Synthesis of Aryl- and Heteroaryl-Substituted 3-Benzyloxyisothiazoles via Suzuki and Negishi Cross-Coupling Reactions

Article abstract of DOI:10.1021/jo035578g

Introduction of aryl and heteroaryl substituents into the 5-position of 3-benzyloxyisothiazole (1) using palladium-catalyzed Suzuki and Negishi cross-coupling reactions was investigated. Attempts to generate synthetically viable nucleophilic species from

Full text of DOI:10.1021/jo035578g

Syn th esis of Ar yl- a n d
Heter oa r yl-Su bstitu ted
3-Ben zyloxyisoth ia zoles via Su zu k i a n d
Negish i Cr oss-Cou p lin g Rea ction s
Birgitte H. Kaae, Povl Krogsgaard-Larsen, and
Tommy N. J ohansen*
Department of Medicinal Chemistry, The Danish University
of Pharmaceutical Sciences, 2 Universitetsparken,
DK-2100 Copenhagen, Denmark
tnj@dfuni.dk
F IGURE 1. Structures of some isoxazole- and isothiazole-
based GABA or Glu receptor ligands.
Received October 27, 2003
Abstr a ct: Introduction of aryl and heteroaryl substituents
into the 5-position of 3-benzyloxyisothiazole (1) using pal-
ladium-catalyzed Suzuki and Negishi cross-coupling reac-
tions was investigated. Attempts to generate synthetically
viable nucleophilic species from 1 for Suzuki- or Negishi-
type cross-couplings were unsuccessful. However, using
3-benzyloxy-5-iodoisothiazole 2 as an intermediate, a range
of aromatic and heteroaromatic substituents were success-
fully introduced under Suzuki or Negishi cross-coupling
conditions in good to excellent yields.
bioisosteric unit. The isothiazole analogues of muscimol
and AMPA, thiomuscimol and thio-AMPA, respectively,
are examples of isothiazole-based compounds active at
GABA and Glu receptors.4,8 Although the 3-hydroxy-
isothiazole unit is less acidic than the 3-hydroxyisoxazole
unit, thio-AMPA and thiomuscimol exhibit pharmacologi-
cal characteristics very similar to those of AMPA and
muscimol, respectively.8,9 Interestingly, however, the
5-tert-butyl analogues of AMPA and thio-AMPA activate
subtypes of Glu receptors differently.10,11
To investigate the scope of substituted 3-hydroxy-
isothiazoles as carboxyl group bioisosteric units notably
for the design of Glu receptor ligands, effective introduc-
tion of a range of aromatic and heteroaromatic substi-
tuents in the 5-position of protected 3-hydroxyisothiazole
was identified as a key synthetic step. For the syntheses
of this type of compounds, a transition-metal-catalyzed
cross-coupling strategy was envisioned to be of particular
interest. Apart from a regiospecific introduction of aryl
substituents in the 5-position of 3,5-dichloroisothiazole-
4-carbonitrile using a Suzuki coupling strategy,12 Negishi
or Suzuki cross-coupling reactions have, so far, not been
reported using the isothiazole parental system, including
O-protected 3-hydroxyisothiazoles. Substituents have
usually been introduced either before cyclization8,13 or via
selective lithiation in the 5-position of 3-benzyloxy-
isothiazole 1.14 We here describe a convergent method
Bioisosteric substitution of acidic 5- or 6-membered
heteroaromatic acidic units for carboxyl groups has been
successfully used in many areas of drug design. One such
example is 3-hydroxyisoxazole, which has been exten-
sively used in the design of subtype-selective ligands for
4-aminobutanoic acid (GABA)1 as well as (S)-glutamate
(Glu)2 receptors in the central nervous system. Thus, the
3-hydroxyisoxazole analogue of GABA, muscimol (Figure
1), a constituent of the mushroom Amanita muscaria
interacting nonselectively with the GABAA-subtype of
GABA receptors,3,4 has been effectively used as a lead
structure for the design of a number of specific GABAA
receptor ligands, including 4,5,6,7-tetrahydroisoxazolo-
[5,4-c]pyridin-3-ol (THIP).3 THIP is currently studied
clinically as a potential drug for the treatment of pain
and insomnia.1
The 3-hydroxyisoxazole analogue of Glu, [(S)-2-amino-
3-(3-hydroxy-5-methyl-4-isoxazolyl)propanoic acid, AMPA]
(Figure 1), is a potent and highly selective agonist, acting
specifically at the AMPA subtype of glutamate receptors.2
Replacement of the 5-methyl substituent of AMPA by a
range of aromatic and, in particular, heteroaromatic
substituents has provided a range of interesting Glu
receptor ligands,5-7 including the 2-furyl-substituted
analogue, 2-Fu-AMPA (Figure 1), which is markedly
more potent than AMPA as an AMPA receptor agonist.7
Compared to 3-hydroxyisoxazole, 3-hydroxyisothiazole
has been much less investigated as a carboxyl group
(5) Ebert, B.; Lenz, S. M.; Brehm, L.; Bregnedal, P.; Hansen, J . J .;
Frederiksen, K.; Bøgesø, K. P.; Krogsgaard-Larsen, P. J . Med. Chem.
