Palladium-catalyzed intramolecular C-arylation of benzylic carbon: Synthesis of 3-benzoxazolylisoindolinones by a sequence of Ugi-4CR/ postfunctionalization

Article abstract of DOI:10.1021/jo800266y

(Chemical Equation Presented) Submitting Ugi-adduct 4 to two consecutive metal-catalyzed intramolecular reactions, namely copper-catalyzed O-arylation and palladium-catalyzed C-arylation of benzylic carbon developed in the course of this study, affords th

Full text of DOI:10.1021/jo800266y

SCHEME 1. From Linear Ugi-Adducts to Heterocycles
Palladium-Catalyzed Intramolecular C-Arylation
of Benzylic Carbon: Synthesis of
3-Benzoxazolylisoindolinones by a Sequence of
Ugi-4CR/Postfunctionalization
Angela Salcedo, Luc Neuville,* and Jieping Zhu*
Institut de Chimie des Substances Naturelles, CNRS,
91198 Gif-sur-YVette Cedex, France
zhu@icsn.cnrs-gif.fr; neuVille@icsn.cnrs-gif.fr
ReceiVed February 1, 2008
of Ugi-adduct 1 (n ) 1) containing two aryl halide functions
and synthesized 1,4-benzodiazepine-2,5-diones 2 and its tetra-
cyclic derivatives 38 by using copper and palladium-catalyzed
cyclization reactions (Scheme 1).9 As a continuation of this
research program, we became interested in the structural
elaboration of the Ugi-adduct 4 (n ) 0, Scheme 1) and have
Submitting Ugi-adduct 4 to two consecutive metal-catalyzed
intramolecular reactions, namely copper-catalyzed O-aryla-
tion and palladium-catalyzed C-arylation of benzylic carbon
developed in the course of this study, affords the benzox-
azolylisoindolinones in good to excellent yields.
3
uncovered a direct intramolecular arylation of benzylic Csp
carbon (5 to 6). Parallel to this work, Yorimitsu and Oshima
have independently developed a palladium-catalyzed arylation
of aryl(azaaryl)methanes, including the R-arylation of 2-ben-
zylbenzoxazole.10 We report herein a two-step conversion of
the Ugi adduct 4 to benzoxazolylisoindolinones 6. The salient
Multicomponent reactions (MCR) offer a unique way to
generate libraries of complex molecules efficiently with a high
degree of diversity1,2 Among them, the Ugi four-component
reaction (Ugi-4CR)3 is without doubt one of the most powerful
transformations that has been extensively investigated for the
past 20 years. Mainly two strategies have been developed around
this reaction to further increase its versatility and the complexity-
generating power: (a) tethering principle, by linking two of the
four reactants together, a number of three-component syntheses
of heterocycles have been developed;1 and (b) postfunctional-
ization, by applying an efficient intramolecular reaction on the
properly functionalized Ugi adducts, a variety of medicinally
relevant heterocycles have been synthesized in only two opera-
tions.4 Using this latter strategy, we have developed a two-step
synthesis of a number of macrocycles including cyclophanes
and cyclodepsipeptides.5–7 We have also reported the elaboration
(4) (a) Marcaccini, S.; Torroba, T. Post-condensation Modifications of the
Passerini and Ugi Reactions; Zhu, J., Bienaymé, H., Eds.; Wiley-VCH:
Weinheim, Germany, 2005; pp 33–75. (b) Akritopoulou, I.; Djuric, S. W.
Heterocycles 2007, 73, 125–147.
(5) (a) Cristau, P.; Vors, J. P.; Zhu, J. Org. Lett. 2001, 3, 4079–4082. (b)
Cristau, P.; Vors, J. P.; Zhu, J. Tetrahedron Lett. 2003, 44, 5575–5578. (c)
Cristau, P.; Vors, J. P.; Zhu, J. QSAR Comb. Sci. 2006, 25, 519–526.
(6) (a) Zhao, G.; Sun, X.; Bienaymé, H.; Zhu, J. J. Am. Chem. Soc. 2001,
123, 6700–6701. (b) Bughin, C.; Zhao, G.; Bienaymé, H.; Zhu, J. Chem. Eur. J.
