Catalyst-controlled regioselective suzuki couplings at both positions of dihaloimidazoles, dihalooxazoles, and dihalothiazoles

Article abstract of DOI:10.1021/jo100148x

(Chemical Equation Presentation) Various dihaloazoles can be monoarylated at a single C-X bond with high selectivity via Suzuki coupling. By changing the palladium catalyst employed, the selectivity can be switched for some dihaloazoles, allowing for Suzuki coupling at the other, traditionally less reactive C-X bond. These conditions are applicable to coupling of a wide variety of aryl-, heteroaryl-, cyclopropyl-, and vinylboronic acids with high selectivities and enable the rapid construction of diverse arrays of diarylazoles in a modular fashion.

Full text of DOI:10.1021/jo100148x

pubs.acs.org/joc
Catalyst-Controlled Regioselective Suzuki Couplings at Both Positions
of Dihaloimidazoles, Dihalooxazoles, and Dihalothiazoles
Neil A. Strotman,*,† Harry R. Chobanian,*,‡ Jiafang He,‡ Yan Guo,‡ Peter G. Dormer,†
Christina M. Jones,† and Janelle E. Steves‡
†Department of Process Chemistry and ‡Department of Basic Research (Medicinal Chemistry),
Merck Research Laboratories, Merck & Co., Inc., P.O. Box 2000, Rahway, New Jersey 07065
neil_strotman@merck.com: harry_chobanian@merck.com
Received January 27, 2010
Various dihaloazoles can be monoarylated at a single C-X bond with high selectivity via Suzuki
coupling. By changing the palladium catalyst employed, the selectivity can be switched for some
dihaloazoles, allowing for Suzuki coupling at the other, traditionally less reactive C-X bond. These
conditions are applicable to coupling of a wide variety of aryl-, heteroaryl-, cyclopropyl-, and
vinylboronic acids with high selectivities and enable the rapid construction of diverse arrays of
diarylazoles in a modular fashion.
Introduction
that was both high-yielding and efficient.8 Greaney further
demonstrated the utility of these 2-aryl-substituted-4-trifloyl
oxazoles by performing Suzuki couplings to generate 2,4-
diaryloxazoles.9 The major drawback of this method is the
lack of ability to vary the C-2 position without having
to prepare each triflate independently.10 More recently,
Greaney made use of 2,4-diiodooxazole as a bifunctional
linchpin to prepare linked oxazoles through sequential
lithium-halogen exchange, protection, and direct aryla-
tion.11 Direct C-H bond arylation of oxazole proceeds in
a stepwise manner based on pKa values (C2 > C5 > C4)
making selective C4 arylation challenging.12 We decided
that 2,4-diiodooxazole and other dihaloazoles were ripe for
attempting selective Suzuki couplings at either C-X bond.13
Oxazoles, imidazoles, and thiazoles are components of
numerous biologically active natural products as well as
pharmaceutical molecules (Figure 1).1-3 While diarylazoles
are common structural motifs in both natural products4 and
drug candidates,5 they are not straightforward to synthesize
in a modular fashion. For example, diaryloxazoles are gen-
erally prepared through the Fischer oxazole synthesis6 or
Robinson-Gabriel synthesis,7 where the oxazole ring is
constructed in the process. An elegant example of the pre-
paration of 2-aryl-substituted-4-trifloyl oxazoles was show-
cased by Panek using a modified Hantzsch oxazole synthesis
(1) Stangeland, E. L.; Sammakia, T. J. Org. Chem. 2004, 69, 2381.
(2) Wiglenda, T; Gust, R. J. Med. Chem. 2007, 50, 1475.
(3) Reader, J. C.; Ellard, J. M.; Boffey, H.; Taylor, S.; Carr, A. D.;
Cherry, M.; Wilson, M.; Owoare, R. B. PCT Int. Appl. 2008, WO
2008139161.
(4) Smith, A. B.; Liu, Z; Hogan, A. L.; Dalisay, D. S.; Molinski, T. F. Org.
Lett. 2009, 11, 3766.
(5) Hughes, R. A.; Thompson, S. P.; Alcaraz, L.; Moody, C. J. J. Am.
