Methylation
on the ring nitrogen is not totally surprising since it is
known in the literature16 that the parent thiazole-2-
amine exists in two tautomeric structures although the
equilibrium lies well on the side of the amine species.
When LDA was used as base, methylation did not
proceed to completion which suggests that LDA does not
abstract the NH-proton very efficiently. Consequently,
this effect might hinder the HD prevention, which is
consistent with our results. To support this hypothesis
other systems with completely substituted amide nitro-
gen in 2-position were synthesized.
Compound 7 was obtained via a straightforward syn-
thesis (Scheme 7) according to the literature.17 Initially,
the pivaloyl group was used again as the protecting group
for the amine functionality because of its stability under
bromination conditions. During our first experiments, we
observed that the pivaloyl group in N-phenyl-N-(thiazol-
2-yl)-2,2-dimethylpropanamide 8 shows a great ten-
dency to migrate into the 5-position of the thiazole ring
under lithiation conditions even at low temperatures
gave complete HD within minutes. We believe that a
complete HD under such conditions occurs due to the
great difference in the acidities of the 4- and 5-position
of the thiazole system.14 Although this finding simplified
the experimental procedure, it also suggested that pre-
vention of the HD could be expected to be rather difficult.
With a convenient methodology for complete HD in our
hands, 4-bromo-5-lithiated intermediate 3a was trapped
with various electrophiles and several substituents were
introduced into the 5-position in good to excellent yields
(46-99%; Table 2, Scheme 4).
An easy confirmation that HD occurred was obtained
by analysis of the 13C spectra of the various products. In
N-(thiazol-2-yl)-2,2-dimethylpropanamide 4,15 the thia-
zole carbons 4 and 5 show δ values of 137.1 ppm (C-4)
and 113.6 ppm (C-5), respectively. Bromination of the
5-position leads to a shielding of the C-5 carbon to 103.6
ppm due to the heavy atom effect of the bromine whereby
the C-4 carbon shift is almost unaffected with a value of
137.6 ppm (Scheme 5). On the other hand, in the
4-brominated compound 3 the C-5 carbon at 111.3 ppm
is almost unaffected compared to the unbrominated
compound 4, whereby the C-4 carbon due to the heavy
atom effect is shifted again to 120.8 ppm. Very similar
effects were found for all investigated HD products
making it easy to determine if a HD or a HD-prevention
product was formed. Additionally the structure of 5d was
confirmed by X-ray analysis (Supporting Information).
The carbon shift for C-4 is in good agreement with the
above-specified characteristic range (118.8 ppm).
Prevention Conditions. The much more difficult
task was to find reaction conditions to prevent the HD
enabling the introduction of electrophiles into the 4-posi-
tion of 5-bromo-N-(thiazol-2-yl)-2,2-dimethylpropanamide
1. To prevent the HD reaction it is necessary that no
unlithiated starting material is present next to the
initially lithiated species, hence, not allowing a metal-
halogen exchange which would start a cascade leading
(16) Forlani, L.; De Maria, P.; Fini, A. J. Chem. Soc., Perkin Trans.
2 1980, 8, 1156.
(17) Maeda, R. S. African ZA 7900673, 1980; Chem. Abstr. 1980,
94, 84105.
(18) Hellwinkel, D.; La¨mmerzahl, F.; Hofmann, G. Chem. Ber. 1983,
116, 3375.
(19) (a) Schmid, M. Ph.D. Thesis, Vienna University of Technology,
1994. (b) Krumpak, B. Ph.D. Thesis, Vienna University of Technology,
1995.
(15) Schiavi, B.; Ahond, A.; Al-Mourabit, A.; Poupat, C.; Chiaroni,
A.; Gaspard, C.; Potier, P. Tetrahedron 2002, 58, 4201.
(20) Krizan, T. D.; Martin, J. C. J. Am. Chem. Soc. 1983, 105, 6155-
6157.
570 J. Org. Chem., Vol. 70, No. 2, 2005

Halogen Dance on Thiazoles
SCHEME 6. N-Methylation Experiment of 1a
a Key: (a) (1) 1.2 equiv of LiH; (2) 1.5 equiv of DMS, 66 °C.