2006, 12, 1174–1184. (c) Bughin, C.; Masson, G.; Zhu, J. J. Org. Chem. 2007,
72, 1826–1829. (d) Pirali, T.; Tron, G.; Masson, G.; Zhu, J. Org. Lett. 2007, 9,
5275–5278.
(7) See also: (a) Beck, B.; Larbig, G.; Mejat, B.; Magnin-Lachaux, M.; Picard,
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Andreana, P. R.; Lee, D.; Schreiber, S. L. Org. Lett. 2003, 5, 4125–4127. (e)
De Greef, M.; Abelin, S.; Belkasmi, K.; Dömling, A.; Orru, R. V. A.;
Wessjohann, L. A. Synlett 2006, 3997–4004.
(8) (a) Cuny, G.; Bois-Choussy, M.; Zhu, J. Angew. Chem., Int. Ed. 2003,
42, 4774–4777. (b) Cuny, G.; Bois-Choussy, M.; Zhu, J. J. Am. Chem. Soc.
2004, 126, 14474–14484. (c) Salcedo, A.; Neuville, L.; Rondot, C.; Retailleau,
P.; Zhu, J. Org. Lett. 2008, 10, 857–860.
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3600 J. Org. Chem. 2008, 73, 3600–3603
10.1021/jo800266y CCC: $40.75 2008 American Chemical Society
Published on Web 04/02/2008

SCHEME 2. Copper-Catalyzed Cyclization of Amide 4a
feature of the present work is the differentiation of two tethered
aryl iodides for the construction of two different heterocycles.
Both benzoxazole and isoindolinone are considered to be
privileged structures in medicinal chemistry11,12 and a compound
combining these two units has been recently patented.13
The amide 4a was initially chosen to investigate its reactivity
under copper catalysis.14 Due to the presence of two aryl halide
functions, two possible reaction pathways leading to benzodi-
azepinedione 7 or benzoxazole 5a15 could be expected. Interest-
ingly, treatment of compound 4 under conditions previously
optimized for the cyclization of amide 1 (CuI, thiophene-2-
carboxylic acid,16 DMSO, K2CO3, 110 °C) afforded exclusively
the benzoxazole 5a in 87% yield via an intramolecular O-
arylation process (Scheme 2).17 The alternative intramolecular
N-arylation leading to benzodiazepinedione was not observed.
This result implied that the oxidative addition of ring A aryl
iodide to Cu(I) occurred preferentially over the ring B coun-
terpart, although ring B is electronically poorer than A and
should thus be more prone to oxidative addition.18 This
regioselectivity is opposite to that observed in the cyclization
of 1. This selective formation of benzoxazole turned out to be
quite general and a range of amides 4 with different R1 and R2
groups, including aliphatic and aromatic ones, readily cyclized
to benzoxazoles 5 in good to excellent yields (Table 1).
However, a low yield of benzoxazole was obtained when R2 )
H and Ph (5b, 5f). Except for 5b and 5d, all other precursors
were prepared by Ugi-4CR from readily accessible aldehydes,
anilines, isocyanides, and carboxylic acids.
The NMR spectra of compounds 5 were rather difficult to
interpret. For example, compound 5a exhibited three different
1
sets of signals in its H NMR spectrum. Variable-temperature
NMR experiments revealed the coalescence of two of them at
348 K. However, a full coalescence was not observed even at
372 K. The presence of rotamers and atropisomers, resulting
from a hindered rotation around the N-CO (a) and Caromatic-CO
bond (b),19 respectively, can be advanced to explain the observed
phenomena.20 Indeed, compound 5, having two rotationally
restricted C-C bonds and one chiral sp3 center, can exist as a
mixture of up to four observable diastereomers on the NMR
time scale (Figure 1).
(11) Recent examples of biologically actives benzoxazoles: (a) Potashman,
M. H.; Bready, J.; Coxon, A.; DeMelfi, T. M., Jr.; DiPietro, L.; Doerr, N.;
Elbaum, D.; Estrada, J.; Gallant, P.; Germain, J.; Gu, Y.; Harmange, J.-C.;
Kaufman, S. A.; Kendall, R.; Kim, J. L.; Kumar, G. L.; Long, A. M.; Neervannan,
S.; Patel, V. F.; Polverino, A.; Rose, P.; van der Plas, S.; Whittington, D.; Zanon,
R.; Zhao, H. J. Med. Chem. 2007, 50, 4351–4373. (b) Easmon, J.; Purstinger,
G.; Thies, K.-S.; Heinisch, G.; Hofmann, J. J. Med. Chem. 2006, 49, 6343–
6350. (c) Sondhi, S. M.; Singh, N.; Kumar, A.; Lozach, O.; Meijer, L. Bioorg.
