Synthesis of 2′-substituted 4-bromo-2,4′-bithiazoles by regioselective cross-coupling reactions

Article abstract of DOI:10.1021/jo025661o

The synthesis of the title compounds (1) was achieved in two steps starting from readily available 2,4-dibromothiazole (2). In a regioselective Pd(O)-catalyzed cross-coupling step, compound 2 was converted into a variety of 2-substituted 4-bromothiazoles

Full text of DOI:10.1021/jo025661o

Syn th esis of 2′-Su bstitu ted 4-Br om o-2,4′-bith ia zoles by
Regioselective Cr oss-Cou p lin g Rea ction s
Thorsten Bach* and Stefan Heuser
Lehrstuhl fu¨r Organische Chemie I, Technische Universita¨t Mu¨nchen, D-85747 Garching, Germany
thorsten.bach@ch.tum.de
Received February 27, 2002
The synthesis of the title compounds (1) was achieved in two steps starting from readily available
2,4-dibromothiazole (2). In a regioselective Pd(0)-catalyzed cross-coupling step, compound 2 was
converted into a variety of 2-substituted 4-bromothiazoles 3 (10 examples, 65-85% yield). Alkyl
and aryl zinc halides were employed as nucleophiles to introduce an alkyl or aryl substituent. The
Sonogashira protocol was followed to achieve an alkynyl-debromination. Bromo-lithium exchange
at carbon atom C-4 and subsequent transmetalation to zinc or tin converted the 4-bromothiazoles
3 into carbon nucleophiles which underwent a second regioselective cross-coupling with another
equivalent of 2,4-dibromothiazole (2). The Negishi cross-coupling gave high yields of the 2′-alkyl-
4-bromo-2,4′-bithiazoles 1a -g (88-97%). The synthesis of the 2′-phenyl- and 2′-alkynyl-4-bromo-
2,4′-bithiazoles 1h -j required a Stille cross-coupling that did not proceed as smoothly as the Negishi
cross-coupling (58-62% yield). The title compounds which were accessible in total yields of 38-
82% are versatile building blocks for the synthesis of 2,4′-bithiazoles.
In tr od u ction
disubstituted bithiazoles have attracted synthetic inter-
est based on the biological properties of their complexes.11
The common approach toward the synthesis of
2′,4-disubstituted 2,4′-bithiazoles relies on the classical
Hantzsch reaction to establish at least one thiazole ring.
This strategy has been employed in several syntheses of
biologically active bithiazoles, e.g., cystothiazoles A and
C,12 myxothiazol,13 micrococcin P,14 and bleomycins.9c In
the synthesis of micrococcinic acid, a degradation product
of the micrococcins, Kelly et al. successfully used the
selective lithium-halogen metal exchange reaction at
2,4-dibromothiazole to establish the substitution pattern
in one ring of a 2′,4-disubstituted 2,4′-bithiazole.15 The
second thiazole ring was formed by a Hantzsch reaction.
Dondoni et al. employed the regioselective functionaliza-
tion of a 2,4-distubstituted thiazole for the synthesis of
bithiazoles.16 In addition, they showed that a regioselec-
tive cross-coupling on a 2,5-dibromothiazole is possible.16b
Our strategy for the synthesis of biologically relevant
five-membered heterocyclic rings centers on regioselective
2′,4-Disubstituted 2,4′-bithiazoles represent an impor-
tant class of natural products which exhibit an intriguing
and diversified spectrum of biological acitivities. Struc-
turally, one can distinguish the less complex cystothia-
zoles,1 melithiazoles,2 and myxothiazoles3 which contain
the bithiazole unit as the only heterocyclic element and
the more complex macrocyclic bithiazole antibiotics (e.g.,
amithiamicines,4 cyclothiazomycin,5 micrococcin P,6 GE
2270,7 and GE 374688) which contain additional thiazole
and pyridine heterocycles as substructures. As a third
class of natural occurring 2,4′-bithiazoles, bleomycins9
and tallysomycins10 are glycopeptide antibiotics which
carry a bithiazole amino acid at their C-terminal position.
In addition to their immediate biological relevance, 2′,4-
(1) Suzuki, Y.; Ojika, M.; Sakagami, Y.; Fudou, R.; Yamanaka, S.
Tetrahedron 1998, 54, 11399-11404.
(2) Boehlendorf, B.; Herrmann, M.; Hecht, H.-J .; Sasse, F.; Forche,
E.; Kunze, B.; Reichenbach, H.; Hoefle, G. Eur. J . Org. Chem. 1999,
2601-2608.
(3) Trowitzsch-Kienast, W.; Wray, V.; Gerth, K.; Reichenbach, H.;
Hoefle, G. Liebigs Ann. Chem. 1986, 93-98 and references cited
therein.
(10) (a) Miyaki, T.; Numata, K.; Nishiyama, Y.; Tenmyo, O.; Hatori,
M.; Imanishi, H.; Konishi, M.; Kawaguchi, H. J . Antibiot. 1981, 34,
665-674. (b) For recent synthetic efforts, see: Szanaidman, M. L.;
Hecht, S. M. Org. Lett. 2001, 3, 2811-2814.
(4) Shimanaka, K.; Takahashi, Y.; Iinuma, H.; Naganawa, H.;
Takeuchi, T. J . Antibiot. 1994, 47, 1153-1159 and references cited
therein.
(5) Aoki, M.; Ohtsuka, T.; Itezono, Y.; Yokose, K.; Furihata, K.; Seto,
H. Tetrahedron Lett. 1991, 32, 221-224 and references cited therein.
(6) Walker, J .; Olesker, A.; Valente, L.; Rabanal, R.; Kukacs, G.
Chem. Commun. 1977, 706-708.
(7) Selva, E.; Ferrari, P.; Kurz, M.; Tavecchia, P.; Colombo, L. J .
Antibiot. 1995, 48, 1039-1042.
(8) Ferrari, P.; Colombo, L.; Stella, S.; Selva, E.; Zerilli, L. F. J .
Antibiot. 1995, 48, 1304-1311.
(9) (a) Umezawa, H.; Maeda, K.; Takeuchi, T.; Okumi, Y. J . Antibiot.
1966, 19, 200-209. (b) Lenkinski, R. E.; Peerce, B. E.; Dallas, J . L.;
Glickson, J . D. J . Am. Chem. Soc. 1980, 102, 131-135. (c) Review:
Boger, D. L.; Cai, H. Angew. Chem., Int. Ed. Engl. 1999, 38, 448-476.
(11) Sasaki, H. Chem. Pharm. Bull. 1994, 42, 1685-1687.
(12) (a) Williams, D. R.; Patnaik, S.; Clark, M. P. J . Org. Chem.
2001, 66, 8463-8469. (b) Kato, K.; Nishimura, A.; Yamamoto, Y.; Akita,
H. Tetrahedron Lett. 2002, 43, 643-645.
(13) Martin, B. J .; Clugh, J . M.; Pattenden, G.; Waldron, I. R.
Tetrahedron Lett. 1993, 34, 5151-5154.
(14) Okumura, K.; Nakamura, Y.; Shin, C.-g. Bull. Chem. Soc. J pn.
1999, 72, 1561-1569.
(15) (a) Kelly, T. R.; J agoe, C. T.; Gu, Z. Tetrahedron Lett. 1991, 32,
4263-4266. (b) Kelly, T. R.; Lang, F. Tetrahedron Lett. 1995, 36, 9293-
9296.
(16) (a) Dondoni, A.; Mastellari, A. R.; Medici, A.; Negrini, E.;
Pedrini, P. Synthesis 1986, 757-760. (b) Dondoni, A.; Fogagnolo;
Medici, A.; Negrini, E. Synthesis 1987, 185-186.
