Synthesis of polycyclic molecules by double C(sp2)-H/C(sp 3)-H arylations with a single palladium catalyst

Article abstract of DOI:10.1021/ol200329e

Polycyclic molecules were obtained in good yields by double C(sp ²)-H/C(sp³)-H arylations mediated by a single palladium/phosphine catalyst. Both double intermolecular/intramolecular and intramolecular/intramolecular C-C couplings we

Full text of DOI:10.1021/ol200329e

ORGANIC
LETTERS
2011
Vol. 13, No. 7
1816–1819
Synthesis of Polycyclic Molecules by
Double C(sp2)-H/C(sp3)-H Arylations
with a Single Palladium Catalyst
Cathleen Pierre and Olivier Baudoin*
ꢀ
Universite Claude Bernard Lyon 1, CNRS UMR 5246 - Institut de Chimie et Biochimie
Moleculaires et Supramoleculaires, CPE Lyon, 43 Boulevard du 11 Novembre 1918,
ꢀ
ꢀ
69622 Villeurbanne, France
olivier.baudoin@univ-lyon1.fr
Received February 3, 2011
ABSTRACT
Polycyclic molecules were obtained in good yields by double C(sp2)-H/C(sp3)-H arylations mediated by a single palladium/phosphine catalyst.
Both double intermolecular/intramolecular and intramolecular/intramolecular C-C couplings were performed successfully, which indicates that
this concept has a broad applicability for the rapid construction of molecular complexity.
In recent years, transition-metal-catalyzed C-H bond
functionalization has emerged as a powerful tool to trans-
form otherwise unreactive C-H bonds into carbon
-carbon or carbon-heteroatom bonds.1,2 In particular,
C-H arylation has become an attractive alternative to
traditional C-C cross-coupling reactions due to the
minimization of stoichiometricmetallicwaste and the costs
associated with the preparation of starting materials.3
Efforts by our group4 and others5,6 in the context of alkane
C(sp3)-H arylation under palladium(0) catalysis have led
to a greater scope for intramolecular reactions, generating
(5) Selected work on intramolecular C(sp3)-H arylation: (a) Dong,
C.-G.; Hu, Q.-S. Angew. Chem., Int. Ed. 2006, 45, 2289. (b) Ren, H.;
Knochel, P. Angew. Chem., Int. Ed. 2006, 45, 3462. (c) Ren, H.; Li, Z.;
Knochel, P. Chem.;Asian J. 2007, 2, 416. (d) Lafrance, M.; Gorelsky,
S. I.; Fagnou, K. J. Am. Chem. Soc. 2007, 129, 14570. (e) Watanabe, T.;
Oishi, S.; Fujii, N.; Ohno, H. Org. Lett. 2008, 10, 1759. (f) Salcedo, A.;
Neuville, L.; Zhu, J. J. Org. Chem. 2008, 73, 3600. (g) Hsiao, C.-C.; Lin,
Y.-K.; Liu, C.-J.; Wu, T.-C.; Wu, Y.-T. Adv. Synth. Catal. 2010, 352,
3267. (h) Rousseaux, S.; Gorelsky, S. I.; Chung, B. K. W.; Fagnou, K.
J. Am. Chem. Soc. 2010, 132, 10692.
(1) Handbook of C-H Transformations; Dyker, G., Ed.; Wiley-VCH:
Weinheim, 2005.
(2) Topics in Current Chemistry, Vol. 292; Yu, J.-Q., Shi, Z., Eds.;
Springer: Heidelberg, 2010.
(3) Selected recent reviews: (a) Campeau, L.-C.; Fagnou, K. Chem.
Commun. 2006, 1253. (b) Alberico, D.; Scott, M. E.; Lautens, M. Chem.
Rev. 2007, 107, 174. (c) McGlacken, G. P.; Bateman, L. M. Chem. Soc.
Rev. 2009, 38, 2447. (d) Bellina, F.; Rossi, R. Tetrahedron 2009, 65,
10269. (e) Ackermann, L.; Vicente, R.; Kapdi, A. R. Angew. Chem., Int.
Ed. 2009, 48, 9792.
(6) Selected work on intermolecular C(sp3)-H arylation: (a) Barder,
T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L. J. Am. Chem. Soc.
2005, 127, 4685. (b) Niwa, T.; Yorimitsu, H.; Oshima, K. Org. Lett.
2007, 9, 2373. (c) Campeau, L.-C.; Schipper, D. J.; Fagnou, K. J. Am.
ꢀ
(4) (a) Baudoin, O.; Herrbach, A.; Gueritte, F. Angew. Chem., Int.
Ed. 2003, 42, 5736. (b) Hitce, J.; Retailleau, P.; Baudoin, O. Chem.;Eur.
J. 2007, 13, 792. (c) Hitce, J.; Baudoin, O. Adv. Synth. Catal. 2007, 349,
2054. (d) Chaumontet, M.; Piccardi, R.; Audic, N.; Hitce, J.; Peglion,
J.-L.; Clot, E.; Baudoin, O. J. Am. Chem. Soc. 2008, 130, 15157.
(e) Chaumontet, M.; Piccardi, R.; Baudoin, O. Angew. Chem., Int. Ed.
2009, 48, 179. (f) Rousseaux, S.; Davi, M.; Sofack-Kreutzer, J.; Pierre,
C.; Kefalidis, C. E.; Clot, E.; Fagnou, K.; Baudoin, O. J. Am. Chem. Soc.
2010, 132, 10706.
ꢀ
Chem. Soc. 2008, 130, 3266. (d) Mousseau, J. J.; Larivee, A.; Charette,
A. B. Org. Lett. 2008, 10, 1641. (e) Wasa, M.; Engle, K. M.; Yu, J.-Q.
J. Am. Chem. Soc. 2009, 131, 9886. (f) Burton, P. M.; Morris, J. A. Org.
ꢀ
Lett. 2010, 12, 5359. (g) Renaudat, A.; Jean-Gerard, L.; Jazzar, R.;
Kefalidis, C. E.; Clot, E.; Baudoin, O. Angew. Chem., Int. Ed. 2010, 49,
7261.
r
10.1021/ol200329e
Published on Web 03/07/2011
2011 American Chemical Society