Med. Chem. 2006, 14, 3758–3765. (d) Vinsova, J.; Cermakova, K.; Tomeckova,
A.; Ceckova, M.; Jampilek, J.; Cermak, P.; Kunes, J.; Dolezal, M.; Staud, F.
Bioorg. Med. Chem. 2006, 14, 5850–5865. (e) Huang, S.-T.; Hsei, I.-J.; Chen,
C. Bioorg. Med. Chem. 2006, 14, 6106–6119. (f) Yoshida, S.; Shiokawa, S.;
Kawano, K.-I.; Ito, T.; Murakami, H.; Suzuki, H.; Sato, Y. J. Med. Chem. 2005,
48, 7075–7079.
The presence of an aryl iodide function in 5 provided a handle
for further structural elaboration. One possible transformations
offered by structure 5sis the direct intramolecular C-arylation
(12) Recent examples of biologically actives isoindolinones: (a) Lee, S.;
Shinji, C.; Ogura, K.; Shimizu, M.; Maeda, S.; Sato, M.; Yoshida, M.; Hashimoto,
Y.; Miyachi, H. Bioorg. Med. Chem. Lett. 2007, 17, 4895–4900. (b) Hardcastle,
I. R.; Ahmed, S. U.; Atkins, H.; Farnie, G.; Golding, B. T.; Griffin, R. J.;
Guyenne, S.; Hutton, C.; Kallblad, P.; Kemp, S. J.; Kitching, M. S.; Newell,
D. R.; Norbedo, S.; Northen, J. S.; Reid, R. J.; Saravanan, K.; Willems, H. M. G.;
Lunec, J. J. Med. Chem. 2006, 49, 6209–6221. (c) Hardcastle, I. R.; Ahmed,
S. U.; Atkins, H.; Calvert, A. H.; Curtin, N. J.; Farnie, G.; Golding, B. T.; Griffin,
R. J.; Guyenne, S.; Hutton, C.; Källblad, P.; Kemp, S. J.; Kitching, M. S.; Newell,
D. R.; Norbedo, S.; Northen, J. S.; Reid, R. J.; Saravanan, K.; Willems, H. M. G.;
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3
of the benzylic Csp carbon. This transformation was therefore
investigated.
To our delight, treatment of a DMSO solution of compound
5a in the presence of Pd(OAc)2 (5 mol %) and KOAc (2 equiv)
at 120 °C afforded benzoxazolylisoindolinones 6a in 35% yield.
3
Although palladium-catalyzed arylation of Csp R to a carbonyl
group is well-established,21 direct arylations of methyleneben-
zoxazoles have, to the best of our knowledge, not been docu-
mented previously.10
Encouraged by this result, we set out to optimize the reaction
conditions by varying the ligand, the base, the solvent, and
the temperature. The results are summarized in Table 2. As
expected, the ligand structure has a dramatic effect on the
reaction efficiency, with PCy3 and ligand L1 (Figure 2) being
the most efficient (entry 5 and 11). The ideal temperature for
this transformation was found to be 90 °C. At lower tempera-
tures (50–90 °C), the reaction became sluggish (entry 2–4).
DMSO proved to be a better solvent than DMF, whereas dioxane
(13) (a) Ethyl 5-(2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxoisoindolin-1-
yl)benzo[d]oxazol-2-ylcarbamate has been reported to modulate kinases activity;
see: Anand, N. K.; Blazey, C. M.; Bowles, O. J.; Bussenius, J.; Costanzo, S.;
Curtis, J. K.; Dubenko, L.; Kennedy, A. R.; Defina, S. C.; Kim, A. I.; Manalo,
J.-C.; Peto, C.; Rice, K. D.; Tsang, T. H.; Joshi, A. A. WO/2005/112932 A2,
December 1, 2005. For reviews on the benefit of combining pharmacophores
for drug development see: (b) Morphy, R.; Rankovic, Z. J. Med. Chem. 2005,
48, 6523–6543. (c) Mammen, M.; Choi, S.-K.; Whitesides, G. M. Angew. Chem.,
Int. Ed. 1998, 37, 2754–2794.