1994, 37, 878-884.
(6) Bang-Andersen, B.; Lenz, S. M.; Skjærbæk, N.; Søby, K. K.;
Hansen, H. O.; Ebert, B.; Bøgesø, K. P.; Krogsgaard-Larsen, P. J . Med.
Chem. 1997, 40, 2831-2842.
(7) Falch, E.; Brehm, L.; Mikkelsen, I.; J ohansen, T. N.; Skjærbæk,
N.; Nielsen, B.; Stensbøl, T. B.; Ebert, B.; Krogsgaard-Larsen, P. J .
Med. Chem. 1998, 41, 2513-2523.
(8) Matzen, L.; Engesgaard, A.; Ebert, B.; Didriksen, M.; Frølund,
B.; Krogsgaard-Larsen, P.; J aroszewski, J . W. J . Med. Chem. 1997,
40, 520-527.
(9) Ebert, B.; Frølund, B.; Diemer, N. H.; Krogsgaard-Larsen, P.
Neurochem. Int. 1999, 34, 427-434.
(10) Stensbøl, T. B.; Borre, L.; J ohansen, T. N.; Egebjerg, J .; Madsen,
U.; Ebert, B.; Krogsgaard-Larsen, P. Eur. J . Pharmacol. 1999, 380,
153-162.
* Corresponding author.
(1) Frølund, B.; Ebert, B.; Kristiansen, U.; Liljefors, T.; Krogsgaard-
Larsen, P. Curr. Top. Med. Chem. 2002, 8, 817-832.
(2) Bra¨uner-Osborne, H.; Egebjerg, J .; Nielsen, E. Ø.; Madsen, U.;
Krogsgaard-Larsen, P. J . Med. Chem. 2000, 43, 2609-2645.
(3) Krogsgaard-Larsen, P.; J ohnston, G. A. R.; Lodge, D.; Curtis, D.
R. Nature (London) 1977, 268, 53-55.
(11) Stensbøl, T. B.; J ensen, H. S.; Nielsen, B.; J ohansen, T. N.;
Egebjerg, J .; Frydenvang, K.; Krogsgaard-Larsen, P. Eur. J . Pharma-
col. 2001, 411, 245-253.
(12) Christoforou, I. C.; Koutentis, P. A.; Rees, C. W. Org. Biomol.
Chem. 2003, 1, 2900-2907.
(4) Krogsgaard-Larsen, P.; Frølund, B.; J ørgensen, F. S.; Schousboe,
A. J . Med. Chem. 1994, 37, 2489-2505.
(13) Lewis, S. N.; Miller, G. A.; Hausman, M.; Szamborski, E. C. J .
Heterocycl. Chem. 1971, 8, 571-580.
10.1021/jo035578g CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/21/2004
J . Org. Chem. 2004, 69, 1401-1404
1401

SCHEME 1a
for the preparation of the zincated species, less than 35%
of product could be obtained in any of the Negishi cross-
coupling reactions investigated (for details see the Sup-
porting Information). In all reactions, the major product
isolated was 1, in which the iodide or zinc halide was
replaced by hydrogen. The reason for this exhange has
not been investigated, but it may be the results of either
reduction of 2 mediated by Pd20 or hydrolysis of the
zincated species of 2.
