Ligand controlled orthogonal base-assisted direct C-H bond arylation in oxa(thia)zole-4-carboxylate series. New insights in nCMD mechanism

Article abstract of DOI:10.1016/j.tet.2013.01.073

Alkyl- and arylphosphines have been screened in competitive C2-H/C5-H direct phenylation of oxa(thia)zole-4-carboxylates using Cs₂CO ₃ and Rb₂CO₃ carbonate bases. nCMD-based C2-H selective direct phenylation was

Full text of DOI:10.1016/j.tet.2013.01.073

Tetrahedron 69 (2013) 4375e4380
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Ligand controlled orthogonal base-assisted direct CeH bond
arylation in oxa(thia)zole-4-carboxylate series. New insights in
nCMD mechanism
a
b
a
a,
*
ꢀ
Laure Theveau , Olivier Querolle , Georges Dupas , Christophe Hoarau
a
ꢀ
ꢀ
INSA et Universite de Rouen Institut de Chimie Organique Fine associe au CNRS (UMR 6014), Place Emile Blondel, Mont Saint Aignan 76131, France
b Janssen Research & Development, Division of Janssen-Cilag S.A., Campus de Maigremont, BP615 27106 Val de Reuil Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Alkyl- and arylphosphines have been screened in competitive C2eH/C5eH direct phenylation of ox-
a(thia)zole-4-carboxylates using Cs2CO3 and Rb2CO3 carbonate bases. nCMD-based C2eH selective direct
phenylation was highly kinetically reduced (or enhanced) in favor (or to the detriment) of CMD-based
direct C5eH phenylation with bromo- and chlorobenzene, respectively, using highly electron-rich li-
gands. These results gave novel experimental proof in favor of the electrophilic substitution-type
mechanism for nCMD process based upon a prior nitrogen-arylpalladium complex interaction that
preludes the deprotonation step.
Received 28 November 2012
Received in revised form 18 January 2013
Accepted 23 January 2013
Available online 1 February 2013
Keywords:
Direct CeH arylation
Palladium catalysis
Selectivity
Ó 2013 Elsevier Ltd. All rights reserved.
Ligand effect
NBO
1. Introduction
concerted mode (nCMD) stays incompletely evidenced and only
few examples have been announced under copper and palladium
Over the past decades, researches on direct CeH bond func-
tionalization reactions have grown dramatically.1 In particular, the
base-assisted Pd(0)-catalyzed direct CeH bond arylation of heter-
oarenes with aryl(pseudo)halides has emerged as an established
alternative to commonly employed standard cross-coupling re-
actions (Scheme 1).2 In addition to step and atom economies, this
method opens innovative routes in diversity and selectivity
through an orthogonal control of various catalytic CeH activation
modes ranging mainly from electrophilic metalation, carbometa-
lation, and metalationedeprotonation (Scheme 1).3e6 However,
this original site-selectivity approach remains sparsely employed
reflecting the need to have constant insights into the controlling-
parameters of CeH activation mechanisms including ancillary
base, ligand, solvent, chelation and halogen effects.7 Metal-
ationedeprotonation is currently the most implied mechanism in
direct CeH arylation of heterocycles with arylhalides. A first con-
certed mode (CMD) is based upon a CePd interaction concomitant
to an internal or external carboxylate and pivalate-assisted ab-
straction of the proton.6,8 A second strong base-dependant non-
catalysis.
Scheme 1. Catalytic cycle for Pd(0)-catalyzed direct CeH coupling of (hetero)aro-
matics with halides and catalytic metalation mechanisms.
* Corresponding author. Tel.: þ33 023 552 2401; fax: þ33 023 552 2962;
e-mail address: christophe.hoarau@insa-rouen.fr (C. Hoarau).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.01.073

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Daugulis Cu(I)-catalyzed direct arylation of azoles under high
basic conditions methodology, which is based upon the previous
formation of the C2-azolylcuprate, represents one of the earliest
examples of nCMD.9 Bellina and Rossi underlined the fact that the
formation of C2-azolylcuprate stays unclear. They suggested a cop-
per-induced reinforcing-acidity effect to facilitate the C2eH
deprotonation step, which could be then ensured with a very weak
base-like CsF or even DMF solvent for Pd(0)/Cu(I)-catalyzed direct
CeH arylation of 1,3-diazoles (Scheme 2a).10 Zhuralev11 and then
StrotmaneChobanian3e proposed also
a
cross-coupling-type
mechanism for direct C2eH arylation of benzoxazole based upon
a Passerini-type reaction for the transmetalation step (Scheme 2b).
