Aryl triflates: Useful coupling partners for the direct arylation of heteroaryl derivatives via Pd-catalyzed C-H activation-functionalization

Article abstract of DOI:10.1039/b715235c

Aryl triflates were found to be suitable partners for the palladium catalyzed direct arylation of heteroaromatics via C-H activation- functionalization. The reaction conditions and the catalyst have a determining influence on the yields. The system combining PPh₃ and Pd(OAc) ₂ using KOAc as base and DMF as solvent promotes the selective 2- or 5-arylations in moderate to high yields. Several heteroaromatics such as furan, thiophene, thiazole or oxazole derivatives have been employed successfully. The electronic properties of the aryl triflates also have a decisive influence on the yields of the coupling products. Electron-rich aryl triflates gave satisfactory results, whereas the electron-poor ones led to the formation of phenols. The Royal Society of Chemistry 2008.

Full text of DOI:10.1039/b715235c

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Aryl triflates: useful coupling partners for the direct arylation of heteroaryl
derivatives via Pd-catalyzed C–H activation–functionalization†
Julien Roger and Henri Doucet*
Received 3rd October 2007, Accepted 31st October 2007
First published as an Advance Article on the web 21st November 2007
DOI: 10.1039/b715235c
Aryl triflates were found to be suitable partners for the palladium catalyzed direct arylation of
heteroaromatics via C–H activation–functionalization. The reaction conditions and the catalyst have a
determining influence on the yields. The system combining PPh3 and Pd(OAc)2 using KOAc as base
and DMF as solvent promotes the selective 2- or 5-arylations in moderate to high yields. Several
heteroaromatics such as furan, thiophene, thiazole or oxazole derivatives have been employed
successfully. The electronic properties of the aryl triflates also have a decisive influence on the yields of
the coupling products. Electron-rich aryl triflates gave satisfactory results, whereas the electron-poor
ones led to the formation of phenols.
To our knowledge, very few examples of couplings of het-
eroaromatics with aryl triflates have been reported so far. This
reaction was described in 1995 by Proudfoot et al. using Pd(PPh3)4
Introduction
Heterobiaryls are important building blocks in organic synthesis
as catalyst.14a The coupling reaction of a functionalized aryl
triflate with oxazole gave the 5-arylated oxazole in 34% yield. A
few years later, Miura and co-workers reported the 3-arylation
of 2-thiophene carboxamide with phenyl triflate in 71% yield
using P(o-biphenyl)(t-Bu)2–Pd(OAc)2 as catalyst and Cs2CO3 as
base.14b The 5-arylation of 4-methylthiazole using phenyl triflate
in the presence of Pd(OAc)2 has also been described.14c Finally, an
intramolecular version of this reaction has been reported.15
Although a few examples of Pd catalyzed arylation of het-
eroaromatics using aryl triflates in moderate to high yields have
been described, to the best of our knowledge, the influence of
the reaction conditions, palladium source and ligand and also the
effect of the nature of the heteroaromatic derivative and of the
substituents on aryl triflates have not been reported. Therefore,
the discovery of an effective and selective procedure allowing high
yields of arylation products for the coupling of a variety of these
challenging substrates is still subject to significant improvement.
due to their biological properties. The coupling reaction of aryl
triflates with heteroaryl halides provides an efficient method for the
preparation of these compounds.1 One of the classical methods to
perform this coupling reaction is to employ an aryl triflate with an
organometallic heteroaryl derivative using a palladium catalyst
(Scheme 1). However, these reactions require the preparation
4–6
of organometallic derivatives such as ArZnX,2,3 ArSnR3 or
7–9
ArB(OR)2 and provide either an organometallic or a salt (MX)
as by-product.
Scheme 1
Since the discovery by Ohta and co-workers of the direct
coupling of aryl halides with heteroaryl derivatives via a C–H bond
activation,10 very exciting results for the coupling of a variety of
heteroaryl derivatives with aryl iodides, bromides and even chlo-
rides have beenreported byseveralgroups.11 Onthe other hand, the
direct coupling of aromatics12,13 and especially heteroaromatics14,15
with aryl triflates via C–H activation–functionalization has at-
tracted less attention. Such coupling reactions would provide an
attractive procedure for the preparation of these compounds due
to the very wide availability, low cost and protection ability of
phenols and also to the common use of protected phenols in total
synthesis. Moreover, the phenolic group can be used as a means to
introduce the desired functionality in the aromatic ring and then
be converted into a carbon–carbon bond via the corresponding
triflate.