SCHEME 7. Synthesis and Lithiation Experiments of Compounds 8 and 9a
a Key: (a) NaH, pivaloyl chloride, THF, reflux; (b) Br2, NEt3, CHCl3, rt; (c) LDA, TMSCl, THF, -100 °C; (d) LDA, THF, -100 °C to rt.
SCHEME 8. Synthesis and HD Experiments with 14a
a Key: (a) DMAP, BOC-anhydride, THF, reflux; (b) Br2, NEt3, CHCl3, rt; (c) LDA, TMSCl, THF, 0 °C.
(-80 °C) to form compound 11 (Scheme 7). This migration
must be an intermolecular process since for sterical
reasons an intramolecular migration is not possible. To
our knowledge this is the first intermolecular migration
of a pivaloyl group observed whereas intramolecular
migrations have already been reported in the literature.18
This observation suggested that 5-bromo compound 9 is
also not a suitable substrate for HD-dance prevention
reactions since again a migration of the protecting group
has to be expected at higher temperatures. At tempera-
tures below -80 °C (-110 to -90 °C) the HD product 10
(69%) was obtained but also at these low temperatures
partial migration of the protecting group to form 11 was
observed.
major product 12 again was accompanied by 8% of the
endocyclic protected compound 13. As expected the BOC
group was not as stable as the pivaloyl group under
bromination conditions and partial loss of the protecting
group during bromination could not be avoided. But still
the desired product 14 was obtained in 53% yield. At low
temperatures, the BOC group was stable enough to
obtain the HD product 15 in good yield (Scheme 8)
without migration of the protecting group. But also with
this substrate no HD prevention products were obtained
(Scheme 8). When HD prevention at elevated tempera-
tures (0 °C, dry THF, 3.3 equiv of LDA, 3.3 equiv of
TMSCl) was studied the protecting group was lost which
was not the case at low temperatures (-80 °C). However,
it did not undergo migration of any kind (inter- or
intramolecular) as was the case with the pivaloyl-
protected substrate.
Consequently, we chose the BOC group as the protect-
ing group since we knew from earlier research that the
BOC group has a lower tendency to migrate under
lithiation conditions.19 Similar to our experience in the
methylation, during the protection step of 1 the required
In the next series of experiments, we intended to study
the effect of a second electron-withdrawing substituent
J. Org. Chem, Vol. 70, No. 2, 2005 571

Stanetty et al.
SCHEME 9. Protection of 16 and HD of 17a
a Key: (a) DMAP, BOC-anhydride, THF, reflux; (b) LDA, TMSCl, THF.
SCHEME 10. HD Prevention on 1a
a Key: (a) (1) 3.3 equiv of LDA + 3.3 equiv of electrophile, -80 °C, THF; (2) 1 equiv of 1, -80 °C to rt.
at the amide nitrogen possibly promoting faster lithiation
at 4-position of the thiazole system. As a test compound
we chose the bis-BOC compound 17 since it was readily
available from 5-bromo-2-thiazolamine (16) (Scheme 9).
To further promote HD prevention the amount of LDA
was increased to 6 equiv and THF and THP were studied
as solvents. The reactions were carried out in a range
between -60 and 0 °C in both solvents. However,
prevention of the HD was not possible as again complete
halogen migration occurred within minutes. One of the
BOC groups was lost during workup.
In Situ Trapping of Initially 4-Lithiated Thiaz-
oles. From the above findings, the HD reaction seems
to be very fast, even at low temperatures. Therefore, the
whole process is already finished before the electrophile
is added to the reaction mixture. The only remaining
option to prevent HDsif possible at allswas to carry out
the lithiation step in the presence of a compatible
electrophile.20 For this final experiment, we chose once
again TMSCl as reactant, based on its stability toward
LDA and its usually fast reaction. A solution of LDA was
prepared and TMSCl was added at -80 °C, followed by
the 5-bromo compound 1. Under these conditions we
finally succeeded to obtain the corresponding prevention
product 19 in 67% yield (Scheme 10). Compound 19 was
formed exclusively, and no HD product was found in the
reaction mixture. On the other hand, when a soft elec-
trophile was used, namely benzophenone, under the same
conditions no prevention product was observed and only
the HD product 5f was isolated. We therefore believe that
not only the applied reaction conditions but also the
properties of the electrophile have a significant influence
on the type of product formed. It seems to be the case
that a soft electrophile like benzophenone reacts too slow
and HD takes place before the benzophenone is attacked
by the initially lithiated species.