Chem. Soc. 2005, 127, 15644.
(6) Cornforth, J. W.; Cornforth, R. H. J. Chem. Soc. 1949, 1028.
(7) Nicolaou, K. C.; Hao, J.; Reddy, M. V.; Rao, P. B.; Rassias, G.;
Snyder, S. A.; Huang, X.; Chen, D.; Brenzovich, W. E.; Giuseppone, N.;
O0Brate, A.; Giannakakou, P. J. Am. Chem. Soc. 2004, 126, 12897.
(8) Langille, N. F.; Dakin, L. A.; Panek, J. S. Org. Lett. 2002, 4, 2485–
2488.
(9) Flegeau, E. F.; Popkin, M. E.; Greaney, M. F. Org. Lett. 2006, 8, 2495.
(10) For an earlier methodology involving selective iodination of oxa-
zoles at C4 via lithiation see: Vedejs, E.; Luchetta, L. M. J. Org. Chem. 1999,
64, 1011.
(11) Flegeau, E. F.; Popkin, M. E.; Greaney, M. F. Org. Lett. 2008, 10,
2717.
(12) (a) Ohnmacht, S. A.; Mamone, P.; Culshaw, A. J.; Greaney, M. F.
Chem. Commun. 2008, 1241–1243. (b) Hichiya, H.; Hirano, K.; Satoh, T.;
Miura, M. Org. Lett. 2009, 11, 1737–1740.
(13) Selective Suzuki couplings of 2,3-dibromo-5-formylpyrroles and
dibromopyridines have been reported: (a) Handy, S. T.; Sabatini, J. J.
Org. Lett. 2006, 8, 1537–1539. (b) Handy, S. T.; Wilson, T.; Muth, A. J. Org.
Chem. 2007, 72, 8496–8500.
DOI: 10.1021/jo100148x
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Published on Web 02/09/2010
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Strotman et al.
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FIGURE 2. Nuclear Overhauser effects observed with C4 arylation
of 2,4-diiodooxazole.
FIGURE 1. Pharmaceutically relevant azoles.
TABLE 1. Effects of Ligand on Phenylation of 2,4-Diiodooxazole
SCHEME 1. Selective Arylation of Dihaloazoles
entrya
ligand
PPh3
X-Phos
DPPF
2
tBu3P-HBF4
3
4
4
C4:C2 phenylationb mono:bis phenylationb
1
2
3
4
5
6
7
8c
1.9:1
1.7:1
1.9:1
1.3:1
0.5:1
2.8:1
7.3:1
1.7:1
2.3:1
4.5:1
14:1
Here we describe a general method for highly selective
monoarylation of several dihaloazoles.14 Our hypothesis was
that these Suzuki couplings would show selectivity for
arylation at C2, allowing for further functionalization at
the typically less reactive C4 or C5 positions (Scheme 1).15,16
This modular approach would allow for rapid introduction
of diversity into oxazole, imidazole, and thiazole structures,
which should be highly valuable for medicinal chemistry
structure activity relationship (SAR) studies. Additionally,
we describe catalyst systems capable of selective arylation at
the traditionally less reactive C4 or C5 positions of azoles,
over the C2 position, giving greater flexibility for SAR.
13:1
0.47:1
0.59:1
1.0:1
0.077:1
aAll reactions were run with 5% Pd(OAc)2, 1:1 ligand/Pd ratio for
bidentate ligands and 2:1 ligand/Pd ratio for monodentate ligands, 3
equiv of K3PO4, with 1.1 equiv of phenyl boronic acid, 0.2 M 2,4-
b
diiodooxazole in THF, at 60 °C for 16 h. Ratio determined from the
crude reaction mixture by LC-MS prior to purification. cACN was used
instead of THF.
Results
Inspired by the work of Greaney et al, we initially inves-
tigated the Suzuki coupling of 2,4-diiodooxazole11 with
phenylboronic acid in the hopes of finding conditions for
regioselective coupling. We were surprised to find that the
preferred site of reaction using palladium and PPh3 was C4
and not C2 as expected.17 In addition to showing 13C NMR
shifts consistent with C4 phenylation, a 1D NOESY experi-
ment on 1-C4 showed a 0.2% NOE from the o-phenyl
protons to the proton at C5 of the oxazole (Figure 2). No
NOE was observed in isomer 1-C2.