10.1021/jo025661o CCC: $22.00 © 2002 American Chemical Society
Published on Web 07/11/2002
J . Org. Chem. 2002, 67, 5789-5795
5789

Bach and Heuser
SCHEME 1. P r efer r ed Sites for a Cr oss-Cou p lin g
on Dibr om in a ted F u r a n s, Ben zofu r a n s, a n d
Th ia zoles
SCHEME 2. Gen er a l Str a tegy for th e Syn th eses of
th e Title Com p ou n d s (1)
SCHEME 3. Cr oss-Cou p lin g a t Ca r bon Atom C-2
of Th ia zole 2 (Cf. Ta ble 1)
Pd(0)- or Ni(0)-catalyzed cross-coupling reactions.17,18 In
dibromo- and tribromohetarenes, a regioselective cross-
coupling can be achieved at the most electron deficient
position because the transition metal acts as a nucleo-
phile in the oxidative addition step. Cross-coupling
reactions which proceed via fast transmetalation and
reductive elimination steps are particularly sensitive
toward this electronic requirement. The regioselective
cross-coupling strategy was successfully applied to
furans,19 thiazoles,20 and benzofurans21 (Scheme 1) and
it appeared as if it was also applicable for the construc-
tion of bithiazoles.22
In this context, the title compounds, 2′-substituted
4-bromo-2,4′-bithiazoles (1), were considered to be at-
tractive target compounds. Their electrophilicity at the
4-position can be favorably used for reactions with a
variety of nucleophiles. The polarity at C-4 can be readily
reversed by bromo-metal exchange to allow for a reac-
tion with electrophiles.
that can react in a second step with another molecule of
compound 2 to the desired product. Only two reaction
steps are necessary to establish the desired carbon
framework.
In the following sections the above-mentioned reactions
are described in more detail. It turned out that the
Sonogashira and the Neghishi cross-coupling reactions
are well-suited for the first C-C bond-forming step. For
the second C-C bond formation Negishi and Stille cross-
coupling reactions were employed depending on the
primary substitution pattern.
Experiments toward a C-C bond formation between
an alkylmetal reagent and the C-2 position of 2,4-
dibromothiazole were conducted with the corresponding
zinc reagents in THF solutions at room temperature
(Scheme 3, Table 1, entries 1-7). The organozinc com-
pounds were prepared by transmetalation of the orga-
nolithium reagents which were either commercially
available (procedure A) or generated by an iodine-
lithium exchange reaction (procedure B). They were used
in excess (2.5 equiv) relative to 2,4-dibromothiazole. To
avoid â-hydride elimination and isomerization, 1,1′-bis-
(diphenylphosphino)ferrocene (dppf)24 was used as the
ligand in all instances. The in situ preparation of the
metal-ligand complex from Pd2(dba)3 (dba ) diben-
zylidene acetone) and dppf was preferable as compared
to the use of the preformed PdCl2(dppf) complex.
In the synthesis of thiazole 3d (entry 4), for example,
the yield obtained with the latter catalyst was 65% as
compared to 80% achieved with Pd2(dba)3/dppf. In gen-
eral, the yields for the cross-coupling of the primary alkyl
zinc reagents (entries 1-5) were slightly higher than
those for the secondary alkyl zinc reagents (entries 6-7).
Resu lts a n d Discu ssion
The general scheme for the synthesis of the title
compounds is outlined below (Scheme 2). Cross-coupling
of an organometallic reagent (RM) with 2,4-dibromothia-
zole (2)23 should occur at the 2-position. Subsequent
bromo-lithium exchange generates a carbon nucleophile
(17) For references on cross-coupling reactions of heterocycles, see:
(a) Li, J . J .; Gribble, G. W. Palladium in Heterocyclic Chemistry;
Pergamon Press: Oxford, UK, 2000. (b) Brandsma, L.; Vasilevsky, S.
F.; Verkruijsse, H. D. Application of Transition Metal Catalysts in
Organic Synthesis; Springer: Berlin, Germany, 1999. (c) Diederich,
F.; Stang, P. J . Metal-Catalyzed Cross-coupling Reactions; Wiley-
VCH: Weinheim, Germany, 1998.
(18) Selected references on regioselective cross-coupling reactions
of five-membered heterocycles: (a) Minato, A.; Tamao, K.; Hayashi,
T.; Suzuki, K.; Kumada, M. Tetrahedron Lett. 1980, 21, 845-848. (b)
Minato, A.; Tamao, K.; Suzuki, K.; Kumada, M. Tetrahedron Lett. 1980,
21, 4017-4020. (c) Karlsson, J . O.; Gronowitz, S.; Frejd, T. J . Org.
Chem. 1982, 47, 374-377. (d) Minato, K.; Suzuki, A.; Tamao, K.;
Kumada, M. J . Chem. Soc., Chem. Commun. 1984, 511-513. (e)
Carpita, A.; Rossi, R. Gazz. Chim. Ital. 1985, 115, 575-583. (f)
Gronowitz, S.; Svensson, A. Isr. J . Chem. 1986, 27, 25-28. (g)
Kaswasaki, I.; Yamashita, M.; Ohta, S. J . Chem. Soc., Chem. Commun.
1994, 2085-2086. (h) Wang, D.; Haseltine, J . J . Heterocycl. Chem.
1994, 31, 1637-1639. (i) Bussenius, J .; Laber, N.; Mu¨ller, T.; Eberbach,
W. Chem. Ber. 1994, 127, 247-260. (j) Wellmar, U.; Gronowitz, S.;
Ho¨rnfeldt, A.-B. J . Heterocycl. Chem. 1995, 32, 1159-1163. (k)
Nicolaou, K. C.; He, Y.; Roschangar, F.; King, N. P.; Vourloumis, D.;
Li, T. Angew. Chem., Int. Ed. 1998, 37, 84-87. (l) Pereira, R.; Iglesias,
B.; de Lera, A. R. Tetrahedron 2001, 57, 7871-7881. (m) Bellina, F.;
Anselmi, C.; Viel, S.; Mannina, L.; Rossi, R. Tetrahedron 2001, 57,
9997-10007.
(19) (a) Bach, T.; Kru¨ger, L. Tetrahedron Lett. 1998, 39, 1729-1732.
(b) Bach, T.; Kru¨ger, L. Synlett 1998, 1185-1186. (c) Bach, T.; Kru¨ger,
L. Eur. J . Org. Chem. 1999, 2045-2057.
(20) Bach, T.; Heuser, S. Tetrahedron Lett. 2000, 41, 1707-1710.
(21) Bach, T.; Bartels, M. Synlett 2001, 1284-1286.
(22) Bach, T.; Heuser, S. Angew. Chem., Int. Ed. 2001, 40, 3184-
3185.
(23) Reynaud, P.; Robba, M.; Moreau, R. C. Bull. Soc. Chim. Fr.
1962, 1735-1738.
(24) Bishop, J . J .; Davison, A.; Katcher, M. L.; Lichtenberg, D. W.;
Merrill, R. E.; Smart, J . C. J . Organomet. Chem. 1971, 27, 241-249.