Results and discussion
Our first goal was to determine the most suitable reaction
conditions for the coupling of phenyl triflate with 2-n-butylfuran
(Scheme 3, Table 1). We observed that the reaction conditions
and nature of the catalyst have a determining influence on the
selectivity of the reaction and yield of 5-phenyl-2-n-butylfuran 1.
In the course of this reaction, the formation of three products
was observed: phenol, biphenyl and 5-phenyl-2-n-butylfuran 1.
The polarity of the solvent has a decisive influence on the yields.
The relatively non-polar solvent ethylbenzene gave no coupling
product, whereas NMP or DMF led to complete conversion of
phenyl triflate with high selectivities in favor of the formation of 1
(Table 1 entries 1–3). On the other hand, DMAc or 2-methoxyethyl
ether led to 1 in low conversions and low to moderate selectivities
(Table 1, entries 4 and 5). Then, we examined the influence of
the base for this reaction. K2CO3 or Cs2CO3 led to the formation
of phenol in 83 and 76% selectivities (Table 1, entries 7 and 8).
Institut Sciences Chimiques de Rennes, UMR 6226 CNRS-Universite´ de
Rennes “Catalyse et Organometalliques”, Campus de Beaulieu, 35042,
Rennes, France. E-mail: henri.doucet@univ-rennes1.fr; Fax: +33-(0)2-23-
23-69-39; Tel: +33-(0)2-23-23-63-84
† Electronic supplementary information (ESI) available: Further experi-
mental data. See DOI: 10.1039/b715235c
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Table 1 Palladium-catalyzed reaction of phenyl triflate with 2-n-butylfuran (Scheme 3)
Ratio phenol :
biphenyl : 1
Conversion of
2-nbutylfuran
Isolated yield
of 1 (%)
Entry
Catalyst
Solvent
Base
Temp./◦C
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
Pd(OAc)2–PPh3
Pd(OAc)2–PPh3
Pd(OAc)2–PPh3
Pd(OAc)2–PPh3
Pd(OAc)2–PPh3
Pd(OAc)2–PPh3
Pd(OAc)2–PPh3
Pd(OAc)2–PPh3
Pd(OAc)2–PPh3
Pd(OAc)2–PPh3
Pd(OAc)2
Pd(OAc)2–P(oTol)3
Pd(OAc)2–P(2-furyl)3
Pd(OAc)2–DPPM
Pd(OAc)2–DPPE
Pd(OAc)2–DPPB
[PdCl(C3H5)]2–PPh3
[PdCl(C3H5)]2–DPPE
PdCl(C3H5)DPPB16
Ethylbenzene
NMP
DMF
DMAc
2-Methoxyethyl ether
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
KOAc
KOAc
KOAc
KOAc
KOAc
NaOAc
K2CO3
Cs2CO3
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
150
150
150
150
150
150
150
150
120
100
150
150
150
150
150
150
150
150
150
—
0
100
100
43
49
43
100
100
85
18
56
98
98
99
100
29
100
100
43
7 : 11 : 82
6 : 4 : 90
25 : 12 : 6
0 : 11 : 38
25 : 13 : 5
83 : 14 : 3
76 : 12 : 12
5 : 5 : 75
3 : 3 : 12
37 : 17 : 2
94 : 0 : 4
96 : 0 : 2
92 : 5 : 2
8 : 5 : 87
25 : 2 : 2
2 : 13 : 85
8 : 20 : 72
25 : 12 : 6
51
27
22
19
28
DMF
Conditions: catalyst: Pd(OAc)2 or PdCl(C3H5)DPPB 0.05 mmol or [PdCl(C3H5)]2 0.025 mmol, PPh3, P(oTol)3 or P(2-furyl)3: 0.1 mmol, DPPM, DPPE
or DPPB: 0.05 mmol, aryl bromide: 1 mmol, 2-nbutylfuran: 2 mmol, base: 2 mmol, 20 h, ratio phenol : biphenyl : 1 determined by GC and NMR,
conversion of the phenyl triflate into phenol, biphenyl and 1.
With these bases, the expected product 1 was obtained only in
trace amounts. The most suitable base appears to be KOAc with
a selectivity of 90% in 1, whereas NaOAc which is less soluble
in DMF gave 1 only as traces (Table 1, entries 3 and 6). The
influence of the base might be explained by the abstraction of
triflate from the arylpalladium triflate intermediate in the presence
of potassium acetate to form an arylpalladium acetate (Scheme 2).