Disappointingly, almost all ligands tested offered poor
selectivity, giving large amounts of the bis-phenylation
product (1-bis) and only a moderate C4:C2 preference as
determined by LC-MS.18 For example, three common,
structurally diverse phosphine ligands, PPh3, X-Phos, and
DPPF, all gave almost identical levels of C4:C2 selectivity
(14) For a review of the extensive work on cross-coupling reactions of
monohaloazoles see: Schnurch, M.; Flasik, R.; Khan, A. F.; Spina, M.;
Mihovilovic, M. D.; Stanetty, P. Eur. J. Org. Chem. 2006, 3283–3307.
(15) The preferred site of lithium halogen exchange in 2,4-diiodooxa-
zole11 and 2,4-dibromothiazole is C2: Martin, T.; Laguerre, C.; Hoarau, C.;
Marsais, F. Org. Lett. 2009, 11, 3690–3693.
FIGURE 3. A selection of phosphine ligands employed in this
study.
(16) The preferred site of SNAr on 2,4-dibromothiazoles with thiols is C2:
Nicolaou, K. C.; Sasmal, P. K.; Rassias, G.; Reddy, M. V.; Altmann, K.-H.;
Wartmann, M.; O0Brate, A.; Giannakakou, P. Angew. Chem., Int. Ed. 2003,
42, 3515–3520.
(Table 1, entries 1-3). However, we found that Xantphos (2)
(Figure 3) was uniquely capable of mediating highly selective
coupling at C4 to give 1-C4, as well as demonstrating high
selectivity for monophenylation (Table 1, entry 4).
We found it particularly surprising that a small number of
ligands gave the opposite regiochemistry from PPh3, show-
ing a preference for coupling at C2 over C4 to give 1-C2
(Table 1, entries 5 and 6). An exhaustive survey of our
(17) Handy0s method for predicting the site of coupling in dihaloheter-
oaromatics using the 1H NMR shifts of the parent non-halogenated com-
pound incorrectly predicts reaction at C2 of 2,4-diiodooxazole and 2,5-
dibromo-1-methylimidazole: Handy, S. T.; Zhang, Y. Chem. Commun. 2006,
299–301.
(18) All LC-MS ratios were estimated by using the LC area percentage at
either 210 or 254 nm.
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TABLE 2. Regioselective Suzuki Cross-Coupling of 2,4-Diiodooxazole with Various Arylboronic Acids
aAll reactions were run on a 1.0 mmol scale, ligand/Pd ratios of 2:1 for monodentate ligands and 1:1 for bidentate ligands, 3 equiv of K3PO4, and
1.1-1.3 equiv of phenyl boronic acid, with 0.2 M [dihaloazole] in THF. bRatio determined from the crude reaction mixture by LC-MS prior to
purification. c15% 4-iodooxazole present. d22% starting material recovered. e5:1 mono:bis. f27% starting material recovered. gPinacolatoboronate ester
with 15 vol % water in THF was used. h6:1 C4:C2 ratio. i5.2:1 C4:C2 ratio.
SCHEME 2. Selective Phenylation of 2,4-Dibromo-1-methylimidazole
collection of ∼200 achiral phosphine ligands revealed that
1,3,5-triaza-7-phosphaadamantane (4), when reacted in
acetonitrile, was capable of high selectivity for the C2 posi-
tion, and showed high selectivity toward monophenylation
(Table 1, entries 7 and 8).
With these two sets of complementary conditions in hand
(ligands 2 and 4), we began to investigate the scope of this
Suzuki coupling reaction (Table 2). We found that 2,4-
diiodooxazole could be cross-coupled selectively at either
C4 or C2 with a variety of electron-rich or electron-poor
arylboronic acids (Table 2, entries 1-8).19 In addition, these
conditions were applicable to vinylboronic acids and hetero-
arylboronic acids such as 2-(N-Boc-pyrrole)- and 3-thienyl-
boronic acid (entries 9-11). In some cases the isolated yields
were low, due to poor mono:bis or poor isomer ratios. For
example, entry 4 shows 54% isolated yield out of only 78%
(19) In the absence of added base, phenylzinc bromide could be coupled
with 2,4-diiodoxazole with use of ligand 2 and under otherwise identical
conditions, giving similar selectivities to those obtained with phenylboronic
acid.