Table 1. Double Intermolecular C(sp2)-H/Intramolecular C(sp3)-H Arylation of Thiophenes and Furansa
a Reactionconditions:heteroarylchloride(1equiv), arylhalide(1.1equiv), Pd(OAc)2 (5mol%), P(Cyp)3•HBF4 (20mol%), K2CO3 (2equiv), PivOH(30
mol %), DMF, 140 °C, 6-24 h. b Yield of the isolated product. c Determined by 1H NMR analysis of the crude reaction mixture. d 1:1 ratio of 1a/4 after 14 h.
various motifs of synthetically useful fused carbocycles
and heterocycles.7 We report herein that intramolecular
C(sp3)-H arylations can be combined with inter- or
intramolecular C-H arylations in the presence of the same
palladium catalyst. These new types of double C-H
arylations8 allow the rapid construction of molecular
complexity and provide an efficient access to original
polycyclic molecules.
The double intermolecular C(sp2)-H/intramolecular
C(sp3)-H arylation of chlorothiophene 1a with aryl ha-
lides 2 was first investigated (Table 1). Individual C-H
arylations at play in this reaction are known,3,4f,9 but we
wondered if a single batch of catalyst was able to perform
both operations in one pot without undergoing deactiva-
tion intermediately. This was observed to be the case, and
(7) Review: Jazzar, R.; Hitce, J.; Renaudat, A.; Sofack-Kreutzer, J.;
Baudoin, O. Chem.;Eur. J. 2010, 16, 2654.
(8) For recent examples of multiple C(sp2)-H arylations: (a) Huang,
Q.; Fazio, A.; Dai, G.; Campo, M. A.; Larock, R. C. J. Am. Chem. Soc.
2004, 126, 7460. (b) Wakui, H.; Kawasaki, S.; Satoh, T.; Miura, M.;
Nomura, M. J. Am. Chem. Soc. 2004, 126, 8658. (c) Kamikawa, K.;
Takemoto, I.; Takemoto, S.; Matsuzaka, H. J. Org. Chem. 2007, 72,
7406. (d) Ohno, H.; Iuchi, M.; Fujii, N.; Tanaka, T. Org. Lett. 2007, 9,
4813. (e) Majumdar, K. C.; Chakravorty, S.; De, N. Tetrahedron Lett.
2008, 49, 3419. (f) Join, B.; Yamamoto, T.; Itami, K. Angew. Chem., Int.
Ed. 2009, 48, 3644. (g) Della Ca’, N.; Maestri, G.; Catellani, M. Chem.;
Eur. J. 2009, 15, 7850. (h) Thirunavukkarasu, V. S.; Parthasarathy, K.;
Cheng, C.-H. Chem.;Eur. J. 2010, 16, 1436. (i) Shibahara, F.; Yama-
guchi, E.; Murai, T. Chem. Commun. 2010, 46, 2471.
Org. Lett., Vol. 13, No. 7, 2011
1817