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Chem. Soc. 1998, 120, 12459. For reviews on copper-mediated bond formation,
see: (a) Beletskaya, I. P.; Cheprakov, A. V. Coord. Chem. ReV. 2004, 248, 2337–
2364. (b) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400–
5449. (c) Kunz, K.; Scholz, U.; Ganzer, D. Synlett 2003, 2428–2439.
(15) (a) Altenhoff, G.; Glorius, F. AdV. Synth. Catal. 2004, 346, 1661–1664.
(b) Evindar, G.; Batey, R. A. J. Org. Chem. 2006, 71, 1802–1808.
(16) Allred, G. D.; Liebeskind, L. S. J. Am. Chem. Soc. 1996, 118, 2748–
2749.
(19) Siddall, T. H.; Garner, R. H. Can. J. Chem. 1966, 44, 2387–2394.
(20) For reviews see: (a) Clayden, J.; Vallverdu, L.; Helliwell, M. Org.
Biomol. Chem. 2006, 4, 2106–2118. (b) Clayden, J. Chem. Commun. 2004, 127–
135. (c) Clayden, J. Tetrahedron Symposium-in-print on axially Chiral Amides.
Tetrahedron 2004, 60, 4325–4558.
(17) The reaction proceeded at 60 °C by replacing the thiophene-2-carboxylic
acid with proline.
(21) (a) Culkin, D. A.; Hartwig, J. F. Acc. Chem. Res. 2003, 36, 234–245.
(b) Gaertzen, O.; Buchwald, S. L. J. Org. Chem. 2002, 67, 465–475. Benzylic
arylation: (c) Inoh, J.-I.; Satoh, T.; Pivsa-Art, S.; Miura, M.; Nomura, M.
Tetrahedron Lett. 1998, 39, 4673–4676. (d) Dong, C.-G.; Hu, Q.-S. Angew.
Chem., Int. Ed. 2006, 45, 2289–2292. (e) Beaudoin, O.; Herrbach, A.; Gueritte,
F. Angew. Chem., Int. Ed. 2003, 42, 5736–5740. (f) Catellani, M.; Motti, E.;
Ghelli, S. Chem. Commun. 2000, 2003–2004. (g) Ren, H.; Knochel, P. Angew.
Chem., Int. Ed. 2006, 45, 3462–3465.
(18) The mechanism of Ullmann-type reaction is not well-established;
therefore alternative explanations could account for the observed regioselectivity.
For recent discussion concerning the mechanism of copper-catalyzed arylation
of nucleophiles, see: (a) Ouali, A.; Spindler, J.-F.; Jutand, A.; Taillefer, M. AdV.
Synth. Catal. 2007, 349, 1906–1916. (b) Ouali, A.; Taillefer, M.; Spindler, J.-
F.; Jutand, A. Organometallics 2007, 26, 65–74.
J. Org. Chem. Vol. 73, No. 9, 2008 3601

TABLE 1. Synthesis of Benzoxazoles by a Sequence of the Ugi-4CR/Copper-Catalyzed O-Arylation
entry
R1
R2
i-Pr
H
i-Pr
yield of linear amide
yield of benzoxazole
1
2
3
4
5
6
7
8
9
CH3
CH3
4a, 83%
4b, (-)a
4c, 48%
4d, (-)a
4e, 58%
4f, 60%
4g, 65%
4h, 94%
4b, 48%
5a, 83%
5b, 26%
5c, 77%
5d, 63%
5e, 66%
5f, 15%
5g, 71%
5h, 68%
5i, 96%
PhCH2
CH2CH2CH2
i-Pr
n-C3H7
Ph
n-C6H13
i-Pr
n-C4H9
n-C4H19
n-C4H9
p-MeOPhCH2
i-Pr
a Synthesized by peptide coupling.
FIGURE 1. Stereochemical elements of benzoxazole 5.