Recently, our group also identified a strong base K3PO4, DBU, and
Cs2CO3-assisted nCMD as operating mechanism for highly selective
Pd(0)-catalyzed direct C2eH arylation of oxa(thia)zole-4-
carboxylates using Cy-JohnPhos in dioxane and DMF, respectively
(Fig. 1, entry 1).12 Deuterium incorporation experiments led to the
production of C2eH and C5eH deuterated oxa(thia)zoles and led us
to discard the cross-coupling-type in favor of an electrophilic
substitution-type mechanism (Scheme 2c).13 Considering this hy-
pothesis, we recently focused our attention on the fact that prior
nitrogenearylpalladium complex interaction may reinforce the
acidity of C2eH proton and also prevent the formation of the ring-
opened tautomer. Indeed, according to Vedej’s observations, the
previous coordination with triethylborate led to the high stability of
the 2-lithiated oxazole.14 In fact, this prior interaction is supposed
to be mainly driven by the electrophilic character of the arylpalla-
dium complex that depends crucially on the electron-donor prop-
erty of the ligand. Moreover, the electrophilic character of the
arylpalladium complex is also dramatically reduced after the
Fig. 1. Previously reported Cs2CO3-assisted nCMD and K2CO3-assisted CMD direct
C2eH/C5eH selective arylation procedures.
energetically-favored and fast displacement of the halogen by the
carbonate base.15
In addition, CMD is identified as a privileged mechanism using
soft K2CO3 base. Interestingly, the direct CeH arylation is mainly
achieved at the energetically-favored C5eH site identified by DFT
calculations.13,16 As consequence, C2eH site could be only reached
under high steric effect using specifically PtBu3 ligand under CMD
process and notably by using PivOH additive for the thiazole model
(Fig. 1). Thus, nCMD and CMD are naturally competitive mecha-
nisms when using hard carbonate bases. In this context, we dis-
closed herein an additional study of the ligand effect on the
behavior of the C2eH/C5eH selectivity under competitive nCMD/
CMD direct CeH phenylation of oxa(thia)zole-4-carboxylates.
Bromo- and chlorobenzene were used as coupling partners with
Rb2CO3 and Cs2CO3 bases. These experiments gave novel experi-
mental insights in strong base-assisted nCMD process.
Scheme 2. Proposed nCMD mechanism in direct C2eH arylation of 1,3-diazolic sys-
tems under different metal catalysis.

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4377
2. Results and discussions
A first set of Cs2CO3-assisted competitive nCMD/CMD direct
CeH phenylation of ethyl oxazole-4-carboxylate experiments was
achieved with various phosphines. Phenyl bromide was selected as
optimized coupling partner to ensure the oxidative addition step
with various phosphines along with preventing the disruption of
the CMD process, which may be encountered by using iodide.17 The
site-selectivity results are ranged from poor to high electron-donor
effect of ligand, measured by the NBO charge (Natural Bond Orbital)
in the Fig. 2a.18 As expected, C2eH selectivity is maintained using
poor electron-donor ligands such as Cy-JohnPhos and PnBu3 that
gave the 2-phenyloxazole 1b in 68% and 70% yields (Fig. 2a, entries
3 and 4). By contrast, the C5eH selective CMD reaction became
kinetically favored using highly sterically hindered and electron-
rich ligands such as PCy3, PtBu2Me, CataXium and PtBu3 (Fig. 2a,
entries 5e8). The comparison of these results with those obtained
through K2CO3-assisted C5eH selective CMD-based direct CeH
phenylation led to three main observations (Fig. 2b).