only possible under certain conditions with electrophiles
stable and reactive enough under such conditions. We
found that TMSCl as a hard electrophile was suitable
for this purpose but when benzophenone as a soft
electrophile was applied under the same reaction condi-
tions only HD product was isolated.
Experimental Section
General Bromination Procedure. The corresponding
N-protected 2-thiazolamine substrate was stirred with NEt3
(1.5 equiv) in dry CHCl3, and Br2 (1.5 equiv) was added
dropwise at room temperature as a 1:1 mixture in the solvent.
The reaction mixture was stirred at room temperature for 3 h
and subsequently washed with satd Na2CO3 solution, satd
Na2S2O5 solution, water, and brine. The aqueous solutions
were all re-extracted with CHCl3. The combined organic layers
were dried over Na2SO4 and filtered, and the solvent was
evaporated. Recrystallization from DIPE (diisopropyl ether)
or purification by MPLC (medium-pressure liquid chromatog-
raphy) using silica gel as stationary phase and EtOAc and PE
(petroleum ether) as mobile phase gave the desired products.
N-(5-Bromothiazol-2-yl)-2,2-dimethylpropanamide,
1: mp 127-129 °C; 84% (6.0 g, 22.80 mmol, beige solid);
1
recrystallized from DIPE; H NMR (CDCl3, 200 MHz) δ 1.32
(s, 9H), 7.36 (s, 1H), 9.66 (bs, 1H); 13C NMR (CDCl3, 50 MHz)
δ 27.0 (q), 39.0 (s), 103.6 (s), 137.6 (d), 159.6 (s), 176.7 (s). Anal.
Calcd for C8H11BrN2OS: C, 36.51; H, 4.21; N 10.65. Found:
C, 36.76; H, 4.16; N, 10.56.
N-(5-Bromothiazol-2-yl)-2,2-dimethyl-N-phenylpropan-
amide, 9: mp 142-144 °C; 79% (0.37 g, 1.09 mmol, beige
1
solid); H NMR (CDCl3, 200 MHz) δ 1.10 (s, 9H), 7.29-7.39
(m, 3H), 7.48-7.57 (m, 3H); 13C NMR (CDCl3, 50 MHz) δ 29.0
(q), 41.7 (s), 104.8 (s), 129.2 (d), 129.7 (d), 130.9 (d), 138.1 (d),
162.2 (s), 177.1 (s). Anal. Calcd for C14H15BrN2OS: C, 49.57;
H, 4.46; N, 8.26. Found: C, 49.79; H, 4.40; N, 8.23.
N-(5-Bromothiazol-2-yl)-N-phenylcarbamic acid 1,1-
dimethylethyl ester, 14: mp 117-119 °C; 47% (606 mg, 1.71
mmol, yellow solid); MPLC PE/EtOAc 8:1; 1H NMR (CDCl3,
200 MHz) δ 1.43 (s, 9H), 7.18-7.27 (m, 3H), 7.38-7.52 (m,
3H); 13C NMR (CDCl3, 50 MHz) δ 28.0 (q), 83.9 (s), 103.3 (s),
128.4 (d), 128.5 (d), 129.3 (d), 138.3 (s), 138.8 (d), 152.7 (s),
162.1 (s).
Conclusion
General Procedure for the Halogen Dance Reaction.
One equivalent of the halide was added dropwise to 3.3 equiv
of LDA in dry THF at 0 °C, and the reaction mixture was
stirred for 15 min until TLC control showed complete HD
reaction. Then 3.3 equiv of the corresponding electrophile was
added at rt and the reaction mixture stirred overnight. The
reaction mixture was diluted with EtOAc, washed with 2 N
During our investigations, we optimized the reaction
conditions for complete HD on the investigated systems.