As Negishi cross-coupling reactions turned out not to
be straightforward, a Suzuki cross-coupling strategy
using the borate ester of 1 was envisioned as an alterna-
tive. Suzuki cross-coupling reactions can tolerate a wide
range of functional groups17 and are used extensively in
organic synthesis. Boronic esters are normally stable,
nonhygroscopic, and nontoxic21 as compared to the tri-
alkylstannyl derivatives used for Stille cross-coupling
reactions.22-24 5-(5,5-Dimethyl[1,3,2]-2-dioxaborianyl)-3-
benzyloxyisothiazole 3 was easily prepared in excellent
yield by in situ trapping of the unstable 5-lithiated
species, in analogy with an earlier report on similar
compounds.25 Suzuki cross-coupling reactions based on
3 were investigated using different electrophiles and
various solvents or solvent combinations, palladium
catalysts, phosphine ligands, and a wide range of bases
(for details see the Supporting Information). In all
reactions, deboronation was observed even at room
temperature, and the major product isolated was 1. As
bulky electron-rich phosphine ligands have been reported
to promote cross-coupling reactions26 and reduce side
reactions,26,27 addition of different phosphine ligands was
investigated, though without any improvements.
An explanation for the observed deboronation of 3 to
1 under the reaction conditions used may be instability
of the otherwise shelf-stable 3 in certain solvents at
elevated temperatures. Therefore, the stability of 3 was
studied at reflux in the solvents used (for details see the
Supporting Information), and within 2 h 1 was obtained
as the major product in all protic solvents studied.
Deboronation has previously been observed mainly for
π-excessive heterocycles under alkaline conditions,28 and
hydrolytic deboronation has been observed in H2O.27 It
has not been possible to completely avoid deboronation
even when using dry and aprotic conditions.
a
Key: (i) LDA, Et2O; (ii) I2, Et2O; (iii) LDA, Et2O, B(O-i-Pr)3;
(iv) AcOH, 2,2-dimethyl-1,3-propanediol; (v) Pd catalyst, phosphine
ligand, base, solvent, electrophile; (vi) PdCl2(PPh3)2, NEt3, DME,
H2O, boron nucleophile; (vii) PdCl2(PPh3)2, PPh3, THF, DMF, zinc
nucleophile.
for direct introduction of aromatic and heteroaromatic
substituents into the 5-position of 1 (Scheme 1).
In principle, Negishi cross-coupling reactions involving
readily available halides and a zinc halide of 1 would
allow the direct introduction of aromatic or heteroaro-
matic substituents in a one-pot procedure. It was at-
tempted to introduce the substituents using procedures
analogous to those reported for the synthesis of thiazole
and oxazole analogues.15,16 Thus, the nucleophile was
generated by selective lithiation of the 5-position of 1
using LDA in Et2O,14 followed by transmetalation at -78
°C using either ZnCl2 or ZnBr2. Various combinations of
electrophiles, palladium catalysts, and phosphine ligands
were used (for details see the Supporting Information).
In all cases, major decomposition was observed, and less
than 5% of the desired products were formed. The known
limited thermal stability of the intermediate, 5-lithio-3-
benzyloxyisothiazole,14 may explain the low yields of
product obtained.
To avoid transmetalation from the 5-lithiated species,
a different strategy was pursued (Scheme 1). 3-Benzyl-
oxy-5-iodoisothiazole 2 was prepared by selective lithia-
tion in the 5-position of 114 followed by addition of I2 in
Et2O. A prerequisite for the formation of 2 in high yield
(95%) is very slow addition of I2. If the I2 was added
quickly, 2 was obtained in markedly lower yield (60%).
Introduction of Zn into 2 to provide a suitable inter-
mediate for Negishi cross-coupling reactions was at-
tempted following two different routes, either by direct
insertion of Zn using activated Zn following a standard
procedure16,17 or by transmetalation of the corresponding
Grignard intermediate with ZnCl2 in analogy with earlier
reported procedures.18,19 Regardless of the method used
Reversing the Suzuki cross-coupling reaction, and
thereby the electronic properties using 2 as the electro-
phile, was investigated. Standard Suzuki cross-coupling
reaction conditions21,23 and a range of aromatic and
heteroaromatic nucleophiles were studied. A suspension
of 2 and PdCl2(PPh3)2 in DME was stirred at room
(19) Kromann, H.; Sløk, F. A.; J ohansen, T. N.; Krogsgaard-Larsen,
P. Tetrahedron 2001, 57, 2195-2201.
(20) Davies, I. W.; Wu, J .; Marcoux, J .-F.; Taylor, M.; Hughes, D.;
Reider, P. J .; Deeth, R. J . Tetrahedron 2001, 57, 5061-5066.