Firstly, nCMD mechanism is clearly selective at C2eH position
with electron-poor ligands whereas CMD is selective at C5eH site
with electron-rich ligands (Fig. 2a). CMD proved to be also much less
effective using Cs2CO3 compared to K2CO3 pointing out that the
steric hindrance of the base-delivering counter-cation penalizes this
mechanism.19 The third important observation is that the CMD
process continued to be selective at C5eH site under high steric
effect with PtBu3 ligand despite of the use of more sterically hin-
dered Cs2CO3 versus K2CO3 bases (Fig. 2a,b, entry 8). This result
could find an explanation on a critical loss of efficiency of the CMD
process at C2eH site, so that it is occurring at the most energetically-
favored CMD C5eH site, combined necessary, with a strong in-
hibition of the competitive C2eH selective nCMD process.
Competitive Rb2CO3-assisted nCMD/CMD direct CeH phenyl-
ation of 1a with phenyl bromide was further executed (Fig. 2c).
Immediately, the nCMD process appeared to be highly penalized
under these less basic conditions. Indeed, a poor C2eH selectivity
(30%) was only observed with Cy-JohnPhos ligand mainly due to
the poor performance of this ligand for the CMD process (Fig. 2c,
entry 3). In addition, an improved CMD reactivity is recovered in
accordance with the use of a less sterically hindered base-
delivering counter-ion. Indeed, CMD proved to be more kineti-
cally favored than the nCMD process with electron-poor ligand
such as P(4-FePh)3 as well as several electron-rich phosphines
(Fig. 2c, entries 1, 5e8). Therefore, unexpectedly, the selectivity is
remained at C5eH site under high steric hindrance using PtBu3 and
despite the significant best performance of the CMD process
(Fig. 2c, entry 8). This last result brings additional experimental
evidences that high electron-donor ligands dramatically penalize
the nCMD reaction, the optimal inhibiting effect being obtained
with PtBu3 ligand (Fig. 2a,c, entry 8).
Same conclusions were then made by achieving identical com-
petitive Rb2CO3- and Cs2CO3-assisted nCMD/CMD direct CeH
phenylation of tert-butyl thiazole-4-carboxylate with phenyl bro-
mide in DMF solvent (Fig. 3). Indeed, the additional screening of
phosphines showed clearly an inversion of selectivity from C2eH to
C5eH site with the most electron-rich PtBu3 with both Rb2CO3 and
Cs2CO3 bases (Fig. 3, entry 7). The phenomenon is even more sig-
nificant than one observed in oxazole-4-carboxylate series since
the tert-butyl protection displays an additional external steric
hindrance effect. Moreover due to the enhancement of the basicity
in a high polar DMF solvent, the C2eH selective nCMD reaction
becomes more competitive toward the C5eH CMD process over
a more important range of phosphines under Cs2CO3 as well as
Rb2CO3 base-assistance.
Having highlighting through ligand-controlled nCMD/CMD
competitive reaction experiments that nCMD implies a prior
Fig. 2. Ligand control on the C2eH/C5eH direct phenylation selectivity of ethyl ox-
azole-4-carboxylate depending on nature of carbonate bases in dioxane.

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L. Theveau et al. / Tetrahedron 69 (2013) 4375e4380
Fig. 3. Ligand control on the C2eH/C5eH directs phenylation selectivity of tert-butyl thiazole-4-carboxylate depending on nature of carbonate bases in DMF.
carbonate coordinated arylpalladium complexenitrogen in-
teraction, we then reasoned that the halogenoarylpalladium
complex immediately generated after the oxidative step should be
a better candidate for the nCMD process. Nevertheless the be-
havior of the halogenoarylpalladium complex depends mainly on
the efficiency of the energetically favored halogen-substitution
reaction achieves by the carbonate base.20,3e Clot and Baudoin
recently proposed an associative SN2-type pathway on tricoordi-
nated palladium(II) center for this halogen-substitution reaction.15
Nevertheless, it is highly kinetically reduced through highly
electron-donor ligand effect. On the basis of this observation, we
decided to examine the evolution of the C2eH/C5eH selectivity in
Cs2CO3- and Rb2CO3-assisted competitive nCMD/CMD direct CeH
phenylation of oxa(thia)zole-4-carboxylate with poor to high
electron-rich phosphines using chlorobenzene as coupling partner.