5790 J . Org. Chem., Vol. 67, No. 16, 2002

2′-Substituted 4-Bromo-2,4′-bithiazoles
TABLE 1. Deta ils for a Set of Regioselective
Cr oss-Cou p lin g Rea ction s Con d u cted w ith Bith ia zole 2
(Cf. Sch em e 3)
SCHEME 4. Negish i Cr oss-Cou p lin g of
2-Alk ylth ia zolyl Zin c Rea gen ts a n d Th ia zole 2
entry
procedurea
catalyst
product
yield [%]b
1
2
3
4
5
6
7
8
9
Ac
Bd
B
B
B
Pd2(dba)3/dppf
Pd2(dba)3/dppf
Pd2(dba)3/dppf
Pd2(dba)3/dppf
Pd2(dba)3/dppf
Pd2(dba)3/dppf
Pd2(dba)3/dppf
PdCl2(PPh3)2
Pd(PPh3)4/CuI
Pd(PPh3)4/CuI
3a
3b
3c
3d
3e
3f
3g
3h
3i
85
73
79
80
85
72
76
83
65
81
A
A
SCHEME 5. Stille Cr oss-Cou p lin g of 4-(2-Alk yn yl)-
a n d 4-(2-P h en yl)th ia zolylsta n n a n es a n d Th ia zole 2
A
Ce
C
10
3j
a
The cross-coupling reactions were conducted at room temper-
ature in THF as the solvent employing substrate 2 (1 equiv) and
b
5 mol % of the given catalyst. Yield of isolated product. c Proce-
dure A: Commercially available organolithium reagent (2.5 equiv)
d
was transmetalated with ZnCl2 (3.75 equiv). Procedure B: The
organolithium reagent was prepared from the corresponding iodide
(2.5 equiv) and tert-butyllithium (5.2 equiv) and was subsequently
transmetalated with ZnCl2 (3.75 equiv). e Procedure C: The alkyne
(1.5 equiv) and N,N-diisopropylamine (1.5 equiv) were employed
as precursors for the alkynylmetal species. 10 mol % of CuI was
used.
be used in Negishi cross-coupling reactions with another
equivalent of 2,4-dibromothiazole (2). As previously
stated, PdCl2(PPh3)2 is a satisfactory catalyst for these
2
2
Csp -Csp type cross-coupling reactions. They proceeded
cleanly as long as the substituent at the 2-position of the
4-thiazolyl zinc reagent was an alkyl group (Scheme 4).
The products 1a -g were obtained in excellent yields (88-
97%). In contrast to the first cross-coupling that was
conducted at ambient temperature, the second cross-
coupling was performed in THF at reflux. Still, there was
no complication with regard to functional groups nor with
regard to the regioselectivity of the cross-coupling. The
total yield of compounds 1a -g over two steps varied
between 64% and 82%. Compound 1f was used as the
pivotal intermediate in our synthesis of cystothiazole E.22
An analogous triflate was later mentioned in another
report on cystothiazole syntheses26 but its synthesis was
not disclosed.
The 2-phenyl- and 2-alkynylthiazolyl zinc reagents
derived from compounds 3h -j did not undergo a Negishi
cross-coupling with thiazole 2 as the electrophile. A
variation of reaction conditions (catalyst, solvent, tem-
perature) remained unsuccessful. Among others, PdCl2-
(PPh3)2, PdCl2(dppf), and NiCl2(dppp) were used as
catalysts. Only unreacted thiazole 2 and debrominated
thiazoles derived from 3h -j were recovered. In search
for other possible reactions the Suzuki and Stille cross-
coupling were considered. The synthesis of aryl boronic
esters is more tedious and often less efficient than the
synthesis of arylstannanes. In addition, there was lit-
erature precedence for an unsatisfactory and low-yielding
(15%) Suzuki cross-coupling on 2,4-dibromothiazole.18j We
consequently started to study the Stille cross-coupling.
The required 4-trimethylstannylthiazoles were prepared
from the bromides 3h -j by bromo-lithium exchange and
subsequent quench with chlorotrimethylstannane. They
were obtained as yellow oils which were not purified but
directly taken into the cross-coupling step (Scheme 5).
The cross-coupling proceeded (Scheme 5) regioselectively
but the yields were lower than in the Negishi cross-
coupling of the 2-alkylthiazolyl zinc reagents. The total
yield in which compounds 1h -j were synthesized from
2 varied between 38% and 51%.
The functional group tolerance was limited by the
preparation of the alkyllithium reagents. An organozinc
reagent that was prepared directly25 from ethyl 5-iodo-
pentanoate did not give a clean and complete conversion
under a variety of conditions. Further studies in this
direction have not yet been undertaken. The amount of
catalyst in the reaction 2 f 3a was varied. A satisfactory
conversion was achieved with a catalyst:substrate ratio
as low as 1:200 (0.5 mol %) without significant deteriora-
tion of the product yield. With less catalyst the reaction
remained incomplete. For the cross-coupling of com-
pounds which did not contain a â-hydrogen atom, the use
of PdCl2(PPh3)2 was sufficient (entry 8). 2-Alkynylthiaz-
oles 3i and 3j (entries 9 and 10) were obtained by a
regioselective Sonogashira cross-coupling. In the former
case, the use of PdCl2(PPh3)2 resulted in some homocou-
pling, which let us employ Pd(PPh3)4 as the catalyst. All
reactions were complete overnight at room temperature
(16 h). The regioselective Sonogashira cross-coupling for
which literature precedence existed18k proceeded even
faster (3-4 h). Side reactions (cross-coupling at C-4 or
disubstitution) were not observed by GC/MS. In some
runs, however, a hydrodebromination of the starting
material 2 to 4-bromothiazole occurred. Spectroscopically,
the regioselectivity of the cross-coupling can be nicely
checked by 13C NMR. The carbon atom at which the
substitution takes place is significantly deshielded (∆δ
) 35-40 ppm if R ) alkyl, aryl; ∆δ ) ca. 15 ppm if R )
alkynyl). To provide an example, the carbon atom C-2 of
2,4-dibromothiazole (2) resonates at 137.6 ppm whereas
the carbon atom C-2 of 2-butyl-4-bromothiazole (3a ) is
responsible for the signal at 172.7 ppm. The signal for
the carbon atom C-4 (δ ) 123.4 ppm) remains essentially
unchanged.
The intermediates 3 obtained in the first coupling step
were transformed into 4-thiazolyllithium compounds by
bromo-lithium exchange. Transmetalation to zinc pro-
vided potential carbon nucleophiles which were ready to
In summary, we have explored a useful and versatile
approach to 2′-substituted 4-bromo-2,4′-bithiazoles. The
(25) Knochel, P.; Yeh, M. C. P.; Berk, S. C.; Talbert, J . J . Org. Chem.
1988, 53, 2392-2394.
(26) Sui, M.; Panek, J . S. Org. Lett. 2001, 3, 2439-2442.
J . Org. Chem, Vol. 67, No. 16, 2002 5791

Bach and Heuser
2871 (s, CHal). 1H NMR: δ 0.91 (t, J ) 7.3 Hz, 3 H), 1.38 (virt.
sext, J = 7.5 Hz, 2 H), 1.73 (virt. quin, J = 7.6 Hz, 2 H), 2.96
(t, J ) 7.7 Hz, 2 H), 7.03 (s, 1 H). 13C NMR: δ 13.6, 22.1, 31.8,
33.2, 115.5, 124.1, 172.7. MS, m/z (%): 221 (6) [M+(81Br)], 219
(7) [M+(79Br)], 206 (5) [M+(81Br) - CH3], 204 (4) [M+(79Br) -
CH3], 192 (25) [M+(81Br) - C2H5], 190 (23) [M+(79Br) - C2H5],
179 (100) [M+(81Br) - C3H6], 177 (99) [M+(79Br) - C3H6], 138
examples we presented demonstrate that the strategy is
general and should be applicable to the synthesis of a
broad variety of bithiazoles. Further reactions at the
carbon atom C-4 have not been studied further. Prece-
dence for a successful Suzuki cross-coupling exists22 and
there is no doubt that other commonly used transforma-
tions of 4-bromothiazoles27 are also suited for the prod-
ucts 1a -j. Further work in our research group centers
on the application of the described method to more
complex, biologically relevant bithiazoles.
(9) [81BrCCHS+], 136 (7) [79BrCCHS+]. Anal. Calcd for C7H10
-
BrNS (220.13): C, 38.19; H, 4.58. Found: C, 37.98; H, 4.50.