(21) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457-2483.
(22) Clerici, F.; Erba, E.; Gelmi, M. L.; Valle, M. Tetrahedron 1997,
53, 15859-15866.
(23) Stanforth, S. P. Tetrahedron 1998, 54, 263-303.
(24) Hassan, J .; Se´vignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M.
Chem. Rev. 2002, 102, 1359-1469.
(14) Bunch, L.; Krogsgaard-Larsen, P.; Madsen, U. J . Org. Chem.
2002, 67, 2375-2377.
(15) J ensen, J .; Skjærbæk, N.; Vedsø, P. Synthesis 2001, 128-134.
(16) Knochel, P.; Perea, J . J . A.; J ones, P. Tetrahedron 1998, 54,
8275-8319.
(17) Prasad, A. S. B.; Stevenson, T. M.; Citineni, J . R.; Nyzam, V.;
Knochel, P. Tetrahedron 1997, 53, 7237-7254.
(18) Yu, D.; Gharavi, A.; Yu, L. J . Am. Chem. Soc. 1995, 117, 11680-
11686.
(25) Kristensen, J .; Lyse´n, M.; Vedsø, P.; Begtrup, M. Org. Lett.
2001, 3, 1435-1437.
(26) Wolfe, J . P.; Singer, R. A.; Yang, B. H.; Buchwald, S. L. J . Am.
Chem. Soc. 1999, 121, 9550-9561.
(27) Goodson, F. E.; Wallow, T. I.; Novak, B. M. Org. Synth. 1997,
75.
(28) Gronowits, S.; Peters, D. Heterocycles 1990, 30, 645-658.
1402 J . Org. Chem., Vol. 69, No. 4, 2004

TABLE 1. Su zu k i a n d Negish i Cr oss-Cou p lin g
Rea ction s P er for m ed Usin g 2 a s th e Electr op h ile
Exp er im en ta l Section
3-Ben zyloxy-5-iod oisoth ia zole (2). Diisopropylamine (1.11
mL, 7.84 mmol) was dissolved in Et2O (60 mL), and n-BuLi (4.90
mL, 1.6 M, 7.84 mmol) was added while stirring at -78 °C. After
20 min, 3-benzyloxyisothiazole 114 (1.00 g, 5.23 mmol) in Et2O
(4.0 mL) was added dropwise, and the reaction was allowed to
stir at -78 °C for 15 min. Iodine (1.59 g, 6.28 mmol) in Et2O (35
mL) was added so slowly that the reaction did not turn red
during the reaction. The reaction was allowed to warm to -40
°C. Saturated NH4Cl(aq) was added, and the reaction was allowed
to reach rt. The phases were separated and the aqueous phase
extracted with Et2O. The combined organic phases were dried
(Na2SO4) and evaporated. CC (toluene/petroleum 1:1) afforded
2 as an oil (1.58 g, 4.98 mmol, 95%): 1H NMR δ 7.46-7.30 (m,
5H), 6.77 (s, 1H), 5.36 (s, 2H); 13C NMR δ 169.1, 136.3, 128.7,
128.4, 128.3, 112.4, 99.5, 70.6. Anal. Calcd for C10H8INOS: C,
37.87; H, 2.54; N, 4.42. Found: C, 38.10; H, 2.37; N, 4.39.
5-(5,5-Dim eth yl[1,3,2]-2-d ioxa bor ia n yl)-3-ben zyloxyiso-
th ia zole (3). n-BuLi (2.18 mL, 1.38 M, 3.0 mmol) was added to
a solution of diisopropylamine (0.42 mL, 3.0 mmol) in Et2O (22
mL) while stirring at -78 °C. After 20 min, B(O-i-Pr)3 (0.92 mL,
4.0 mmol) was added, and the reaction was allowed to stir for 5
min at -78 °C before dropwise addition of 1 (382 mg, 2.0 mmol)
in Et2O (1.5 mL). The reaction was allowed to stir at -78 °C for
3.5 h, after which time the cooling bath was removed. After 15
min, glacial acetic acid (0.18 mL) was slowly added. 2,2-
Dimethyl-1,3-propanediol (312 mg, 3.0 mmol) was added with
stirring at rt. After 2.5 h,CH2Cl2 was added, and the resulting
organic phase was washed with saturated NH4Cl(aq), saturated
NaHCO3(aq), and H2O. Drying (Na2SO4) of the organic phase and
evaporation of the solvent afforded crude 3 (540 mg, 1.78 mmol,
89%): 1H NMR δ 7.50-7.32 (m, 5H), 6.90 (s, 1H), 5.41 (s, 2H),
3.76 (s, 4H), 1.03 (s, 6H); 13C NMR δ 170.1, 148.8, 136.7, 128.5,
128.0, 117.8, 112.0, 72.4, 70.6, 32.0, 21.8. An analytical sample
was recrystallized from Et2O and petroleum (clear colorless
crystals, mp 82-83 °C). Anal. Calcd for C15H18BNO3S: C, 59.42;
H, 5.98; N, 4.62. Found: C, 59.47; H, 6.12; N, 4.58.