Two main reasons led to this choice (i) The PdeCl bond is stronger
than PdeBr bond and the chloride is then harder to substitute from
palladium than bromide through a SN2-type substitution;21 (ii) the
chloroarylpalladium(II) complex, generated beyond oxidative ad-
dition step, displays a more important electrophilic character than
its brominated complex and may interact more strongly with the
substrate. The results are depicted in Figs. 4 and 5 and are directly
compared to those obtained with phenyl bromide under the same
catalysis. As expected, the C2eH selective nCMD reaction was
found to be immediately more predominant with the chloride
partner when high electron-rich ligands were employed, in-
terestingly, in both oxazole and thiazole series (Fig. 4, entries 3e5
and Fig. 5, entries 3 and 5). Herein, the ligand acts as an inhibitor of
the halogen-substitution reaction to increase the life-time of the
chloroarylpalladium complex. This latter complex proved to be
reactive in the nCMD process.
Fig. 4. Halide control on the Cs2CO3-assisted C2eH/C5eH direct phenylation selec-
tivity of ethyl oxazole-4-carboxylate in dioxane.
pointed out our previously proposed nCMD mechanism (Scheme
2b), based upon a prior arylpalladium complex-nitrogen in-
teraction to prelude the deprotonation step. This study allows also
to refine the nCMD mechanism as depicted in Scheme 3. As stan-
dard route, the halogenoarylpalladium complex delivered by oxi-
dative addition of halides to Pd(0) is subsequently engaged in
3. Conclusion
This present ligand- and/or halogen-controlled competitive
nCMD/CMD direct CeH phenylation of oxa(thia)zole-4-carboxylate

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L. Theveau et al. / Tetrahedron 69 (2013) 4375e4380
4379
First, intramolecular nCMD reaction could be highly kinetically
reduced by using highly electron-donor ligands, notably PtBu3, in
favor of the C5eH selective CMD reaction (Scheme 3, route B).
Moreover, the chloride-substitution reaction could be kinetically
reduced through the use of high electron-rich ligands to allow the
nCMD reaction with a high electrophilic chloroarylpalladium com-
plex through an intermolecular deprotonation process (Scheme 3,
route C).
4. Experimental section
4.1. General
All experiments were carried out under a nitrogen atmosphere
in oven-dried screw-caped sealed tubs. The ethyl oxazole-4-
carboxylate 1a and tert-butyl thiazole-4-carboxylate 2a were pre-
pared according to our previously reported procedure.12 Palladium
acetate, phosphonium salts ligands, phosphine ligands, and halides
were purchased from major chemical suppliers and were used as
received. Palladium acetate and ligands were stored in desiccators
as well as cesium, rubidium and potassium carbonate bases after
drying over P2O5. Extra dry dioxane and DMF, stored on AcrosealÒ
microsieves, were purchased from Acros. Chromatography columns
were performed using silica gel (mesh size 60e80 mesh). 1H NMR
and 13C NMR spectra were recorded at 300 MHz (Bruker). Chemical
€
Fig. 5. Halide control on the Rb2CO3-assisted C2eH/C5eH direct phenylation selec-
tivity of tert-butyl thiazole-4-carboxylate in DMF.
shifts (d) are given as parts per million relative to the residual
solvent peak. Melting points are uncorrected. IR spectra were ob-
tained with Bomen MB-100 or PerkineElmer Spectrum 100 FT IR
spectrometers. Microanalyses were carried out at the analytical
laboratory of our Department (IRCOF).
energetically favored halogen-substitution reaction leading to the
carbonate coordinated arylpalladium complex in which an intra-
molecular abstraction of the C2eH proton takes place (Scheme 3,
route A). This standard route could be confirmed indirectly by two
main observations.
4.2. General procedure for the direct arylation of oxa(thia)
zole-4-carboxylate derivatives with halogenoarenes through
carbonate-assisted nCMD/CMD reaction competition
Oxazole or thiazole-4-carboxylate derivative (0.35 mmol or
0.27 mmol) was placed in a dried-oven sealed tub (10 ml) con-
taining a magnetic stir bar with Pd(OAc)2 (5 mol %), ligand
(10 mol %) and carbonate base (2 equiv). A solution of halide
(1 equiv) in dry dioxane or DMF (1 ml) was added. The resulting
mixture was purged with nitrogen and stirred at 110 ꢀC for 18 h.