This complex would be more reactive in the subsequent steps of
the catalytic cycle.
effective catalyst for this arylation reaction and gave a high
selectivity in favor of 1, whereas the two other phosphines led
almost exclusively to the formation of phenol (Table 1, entries 3,
12 and 13). This is probably due to the steric and electronic
properties of these ligands which could led to a slower oxidative
addition of the aryl triflate to palladium. P(2-furyl)3 possess
a weaker r-donicity compared to PPh3 and P(o-Tol)3 is more
congested. The use of the bidentate ligands DPPM or DPPB did
not lead to better results with, again, a predominant formation
of phenol (Table 1, entries 14 and 16). On the other hand, DPPE
associated to Pd(OAc)2 gave a high selectivity in favor of 1, but a
low isolated yield (Table 1, entry 15). The palladium source has
also an influence on the selectivity and the yield of the reaction.
Although relatively high selectivities in favor of the formation of 1
were observed using [PdCl(C3H5)]2 associated to PPh3 or DPPE,
relatively low isolated yields were obtained (Table 1, entries 17–19).
The direct arylation of 2-n-butylfuran using aryl triflates
appears to be much more sensitive to the reaction conditions and
catalyst precursor than using aryl bromides.11f This could be the
result both of a lower stability of aryl triflates in the reaction
conditions (formation of phenol) and also of a lower reactivity or
stability of the ArPd+ OTf− intermediates.
Scheme 2
Several mechanisms have been suggested for the C–H
activation–functionalization of heteroarenes.11b With furans, thio-
phenes or thiazoles we believe that the reaction might proceed via
a classical oxidative addition of the aryl triflate to a palladium(0)
complex followed by a Heck type insertion of the heteroaromatic
derivative. On this intermediate the Pd on carbon 4 and the H
on carbon 5 of furan, thiophene or thiazole are anti. As anti b-
eliminations are unfavored, we assume that a base-assisted elimi-
nation of the proton on carbon 5 followed by an aromatization and
elimination of Pd occurs. Then, a reductive elimination assisted by
the base regenerates the Pd(0). In the presence of benzoxazole, an
electrophilic aromatic substitution type mechanism seems more
likely.
Scheme 3
Then, we examined the influence of the catalyst precursor on
this reaction using several mono- or diphosphine ligands. Initially
we performed the reaction with Pd(OAc)2 without added ligand,
but the reaction gave a very low yield of 1: 2% (Table 1, entry 11).
Three monophosphines were employed, PPh3, P(o-Tol)3 and P(2-
furyl)3. The system combining Pd(OAc)2 and PPh3 is a particularly
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Then, we tried to evaluate the scope and limitations of this
procedure using several heteroaryl derivatives and aryl triflates
(Scheme 4). A survey of these couplings is provided in Table 2.
A variety of heteroarenes are tolerated. Using the substituted
furan derivative 2-furylacetone with phenyl triflate, the coupling
product 2 was obtained in a modest 28% yield (Table 2, en-
try 1). Thiophenes are suitable reactants for such couplings. 2-n-
Butylthiophene or thiophene 2-carbonitrile gave the 5-phenylated
thiophenes 3 and 4 in 69 and 64% yields (Table 2, entries 2 and 3).
Then, we examined the reactivity of two thiazole derivatives. Us-
ing 2-n-propylthiazole or 2-ethyl-4-methylthiazole, the 5-arylated
products 5 and 6 were obtained in 78 and 37% yields, respectively
(Table 2, entries 4 and 5). In the presence of benzoxazole, slightly
different reaction conditions had to be employed in order to obtain
a high yield of coupling product. With this substrate, the reaction
performed with KOAc as base led to a low yield of 7, whereas the
use of the more soluble base Cs2CO3 led to 7 in a very high yield
of 81% (Table 2, entry 6). The presence of this base might favor a
deprotonation of benzoxazole.
determining influence on the reaction selectivities and yields. If
the electron-donating substituents support the reactions, on the
other hand, electron-withdrawing substituents are unfavorable. A
wide range of heteroaromatics such as furan, thiophene, thiazole
or oxazole derivatives have been successfully employed. Moreover,
this procedure is very simple, economically attractive due to the
easy access to several heteroaromatics and phenols, and employs
commercially available ligand and catalyst precursors.
Experimental
General
All reactions were run under argon using vacuum lines and
oven-dried Schlenk tubes. Commercial heteroarenes and phenyl
triflate were employed. The other aryl triflates were prepared
by stirring of the phenol derivative (1 eq.) and triflic anhydride
(1 eq.) in dry dichloromethane at 0 ◦C during 3 hours followed by
hydrolysis, extraction with dichloromethane, separation, drying
and purification on silica gel. The reactions were followed by GC.