4-Br om o-2-isop r op ylth ia zole (3f). The reaction was car-
ried out on the same scale as described for general procedure
A employing 7.1 mL of an isopropyllithium solution (0.7 M in
pentane) (5.0 mmol). A total of 295 mg (72%) of 3f was obtained
as a colorless oil (P/Et2O ) 95/5 as eluent). Rf 0.30 (P/Et2O )
95/5). IR (film): v˜ 3122 cm-1 (m, CHar), 2968 (s, CHal). 1H
NMR: δ 1.37 (d, J ) 7.0 Hz, 6 H), 3.28 (sept, J ) 7.0 Hz, 1 H),
7.05 (s, 1 H). 13C NMR: δ 22.8, 33.4, 115.2, 124.1, 180.0. MS,
m/z (%): 207 (46) [M+(81Br)], 205 (43) [M+(79Br)], 192 (100)
[M+(81Br) - CH3], 190 (98) [M+(79Br) - CH3], 138 (14)
[81BrCCHS+], 136 (13) [79BrCCHS+], 126 (50) [M+ - Br]. Anal.
Calcd for C6H8BrNS (206.10): C, 34.94; H, 3.91. Found: C,
34.79; H, 4.01.
Exp er im en ta l Section
Gen er a l. All reactions involving water-sensitive chemicals
were carried out in flame-dried glassware with magnetic
stirring under Ar. Tetrahydrofuran (THF) and diethyl ether
(Et2O) were distilled from potassium immediately prior to use.
N,N-Disopropylamine was distilled from calcium hydride. The
employed alkynes were distilled immediately prior to use. Pd-
(PPh3)4,28 PdCl2(PPh3)2,29 PdCl2(dppf),30 Pd2(dba)3,31 and dppf
were prepared according to literature procedures. All other
chemicals were either commercially available or prepared
according to the cited references. 1H and 13C NMR spectra were
recorded in CDCl3 as solvent at 303 K. Chemical shifts are
reported relative to tetramethylsilane as an internal standard
or to distinguished solvent signals. Apparent multiplets which
occur as a result of the accidental equality of coupling
constants of magnetically nonequivalent protons are marked
as virtual (virt.). Combustion analyses were conducted by the
microanalytical laboratory Beller (Go¨ttingen). MS spectra were
recorded in the EI mode at an ionization energy of 70 eV. TLC
was performed on aluminum sheets (0.2 mm silica gel 60 F254).
Detection was done by UV or coloration with ceric ammonium
molybdate (CAM). Flash chromatography was performed on
silica gel 60 (230-400 mesh) (ca. 100 g for 1 g of material to
be separated) with the eluent given in brackets. Common
solvents [THF, Et2O, ethyl acetate (EtOAc), and pentane (P)]
were distilled prior to use.
Gen er a l P r oced u r e A for Negish i Cr oss-Cou p lin g
Rea ction s to 2-Su bstitu ted 4-Br om oth ia zoles. A solution
of the commercially available organolithium compound (5.0
mmol) was added at -78 °C to 15 mL of a 0.5 M solution of
ZnCl2 (7.5 mmol) in THF. The resulting mixture was stirred
at room temperature for 30 min and was added via syringe to
a solution of 486 mg of 2,4-dibromothiazole (2) (2.0 mmol), 46
mg of Pd2(dba)3 (0.1 mmol), and 56 mg of dppf (0.1 mmol) in
10 mL of THF. After being stirred for 16 h at room temperature
the reaction was quenched with 10 mL of saturated NH4Cl
solution and the aqueous layer was extracted with Et2O (3 ×
20 mL). The combined organic layers were washed with brine
(20 mL). After drying over Na2SO4 and filtration, the solvent
was removed and the residue was purified by flash chroma-
tography.
4-Br om o-2-sec-bu tylth ia zole (3g). The reaction was car-
ried out as described for general procedure A starting with
972 mg of 2,4-dibromothiazole (2) (4.0 mmol), 7.6 mL of a sec-
butyllithium solution (1.3 M in pentane) (10.0 mmol), 30 mL
of a ZnCl2 solution (0.5 M in THF) (15 mmol), 92 mg of Pd2-
(dba)3 (0.2 mmol), and 112 mg of dppf (0.2 mmol). A total of
667 mg (76%) of 3g was obtained as a yellow oil (P/Et2O )
98/2 as eluent). Rf 0.37 (P/Et2O ) 97/3). IR (film): v˜ 3123 cm-1
1
(w, CHar), 2965 (s, CHal), 2930 (m, CHal). H NMR: δ 0.90 (t,
J ) 7.4 Hz, 3 H), 1.33 (d, J ) 7.0 Hz, 3 H), 1.65 (virt. dquin,
J = 7.0 Hz, J = 14.0 Hz, 1 H), 1.78 (virt. dquin, J = 7.0 Hz, J
= 14.0 Hz, 1 H), 3.06 (virt. sext, J = 7.0 Hz, 1 H), 7.05 (s, 1
H). 13C NMR: δ 11.6, 20.4, 30.5, 40.3, 115.2, 124.0, 178.1. MS,
m/z (%): 221 (21) [M+(81Br)], 219 (19) [M+(79Br)], 206 (33)
[M+(81Br) - CH3], 204 (30) [M+(79Br) - CH3], 193 (100)
[M+(81Br) - C2H4], 191 (96) [M+(79Br) - C2H4], 179 (12)
[M+(81Br) - C3H6], 177 (10) [M+(79Br) - C3H6]. Anal. Calcd
for C7H10BrNS (220.13): C, 38.19; H, 4.58. Found: C, 38.23;
H, 4.60.
4-Br om o-2-p h en ylth ia zole (3h ). The reaction was carried
out on the same scale as described for general procedure A
employing 2.8 mL of a phenyllithium solution (1.8 M in
cyclohexan/Et2O ) 70/30) (5.0 mmol) and 70 mg of PdCl2-
(PPh3)2 (0.1 mmol) as the catalyst instead of Pd2(dba)3/dppf.
A total of 398 mg (83%) of 3h was obtained as a red solid (P/
Et2O ) 96/4 as eluent). Rf 0.22 (P/Et2O ) 97/3). Mp: 65 °C.
IR (KBr): v˜ 3120 cm-1 (w, CHar). 1H NMR: δ 7.19 (s, 1 H),
7.42-7.43 (m, 3 H), 7.90-7.93 (m, 2 H). 13C NMR: δ 116.4,
126.1, 126.4, 129.0, 130.7, 132.6, 169.0. MS, m/z (%): 241 (100)
[M+(81Br)], 239 (98) [M+(79Br)], 138 (62) [81BrCCHS+], 136 (58)
[79BrCCHS+]. HRMS m/z calcd for C9H6BrNS (M+) 238.9404,
found 238.9406.