We also demonstrated that various electrophiles can be
introduced in the 5-position creating in the same step a
new reactive center in the 4-position. On the other hand,
we showed that prevention of the HD is very difficult and
572 J. Org. Chem., Vol. 70, No. 2, 2005

Halogen Dance on Thiazoles
HCl, water, and brine, dried over Na2SO4, and filtered and
the solvent evaporated. Purification by MPLC or recrystalli-
zation from DIPE gave the corresponding products.
N-(4,5-Dibromothiazol-2-yl)-2,2-dimethylpropana-
mide, 2: mp 112-114 °C; 93% (6.05 g, 17.69 mmol, brown
solid); MPLC DIPE; 1H NMR (CDCl3, 200 MHz) δ 1.31 (s, 9H),
9.03 (bs, 1H); 13C NMR (CDCl3, 50 MHz) δ 27.0 (q), 39.1 (s),
101.8 (s), 123.7 (s), 158.3 (s), 176.7 (s). Anal. Calcd for C8H10-
Br2N2OS‚0.15C6H14O (DIPE): C, 29.91; H, 3.41; N, 7.84.
Found: C, 29.96; H, 3.26; N, 7.88.
N-(4-Bromothiazol-2-yl)-2,2-dimethylpropanamide, 3:
pale yellow, slowly crystallizing (from DIPE) solid; mp 90-97
°C; 99% (0.50 g, 1.90 mmol); 1H NMR (CDCl3, 200 MHz) δ 1.32
(s, 9H), 6.85 (s, 1H), 8.93 (bs, 1H); 13C NMR (CDCl3, 50 MHz)
δ 27.1 (q), 39.1 (s), 111.3 (d), 120.8 (s), 158.7 (s), 176.4 (s). Anal.
Calcd for C8H11BrN2OS: C, 36.51; H, 4.21; N, 10.65. Found:
C, 36.74; H, 4.06; N, 10.54.
N-(4-Bromo-5-formylthiazol-2-yl)-2,2-dimethylpropan-
amide, 5a: mp 219-221 °C; 92% (1.02 g, 3.50 mmol, colorless
solid); MPLC PE/EtOAc 4:1; 1H NMR (CDCl3, 200 MHz) δ 1.34
(s, 9H), 9.13 (bs, 1H), 9.94 (s, 1H); 13C NMR (CDCl3, 50 MHz)
δ 27.0 (q), 39.5 (s), 126.6 (s), 133.0 (s), 163.7 (s), 176.8 (s), 183.3
(d). Anal. Calcd for C9H11BrN2O2S: C, 37.13; H, 3.81; N, 9.62.
Found: C, 36.97; H, 3.83; N, 9.34.
N-[4-Bromo-5-(1-hydroxycyclohex-1-yl)thiazol-2-yl]-
2,2-dimethylpropanamide, 5b: mp 147-149 °C; 73% (0.50
g, 1.39 mmol, colorless powder); MPLC PE/EtOAc 10:1; 1H
NMR (CDCl3, 200 MHz) δ 1.30 (s, 9H), 1.60-2.25 (m, 10H),
2.65 (bs, 1H), 8.88 (bs, 1H); 13C NMR (CDCl3, 50 MHz) δ 21.7
(t), 25.0 (t), 27.1 (q), 36.9 (t), 39.1 (s), 72.1 (s), 114.4 (s), 135.9
(s), 156.1 (s), 176.1 (s). Anal. Calcd for C14H21BrN2O2S: C,
46.54; H, 5.86; N, 7.75. Found: C, 46.66; H, 5.60; N, 7.56.
N-(4-Bromo-5-iodothiazol-2-yl)-2,2-dimethylpropana-
mide, 5c: mp 127-129 °C; 76% (5.61 g, 14.44 mmol, pale
yellow solid); MPLC PE/EtOAc 10:1; 1H NMR (CDCl3, 200
MHz) δ 1.31 (s, 9H), 8.97 (bs, 1H); 13C NMR (CDCl3, 50 MHz)
δ 27.0 (q), 39.0 (s), 66.9 (s), 130.1 (s), 162.5 (s), 176.6 (s). Anal.