TABLE 2. Palladium-Catalyzed C-Arylation, Survey of Reaction
Conditionsa
FIGURE 2. Ligand structure.
entry
ligand
solvent
base
temp (°C)
yield (%)
35
14
11
48
62
60
53
1
2
3
4
5
6
7
8
DMSO
Dioxane
THF
KOAc
120
50–90
50–90
50–90
90
110
110
90
90
90
90
90
PCy3
PCy3
PCy3
PCy3
L1
PCy3
PCy3
PCy3
PCy3
L1
L2
L3
L4
L5
L6
PCy3
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
KOAc
DMF
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
LiOtBu
KOtBu
43
45
9
10b
11
12
13
14
15
16
17c
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
degradation
66
41
29
52
24
45
90
90
90
90
90
no reaction
a All reactions were carried out under an argon atmosphere with 0.05
equiv of Pd(OAc)2, 1.5 equiv of base, C 0.2 M. b 3.0 equiv of base.
c 0.05 equiv of Pd(dba)2.
or THF were rather poor reaction media (entry 2,3). Sodium
tert-butoxide stood out as a base, and a counterion effect was
observed since lithium and potassium tert-butoxide provided
inferior results under otherwise identical conditions (entries 5,
8, and 9). Using excess base was detrimental to the reaction
(entry 10) and 1.5 equiv was found to be optimal (entry 10).
To probe the scope and limitation of this direct C-arylation
process, a range of substituted benzoxazole amides were next
submitted to the optimized cyclization condition. Results are
shown in Figure 3. In most cases, cyclization proceeded
smoothly to afford the desired compounds in moderate to good
FIGURE 3. Synthesis of isoindolinone by an intramolecular palladium-
3
catalyzed Csp -arylation.
yields. However, compounds 5b (R2 ) H) and curiously 5f (R2
) Ph), having a more acidic proton, led only to the destruction
of the starting materials. In the case of proline-derived benzox-
azole, partial hydrolysis of the benzoxazole occurred, leading
to 6d and 6d′ in yields of 23% and 20%, respectively. Both
3602 J. Org. Chem. Vol. 73, No. 9, 2008

with water and extracted with AcOEt. The organic phase was
washed with NH4Cl, dried over Na2SO4, and concentrated in vacuo.
The residue was purified by flash chromatography (SiO2, heptane/
AcOEt ) 3/1) to give the product 5a (81 mg, 87%) as a yellow
structures have been confirmed by X-ray analysis (cf. Supporting
Information).
Finally, the N-(4-methoxybenzyl) group in 6i was readily
removed under mild acidic conditions (CF3CO2H-anisole, 80 °C)
to afford the unprotected isoindolinone 8 in 78% yield.
In conclusion, we documented a direct intramolecular C-
arylation of methylenebenzoxazole. Starting from an Ugi-adduct
having two aryl iodide units, regiospecific sequential intramo-
lecular O- and C-arylation reactions led to an efficient synthesis
of 3-substituted 3-benzoxazolylisoindolinones. In combination
with the versatile Ugi four-component reaction, highly func-
tionalized heterocycles can thus be easily prepared in three steps
from readily accessible starting materials.
1
solid. Multiple isomers. Mp 126–128 °C. H NMR (500 MHz,
CDCl3, 298 K) (ppm) δ 0.69, 074 (d, J ) 6.0 Hz, 3H), 1.04, 1.10
(d, J ) 6.4 Hz, 3H, H18), 2.54–2.65 (m, 1H), 2.69 (s, 3H), 4.34,
5.84 (d, J ) 11.5 Hz, 1H), 6.95–7.19 (m, 2H), 7.27–7.37 (m, 3H),
7.47–7.48 (m, 1H), 7.66–7.69 (m, 2H). IR ν 3051, 2962, 2924,
2872, 1642, 1610, 1584, 1562, 1468, 1453, 1394, 1328, 1314, 1241,
1153, 1070, 1014, 863, 742 cm-1. HRMS for C19H19IN2O2 [M +
Na] calcd 457.0385, found 457.0389.