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TABLE 3. Regioselective Suzuki Cross-Coupling of Dihaloimidazoles with Various Arylboronic Acids
aAll reactions were run on a 1.0 mmol scale, ligand/Pd ratios of 2:1 for monodentate ligands and 1:1 for bidentate ligands, 3 equiv of K3PO4, and 1.1
equiv of phenyl boronic acid, with 0.2 M [dihaloazole] in THF. bRatio determined from the crude reaction mixture by LC-MS prior to purification. c42%
starting material recovered. dEmployed 10% Pd2dba3 instead of Pd(OAc)2 and 1.4 equiv of boronic acid. 30% starting material recovered. e29% starting
material recovered. f19% starting material recovered.
SCHEME 3. Selective Phenylation of 2,5-Dibromo-1-methyli-
midazole
conversion. At elevated temperatures or longer reaction
times necessary to cross couple 3-pyridyl boronic acids with
2 or 4, other processes such as dehalogenation and homo-
coupling became competitive.
We next attempted to apply these conditions developed for
2,4-diiodooxazole to other commercially available dihalo-
azoles. We expected that 2,4-dibromo-1-methylimidazole
would have similar ligand-dependent reactivity to 2,4-di-
iodoxazole. However, we were surprised to find that the
major site of reaction for ligand 4, as well as for 2, was C2 to
give 7-C2 almost exclusively (Scheme 2). Further experi-
ments revealed that no ligand in our collection provided any
appreciable reaction at C4, which was the more reactive
position observed for 2,4-diiodoxazole. While ligand 4, and
surprisingly 2, were among the best in terms of mono:bis
ratio (∼6:1), one ligand (tri(4-fluorophenyl)phosphine (5),
Figure 3) was found to yield superior results of 18:1 mono:
bis. Again, 1D NOESY experiments were employed to
possible yield based on the mono:bis and isomer ratios, and
assuming full conversion.20 Unfortunately, pyridyl, pyrimi-
dinyl, and quinolyl boronic acids showed no more than a
trace (<3%) of product with these catalysts due to negligible
(20) The maximum yield in this reaction is equal to (major isomer/(major
isomer þ minor isomer)) multiplied by (mono/(mono þ bis) = (5.7/6.7) ꢀ
(11/12) = 0.78. This yield can be further reduced by incomplete conversion of
dihaloazole, caused by consumption of ArB(OH)2 to form the bis compound.
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TABLE 4. Regioselective Suzuki Cross-Coupling of Dibromothiazoles with Various Boronic Acids
aAll reactions were run on a 0.5-2.0 mmol scale, with ligand/Pd ratio 1:1, 3 equiv of K3PO4, and 1.1 equiv of phenyl boronic acid, with 0.2 M
dihaloazole in THF. bRatio determined from the crude reaction mixture by LC-MS prior to purification. c1.1 equiv of n-propylzinc bromide and no base
was used.
behavior. The 2,5-dibromo-1-methylimidazole showed
reactivity analogous to 2,4-diiodooxazole, rather than to
2,4-dibromo-1-methylimidazole. C2 was quite unreactive in
2,5-dibromo-1-methylthiazole, and the only ligand that pro-
moted selective cross-coupling at this position was 4 (33:1
C2/C5), also the most selective ligand for coupling at C2
of 2,4-diiodooxazole (Scheme 3). Position C5, on the other
hand, was far more reactive and was favored by every
ligand in our collection other than 4. While 2 gave only
low selectivity for C5 of 2,5-dibromo-1-methylimidazole
(1.9:1 C5/C2), it was found that several ligands21 displayed
superior performance, with bis(p-sulfonatophenyl)phenyl-
phosphine dihydrate dipotassium salt (6) giving the best
balance of reactivity, C2:C5 selectivity (23:1), and mono:
bis selectivity (4.3:1). The assignments of 5-bromo-2-phenyl-
1-methylimidazole (8-C2) and 2-bromo-5-phenyl-1-methyli-
FIGURE 4. Ligand-Dependent Reactivity of Dihaloazoles toward
Pd-Catalyzed Suzuki Coupling.
midazole (8-C5), resulting from cross coupling with ligands
establish the regiochemistry of the major product as 7-C2
(Scheme 2).