Gen er a l P r oced u r e
B for Negish i Cr oss-Cou p lin g
4-Br om o-2-bu tylth ia zole (3a ). The reaction was carried
out on the same scale as described for general procedure A
employing 2.0 mL of a n-butyllithium solution (2.5 M in
hexanes) (5.0 mmol). A total of 375 mg (85%) of 3a was
obtained as a yellow oil (P/Et2O ) 97/3 as eluent). Rf 0.43 (P/
Et2O ) 95/5). IR (film): v˜ 3123 cm-1 (m, CHar), 2957 (s, CHal),
Rea ction s to 2-Su bstitu ted 4-Br om oth ia zoles. A 6.9-mL
sample of a 1.5 M solution of tert-butyllithium in pentane (10.4
mmol) was added at -78 °C to a solution of a primary alkyl
iodide (5.0 mmol) in 8 mL of Et2O.32 After the mixture was
stirred at -78 °C for 1 h, 15 mL of a 0.5 M solution of ZnCl2
(7.5 mmol) in THF was added. The resulting mixture was
stirred at room temperature for 30 min and was added via
syringe to a solution of 486 mg of 2,4-dibromothiazole (2) (2.0
mmol), 46 mg of Pd2(dba)3 (0.1 mmol), and 56 mg of dppf (0.1
mmol) in 10 mL of THF. After being stirred for 16 h at room
temperature the reaction was quenched with 10 mL of
saturated NH4Cl solution and the aqueous layer was extracted
with Et2O (3 × 20 mL). The combined organic layers were
washed with brine (20 mL). After drying over Na2SO4 and
(27) (a) Liebscher, J . In Methoden der Organischen Chemie (Houben-
Weyl), 4te Aufl.; Schaumann, E., Ed.; Thieme, Stuttgart, Germany,
1994; Vol. E 8b, pp 1-398. (b) Kikelj, D.; Urleb, U. In Science of
Synthesis; Schaumann, E., Ed.; Thieme, Stuttgart, Germany, 2002; Vol.
11, pp 627-833.
(28) Coulson, D. R. Inorg. Synth. 1972, 13, 121-124.
(29) Hartley, F. R. Organomet. Chem. Rev., Sect. A 1970, 6, 119-
137.
(30) Hayashi, T.; Konishi, M.; Kumada, M.; Higuchi, T.; Hirotsu,
K. J . Am. Chem. Soc. 1984, 106, 158-163.
(31) Ukai, T.; Kawazura, H.; Ishii, Y. J . Organomet. Chem. 1974,
65, 253-266.
(32) Negishi, E.-i.; Swanson, D. R.; Rousset, C. J . J . Org. Chem.
1990, 55, 5406-5409.
5792 J . Org. Chem., Vol. 67, No. 16, 2002

2′-Substituted 4-Bromo-2,4′-bithiazoles
filtration, the solvent was removed and the residue was
purified by flash chromatography.
of Et2O were added and the aqueous layer was extracted with
Et2O (2 × 20 mL). The combined organic layers were washed
with brine (20 mL). After drying over Na2SO4 and filtration,
the solvent was removed and the residue was purified by flash
chromatography.
4-Br om o-2-isobu tylth ia zole (3b). The reaction was car-
ried out on the same scale as described for general procedure
B employing 920 mg of isobutyl iodide (5.0 mmol) and 6.9 mL
of a tert-butyllithium solution (1.5 M in pentane) (10.4 mmol).
A total of 320 mg (73%) of 3b was obtained as a red oil (P/
Et2O ) 97/3 as eluent). Rf 0.44 (P/Et2O ) 95/5). IR (film): v˜
4-Br om o-2-(3,3-d im eth yl-1-bu tyn yl)th ia zole (3i). The
reaction was carried out on the same scale as described for
general procedure C employing 246 mg of 3,3-dimethyl-1-
butyne (3.0 mmol). A total of 317 mg (65%) of 3i was obtained
as a yellow solid (P/Et2O ) 98.5/1.5 as eluent). Rf 0.45 (P/Et2O
) 97/3). Mp: 67 °C. IR (KBr): v˜ 3118 cm-1 (m, CHar), 2971
1
3123 cm-1 (w, CHar), 2958 (s, CHal), 2869 (m, CHal). H NMR:
δ 0.97 (d, J ) 6.6 Hz, 6 H), 2.09 (virt. nonet, J = 6.8 Hz, 1 H),
2.84 (d, J ) 7.0 Hz, 2 H), 7.05 (s, 1 H). 13C NMR: δ 22.2, 29.7,
42.5, 115.7, 124.2, 171.5. MS, m/z (%): 221 (12) [M+(81Br)], 219
(11) [M+(79Br)], 206 (15) [M+(81Br) - CH3], 204 (15) [M+(79Br)
- CH3], 179 (100) [M+(81Br) - C3H6], 177 (98) [M+(79Br) -
C3H6]. HRMS m/z calcd for C7H10BrNS (M+) 220.9697, found
220.9702.
4-Br om o-2-p h en yleth ylth ia zole (3c). The reaction was
carried out on the same scale as described for general
procedure B employing 1.16 g of 2-iodoethylbenzene (5.0 mmol)
and 6.9 mL of a tert-butyllithium solution (1.5 M in pentane)
(10.4 mmol). A total of 424 mg (79%) of 3c was obtained as a
white solid (P/Et2O ) 95/5 as eluent). Rf 0.30 (P/Et2O ) 95/5).
Mp: 82 °C. IR (KBr): v˜ 3078 cm-1 (s, CHar), 2931 (w, CHal).
1H NMR: δ 3.10 (t, J ) 8.2 Hz, 2 H), 3.31 (t, J ) 8.2 Hz, 2 H),
7.07 (s, 1 H), 7.19-7.29 (m, 5 H). 13C NMR: δ 35.2, 35.7, 115.9,
124.3, 126.5, 128.4, 128.6, 139.9, 171.2. MS, m/z (%): 269 (43)
[M+(81Br)], 267 (41) [M+(79Br)], 188 (18) [M+ - Br], 91 (100)
[C7H7+]. Anal. Calcd for C11H10BrNS (268.17): C, 49.27; H,
3.76. Found: C, 49.16; H, 3.65.
1
(m, CHal). H NMR: δ 1.31 (s, 9 H), 7.11 (s, 1 H). 13C NMR: δ
28.3, 30.2, 72.1, 105.5, 117.6, 125.2, 150.5. MS, m/z (%): 244
(100) [M+(81Br) - H], 242 (98) [M+(79Br) - H], 230 (77)
[M+(81Br) - CH3], 228 (73) [M+(79Br) - CH3]. Anal. Calcd for
C9H10BrNS (244.15): C, 44.28; H, 4.13. Found: C, 44.60; H,
4.33.
4-Br om o-2-p h en yleth yn ylth ia zole (3j). The reaction was
carried out on the same scale as described for general
procedure C employing 306 mg of phenylethyne (3.0 mmol). A
total of 428 mg (81%) of 3j was obtained as a yellow solid (P/
Et2O ) 95/5 as eluent). Rf 0.29 (P/Et2O ) 95/5). Mp: 74 °C.
1
IR (KBr): v˜ 3118 cm-1 (w, CHar), 2208 (m, CdC). H NMR: δ
7.22 (s, 1 H), 7.32-7.39 (m, 3 H), 7.54-7.57 (m, 2 H). 13C
NMR: δ 81.4, 95.4, 118.6, 120.9, 125.9, 128.5, 129.5, 132.0,
149.7. MS, m/z (%): 265 (98) [M+(81Br)], 263 (100) [M+(79Br)],
138 (33) [81BrCCHS+], 136 (30) [79BrCCHS+]. HRMS m/z calcd
for C11H6BrNS (M+) 264.9384, found 264.9384.
Gen er a l P r oced u r e
D for Negish i Cr oss-Cou p lin g
4-Br om o-2-(4-ch lor obu tyl)th ia zole (3d ). The reaction
was carried out on the same scale as described for general
procedure B employing 1.09 g of 4-chloro-1-iodobutane (5.0
mmol) and 6.9 mL of a tert-butyllithium solution (1.5 M in
pentane) (10.4 mmol). A total of 407 mg (80%) of 3d was
obtained as a red oil (P/Et2O ) 90/10 as eluent). Rf 0.30 (P/
Et2O ) 90/10). IR (film): v˜ 3121 cm-1 (m, CHar), 2953 (m, CHal).