1H (200 or 300 MHz), 13C (50 MHz) spectra were recorded for
CDCl3 solutions. Chemical shift (d) are reported in ppm relative
to CDCl3 (1H: 7.25 and 13C: 77.0). Flash chromatography was
performed on silica gel (230–400 mesh).
Representative procedure for palladium-catalysed couplings of
heteroaryls with aryl triflates
Scheme 4
The aryl triflate (1 mmol), heteroaryl derivative (2 mmol), KOAc
(0.196 mg, 2 mmol) (Cs2CO3, 0.651 mg, 2 mmol, instead of
KOAc for the reactions with benzoxazole), Pd(OAc)2 (0.011 mg,
0.05 mmol) and PPh3 (0.026 mg, 0.1 mmol) were dissolved in
DMF (3 mL) under an argon atmosphere. The reaction mixture
was stirred at 150 ◦C for 20 h. The solution was diluted with H2O
(10 mL) (KOH–H2O solution for the reactions with benzoxazole),
then the product was extracted with CH2Cl2. The combined
organic layer was dried over MgSO4 and the solvent was removed
in vacuo. The crude product was purified by silica gel column
chromatography.
Although several heteroaromatics are tolerated and gave the
biaryls in moderate to high yields, the influence of the substituents
on the aryl triflate is more important. First, we studied the
reactivity of electron-deficient aryl triflates such as 4-nitrophenyl
triflate or 4-benzoylphenyl triflate. However, with these sub-
strates, the expected coupling products were not observed, and a
complete conversion of the aryl triflates into the corresponding
phenols was observed (Table 2, entries 15 and 16). On the
other hand, using 2-naphthyl triflate or the electron-rich 4-
methoxyphenyl-, 3,5-dimethoxyphenyl-, 4-tert-butylphenyl- and
3-N,N-dimethylaminophenyl triflates, the expected coupling prod-
ucts 8–16 were obtained in good yields (Table 2, entries 7–15). For
example, the reaction of 2-naphthyl triflate with 2-n-butylfuran,
2-n-propylthiazole or benzoxazole gave the arylated products
in 53–86% yields. It should be noted that, for these reactions,
the phenylated products 1, 4, 5 and 7 were also observed as
side-products. The formation of these products comes from the
cleavage of the P–Ph bond of triphenylphosphine assisted by the
Pd complex. Such behaviour is already known in other organic
reactions where the catalytic system comprises palladium and
phosphine ligands.17
2-n-Butyl-5-phenylfuran (1)11f
This compound was prepared according to the representative
procedure with phenyl triflate (0.226 g, 1 mmol), 2-n-butylfuran
(0.248 g, 2 mmol) and the Pd complex (0.05 mmol) in 102 mg, 51%
yield as an oil.
1-(5-Phenylfuran-2-yl)-propan-2-one (2)18
This compound was prepared according to the representative
procedure with phenyl triflate (0.226 g, 1 mmol), 2-furylacetone
(0.248 g, 2 mmol) and the Pd complex (0.05 mmol) in 56 mg, 28%
yield as an oil.
Conclusion
In conclusion, electron-rich aryl triflates are useful reactants in
palladium-catalyzed direct arylation of heteroaromatics. However,
the reaction is extremely sensitive to the reaction conditions,
catalyst precursor and ligand. The best catalytic system appears
to be Pd(OAc)2–PPh3 with KOAc as base in most cases and DMF
as solvent. The electronic properties of the aryl triflate have a
2-n-Butyl-5-phenylthiophene (3)
This compound was prepared according to the representative pro-
cedure with phenyl triflate (0.226 g, 1 mmol), 2-n-butylthiophene
(0.280 g, 2 mmol) and the Pd complex (0.05 mmol) in 149 mg, 69%
yield as an oil.