We next investigated how 2,5-dibromo-1-methylimida-
zole compares to the 2,4-isomer and observed dichotomous
(21) Several diverse ligands showed high C5 selectivity for this particular
dibromide including 3,4,5,6-tetramethyl-tBu-XPhos, dppb monoxide,
1-diisopropylphoshino-2-dimethylaminoindene, and SiPr-HBF4. It was dis-
covered in subsequent experiments that phosphine-free palladium gave
comparable results to palladium with 6.
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4 and 6, respectively, were established by 1D NOESY
experiments (Scheme 3).
free palladium, which undergo slow oxidative addition, only
inserted at the most active positions of each electrophile (C2 for
dibromothiazoles and 2,4-dibromo-1-methylimidazole, C4 for
2,4-diiodooxazole, C5 for 2,5-dibromo-1-methylimidazole)
(Figure 4). However, we hypothesize that the trans binding
mode of Xantphos (2) to Pd is also responsible in part for its
unique reactivity. On the other hand, more active ligands such
as mono-, di-, and trialkylphosphines were able to insert into
the less active positions as well, leading to mixtures of regioi-
somers and large amounts of bis-arylated species. However, for
reasons that are not yet understood, some highly electron-rich
ligands (4, tBu3P, 3) tended to prefer oxidative addition at the
less reactive C2 positions of 2,4-diiodooxazole and 2,5-dibromo-
1-methylimidazole (Figure 4). However, there are numerous
exceptions to this electronic trend. For example, 3,4,5,6-tetra-
methyl-tBu-XPhos and SiPr-HBF4, both electron-rich ligands,
offered high selectivity for the C5 position of 2,5-dibromo-
1-methylimidazole.26 Also, DPPF and DTBPF both prefer C4
oxidative insertion for 2,4-diiodooxazole, while 3, a hybrid of
these two ligands, anomalously prefers C2 insertion.27 These
findings suggest that the regiochemical preference imparted by
different ligands is a complex mixture of steric and electronic
effects which are not fully understood.
We investigated the scope of selective Suzuki couplings of
dibromo-1-methylimidazoles with a variety of boronic acids.
2,4-Dibromo-1-methylimidazole could be coupled with elec-
tron-rich or electron-poor arylboronic acids, as well as with
heteroaryl- and vinylboronic acids with high yields and
regioselectivites (Table 3, entries 1-6). It could also be
coupled with 3-quinolineboronic acid in moderate yield by
switching to Pd2(dba)3 from Pd(OAc)2 and increasing the
catalyst loading (entry 7). By employing either ligand 4 or 6,
2,5-dibromo-1-methylimidazole could be selectively coupled
at either C2 or C5 with electron-rich or electron-poor
arylboronic acids (Table 3, entries 8-14).
We compared 2,5-diiodo-1-methylimidazole to the corre-
sponding dibromide and observed very similar reactivity. As
with 2,5-dibromo-1-methylimidazole, C5 was the major site
of reaction of 2,5-diiodooxazole (as confirmed by 1D
NOESY), although ligand 6 gave slow conversion and poor
C5:C2 and mono:bis selectivities. However, faster conver-
sion and high selectivities were obtained by employing ligand
2 (Table 3, entry 15). Additionally, ligand 4 provided highly
selective cross-coupling (21:1 C2:C4, >100:1 mono/bis)
at C2 of 2,5-diiodo-1-methylimidazole, as it had with the
2,5-dibromo analogue.22
Conclusions
Finally, we studied selective Suzuki couplings of dibro-
mothiazoles.23 Ligand 2 proved very reactive and highly selec-
tive for C2 of 2,4- and 2,5-dibromothiazoles, requiring only
2.5% Pd and never producing any detectable minor isomer.