Calcd for C8H10BrIN2OS: C, 24.70; H, 2.59; N, 7.20. Found:
C, 25.00; H, 2.67; N, 7.22.
N-[4-Bromo-5-(hydroxyphenylmethyl)thiazol-2-yl]-2,2-
dimethylpropanamide, 5d: mp 154-156 °C; 86% (0.60 g,
1.63 mmol, beige solid); MPLC PE/EtOAc 10:1; 1H NMR
(CDCl3, 200 MHz) δ 1.28 (s, 9H), 2.48 (bs, 1H), 6.09 (s, 1H),
7.28-7.42 (m, 3H), 7.45-7.53 (m, 2H), 8.81 (bs, 1H); 13C NMR
(CDCl3, 50 MHz) δ 27.0 (q), 39.1 (s), 70.5 (d), 118.8 (s), 125.9
(d), 128.2 (d), 128.7 (d), 131.2 (s), 141.7 (s), 158.3 (s), 176.4 (s).
Anal. Calcd for C15H17BrN2O2S: C, 48.79; H, 4.64; N, 7.59.
Found: C, 48.82; H, 4.54; N, 7.54.
N-(4-Bromo-5-trimethylsilylthiazol-2-yl)-2,2-dimethyl-
propanamide, 5e: mp 199-201 °C; 74% (0.189 g, 0.56 mmol,
colorless crystals); MPLC PE/EtOAc 10:1; 1H NMR (CDCl3, 200
MHz) δ 0.37 (s, 9H), 1.30 (s, 9H), 9.50 (bs, 1H); 13C NMR
(CDCl3, 50 MHz) δ -0.8 (q), 27.0 (q), 39.2 (s), 121.4 (s), 126.6
(s), 162.1 (s), 176.7 (s). Anal. Calcd for C11H19BrN2OSSi: C,
39.40; H, 5.71; N, 8.35. Found: C, 39.68; H, 5.66; N, 8.13.
N-(4-Bromo-5-trimethylsilylthiazol-2-yl)-N-phenylcar-
bamic acid 1,1-dimethylethyl ester, 15: mp 114-116 °C;
97% (0.35 g, 0.82 mmol, colorless crystals); MPLC PE/EtOAc
1
8:1; H NMR (CDCl3, 200 MHz) δ 0.38 (s, 9H), 1.42 (s, 9H),
7.16-7.25 (m, 2H), 7.31-7.49 (m, 3H); 13C NMR (CDCl3, 50
MHz) δ -0.7 (q), 28.0 (q), 83.7 (s), 121.7 (s), 127.2 (s), 128.1
(d), 128.3 (d), 129.1 (d), 139.0 (s), 152.8 (s), 165.2 (s). Anal.
Calcd for C17H23BrN2O2SSi: C, 47.77; H, 5.42; N, 6.55.
Found: C, 48.01; H, 5.31; N, 6.46.
N-(4-Bromo-5-trimethylsilylthiazol-2-yl)carbamic acid
1,1-dimethylethyl ester, 18: mp 143-145 °C; 76% (0.07 g,
1
0.20 mmol, pale yellow solid); MPLC PE/EtOAc 6:1; H NMR
(CDCl3, 200 MHz) δ 0.36 (s, 9H), 1.52 (s, 9H), 10.10 (bs, 1H);
13C NMR (CDCl3, 50 MHz) δ -0.8 (q), 28.1 (q), 82.8 (s), 119.9
(s), 126.5 (s), 152.5 (s), 164.4 (s).