Gen er a l P r oced u r e for Su zu k i Cr oss-Cou p lin g Rea c-
tion s Usin g 2 a s Electr op h ile. 3-Ben zyloxyisoth ia zoles 4a -
d ,f,g. PdCl2(PPh3)2 (35 mg, 0.05 mmol) was added to a solution
of 2 (314 mg, 0.99 mmol) in DME (34 mL), and the reaction was
stirred at rt for 15 min. NEt3 (5.5 mL), the appropriate
nucleophile (1.28 mmol), and H2O (34 mL) were added. Stirring
was continued at 50 °C until 2 disappeared. H2O was added,
and the mixture was extracted with Et2O. The combined organic
phases were washed with H2O, 2 M NaOH(aq), and H2O and then
dried (Na2SO4) and evaporated to afford crude 4.
3-Ben zyloxy-5-p h en ylisoth ia zole (4a ). The reaction was
carried out as described in the general procedure using phenyl-
boronic acid as nucleophile. The reaction was complete in 2 h.
CC (toluene/petroleum 1:1) afforded 4a as an oil, which crystal-
lized upon standing to yield 4a as clear colorless crystals (82%,
mp 34-35 °C): 1H NMR δ 7.57-7.32 (m, 10H), 6.82 (s, 1H) 5.43
(s, 2H); 13C NMR δ 169.1, 167.3, 136.7, 131.2, 129.9, 129.3, 128.7,
128.4, 128.3, 126.3, 108.2, 70.3. Anal. Calcd for C16H13NOS: C,
71.88; H, 4.90; N, 5.24. Found: C, 71.67; H, 4.97; N, 5.21.
3-Ben zyloxy-5-(2-th ien yl)isoth ia zole (4b). The reaction
was carried out as described in the general procedure using
2-thienylboronic acid as nucleophile. The reaction was complete
in 1 h. FC (toluene/petroleum 1:1) afforded 4b as an oil (88%):
1H NMR δ 7.47-7.33 (m, 6H), 7.25 (d, 1H, J ) 3.5 Hz), 7.05
(dd, 1H, J ) 5.2, 3.5 Hz), 6.69 (s, 1H), 5.41 (s, 2H); 13C NMR δ
168.6, 159.6, 136.6, 133.1, 128.7, 128.31, 128.25, 128.23, 127.2,
126.3, 108.5, 70.4; HRMS calcd for C14H11NOS2 273.0282, found
273.0283 (+0.04 ppm). Anal. Calcd for C14H11NOS2: C, 61.51;
H, 4.06; N, 5.12. Found: C, 62.56; H, 4.18; N, 4.98.
isolated yield (%)
product
R
Suzuki
Negishi
4a
4b
4c
4d
4e
4f
phenyl
82
88
86
71
np
94
69
95
63
npa
np
48
np
np
2-thienyl
3-thienyl
2-furyl
2-pyridyl
3-pyridyl
4-pyridyl
4g
a
np: not performed.
temperature for 15 min, after which time the nucleophile,
NEt3, and H2O were added, and the reaction was heated
to 50 °C until disappearance of 2 as monitored by TLC.
Using this procedure, it was possible to introduce π-elec-
tron rich as well as π-electron deficient substituents 4a -
d ,f,g (Table 1). The isolated yields were good to excellent
(69-94%), and hardly any homocouplings were observed.
The reaction was quite robust, being neither water nor
air sensitive except in a few cases in which the nucleo-
philes used were air sensitive.