1H NMR: δ 1.81-1.98 (m, 4 H), 3.02 (t, J ) 7.4 Hz, 2 H), 3.54
(t, J ) 6.3 Hz, 2 H), 7.07 (s, 1 H). 13C NMR: δ 26.9, 31.6, 32.7,
44.3, 115.9, 124.4, 171.6. MS, m/z (%): 257 (7) [M+(81Br37Cl)],
255 (30) [M+(81Br), M+(79Br37Cl)], 253 (22) [M+(79Br35Cl)], 220
(100) [M+(81Br) - Cl], 218 (98) [M+(79Br) - Cl], 206 (12)
[M+(81Br) - CH2Cl], 204 (13) [M+(79Br) - CH2Cl], 192 (84)
[M+(81Br) - (CH2)2Cl], 190 (87) [M+(79Br) - (CH2)2Cl], 178 (46)
[M+(81Br) - (CH2)3Cl], 176 (45) [M+(79Br) - (CH2)3Cl]. Anal.
Calcd for C7H9BrClNS (254.58): C, 33.03; H, 3.56. Found: C,
33.18; H, 3.55.
Rea ction s to 2’-Su bstitu ted 4-Br om o-2,4’-bith ia zoles. A
1.4-mLsample of a 1.5 M solution of tert-butyllithium in
pentane (2.1 mmol) was added at -78 °C to a solution of 1.0
mmol of bromothiazole 3 in 5 mL of THF. After the mixture
was stirred at -78 °C for 10 min, 3.0 mL of a 0.5 M solution
of ZnCl2 (1.5 mmol) in THF was added. The resulting mixture
was stirred at room temperature for 30 min and a mixture of
187 mg of 2,4-dibromothiazole (2) (0.77 mmol) and 27 mg of
PdCl2(PPh3)2 (38.5 µmol) in 5 mL of THF was added via
syringe. After refluxing for 16 h the reaction was quenched
with 10 mL of saturated NH4Cl solution and the aqueous layer
was extracted with Et2O (3 × 20 mL). The combined organic
layers were washed with brine (20 mL). After drying over Na2-
SO4 and filtration, the solvent was removed and the residue
was purified by flash chromatography.
4-Br om o-2′-bu tyl-2,4′-bith ia zole (1a ). The reaction was
carried out as described for general procedure D starting with
180 mg of bromothiazole 3a (0.82 mmol), 153 mg of 2,4-
dibromothiazole (2) (0.63 mmol), 1.15 mL of a tert-butyllithium
solution (1.5 M in pentane) (1.72 mmol), 2.4 mL of a ZnCl2
solution (0.5 M in THF) (1.2 mmol), and 22 mg of PdCl2(PPh3)2
(32 µmol). A total of 183 mg (96%) of 1a was obtained as a
yellow solid (P/Et2O ) 95/5 as eluent). Rf 0.17 (P/Et2O ) 95/
5). Mp: 66 °C. IR (KBr): v˜ 3120 cm-1 (w, CHar), 2950 (m, CHal).
1H NMR: δ 0.95 (t, J ) 7.4 Hz, 3 H), 1.44 (virt. sext, J = 7.4
Hz, 2 H), 1.78 (virt. quin, J = 7.7 Hz, 2 H), 3.01 (t, J ) 7.7 Hz,
2 H), 7.19 (s, 1 H), 7.85 (s, 1 H). 13C NMR: δ 13.7, 22.2, 31.9,
33.1, 116.0, 117.1, 125.9, 147.7, 167.7, 172.6. MS, m/z (%): 304
(22) [M+(81Br)], 302 (20) [M+(79Br)], 275 (23) [M+(81Br) - C2H5],
273 (20) [M+(79Br) - C2H5], 262 (100) [M+(81Br) - C3H6], 260
(96)[M+(79Br)-C3H6],138 (8)[81BrCCHS+],136 (7)[79BrCCHS+].
HRMS m/z calcd for C10H11BrN2S2 (M+) 301.9547, found
301.9553.
4-Br om o-2-[6-(ter t-b u t yld im et h ylsiloxy)h exyl]t h ia z-
ole (3e). The reaction was carried out on the same scale as
described for general procedure B employing 1.71 g of 1-iodo-
6-(tert-butyldimethylsiloxy)hexane33 (5.0 mmol) and 6.9 mL of
a tert-butyllithium solution (1.5 M in pentane) (10.4 mmol). A
total of 642 mg (85%) of 3e was obtained as a red oil (P/Et2O
) 98/2 as eluent). Rf 0.53 (P/Et2O ) 95/5). IR (film): v˜ 3124
1
cm-1 (w, CHar), 2979 (s, CHal). H NMR: δ 0.02 (s, 6 H), 0.87
(s, 9 H), 1.34-1.38 (m, 4 H), 1.49 (quin, J ) 6.5 Hz, 2 H), 1.77
(quin, J ) 7.5 Hz, 2 H), 2.97 (t, J ) 7.8 Hz, 2 H), 3.57 (t, J )
6.3 Hz, 2 H), 7.05 (s, 1 H). 13C NMR: δ -5.3, 18.3, 25.5, 26.0,
28.8, 29.8, 32.6, 33.5, 63.0, 115.6, 124.1, 172.7. MS, m/z (%):
364 (3) [M+(81Br) - CH3], 362 (3) [M+(79Br) - CH3], 322 (100)
t
t
[M+(81Br) - Bu], 320 (96) [M+(79Br) - Bu]. HRMS m/z calcd
for C11H18BrNOSSi (M+ - Bu) 320.0140, found 320.0135.
t
Gen er a l P r oced u r e C for Son oga sh ir a Cr oss-Cou p lin g
Rea ction s to 2-Su bstitu ted 4-Br om oth ia zoles. A solution
of 3.0 mmol of the alkyne in 1 mL of THF was added via
syringe to a mixture of 486 mg of 2,4-dibromothiazole (2) (2.0
mmol), 304 mg of N,N-diisopropylamine (3.0 mmol), 38 mg of
CuI (0.2 mmol), and 114 mg of Pd(PPh3)4 (0.1 mmol) in 5 mL
of THF during 1 h via syringe pump. After the mixture was
stirred for 3 h at room temperature, 5 mL of H2O and 30 mL
4-Br om o-2′-isobu tyl-2,4′-bith ia zole (1b). The reaction
was carried out as described for general procedure D starting
with 120 mg of bromothiazole 3b (0.55 mmol), 102 mg of 2,4-
dibromothiazole (2) (0.42 mmol), 0.76 mL of a tert-butyllithium
solution (1.5 M in pentane) (1.1 mmol), 1.6 mL of a ZnCl2
solution (0.5 M in THF) (0.8 mmol), and 15 mg of PdCl2(PPh3)2
(21 µmol). A total of 111 mg (88%) of 1b was obtained as a
yellow solid (P/Et2O ) 95/5 as eluent). Rf 0.17 (P/Et2O ) 95/
5). Mp: 95 °C. IR (KBr): v˜ 3120 cm-1 (w, CHar), 2950 (m, CHal).
1H NMR: δ 1.02 (d, J ) 6.6 Hz, 6 H), 2.15 (virt. nonet, J = 6.8
(33) Lamba, J . J . S.; Tour, J . M. J . Am. Chem. Soc. 1994, 116,
11723-11736.
J . Org. Chem, Vol. 67, No. 16, 2002 5793

Bach and Heuser
Hz, 1 H), 2.91 (d, J ) 7.2 Hz, 2 H), 7.24 (s, 1 H), 7.90 (s, 1 H).