N-[5-Bromo-3-methylthiazol-2(3H)-ylidene]-2,2-dimeth-
ylpropanamide, 6. Substance 1 (0.5 g, 1.90 mmol) was
dissolved in 5 mL of dry THF under argon atmosphere. A 1.2
equiv (20 mg) portion of LiH was added carefully and the
reaction mixture refluxed for 30 min. Subsequently, the
reaction was cooled to 0 °C, and 1.5 equiv of dimethyl sulfate
(0.36 g, 2.85 mmol) was added. The reaction mixture was
warmed to room temperature, diluted with EtOAc, washed
with 2 N HCl, water, and brine, dried over Na2SO4, and filtered
and the solvent evaporated. Recrystallization from DIPE gave
6: 98% (0.52 g, 1.88 mmol, colorless crystals); mp 165-166
°C; 1H NMR (CDCl3, 200 MHz) δ 1.26 (s, 9H), 3.68 (s, 3H),
6.92 (s, 1H); 13C NMR (CDCl3, 50 MHz) δ 27.8 (q), 35.5 (q),
40.5 (s), 98.1 (s), 126.2 (d), 167.3 (s), 188.6 (s). Anal. Calcd for
C9H13BrN2OS: C, 39.00; H, 4.73; N, 10.11. Found: C, 39.14;
H, 4.55; N, 10.09.
2,2-Dimethyl-N-phenyl-N-(thiazol-2-yl)propanamide,
8. Compound 7 (2.84 g, 16.1 mmol) was stirred in 50 mL of
dry THF, and NaH (0.46 g, 19.3 mmol) was added in small
portions over a period of 15 min. The reaction mixture was
stirred at rt for 1 h, and then pivaloyl chloride (2.33 g, 19.3
mmol) was added dropwise. After being refluxed overnight,
the reaction mixture was diluted with EtOAc (150 mL) and
poured onto water. The organic layer was washed with 2 N
HCl, water, and brine, dried over Na2SO4, filtered, and
concentrated. MPLC PE:EtOAc 6:1 gave 3.30 g (12.67 mmol,
79%) of 8 as a pale yellow solid: mp 116-117 °C; 1H NMR
(CDCl3, 200 MHz) δ 1.11 (s, 9H), 6.98 (d, 3.6 Hz, 1H), 7.31-
7.43 (m, 3H), 7.44-7.57 (m, 3H); 13C NMR (CDCl3, 50 MHz) δ
29.0 (q), 41.7 (s), 114.6 (d), 129.0 (d), 129.2 (d), 130.7 (d), 137.4
(d), 140.0 (s), 162.7 (s), 176.8 (s). Anal. Calcd for C14H16N2OS:
C, 64.59; H, 6.19; N, 10.76. Found: C, 64.68; H, 5.93; N, 10.83.
2,2-Dimethyl-(2-phenylaminothiazol-5-yl)propan-1-
one, 11. A solution of 8 in 1 mL of dry THF (0.2 g, 0.77 mmol,
1 equiv) was added dropwise at -80 °C to a solution of 1.1
equiv of LDA in 3 mL of dry THF. The reaction mixture was
slowly warmed to room temperature and then poured onto
water and extracted three times with EtOAc. The organic
layers were combined and washed with brine, dried over Na2-
SO4, and filtered, and the solvent was evaporated. Recrystal-
lization from DIPE gave 95% 11 (0.19 g, 0.73 mmol) as beige
1
N-[4-Bromo-5-(diphenylhydroxymethyl)thiazol-2-yl]-
2,2-dimethylpropanamide, 5f: mp 144-145 °C; 46% (0.23
g, 0.52 mmol, colorless solid); MPLC PE/EtOAc 10:1; 1H NMR
(CDCl3, 200 MHz) δ 1.26 (s, 9H), 3.93 (bs, 1H), 7.27-7.43 (m,
10H), 8.85 (bs, 1H); 13C NMR (CDCl3, 50 MHz) δ 27.0 (q), 39.0
(s), 78.2 (s), 119.1 (s), 127.3 (d), 128.1 (d), 128.2 (d), 134.0 (s),
144.6 (s), 156.9 (s), 176.3 (s).