A general drawback of the Suzuki cross-coupling
reactions is the limited access of boronic acids or boronic
esters of aromatic and heteroaromatic compounds. Thus,
3-benzyloxy-5-(2-pyridyl)isothiazole 4e was not synthe-
sized using the above-mentioned Suzuki reaction as no
2-substituted boron derivative of pyridine is commercially
available. Instead, a Negishi-type reaction based on 2 as
electrophilic reagent was examined (Scheme 1). In ad-
dition to 2-iodopyridine, iodobenzene and 2-bromo-
thiophene were investigated in this Negishi cross-
coupling reaction, representing π-deficient, “π-neutral”,
and π-excessive nucleophiles, respectively. A number of
methods for creating the nucleophilic reagent were
investigated, including lithiation followed by transmeta-
lation to Zn,15 oxidative insertion of previously activated
Zn,17 or transmetalation from the Grignard reagent.18
Best results were obtained when the nucleophiles were
generated using insertion of magnesium followed by
transmetalation to Zn, after which time PdCl2(PPh3)2,
PPh3, and 2 in THF solution were added, and the reaction
was heated to 75 °C overnight. The conversion rates were
good to excellent, affording the desired products 4a ,b,e
in 48-95% yields (Table 1).
In conclusion, we have developed two methods for
direct and convergent introduction of aromatic and
heteroaromatic substituents into the 5-position of 3-ben-
zyloxyisothiazole (1). The reactions studied are work-
efficient, and the isolated yields are good to excellent. The
two methods are complementary to one another as a wide
range of functional groups are tolerated in Suzuki cross-
coupling reactions, whereas a large number of com-
mercially available halogen substituted aromatic and
heteroaromatic compounds are known as possible reac-
tants in the Negishi cross-coupling reactions.
3-Ben zyloxy-5-(3-th ien yl)isoth ia zole (4c). The reaction
was carried out as described in the general procedure using
3-thienylboronic acid as nucleophile. The reaction was complete
in 1.5 h. FC (toluene/petroleum 1:1) afforded 4c as an oil (86%):
1H NMR δ 7.48 (dd, 1H, J ) 2.7, 1.1 Hz), 7.46-7.31 (m, 6H),
7.22 (dd, 1H, J ) 5.0, 1.1 Hz), 6.69 (s, 1H), 5.40 (s, 2H); 13C NMR
δ 168.9, 161.3, 136.6, 132.1, 128.7, 128.3, 128.3, 127.2, 126.0,
J . Org. Chem, Vol. 69, No. 4, 2004 1403

123.0, 108.2, 70.4; HRMS calcd for C14H11NOS2 273.0282, found
273.0271 (-3.9 ppm). Anal. Calcd for C14H11NOS2: C, 61.51; H,
4.06; N, 5.12. Found: C, 62.17; H, 4.05; N, 4.98.
(2) Negish i Cr oss-Cou p lin g Rea ction . A solution of 2 (168
mg, 0.53 mmol) in THF (1 mL), PdCl2(PPh3)2 (18 mg, 0.026
mmol), and PPh3 (21 mg, 0.079 mmol) was added to the solution
containing the nucleophile, and the mixture was heated to 75
°C for 15 h. H2O was added, and the resulting mixture was
extracted with CH2Cl2. Drying of the organic phases (Na2SO4)
and evaporation gave crude 4.
3-Ben zyloxy-5-p h en ylisoth ia zole (4a ). The reaction was
carried out as described in the general procedure. However, a
solution of PhMgCl (0.37 mL, 1.66 M in THF, 0.59 mmol) diluted
with THF (1.5 mL) was used in the transmetalation reaction.
CC (toluene/petroleum 1:1) afforded 4a as a clear oil (95%),
which crystallized upon standing. 1H, 13C, and mp were identical
to 4a isolated by Suzuki cross-coupling.
3-Ben zyloxy-5-(2-th ien yl)isoth ia zole (4b). The reaction
was carried out as described in the general procedure. The
nucleophile was generated using 2-bromothiophene. FC (toluene/
petroleum 1:1) afforded 4b (63%) with data identical to 4b
isolated by Suzuki cross-coupling.
3-Ben zyloxy-5-(2-p yr id yl)isoth ia zole (4e). The reaction
was carried out as described in the general procedure. The
nucleophile was generated using 2-iodopyridine. CC (toluene/
EtOAc 1:1) afforded 4e as an oil (48%): 1H NMR δ 8.54 (bd, 1H,
J ) 4.7 Hz), 7.73-7.12 (m, 8H), 6.94 (s, 1H), 5.37 (s, 2H); 13C
NMR δ 167.3, 150.0, 137.2, 136.6, 132.4, 128.7, 128.5, 128.31,
128.26, 124.2, 119.6, 108.5, 70.4; HRMS calcd for C14H11N2OS
268.0670, found 268.0677 (+2.3 ppm).