13C NMR: δ 22.2, 29.7, 42.1, 116.2, 117.2, 125.8, 147.6, 163.7,
171.4. MS, m/z (%): 304 (25) [M+(81Br)], 302 (24) [M+(79Br)],
289 (16) [M+(81Br) - CH3], 287 (15) [M+(79Br) - CH3], 262 (100)
[M+(81Br) - C3H6], 260 (95) [M+(81Br) - C3H6], 138 (9)
33.7, 116.1, 117.6, 126.2, 147.9, 164.3, 179.3. MS, m/z (%): 290
(85) [M
+(81Br)], 288 (100) [M+(79Br)], 275 (80) [M+(81Br) - CH3],
273 (76) [M+(79Br) - CH3], 138 (26) [81BrCCHS+], 136 (24)
[79BrCCHS+]. Anal. Calcd for C9H9N2S2 (289.22): C, 37.38; H,
3.14. Found: C, 37.48; H, 3.03.
[81BrCCHS+], 136 (8) [79BrCCHS+]. HRMS m/z calcd for C10H11
-
4-Br om o-2′-sec-b u t yl-2,4′-b it h ia zole (1g). The reaction
was carried out as described for general procedure D starting
with 398 mg of bromothiazole 3g (1.81 mmol), 340 mg of 2,4-
dibromothiazole (2) (1.40 mmol), 2.5 mL of a tert-butyllithium
solution (1.5 M in pentane) (3.75 mmol), 5.5 mL of a ZnCl2
solution (0.5 M in THF) (2.75 mmol), and 49 mg of PdCl2-
(PPh3)2 (70 µmol). A total of 403 mg (95%) of 1g was obtained
as a yellow solid (P/Et2O ) 97/3 as eluent). Rf 0.21 (P/Et2O )
97/3). Mp: 36 °C. IR (KBr): v˜ 3120 cm-1 (m, CHar), 2956 (m,
BrN2S2 (M+) 301.9547, found 301.9549.
4-Br om o-2′-p h en yleth yl-2,4′-bith ia zole (1c). The reac-
tion was carried out as described for general procedure D
starting with 216 mg of bromothiazole 3c (0.81 mmol), 151
mg of 2,4-dibromothiazole (2) (0.62 mmol), 1.13 mL of a tert-
butyllithium solution (1.5 M in pentane) (1.69 mmol), 2.4 mL
of a ZnCl2 solution (0.5 M in THF) (1.2 mmol), and 22 mg of
PdCl2(PPh3)2 (32 µmol). A total of 193 mg (89%) of 1c was
obtained as a white solid (P/Et2O ) 92/8 as eluent). Rf 0.21
(P/Et2O ) 90/10). Mp: 126 °C. IR (KBr): v˜ 3122 cm-1 (m,
CHar), 2925 (w, CHal). 1H NMR: δ 3.15 (t, J ) 7.9 Hz, 2 H),
3.36 (t, J ) 7.9 Hz, 2 H), 7.23 (s, 1 H), 7.21-7.32 (m, 5 H),
7.87 (s, 1 H). 13C NMR: δ 35.0, 35.6, 116.2, 117.2, 125.9, 126.5,
128.5, 128.6, 140.0, 147.7, 163.6, 171.2. MS, m/z (%): 352 (100)
[M+(81Br)], 350 (96) [M+(79Br)], 275 (27) [M+(81Br) - C6H5], 273
(25) [M+(79Br) - C6H5], 261 (12) [M+(81Br) - CH2C6H5], 259
(10) [M+(79Br) - CH2C6H5], 91 (97) [C7H7+]. Anal. Calcd for
1
CHal). H NMR: δ 0.94 (t, J ) 7.4 Hz, 3 H), 1.38 (d, J ) 6.8
Hz, 3 H), 1.70 (virt. dquin, J = 7.0 Hz, J = 14.0 Hz, 1 H), 1.84
(virt. dquin, J = 7.0 Hz, J = 14.0 Hz, 1 H), 3.12 (virt. sext, J
= 7.0 Hz, 1 H), 7.19 (s, 1 H), 7.86 (s, 1 H). 13C NMR: δ 11.6,
20.6, 30.6, 40.1, 115.6, 117.1, 125.8, 147.5, 163.9, 178.1. MS,
m/z (%): 304 (45) [M+(81Br)], 302 (43) [M+(79Br)], 289 (33)
[M+(81Br) - CH3], 287 (31) [M+(79Br) - CH3], 276 (100)
[M+(81Br) - C2H4], 274 (96) [M+(79Br) - C2H4], 138 (18)
[81BrCCHS+], 136 (17) [79BrCCHS+]. Anal. Calcd for C10H11
-
C
14H11BrN2S2 (351.29): C, 47.87; H, 3.16. Found: C, 47.68;
H, 3.22.
4-Br om o-2′-(4-ch lor obu tyl)-2,4′-bith ia zole (1d ). The re-
BrN2S2 (303.24): C, 39.61; H, 3.66. Found: C, 39.48; H, 3.53.
Gen er a l P r oced u r e E for Stille Cr oss-Cou p lin g Rea c-
tion s to 2’-Su bstitu ted 4-Br om o-2,4’-bith ia zoles. A 1.4-mL
sample of a 1.5 M solution of tert-butyllithium in pentane (2.1
mmol) was added at -78 °C to a solution of 1.0 mmol of
bromothiazole 3 in 5 mL of Et2O. After the mixture was stirred
at -78 °C for 10 min, 1 mL of a 1.0 M solution of Me3SnCl
(1.0 mmol) in THF was added. The resulting mixture was
stirred at room temperature for 2 h and 20 mL of Et2O and 5
mLof H2O were added. The organic layer was dried over Na2-
SO4 and after filtration, the solvent was removed and the
residue was dissolved in 8 mL of toluene to which 243 mg of
2,4-dibromothiazole (2) (1.0 mmol) and 58 mg of Pd(PPh3)4 (50
µmol) were added, and the solution was degassed. After
refluxing for 16 h, 5 mL of H2O was added and the aqueous
layer was extracted with Et2O (3 × 20 mL). The combined
organic layers were washed with brine (20 mL). After drying
over Na2SO4 and filtration, the solvent was removed and the
residue was purified by flash chromatography.
action was carried out as described for general procedure D
starting with 414 mg of bromothiazole 3d (1.63 mmol), 304
mg of 2,4-dibromothiazole (2) (1.25 mmol), 2.28 mL of a tert-
butyllithium solution (1.5 M in pentane) (3.42 mmol), 4.9 mL
of a ZnCl2 solution (0.5 M in THF) (2.45 mmol), and 45 mg of
PdCl2(PPh3)2 (64 µmol). A total of 383 mg (91%) of 1c was
obtained as a white solid (P/EtOAc ) 80/20 as eluent). Rf 0.17
(P/EtOAc ) 80/20). Mp: 49 °C. IR (KBr): v˜ 3082 cm-1 (w,
CHar), 2955 (w, CHal). 1H NMR: δ 1.86-2.01 (m, 4 H), 3.05 (t,
J ) 7.6 Hz, 2 H), 3.57 (t, J ) 6.5 Hz, 2 H), 7.20 (s, 1 H), 7.87
(s, 1 H). 13C NMR: δ 26.9, 31.7, 32.5, 44.4, 116.2, 117.3, 125.9,
147.8, 163.5, 171.4. MS, m/z (%): 340 (10) [M+(81Br37Cl)], 338
(33) [M+(81Br35Cl), M+(79Br37Cl)], 336 (24) [M+(79Br35Cl)], 303
(100) [M+(81Br) - Cl], 301 (98) [M+(79Br) - Cl], 275 (74)
[M+(81Br) - CH2CH2Cl], 273 (69) [M+(79Br) - CH2CH2Cl], 138
(17) [81BrCCHS+], 136 (18) [79BrCCHS+]. HRMS m/z calcd for
C
10H10BrClN2S2 (M+) 335.9157, found 335.9155.