N-(4-Bromo-5-trimethylsilylthiazol-2-yl)-2,2-dimethyl-
N-phenylpropanamide, 10: mp 138-139 °C; 69% (0.16 g,
0.57 mmol, colorless solid); recrystallized from DIPE; 1H NMR
(CDCl3, 200 MHz) δ 0.37 (s, 9H), 1.09 (s, 9H), 7.28-7.38 (m,
2H), 7.43-7.53 (m, 3H); 13C NMR (CDCl3, 50 MHz) δ -0.8 (q),
29.1 (q), 41.9 (s), 122.7 (s), 127.3 (s), 129.1 (d), 129.4 (d), 130.7
(d), 139.4 (s), 165.7 (s), 176.6 (s). Anal. Calcd for C17H23BrN2-
OSSi: C, 49.63; H, 5.63; N, 6.81. Found: C, 49.83; H, 5.47; N,
6.80.
solid: mp 148-150 °C; H NMR (CDCl3, 200 MHz) δ 1.36 (s,
9H), 7.11-7.23 (m, 1H), 7.30-7.50 (m, 4H), 7.99 (s, 1H), 9.46
(bs, 1H); 13C NMR (CDCl3, 50 MHz) δ 28.2 (q), 43.7 (s), 119.3
(d), 124.5 (d), 127.4 (s), 129.7 (d), 139.3 (s), 144.6 (d), 170.1
(s), 198.1 (s).
BOC Protection of 2-Thiazolamines 7 and 16. The
corresponding 2-thiazolamine (7 or 16, 1 equiv) was refluxed
in dry THF in the presence of a catalytic amount of DMAP.
Then pyrocarbonic acid di-tert-butyl ester (1.5 equiv for
preparation of 12, 2.4 equiv for preparation of 17) was
dissolved in dry THF, added dropwise to the reaction mixture,
and refluxed overnight. The reaction solution was poured onto
ice-water and neutralized with a few drops of 2 N HCl. The
resulting solution was extracted three times with Et2O, and
the combined organic layers were washed with water and
brine, dried over Na2SO4, filtered, and concentrated. If neces-
J. Org. Chem, Vol. 70, No. 2, 2005 573

Stanetty et al.
sary the product was purified by flash column chromatography
using NEt3 basic silica gel.
for compound 5d were collected with a Philips PW1100 four-
circle diffractometer and for compounds 6 and 13 with a
Bruker AXS Smart CCD diffractometer, both instruments
operating with graphite-monochromatized Mo KR radiation.
Structure solution and refinement was performed with the
Bruker AXS SHELXTL software. Full crystallographic data
are given in the Supporting Information.
Compound 5d: C15H17BrN2O2S, FW ) 369.28, crystals from
ethanol, monoclinic, C2/c, a ) 21.693(2) Å, b ) 7.426(1) Å, c )
21.271(2) Å, â ) 111.72(1)°, V ) 3183.5(4) Å3, Z ) 8, T ) 298
K, R1 ) 0.041 for 2290 observed reflections (I > 2σ(I)) and
195 parameters. The structure contains one kind of molecules
mutually linked via intermolecular hydrogen bonds O(1)-
H(1o)- - -N(1′) and N(2)-H(2n)- - -O(1′).
Compound 6: C9H13BrN2OS, FW ) 277.18, crystals from
ethanol, monoclinic, P21/m, a ) 11.978(1) Å, b ) 7.115(1) Å, c
) 14.319(2) Å, â ) 99.461(2)°, V ) 1203.7(2) Å3, Z ) 4, T )
297 K, R1 ) 0.041 for 1735 observed reflections and 164
parameters. The structure contains two independent molecules
of symmetry Cs with similar bond lengths and conformation.
Compound 13: C14H16N2O2S, FW ) 276.35, crystals from
ethanol, monoclinic, P21/c, a ) 9.010(1) Å, b ) 10.954(1) Å, c
) 30.086(2) Å, â ) 91.797(2)°, V ) 2870.4(4) Å3, Z ) 8, T )
173 K, R1 ) 0.050 for 3968 observed reflections (I > 2σ(I))
and 349 parameters. The structure contains two independent
molecules of similar bond lengths but notably different con-
formation with respect to phenyl ring orientation.