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Table 2 Palladium-catalyzed reaction of aryl triflates with heteroarenes (Scheme 4)
Entry
1
Aryl triflate
Heteroarene
Product
Yield (%)
28
Phenyl triflate
2-Furylacetone
2
3
4
Phenyl triflate
Phenyl triflate
Phenyl triflate
2-n-Butylthiophene
Thiophene 2-carbonitrile
2-n-Propylthiazole
69
64
78
5
6
Phenyl triflate
Phenyl triflate
2-Ethyl-4-methylthiazole
Benzoxazole
37
81a
7
8
2-Naphthyl triflate
2-Naphthyl triflate
2-n-Butylfuran
53
62
2-n-Propylthiazole
9
2-Naphthyl triflate
Benzoxazole
Benzoxazole
86a
78a
10
4-Methoxyphenyl triflate
11
12
3-N,N-Dimethylaminophenyl triflate
3-N,N-Dimethylaminophenyl triflate
2-n-Propylthiazole
69
Benzoxazole
57a
13
4-tert-Butylphenyl triflate
2-n-Propylthiazole
58
14
15
4-tert-Butylphenyl triflate
Thiophene 2-carbonitrile
64
61
3,5-Dimethoxyphenyl triflate
2-n-Propylthiazole
16
17
4-Nitrophenyl triflate
4-Benzoylphenyl triflate
Benzoxazole
Benzoxazole
—
—
0a
0a
Conditions: Pd(OAc)2: 0.05 mmol, PPh3: 0.1 mmol, aryl triflate: 1 mmol, heteroarene: 2 mmol, KOAc: 2 mmol, DMF, 20 h, 150 ◦C, isolated yields.a Cs2CO3:
2 mmol instead of KOAc as base.
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1H (200 MHz) NMR spectra: d = 0.99 (t, J = 7.5 Hz, 3 H), 1.48
(sext., J = 7.5 Hz, 2 H), 1.73 (quint., J = 7.5 Hz, 2 H), 2.86 (t, J =
7.5 Hz, 2 H), 6.79 (d, J = 3.6 Hz, 1 H), 7.17 (d, J = 3.6 Hz, 1 H),
7.30 (t, J = 7.5 Hz, 1 H), 7.42 (t, J = 7.5 Hz, 2 H), 7.71 (d, J =
8.5 Hz, 2 H).
13C (50 MHz) NMR spectra: d = 14.4, 22.9, 30.7, 32.5, 107.0,
107.6, 121.8, 122.7, 126.9, 127.9, 128.3, 128.6, 129.1, 129.4, 132.8,
133.0, 134.2, 147.3.
Anal. Calcd. for C18H18O: C, 86.36; H, 7.25. Found: C, 86.54;
H, 7.41%.
13C (50 MHz) NMR spectra: d = 13.8, 22.2, 29.9, 33.7, 122.6,
125.0, 125.5, 126.9, 128.8, 134.8, 141.6, 145.7.
Anal. Calcd. for C14H16S: C, 77.72; H, 7.45. Found: C, 77.81; H,
7.19%.
4-Naphthalen-2-yl-2-n-propylthiazole (9)
This compound was prepared according to the representative
procedure with 2-naphthyl triflate (0.276 g, 1 mmol), 2-n-
propylthiazole (0.254 g, 2 mmol) and the Pd complex (0.05 mmol)
in 157 mg, 62% yield as an oil.
5-Phenylthiophene-2-carbonitrile (4)19
This compound was prepared according to the representative
procedure with phenyl triflate (0.226 g, 1 mmol), thiophene-2-
carbonitrile (0.218 g, 2 mmol) and the Pd complex (0.05 mmol) in
119 mg, 64% yield as a white solid.
1H (200 MHz) NMR spectra: d = 1.09 (t, J = 7.5 Hz, 3 H), 1.90
(sext., J = 7.5 Hz, 2 H), 3.04 (t, J = 7.5 Hz, 2 H), 7.28 (m, 2 H),
7.52 (d, J = 7.5 Hz, 1 H), 7.70–7.88 (m, 3 H), 7.98 (s, 2 H).
13C (50 MHz) NMR spectra: d = 14.1, 23.8, 36.0, 123.1, 124.9,
125.7, 126.7, 127.2, 128.2, 129.2, 130.8, 133.3, 134.0, 138.3, 148.3,
171.3.
5-Phenyl-2-n-propylthiazole (5)
Anal. Calcd. for C16H15NS: C, 75.85; H, 5.97. Found: C, 75.70;
H, 6.09%.
This compound was prepared according to the representative pro-
cedure with phenyl triflate (0.226 g, 1 mmol), 2-n-propylthiazole
(0.254 g, 2 mmol) and the Pd complex (0.05 mmol) in 159 mg, 78%
yield as an oil.
2-Naphthalen-2-yl-benzoxazole (10)21
1H (200 MHz) NMR spectra: d = 1.06 (t, J = 7.5 Hz, 3 H), 1.88
(sext., J = 7.5 Hz, 2 H), 3.01 (t, J = 7.5 Hz, 2 H), 7.20–7.40 (m,
3 H), 7.47 (d, J = 7.8 Hz, 2 H), 7.80 (s, 1 H).
This compound was prepared according to the representative
procedure with 2-naphthyl triflate (0.276 g, 1 mmol), benzoxazole
(0.238 g, 2 mmol) and the Pd complex (0.05 mmol) in 211 mg, 86%
yield as an oil.