3-Ben zyloxy-5-(2-fu r yl)isoth ia zole (4d ). The reaction was
carried out as described in the general procedure using 2-furyl-
boronic acid as nucleophile. The reaction was complete in 15 h.
FC (toluene/petroleum 1:1) afforded 4d as a yellow oil (71%):
1H NMR δ 7.48-7.34 (m, 6H), 6.75 (s, 1H), 6.67 (d, 1H, J ) 3.5
Hz), 6.50 (dd, 1H, J ) 3.5, 1.8 Hz), 5.41 (s, 2H); 13C NMR δ 168.3,
155.2, 145.9, 143.1, 136.2, 128.3, 128.0, 127.9, 111.8, 108.5, 106.4,
70.2; HRMS calcd for C14H11NO2S 257.0510, found 257.0527
(+6.6 ppm).
3-Ben zyloxy-5-(3-p yr id yl)isoth ia zole (4f). The reaction
was carried out as described in the general procedure using
3-([1,3,2]-2-dioxaborianyl)pyridine as nucleophile. The reaction
was complete in 1.5 h. CC (toluene/EtOAc 1:1) afforded 4f as a
brown oil that crystallized to light brown crystals upon standing
(94%): 1H NMR δ 8.83 (d, 1H, J ) 1.8 Hz), 8.65 (dd, 1H, J )
5.3, 1.8 Hz), 7.83 (td, 1H, J ) 8.2, 1.8 Hz), 7.50-7.35 (m, 6H),
6.87 (s, 1H), 5.44 (s, 2H); 13C NMR δ 169.1, 163.3, 150.7, 147.1,
136.4, 133.5, 128.7, 128.4, 128.3, 127.4, 123.0, 109.3, 70.6; HRMS
calcd for C14H11N2OS 268.0670, found 268.0665 (-1.9 ppm). An
analytical sample was recrystallized from Et2O and petroleum
(mp 59-60 °C).
3-Ben zyloxy-5-(4-p yr id yl)isoth ia zole (4g). The reaction
was carried out as described in the general procedure using
4-pyridylboronic acid as nucleophile. The reaction was complete
in 2 h. CC (toluene/EtOAc 1:1) afforded 4g as an oil that
crystallized to light brown crystals upon standing (69%, mp 60-
61 °C): 1H NMR δ 8.70 (dd, 2H, J ) 4.7, 1.8 Hz), 7.49-7.35 (m,
7H), 6.95 (s, 1H), 5.44 (s, 2H); 13C NMR δ 169.1, 164.0, 150.9,
138.2, 136.3, 128.7, 128.4, 128.3, 120.4, 110.0, 70.7; HRMS calcd
for C14H11N2OS 268.0670, found 268.0676 (+2.2 ppm). Anal.
Calcd for C15H12N2OS: C, 67.14; H, 4.51; N, 10.44. Found: C,
66.98; H, 4.53; N, 10.13.
Gen er a l P r oced u r e for Negish i Cr oss-Cou p lin g Rea c-
tion s Usin g 2 a s Electr op h ile. 3-Ben zyloxyisoth ia zoles
4a ,b,e. (1) Gen er a tion of th e Nu cleop h ile. The aromatic or
heteroaromatic halide (0.59 mmol) was added to a suspension
of Mg (16 mg, 0.66 mmol) in THF (0.25 mL), and the reaction
was heated to 50 °C for 1 h. The reaction was cooled to 0 °C,
ZnCl2 (90 mg, 0.66 mmol) was added, and the mixture was
stirred at rt for 1 h.
Ack n ow led gm en t. We gratefully acknowledge the
Mass Spectrometry Research Unit, University of Copen-
hagen, Denmark, for perfoming HRMS and the Analyti-
cal Research Department, H. Lundbeck A/S, Denmark,
as well as the Department of Elemental Analysis,
University of Copenhagen, Denmark, for perfoming
elemental analyses.
Su p p or tin g In for m a tion Ava ila ble: Procedures for the
1
attempted cross-coupling reactions. H and 13C NMR spectra
for all new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
J O035578G
1404 J . Org. Chem., Vol. 69, No. 4, 2004