This is in stark contrast to 2,4-diiodooxazole and 2,5-dibromo-
1-methylimidazole, where 2showed minimal reaction at C2, and
high selectivity at C4 or C5, respectively. The selectivity of the
dibromothiazoles mirrored that of 2,4-dibromo-1-methylimida-
zole, where C2 was the more reactive position and no ligand was
We have developed methods for highly selective Suzuki
couplings of dihaloimidazoles, dihalooxazoles, and dihalo-
thiazoles, providing efficient access to a wide array of valu-
able mono- or bis-functionalized azoles. These reactions
exhibit a broad substrate scope, with numerous aryl and
heteroaryl boronic acids being coupled. These methods
should prove highly valuable to chemists wishing to prepare
diverse arrays of imidazoles, oxazoles, or thiazoles in a
modular fashion. Additionally, we discovered a ligand cap-
able of selective cross couplings at C2 of 2,4-diiodooxazole
and 2,5-dibromo-1-methylthiazole, giving access to both
regioisomeric products. This will allow for selective arylation
(or alkylation, vinylation) at the typically less reactive C-X
bond, and further functionalization at C4 or C5 by metala-
tion and subsequent reaction or cross-coupling. The ability
to cross couple at either C-X bond of these azoles would
allow for a specific aryl group to be installed at either
position, and then for a wide variety of coupling partners
to be added at the other C-X bond. Studies are underway to
develop more selective catalysts and extend this methodol-
ogy to different types of cross-coupling reactions.
1
identified to give selectivity for the less reactive position. H
NMR spectra of 4-bromo-2-phenylthiazole and 5-bromo-2-
phenylthiazole were matched to literature spectra, confirming
the assigned regiochemistry of these compounds.24,25
These conditions were used to cross-couple, with high
yields, a wide variety of electron-rich, electron-poor, and
sterically hindered arylboronic acids. This same set of con-
ditions also proved useful for cross-coupling of heteroaryl-
boronic acids and cyclopropylboronic acid (Table 4).
Additionally, when K3PO4 was omitted, these conditions
were suitable for a Negishi coupling of 1-propylzinc bromide
with 2,4-dibromothiazole, giving the monoalkylated product
in very high yield (entry 9).
Experimental Section
Discussion
General Procedure for Suzuki Cross-Coupling Reactions. This
will be demonstrated with the preparation of 4-bromo-2-phe-
nylthiazole:
The dependence of the relative rates of C2 vs C4 or C5
coupling on the identity of the ligand is highly complex. In
general, electron-deficient ligands (2, 5, and 6) or phosphine-
(22) The identity of 5-iodo-1-methyl-2-phenylimidazole was determined
solely by LC-MS and showed a very different retention time than its isomer
2-iodo-1-methyl-5-phenylimidazole. This product readily decomposed upon
attempted isolation.
(23) A highly selective Negishi coupling at C2 of 2,4-dibromothiazole has
been reported as part of a total synthesis: Bach, T.; Heuser, S. Angew. Chem.,
Int. Ed. 2001, 40, 3184–3185.
Under nitrogen Pd(OAc)2 (8.4 mg, 0.038 mmol, 2.5%) was
combined with Xantphos (2) (22 mg, 0.038 mmol, 2.5%) in
(26) We hypothesize that catalyst formation may be slow or problematic
with these two ligands and 6, allowing phosphine-free palladium to affect the
majority of the oxidative addition at C5.
(27) On the basis of its reactivity, we postulate that 3 behaves as a bulky,
electron-rich, monodentate phosphine (only binding through the (tBu)2P
phosphorus), similar to tBu3P, rather than as a bidentate phosphine.
(24) Bach, T.; Heuser, S. J. Org. Chem. 2002, 67, 5789–5795. Vachal, P.;
Toth, L. M. Tetrahedron Lett. 2004, 45, 7157–7161.
(25) Since one 1H NMR resonance of 5-bromo-2-phenylthiazole did not
match that reported in the literature, we compared it to an authentic
commercial sample, which matched our cross-coupling product perfectly.