After filtration on CeliteÒ and concentration under vacuo, the crude
product was purified by flash column chromatography on silica gel
using a mixture of petroleum ethereEthyl acetate as eluent to give
pure arylated products 1bed and 2bed.
4.2.1. Ethyl 2-phenyloxazole-4-carboxylate (1b). Following the
general procedure using 1a (50 mg, 0.35 mmol) with bromo-
benzene (37
ml, 0.35 mmol), PnBu3 (7 ml, 0.035 mmol), cesium
carbonate (228 mg, 0.70 mmol) in dioxane (0.35 M). Standard
workup followed by flash chromatography (petroleum ether-
eEtOAc/8:2, Rf¼0.4) afforded the title compound (52 mg, 70%) as
a white solid (mp¼66e67 ꢀC). 1H NMR (CDCl3, 300 MHz)
¼1.38 (t,
d
3H, J¼7.2 Hz), 4.40 (q, 2H, J¼7.2 Hz), 7.44e7.46 (m, 3H), 8.07e8.11
(m, 2H), 8.25 (s, 1H); 13C NMR (CDCl3, 75 MHz)
d
¼14.4, 61.4, 126.5,
3136, 3080,
126.9, 128.9, 131.2, 134.8, 143.7, 161.4, 162.5. IR (KBr)
n
2962, 900, 1727, 1610, 1563 cmꢁ1; Anal. Calcd for C12H11NO3 (217.2):
C, 66.35; H, 5.10; N, 6.45. Found: C, 66.54; H, 5.35; N, 6.38.
4.2.2. Ethyl 5-phenyloxazole-4-carboxylate (1c). Following the
general procedure using 1a (50 mg, 0.35 mmol) with bromo-
benzene (37
ml, 0.35 mmol), PCy3$HBF4 (12.9 mg, 0.035 mmol),
potassium carbonate (96 mg, 0.70 mmol) in dioxane (0.35 M).
Standard workup followed by flash chromatography (petroleum
ethereEtOAc/8:2, Rf¼0.2) afforded the title product (44 mg, 59%) as
Scheme 3. Ligand and halide control for orthogonal C2eH/C5eH selective direct
phenylation of oxa(thia)zole-4-carboxylate series through intramolecular nCMD (route
A), intermolecular nCMD (route C) or CMD (route B).
a white solid (mp<50 ꢀC). 1H NMR (CDCl3, 300 MHz)
d
¼1.39 (t, 3H,

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L. Theveau et al. / Tetrahedron 69 (2013) 4375e4380
4380
K.; Sekizawa, H.; Itami, K. J. Am. Chem. Soc. 2009, 131, 14622e14623; (e) Strot-
man, N. A.; Chobanian, H. R.; Guo, Y.; He, J.; Wilson, J. E. Org. Lett. 2010, 12,
3578e3581; (f) Wasa, M.; Worell, B. T.; Yu, J.-Q. Angew. Chem., Int. Ed. 2010, 49,
1275e1277; (g) Lapointe, D.; Markiewicz, T.; Whipp, C. J.; Toderian, A.; Fagnou,
K. J. Org. Chem. 2011, 76, 749e759; (h) Guo, P.; Min Joo, J.; Rakshit, S.; Sames, D.
J. Am. Chem. Soc. 2011, 133, 16338e16341; (i) Si Larbi, K.; Fu, H. Y.; Laidaoui, N.;
Beydoun, K.; Miloudi, A.; El Abed, D.; Djabbar, S.; Doucet, H. ChemCatChem
2012, 4, 815e823.
J¼7.2 Hz), 4.41 (q, 2H, J¼7.2 Hz), 7.45e7.47 (m, 3H), 7.90 (s, 1H),
8.04e8.07 (m, 2H); 13C NMR (CDCl3, 75 MHz)
d
¼14.3, 61.5, 126.7,
126.8, 128.5, 130.5, 149.1, 155.6, 162.0; IR (KBr)
n 3109, 2977, 1719,
1583, 1495, 1370, 1226, 1189, 1066, 762, 686, 643 cmꢁ1; Anal. Calcd
for C12H11NO3 (217.2): C, 66.35; H, 5.10; N, 6.45. Found: C, 66.27; H,
5.04; N, 6.58.