N-Phenyl-N-(thiazol-2-yl)carbamic acid 1,1-dimethyl-
ethyl ester, 12: mp 103-104 °C; 82% (205 mg, 0.74 mmol,
beige solid); MPLC PE/EtOAc 8:1; 1H NMR (CDCl3, 200 MHz)
δ 1.43 (s, 9H), 6.95 (d, 3.6 Hz, 1H), 7.20-7.29 (m, 2H), 7.34 (d,
3.6 Hz, 1H), 7.37-7.52 (m, 3H); 13C NMR (CDCl3, 50 MHz) δ
27.9 (q), 83.2 (s), 113.8 (d), 128.1 (d), 128.3 (d), 129.1 (d),
138.0 (d), 139.5 (s), 152.7 (s), 162.4 (s). Anal. Calcd for
C14H16N2O2S: C, 60.85; H, 5.84; N, 10.14. Found: C, 61.12;
H, 5.62; N, 10.23.
2,3-Dihydro-2-phenyliminothiazole-3-carboxylic acid
1,1-dimethylethyl ester, 13: mp 99-102 °C; 8% (as byprod-
uct, 0.02 g, 0.07 mmol, colorless crystals); MPLC PE/EtOAc
8:1; 1H NMR (CDCl3, 200 MHz) δ 1.60 (s, 9H), 5.89 (d, 5.4 Hz,
1H), 6.95-7.15 (m, 4H), 7.25-7.40 (m, 3H); 13C NMR (CDCl3,
50 MHz) δ 27.9 (q), 84.4 (s), 101.1 (d), 120.6 (d), 123.5 (d), 123.9
(d), 129.3 (d), 147.7 (s), 151.7 (s), 154.7 (s).
N-(5-Bromothiazol-2-yl)azabis(biscarbonic acid bis-
1,1-dimethylethyl ester), 17: mp 80-81 °C; 55% (1.16 g,
3.06 mmol, colorless solid); MPLC PE/EtOAc 10:1; 1H NMR
(CDCl3, 200 MHz) δ 1.51 (s, 18H), 7.37 (s, 1H); 13C NMR
(CDCl3, 50 MHz) δ 27.7 (q), 85.1 (s), 105.5 (s), 139.5 (d), 149.3
(s), 158.5 (s).
N-(5-Bromo-4-trimethylsilylthiazol-2-yl)-2,2-dimethyl-
propanamide, 19. To a solution of 3.3 equiv of LDA was
added 3.3 equiv of TMSCl at -80 °C. Compound 1 (0.2 g, 0.76
mmol, 1 equiv) was added at the same temperature and the
reaction mixture stirred at -80 °C for 30 min. After the
mixture was warmed to rt within 1 h water was added and
the resulting mixture extracted three times with EtOAc. The
organic layers were combined and washed with brine, dried
over Na2SO4, and filtered, and the solvent was evaporated.
Subsequent MPLC PE/EtOAc 10:1 gave 19 (0.17 g, 0.51 mmol,
Acknowledgment. This project was supported by
Syngenta Crop Protection, Basel, Switzerland. We
thank Prof. Johannes Fro¨hlich, Vienna University of
Technology, for fruitful discussions in the field of HD
reactions.
1
colorless solid): mp 170-172 °C; 67%; H NMR (CDCl3, 200
Supporting Information Available: X-ray crystal struc-
ture data for compounds 5d, 6, and 13 including crystal-
lographic tables, ORTEP diagrams, and CIF files as well as
1H-13C and DEPT (where of importance) NMR spectra for all
new compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
MHz) δ 0.36 (s, 9H), 1.32 (s, 9H), 8.78 (bs, 1H); 13C NMR
(CDCl3, 50 MHz) δ -0.9 (q), 27.1 (q), 39.0 (s), 111.3 (s), 151.5
(s), 158.4 (s), 176.1 (s). Anal. Calcd for C11H19BrN2OSSi‚
0.27C6H14O (DIPE): C, 41.77; H, 6.33; N, 7.72. Found: C,
42.03; H, 5.95; N, 8.20.
Single-Crystal X-ray Diffraction Analysis of Com-
pounds 5d, 6, and 13. Single-crystal X-ray diffraction data
JO0484326
574 J. Org. Chem., Vol. 70, No. 2, 2005