13C (50 MHz) NMR spectra: d = 14.0, 23.7, 35.9, 132.8, 147.3,
126.9, 128.3, 129.6, 132.0, 170.8.
2-(4-Methoxyphenyl)benzoxazole (11)22
Anal. Calcd. for C12H13NS: C, 70.89; H, 6.45. Found: C, 71.04;
H, 6.49%.
This compound was prepared according to the representative
procedure with 4-methoxyphenyl triflate (0.254 g, 1 mmol),
benzoxazole (0.238 g, 2 mmol) and the Pd complex (0.05 mmol)
in 176 mg, 78% yield as a white solid.
2-Ethyl-4-methyl-5-phenylthiazole (6)
This compound was prepared according to the representative
procedure with phenyl triflate (0.226 g, 1 mmol), 2-ethyl-4-
methylthiazole (0.254 g, 2 mmol) and the Pd complex (0.05 mmol)
in 75 mg, 37% yield as an oil.
1H (200 MHz) NMR spectra: d = 1.42 (t, J = 7.5 Hz, 3 H), 2.49
(s, 3 H), 3.02 (q, J = 7.5 Hz, 2 H), 7.34–7.44 (m, 5 H).
13C (50 MHz) NMR spectra: d = 14.7, 16.5, 27.3, 127.9, 129.0,
129.6, 129.9, 132.8, 147.3, 170.7.
5-(3-N,N-Dimethylaminophenyl)-2-n-propylthiazole (12)
This compound was prepared according to the representative
procedure with 3-N,N-dimethylaminophenyl triflate (0.269 g,
1 mmol), 2-n-propylthiazole (0.254 g, 2 mmol) and the Pd complex
(0.05 mmol) in 170 mg, 69% yield as an oil.
1H (200 MHz) NMR spectra: d = 1.03 (t, J = 7.6 Hz, 3 H), 1.94
(sext., J = 7.6 Hz, 2 H), 2.95 (t, J = 7.6 Hz, 2 H), 2.96 (s, 6 H),
6.71 (dd, J = 8.0, 2.3 Hz, 1 H), 6.86 (s, 1 H), 6.91 (d, J = 7.7 Hz,
1 H), 7.26 (t, J = 8.0 Hz, 1 H), 7.83 (s, 1 H).
Anal. Calcd. for C12H13NS: C, 70.89; H, 6.45. Found: C, 70.71;
H, 6.58%.
2-Phenylbenzoxazole (7)20
13C (50 MHz) NMR spectra: d = 14.2, 23.8, 36.0, 41.0, 110.9,
112.7, 115.5, 130.1, 132.7, 137.7, 139.8, 151.3, 170.7.
Anal. Calcd. for C14H18N2S: C, 68.25; H, 7.36. Found: C, 68.41;
H, 7.44%.
This compound was prepared according to the representative
procedure with phenyl triflate (0.226 g, 1 mmol), benzoxazole
(0.238 g, 2 mmol) and the Pd complex (0.05 mmol) in 158 mg,
81% yield as a white solid.
[3-(Benzoxazol-2-yl)phenyl]dimethylamine (13)
2-n-Butyl-5-naphthalen-2-yl-furan (8)
This compound was prepared according to the representative
procedure with 3-N,N-dimethylaminophenyl triflate (0.269 g,
1 mmol), benzoxazole (0.238 g, 2 mmol) and the Pd complex
(0.05 mmol) in 136 mg, 57% yield as an oil.
This compound was prepared according to the representative pro-
cedure with 2-naphthyl triflate (0.276 g, 1 mmol), 2-n-butylfuran
(0.248 g, 2 mmol) and the Pd complex (0.05 mmol) in 133 mg, 53%
yield as an oil.
1H (200 MHz) NMR spectra: d = 0.96 (t, J = 7.5 Hz, 3 H), 1.29
(sext., J = 7.5 Hz, 2 H), 1.64 (quint., J = 7.5 Hz, 2 H), 2.74 (t, J =
7.5 Hz, 2 H), 6.14 (d, J = 3.0 Hz, 1 H), 6.70 (d, J = 3.0 Hz, 1 H),
7.28–7.90 (m, 6 H), 8.08 (s, 1 H).
1H (200 MHz) NMR spectra: d = 3.08 (s, 6 H), 6.88 (dd, J =
8.0, 2.3 Hz, 1 H), 7.30–7.45 (m, 3 H), 7.50–7.75 (m, 3 H), 7.80 (m,
1 H).
13C (50 MHz) NMR spectra: d = 41.0, 110.9, 111.4, 116.0, 116.2,
120.3, 124.9, 125.3, 128.1, 130.0, 142.5, 151.1, 164.3.