4. For direct substitutive coupling reports evoking an electrophilic-type mecha-
nism: (a) Catellani, M.; Chiusoli, P. J. Organomet. Chem. 1992, 425, 151e154; (b)
Pivsa-Art, S.; Datoh, T.; Kawamura, Y.; Miura, M.; Nomura, M. Bull. Chem. Soc. Jpn.
1998, 71, 467e473; (c) Glover, B.; Harvey, K. A.; Liu, B.; Sharp, M. J.; Tymoschenko,
M. F. Org. Lett. 2003, 5, 301e304; (d) Hoarau, C.; Du Fou de Kerdaniel, A.; Bracq, N.;
Grandclaudon, P.; Couture, A.; Marsais, F. Tetrahedron Lett. 2005, 46, 8573e8577;
(e) Chiong, H. A.; Daugulis, O. Org. Lett. 2007, 9, 1449e1451.
4.2.3. tert-Butyl 2-phenylthiazole-4-carboxylate (2b). Following the
general procedure using 2a (50 mg, 0.27 mmol) with bromo-
benzene (28 m
l, 0.27 mmol), PtBu2Me$HBF4 (6.7 mg, 0.027 mmol),
cesium carbonate (175 mg, 0.54 mmol) in DMF (0.27 M). Standard
workup followed by flash chromatography (petroleum ether-
eEtOAc/9:1, Rf¼0.2) afforded the title product (64 mg, 91%) as
5. For direct substitutive couplings reports evoking
a carbopalladation-type
mechanism: (a) Gozzi, C.; Lavenot, L.; Ilg, K.; Panalva, V.; Lemaire, M. Tetrahe-
dron Lett. 1997, 38, 8867e8870; (b) Lavenot, L.; Gozzi, C.; Ilg, K.; Penalva, V.;
Lemaire, M. J. Organomet. Chem. 1998, 567, 49e55; (c) Tang, S.-Y.; Guo, Q.-X.; Fu,
Y. Chem.dEur. J. 2011, 17, 13866e13876; (d) Steinmetz, M.; Ueda, K.; Grimme, S.;
Yamaguchi, J.; Kirchberg, S.; Itami, K.; Studer, A. Chem.dAsian. J. 2012, 7,
1256e1260.
a white solid (mp¼78 ꢀC). 1H NMR (CDCl3, 300 MHz)
¼1.62 (s, 9H),
d
7.42e7.45 (m, 3H), 7.99e8.03 (m, 2H), 8.02 (s, 1H); 13C NMR (CDCl3,
75 MHz)
168.6; IR (KBr)
d
¼28.3, 82.1, 126.4, 127.0, 129.0, 130.7, 133.0, 149.5, 160.6,
n
3112, 2993, 2976, 2932, 1714 cmꢁ1; Anal. Calcd for
6. For selected direct substitutive couplings reports evoking a concerted metal-
C12H11NO3 (261.34): C, 64.34; H, 5.79; N, 5.36; S, 12.27 Found: C,
64.38; H, 5.86; N, 5.31; S, 12.25.
ꢀ
lationedeprotonation type mechanism, see (a) Gonzalez, J. J.; García, N.;
ꢀ
Gomez-Lor, B.; Echavarren, A. M. J. Org. Chem. 1997, 62, 1286e1291; (b) García-
Cuadrado, D.; Braga, A. A. C.; Maseras, F.; Echavarren, A. M. J. Am. Chem. Soc.
2006, 128, 1066e1067; (c) Campeau, L.-C.; Fagnou, K. Chem. Commun. 2006,
1253e1264; (d) Campeau, L.-C.; Stuart, D. R.; Leclerc, J.-P.; Bertrand-Laperle, M.;
Villemure, E.; Sun, H.-Y.; Lasserre, S.; Guimond, N.; Lecavallier, M.; Fagnou, K. J.