General Procedure for Formation of Isoindol-1-ones. To a
solution of 5a (100 mg, 0.23 mmol) in DMSO (5 mL, 0.05 M)
was added Pd(OAc)2 (2.5 mg, 0.01 mmol), XPhos (14 mg, 0.03
mmol), and NaOtBu (33 mg, 0.35 mmol). The mixture was stirred
overnight at 90 °C. The reaction mixture was washed with water,
then extracted with AcOEt. The organic extracts were washed with
brine, dried over Na2SO4, and evaporate to dryness. The residue
was purified by flash chromatography (SiO2, heptane/AcOEt ) 3/1)
to give the product 6a (47 mg, 66%) as a yellow solid. Mp 126–128
°C. 1H NMR (500 MHz, CDCl3, 298 K) (ppm) δ 0.77 (d, J ) 6.8
Hz, 3H), 1.11 (d, J ) 6.8 Hz, 3H), 3.16 (s, 3H), 3.20 (m, 1H),
7.31–7.37 (m, 2H), 7.42–7.47 (m, 1H), 7.51–7.60 (m, 3H),
7.73–7.76 (m, 1H), 7.90–7.94 (m, 1H). 13C NMR (75 MHz, CDCl3,
293 K) (ppm) δ 16.5, 17.4, 26.8, 33.0, 70.9, 110.8, 120.4, 123.7,
123.8, 124.6, 125.5, 129.1, 131.5, 132.5, 140.6, 143.0, 150.5, 163.5,
168.4. IR ν 2961, 2921, 2849, 1784, 1698, 1454, 1384, 1240, 1103,
1015, 730 cm-1. HRMS for C19H18N2O2 [M + Na] calcd 329.1262,
found 329.1256.
Experimental Section
General Procedure for the Ugi-Reaction. To a solution of
methylamine hydrochloride (75.5 mg, 1.12 mmol) in methanol
(0.2M) was added triethylamine (160 µL, 1.14 mmol). The mixture
was stirred for 15 min, then isobutyraldehyde (78.5 mg, 1.09 mmol)
was added and the stirring was continued for 15 min. 2-Iodobenzoic
acid (277.8 mg, 1.12 mmol) was added followed by 1-iodo-2-
isocyanobenzene (258.8 mg, 1.13 mmol). After being stirred at room
temperature for 8 h, the reaction mixture was concentrated in vacuo.
The residue was purified by flash chromatography (SiO2, heptane/
AcOEt ) 3/1) to give the product 4a (508 mg, 83%) as a yellow
solid. Mp 160–162 °C. 1H NMR (500 MHz, CDCl3, 298 K) (ppm)
δ 1.13 (m, 6H), 1.25–1.27 (m, 1H), 2.84 (s, 3H), 4.96 (d, J ) 9.8
Hz, 1H), 6.85 (br s, 1H), 7.08 (td, J ) 7.9 and 1.5 Hz, 1H), 7.20
(d, J ) 7.9 Hz, 1H), 7.33 (t, J ) 6.9 Hz, 1H), 7.39 (t, J ) 7.3 Hz,
1H), 7.81 (m, 2H), 8.19–8.28 (m, 1H), 8.39 (s, 1H). 13C NMR (75
MHz, CDCl3, 293 K) (ppm) δ 19.8, 19.9, 25.5, 32.1, 57.2, 90.1,
94.5, 122.0, 122.4, 122.6, 126.1, 128.4, 128.9, 130.4, 138.6, 139.3,
139.4, 171.9, 172.0 (CdO). IR ν 3250, 2920, 2850, 1697, 1628,
1583, 1518, 1465, 1432, 1398, 1177, 1073, 1014 cm-1. HRMS for
C19H20I2N2O2 [M + Na] calcd 584.9508, found 584.9527.
Acknowledgement. Financial support from the CNRS and
this institute is gratefully acknowledged. A.S. thanks this
institute for a doctoral fellowship. We also thank Marie-Therese
Martin of this institute for helpful discussions.
Supporting Information Available: Data and copies of 1H
spectra for compounds 5, 6, and 8, copies of 13C NMR spectra
for 6, and X-ray ORTEP for 6d and 6d′. This material is
available free of charge via the Internet at http://pubs.acs.org.
General Procedure for Formation of Benzoxazoles. To a
solution of compound 4a (120 mg, 0.21 mmol) in DMSO (10 mL,
0.02M) was added CuI (4 mg, 0.02 mmol), K2CO3 (58 mg, 0.42
mmol), and thiophene-2-carboxylic acid (5.4 mg, 0.04 mmol). After
being stirred overnight at 110 °C, the reaction mixture was diluted
JO800266Y
J. Org. Chem. Vol. 73, No. 9, 2008 3603