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Anal. Calcd. for C15H14N2O: C, 75.61; H, 5.92. Found: C, 75.78;
H, 5.87%.
5 For selected examples of 2-arylations of thiophene derivatives via Stille
coupling using aryl triflates: (a) G. T. Crisp and S. Papadopoulos,
Aust. J. Chem., 1988, 41, 1711; (b) A. Busch, V. Gautheron Chapoulaud,
J. Audoux, N. Ple and A. Turck, Tetrahedron, 2004, 60, 5373; (c) M.
Torrado, C. F. Masaguer and E. Ravina, Tetrahedron Lett., 2007, 48,
323.
5-(4-tert-Butylphenyl)-2-n-propylthiazole (14)
6 For selected examples of 2-arylations of thiazole derivatives via Stille
coupling using aryl triflates: S. G. Cockerill, H. J. Easterfield and J. M.
Percy, Tetrahedron Lett., 1999, 40, 2601.
This compound was prepared according to the representative
procedure with 4-tert-butylphenyl triflate (0.282 g, 1 mmol), 2-n-
propylthiazole (0.254 g, 2 mmol) and the Pd complex (0.05 mmol)
in 151 mg, 58% yield as an oil.
1H (200 MHz) NMR spectra: d = 1.03 (t, J = 7.6 Hz, 3 H), 1.32
(s, 9 H), 1.92 (sext., J = 7.6 Hz, 2 H), 2.96 (t, J = 7.6 Hz, 2 H),
7.40 (d, J = 7.8 Hz, 2 H), 7.45 (d, J = 7.8 Hz, 2 H), 7.80 (s, 1 H).
13C (50 MHz) NMR spectra: d = 13.6, 23.2, 31.1, 34.5, 35.5,
125.8, 126.2, 128.7, 137.1, 138.2, 151.0, 170.1.
7 For selected examples of 2-arylations of furan derivatives via Suzuki
coupling using aryl triflates: (a) A. Huth, I. Beetz and I. Schumann,
Tetrahedron, 1989, 45, 6679; (b) W. C. Shieh and J. A. Carlson, J. Org.
Chem., 1992, 57, 379; (c) A. G. Chittiboyina, C. R. Reddy, E. B. Watkins
and M. A. Avery, Tetrahedron Lett., 2004, 45, 1689; (d) C. Pain, S.
Celanire, G. Guillaumet and B. Joseph, Tetrahedron, 2003, 59, 9627;
(e) Y. Okada, M. Yokozawa and J. Nishimura, Synlett, 2005, 352.
8 For selected examples of arylations of thiophene derivatives via Suzuki
coupling using aryl triflates: (a) C. Coudret and V. Mazenc, Tetrahedron
Lett., 1997, 38, 5293; (b) G. McCort, O. Duclos, C. Cadilhac and
E. Guilpain, Tetrahedron Lett., 1999, 40, 6211; (c) M. Frigoli, C.
Moustrou, A. Samat and R. Guglielmetti, Eur. J. Org. Chem., 2003,
2799; (d) B. Appel, N. N. R. Saleh and P. Langer, Chem.–Eur. J., 2006,
12, 1221; (e) J. E. Gautrot, P. Hodge, D. Cupertino and M. Helliwell,
New J. Chem., 2006, 30, 1801.
Anal. Calcd. for C16H21NS: C, 74.08; H, 8.16. Found: C, 73.99;
H, 8.27%.
5-(4-tert-Butylphenyl)thiophene-2-carbonitrile (15)
This compound was prepared according to representative proce-
dure with 4-tert-butylphenyl triflate (0.282 g, 1 mmol), thiophene-
2-carbonitrile (0.218 g, 2 mmol) and the Pd complex (0.05 mmol)
in 154 mg, 64% yield as an oil.
9 For an example of 5-arylation of oxazole via Suzuki coupling using an
aryl triflate: E. F. Flegeau, M. E. Popkin and M. F. Greaney, Org. Lett.,
2006, 8, 2495.
10 A. Ohta, Y. Akita, T. Ohkuwa, M. Chiba, R. Fukunaga, A. Miyafuji,
T. Nakata, N. Tani and Y. Aoyagi, Heterocycles, 1990, 31, 1951.
11 For reviews or recent results on Pd-catalyzed C–H activation–
functionalizationof aryls see: (a) C. Campeau and K. Fagnou, Chem.