Am. Chem. Soc. 2009, 131, 3291e3306; (e) Ackermann, L. Chem. Rev. 2011, 111,
4.2.4. tert-Butyl 5-phenylthiazole-4-carboxylate (2c). Following the
general procedure using 2a (50 mg, 0.27 mmol) with bromobenzene
(28
ml, 0.27 mmol), PCy3$HBF4 (10 mg, 0.027 mmol), potassium
ꢀ
1315e1345; (f) Grosse, S.; Pillard, C.; Massip, S.; Leger, J.-M.; Jarry, C.; Bourg, B.;
Bernard, P.; Guillaumet, G. Chem.dEur. J. 2012, 18, 14943e14947.
carbonate (75 mg, 0.54 mmol) in DMF (0.27 M). Standard workup
followed by flash chromatography (petroleum ethereEt2O/8:2,
Rf¼0.1) afforded the title product (41 mg, 59%) as a white solid
7. (a) Chiong, H. A.; Pham, Q.-N.; Daugulis, O. J. Am. Chem. Soc. 2007, 129,
ꢀ
9879e9884; (b) Liegault, B.; Petrov, I.; Gorelsky, S. I.; Fagnou, K. J. Org. Chem.
(mp¼52e54 ꢀC).1H NMR (CDCl3, 300 MHz)
d
¼1.39 (s, 9H), 7.41e7.44
¼27.9, 82.2, 128.3,
3073, 2972,
2010, 75, 1047e1060; (c) Sun, H.-Y.; Gorelsky, S. I.; Stuart, D. R.; Campeau, L.-C.;
Fagnou, K. J. Org. Chem. 2010, 75, 8180e8189; (d) Rene, O.; Fagnou, K. Adv. Synth.
Catal. 2010, 352, 2116e2120; (e) Gorelsky, S.; Lapointe, D.; Fagnou, K. J. Org.
Chem. 2012, 77, 658e668; (f) Petit, A.; Flygare, J.; Miller, A. T.; Winkel, G.; Ess, D.
H. Org. Lett. 2012, 14, 3680e3683.
8. For selected reports on PivOH additive positive-effect in transition metal-
catalyzed substitutive coupling of heteroaromatics via CMD-type mechanism,
see: (a) Lafrance, M.; Fagnou, K. J. Am. Chem. Soc. 2006, 128, 16496e16497; (b)
Balcells, D.; Clot, E.; Eisenstein, O. Chem. Rev. 2010, 110, 749e823.
9. (a) Do, H.-Q.; Kashif Khan, R. M.; Daugulis, O. J. Am. Chem. Soc. 2008, 130,
15185e15192; (b) Daugulis, O.; Do, H.-Q.; Shabashov, D. Acc. Chem. Res. 2009,
42, 1074e1086.
(m, 5H), 8.75 (s, 1H); 13C NMR (CDCl3, 75 MHz)
d
129.1, 130.1, 130.9, 143.4, 144.9, 151.3, 161.3; IR (KBr)
n
1715, 1139 cmꢁ1; Anal. Calcd for C12H11NO3 (261.34): C, 64.34; H,
5.79; N, 5.36; S, 12.27 Found: C, 64.60; H, 5.82; N, 5.38; S, 12.33.
Acknowledgements
We gratefully acknowledge Dr. Lieven Meerpoel for useful dis-
cussions during this work and also, Janssen R&D for financial sup-
port. We thank the Centre de ressources Informatiques de haute-
Normandie (CRIHAN) for software optimization and kind techni-
cal support.
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ꢀ
13. Theveau, L.; Verrier, C.; Lassalas, P.; Martin, T.; Dupas, G.; Querolle, O.; Van
Supplementary data
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16. Free Gibbs energy of activation for acetate-assisted C2eH and C5eH CMD-TS
were calculated through DFT calculations using B3LYP method. Calculated
value for C2eH and C5eH CMD-TS of methyl oxazole-4-carboxylate are 22.
9 kcal molꢁ1 and 23.3 kcal molꢁ1, respectively, that is, 1.5 kcal molꢁ1of differ-
ence. See the Supplementary data of Ref. 13.
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2013.01.073.
References and notes
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L.-C.; Parisien, M.; Jean, A.; Fagnou, K. J. Am. Chem. Soc. 2006, 128, 581e590.
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