4-Br om o-2′-p h en yl-2,4′-bith ia zole (1h ). The reaction was
carried out as described for general procedure E starting with
103 mg of bromothiazole 3h (429 µmol), 104 mg of 2,4-
dibromothiazole (2) (429 µmol), 0.6 mL of a tert-butyllithium
solution (1.5 M in pentane) (901 µmol), 429 µL of a Me3SnCl
solution (1 M in THF) (429 µL), and 24 mg of Pd(PPh3)4 (22
µmol). A total of 85 mg (61%) of 1h was obtained as a white
solid (P/Et2O ) 95/5 as eluent). Rf 0.24 (P/Et2O ) 93/7). Mp:
4-Br om o-2′-[6-(ter t-b u t yld im et h ylsiloxy)-h exyl]-2,4′-
bith ia zole (1e). The reaction was carried out as described for
general procedure D starting with 73 mg of bromothiazole 3e
(193 µmol), 36 mg of 2,4-dibromothiazole (2) (149 µmol), 270
µL of a tert-butyllithium solution (1.5 M in pentane) (405 µmol),
580 µL of a ZnCl2 solution (0.5 M in THF) (290 µmol), and 5.2
mg of PdCl2(PPh3)2 (7.5 µmol). A total of 65 mg (94%) of 1e
was obtained as a white solid (P/Et2O ) 97/3 as eluent). Rf
0.37 (P/Et2O ) 95/5). Mp: 57 °C. IR (KBr): v˜ 3125 cm-1 (m,
1
164 °C. IR (KBr): v˜ 3112 cm-1 (m, CHar). H NMR: δ 7.24 (s,
1
1 H), 7.44-7.46 (m, 3 H), 7.98-8.00 (m, 2 H), 7.99 (s, 1 H).
13C NMR: δ 116.5, 117.5, 126.0, 126.7, 129.1, 130.7, 132.8,
149.0, 163.6, 168.9. MS, m/z (%): 324 (100) [M+(81Br)], 322 (96)
[M+(79Br)], 138 (15) [81BrCCHS+], 136 (14) [79BrCCHS+]. Anal.
Calcd for C12H7BrN2S2 (323.23): C, 44.59; H, 2.18. Found: C,
44.65; H, 2.13.
CHar), 2931 (s, CHal). H NMR: δ 0.02 (s, 6 H), 0.87 (s, 9 H),
1.36-1.45 (m, 4 H), 1.52 (quin, J ) 6.7 Hz, 2 H), 1.82 (quin, J
) 7.5 Hz, 2 H), 3.01 (t, J ) 7.7 Hz, 2 H), 3.59 (t, J ) 6.5 Hz,
2 H), 7.19 (s, 1 H), 7.85 (s, 1 H). 13C NMR: δ -5.3, 18.4, 25.5,
26.0, 28.9, 29.9, 32.7, 33.3, 63.1, 116.0, 117.2, 125.9, 147.7,
163.7, 172.7. MS, m/z (%): 449 (4) [M+(81Br)], 447 (3) [M+(79Br)],
405 (100) [M+(81Br) - tBu], 403 (85) [M+(79Br) - tBu], 75 (44).
Anal. Calcd for C18H29BrN2OS2Si (461.56): C, 46.84; H, 6.33.
Found: C, 46.89; H, 6.30.
4-Br om o-2′-(3,3-dim eth ylbu t-1-yn yl)-2,4′-bith iazole (1i).
The reaction was carried out as described for general procedure
E starting with 100 mg of bromothiazole 3i (410 µmol), 100
mg of 2,4-dibromothiazole (2) (410 µmol), 0.57 mL of a tert-
butyllithium solution (1.5 M in pentane) (860 µmol), 410 µL
of a Me3SnCl solution (1 M in THF) (410 µL), and 24 mg of
Pd(PPh3)4 (22 µmol). A total of 85 mg (58%) of 1i was obtained
as a white solid (P/Et2O ) 95/5 as eluent). Rf 0.23 (P/Et2O )
95/5). Mp: 136 °C. IR (KBr): v˜ 3122 cm-1 (m, CHar), 2968 (m,
4-Br om o-2′-isop r op yl-2,4′-bith ia zole (1f). The reaction
was carried out as described for general procedure D starting
with 268 mg of bromothiazole 3f (1.3 mmol), 243 mg of 2,4-
dibromothiazole (2) (1.0 mmol), 1.8 mL of a tert-butyllithium
solution (1.5 M in pentane) (2.7 mmol), 4.0 mL of a ZnCl2
solution (0.5 M in THF) (2.0 mmol), and 35 mg of PdCl2(PPh3)2
(50 µmol). A total of 281 mg (97%) of 1c was obtained as a
white solid (P/Et2O ) 97/3 as eluent). Rf 0.67 (P/EtOAc ) 75/
25). Mp: 41 °C. IR (KBr): v˜ 3114 cm-1 (m, CHar), 2955 (w,
CHal). 1H NMR: δ 1.36 (d, J ) 6.8 Hz, 6 H), 3.28 (sept, J )
6.8 Hz, 1 H), 7.16 (s, 1 H), 7.80 (s, 1 H). 13C NMR: δ 23.5,
1
CHal), 2221 (s, CdC). H NMR: δ 1.36 (s, 9 H), 7.24 (s, 1 H),
7.95 (s, 1H). 13C NMR: δ 28.3, 30.3, 72.3, 105.4, 117.6, 117.7,
126.0, 148.3, 150.5, 162.9. MS, m/z (%): 328 (100) [M+(81Br)],
326 (96) [M+(79Br)], 313 (84) [M+(81Br) - CH3], 311 (78)
[M+(79Br) - CH3], 138 (13) [81BrCCHS+], 136 (11) [79BrCCHS+].
5794 J . Org. Chem., Vol. 67, No. 16, 2002

2′-Substituted 4-Bromo-2,4′-bithiazoles
Anal. Calcd for C12H11BrN2S2 (327.27): C, 44.04; H, 3.39.
Found: C, 44.01; H, 3.30.
[81BrCCHS+], 136 (22) [79BrCCHS+]. Anal. Calcd for C14H7-
BrN2S2 (347.26): C, 48.42; H, 2.03. Found: C, 48.29; H, 2.00.
4-Br om o-2′-p h en yleth yn yl-2,4′-bith ia zole (1j). The reac-
tion was carried out as described for general procedure E
starting with 100 mg of bromothiazole 3j (379 µmol), 93 mg of
2,4-dibromothiazole (2) (379 µmol), 0.53 mL of a tert-butyl-
lithium solution (1.5 M in pentane) (795 µmol), 379 µL of a
Me3SnCl solution (1 M in THF) (379 µmol), and 22 mg of Pd-
(PPh3)4 (19 µmol). A total of 82 mg (58%) of 1j was obtained
as a white solid (P/Et2O ) 95/5 as eluent). Rf 0.13 (P/Et2O )
95/5). Mp: 178 °C. IR (KBr): v˜ 3113 cm-1 (w, CHar), 2210 (m,
CdC). 1H NMR: δ 7.25 (s, 1 H), 7.35-7.42 (m, 3 H), 7.59-
7.61 (m, 2 H), 8.04 (s, 1 H). 13C NMR: δ 81.6, 95.4, 117.9, 118.3,
121.0, 126.1, 128.6, 129.9, 132.1, 148.8, 149.7, 162.8. MS, m/z
(%): 348 (100) [M+(81Br)], 346 (96) [M+(79Br)], 138 (24)
Ack n ow led gm en t. Support of this research by the
Deutsche Forschungsgemeinschaft (Ba 1372-5/2) and by
the Fonds der Chemischen Industrie is gratefully ac-
knowledged. We thank the Degussa AG (Hanau-Wolf-
gang) for a generous gift of PdCl2.
Su p p or tin g In for m a tion Ava ila ble: Spectra of com-
pounds 1a -j and 3a -j. This material is available free of
charge via the Internet at http://pubs.acs.org.
J O025661O
J . Org. Chem, Vol. 67, No. 16, 2002 5795