Commun., 2006, 1253; (b) D. Alberico, M. E. Scott and M. Lautens,
Chem. Rev., 2007, 107, 174; (c) T. Satoh and M. Miura, Chem. Lett.,
2007, 36, 200; (d) J.-P. Leclerc and K. Fagnou, Angew. Chem., Int.
Ed., 2006, 45, 7781; (e) N. R. Deprez, D. Kalyani, A. Krause and
M. S. Sanford, J. Am. Chem. Soc., 2006, 128, 4972; (f) J.-Q. Yu, R.
Giri and X. Chen, Org. Biomol. Chem., 2006, 4041; (g) A. Battace,
M. Lemhadri, T. Zair, H. Doucet and M. Santelli, Organometallics,
2007, 26, 472; (h) A. Chiong and O. Daugulis, Org. Lett., 2007, 9, 1449;
(i) A. L. Gottumukkala and H. Doucet, Eur. J. Inorg. Chem., 2007,
3629; (j) D. G. Hulcoop and M. Lautens, Org. Lett., 2007, 9, 1761.
12 For examples of Pd-catalyzed direct arylations of aromatic derivatives
via C–H activation using aryl triflates: (a) T. Hosoya, E. Takashiro,
T. Matsumoto and K. Suzuki, J. Am. Chem. Soc., 1994, 116, 1004;
(b) G. Bringmann, A. Wuzik, J. Kraus, K. Peters and E.-M. Peters,
Tetrahedron Lett., 1998, 39, 1545; (c) L. Wang and P. B. Shevlin,
Tetrahedron Lett., 2000, 41, 285; (d) Y. Kametani, T. Satoh, M. Miura
and M. Nomura, Tetrahedron Lett., 2000, 41, 2655; (e) H. Nishioka,
Y. Shoujiguchi, H. Abe, Y. Takeuchi and T. Harayama, Heterocycles,
2004, 64, 463.
1H (200 MHz) NMR spectra: d = 1.30 (s, 9 H), 7.22 (d, J =
4.0 Hz, 1 H), 7.43 (d, J = 8.2 Hz, 2 H), 7.53 (d, J = 8.2 Hz, 2 H),
7.57 (d, J = 4.0 Hz, 1 H).
13C (50 MHz) NMR spectra: d = 31.1, 34.8, 107.7, 114.5, 122.8,
126.1, 126.2, 129.5, 138.3, 152.0, 152.9.
Anal. Calcd. for C15H15NS: C, 74.65; H, 6.26. Found: C, 74.89;
H, 6.07%.
5-(3,5-Dimethoxyphenyl)-2-n-propylthiazole (16)
This compound was prepared according to representative proce-
dure with 3,5-dimethoxyphenyl triflate (0.286 g, 1 mmol), 2-n-
propylthiazole (0.254 g, 2 mmol) and the Pd complex (0.05 mmol)
in 161 mg, 61% yield as an oil.
1H (200 MHz) NMR spectra: d = 1.03 (t, J = 7.6 Hz, 3 H), 1.92
(sext., J = 7.6 Hz, 2 H), 2.96 (t, J = 7.6 Hz, 2 H), 3.82 (s, 6 H),
6.41 (s, 1 H), 6.62 (s, 2 H), 7.78 (s, 1 H).
13C (50 MHz) NMR spectra: d = 14.1, 23.8, 35.9, 55.8, 100.3,
13 L. Ackermann, A. Althammer and R. Born, Angew. Chem., Int. Ed.,
2006, 45, 2619.
105.3, 122.5, 133.7, 138.2, 161.5.
14 (a) J. R. Proudfoot, K. D. Hargrave, S. R. Kapadia, U. R. Patel, K. G.
Grozinger, D. W. McNeil, E. Cullen, M. Cardozo, L. Tong, T. A. Kelly,
J. Rose, E. David, S. C. Mauldin, V. U. Fuchs, J. Vitous, M. Hoermann,
J. M. Klunder, P. Raghavan, J. W. Skiles, P. Mui, D. D. Richman, J. L.
Sullivan, C.-K. Shih, P. M. Grob and J. Adams, J. Med. Chem., 1995,
38, 4830; (b) T. Okazawa, T. Satoh, M. Miura and M. Nomura, J. Am.
Chem. Soc., 2002, 124, 5286; (c) O. Hara, T. Nakamura, F. Sato, K.
Makino and Y. Hamada, Heterocycles, 2006, 68, 1.
Anal. Calcd. for C14H17NO2S: C, 63.85; H, 6.51. Found: C,
63.70; H, 6.57%.
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174 | Org. Biomol. Chem., 2008, 6, 169–174
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