1738 J. Org. Chem. Vol. 75, No. 5, 2010

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degassed THF (7.5 mL). After stirring for 5 min, this solution
was transferred to a separate vessel under nitrogen containing
2,4-dibromothiazole (364 mg, 1.5 mmol), phenylboronic acid
(196 mg, 1.6 mmol, 1.07 equiv), and K3PO4 (955 mg, 4.5 mmol,
3 equiv). The sealed vessel was heated at 60 °C for 18 h. Upon
cooling to room temperature, LC-MS showed 100% conversion
of starting material, 19.5:1 mono:bis product ratio, and >100:1
C2:C4 product isomer ratio. The reaction mixture was filtered
and the solid was washed with DCM. The solvents were
removed by rotary evaporation and the title compound was
purified by column chromatography (silica gel, EtOAc/hexane)
to give a white waxy solid (0.264 mg, 73%, mp 80 °C (lit.28 mp
77-78 °C)).
vessel under nitrogen containing 2,4-dibromothiazole (243
mg, 1.0 mmol) and propylzinc bromide (2.2 mL, 0.5 M
solution in THF, 1.1 mmol, 1.1 equiv). The sealed vessel
was heated at 80 °C for 18 h. Upon cooling to room
temperature, LC-MS showed 100% conversion of starting
material, >100:1 mono:bis product ratio, and >100:1 C2:
C4 product isomer ratio. The reaction mixture was filtered
and the solid was washed with DCM. The solvents were
removed by rotary evaporation and the title compound was
purified by column chromatography (silica gel, EtOAc/
hexane) to give a white powder (0.184 mg, 89%, mp
98-100 °C).
1H NMR (500 MHz, CD3Cl3) δ 7.23 (s, 1H), 7.46 (m, 3H),
7.95 (dd, J = 7.5, 2.5 Hz, 2H); 1H NMR (500 MHz,
CD3COCD3) δ 7.54 (m, 3H), 7.68 (s, 1H), 7.99 (m, 2H); 13C
NMR (125 MHz, CDCl3) δ 116.6, 126.2, 126.5, 129.2, 130.9,
1H NMR (500 MHz, CDCl3) δ 1.00 (t, J = 7.0 Hz, 3H), 1.80
(sextet, J = 7.0 Hz, 2H), 2.96 (t, J = 7.5 Hz, 2H), 7.06 (s, 1H);
13C NMR (126 MHz, CDCl3) δ 13.5, 23.2, 35.4, 115.6, 124.0,
172.5; LCMS [M þ H]þ calcd for C6H8BrNS Hþ 205.9, found
3
132.7, 169.2; LCMS [M þ H]þ calcd for C9H6BrNS Hþ 239.95,
205.9; HRMS (ESI) [M þ H]þ calcd for C6H8BrNS Hþ
3
3
found 239.92; HRMS (ESI) [M þ H]þ calcd for C9H6BrNS Hþ
205.9639, found 205.9639.
3
239.9482, found 239.9491.
Negishi Cross-Coupling To Prepare 4-Bromo-2-propylthia-
zole. Under nitrogen Pd(OAc)2 (11.2 mg, 0.05 mmol, 5%) was
combined with Xantphos (2)
Acknowledgment. The authors gratefully acknowledge
Ms. Huifang Yao, Dr. Vincent Tong, and Ms. Kate Rausted
for help in obtaining HRMS data. The authors would also
like to thank Dr. Thomas Weingarten, Dr. Wendy Cornell,
and Dr. Gene Fluder for helpful computational discussions,
and Dr. Jonathan Wilson for helpful chemistry discussions.
(29 mg, 0.05 mmol, 5%) in degassed THF (2.5 mL). After
stirring for 5 min, this solution was transferred to a separate
Supporting Information Available: Experimental proce-
dures, tabulated characterization data, and NMR spectra for
all products. This material is available free of charge via the
Internet at http://pubs.acs.org.
(28) Begtrup, M.; Hansen, L. B. L. Acta Chem. Scand. 1992, 46, 372–383.
J. Org. Chem. Vol. 75, No. 5, 2010 1739