the best results were obtained using the Pd(OAc)2/tricy-
clopentylphosphine [P(Cyp)3] catalyst previously devel-
oped for intramolecular arylation,4f in the presence of
catalytic pivalic acid10 and K2CO3 in DMF at 140 °C.
Remarkably, only 1.1 equiv of aryl halide was sufficient to
achieve complete conversion under these conditions. The
reaction proceeded more efficiently with aryl halides 2
bearing an ortho or meta electron-withdrawing or neutral
group (entries 2-8), whereas other aryl bromides such as
bromobenzene (entry 1) and p-bromotoluene (entry 9)
gave mixtures of unreacted 1a, mono-C(sp2)-H arylation
(4), and bis-arylation (3) products.
Interestingly, intermolecular C(sp2)-H arylation oc-
curredbeforeintramolecularC(sp3)-H arylation witharyl
bromides, as shown by the observation of compound 4 and
the absence of compound 5 at incomplete substrate con-
version. In addition, the diastereoselectivity observed for
products 3 that were obtained in the presence of aryl
bromides was usually higher (dr g 5:1) than that observed
for product 5 that was obtained in the absence of aryl
bromide (dr = 4:1). When o-chlorotoluene was employed
as the coupling partner (entry 3) instead of o-bromo-
toluene (entry 2), intramolecular C(sp3)-H arylation oc-
curred first, as shown by the observation of compound 5
and the absence of compound 4 at incomplete substrate
conversion. The 4:1 diastereoselectivity observed for 3b in
this case (entry 3) is also consistent with this analysis. With
the studied aryl bromides 2, oxidative addition of the
C-Br bond to Pd seems to occur first and the Pd catalyst
is thus committed first to the intermolecular C(sp2)-H
arylation. In contrast, with o-chlorotoluene, oxidative
addition seems to occur first from the more electron-
deficient heteroarene C-Cl bond and thus intramolecular
C(sp3)-H arylation is taking place first. Additional factors
such as the accelerating effect of the heteroarene chlorine
atom on the intermolecular C(sp2)-H arylation11 and the
difference in C(sp3)-H and C(sp2)-H bond strengths may
also be at play in this double C-H arylation process.
Interestingly, furan 1b could be arylated successfully,
similar to thiophene 1a (entries 10-12), although longer
reaction times were required due to the lower reactivity of
the furan motif toward intermolecular C(sp2)-H aryla-
tion. Major diastereoisomers 3 obtained from this double
arylation process all possessed the cis configuration, as
determined by NOESY experiments and by X-ray diffrac-
tion analysis for compound 3f (Figure 1). The latter
revealed a highly planar biaryl structure, indicating that
the difference in diastereoselectivities observed with the
various aryl bromides arise from electronic factors rather
than from steric ones.
Figure 1. X-ray crystal structure of compound 3f (30% prob-
ability ellipsoids plot).
compounds (see the Supporting Information), were stu-
died as a proof of concept (Table 2). The same reaction
conditions as those in the mixed inter/intramolecular
arylation (Table 1) were employed, with the exception of
pivalic acid which was not required to obtain optimal
yields in this case.12 Under these conditions, fused tetra-
cyclic compounds 7a-d were obtained in good yields and
with comparable diastereoselectivities, regardless of the
electron-withdrawing/-donating nature of the R substitu-
ent on the haloarene ring. Monitoring these reactions
at incomplete conversion revealed that intramolecular
C(sp2)-H arylation preceded intramolecular C(sp3)-H
arylation with X = Br, which again results probably from
the faster initial oxidative addition of the C-Brbond tothe
Pd catalyst. The same reactivity trend was observed with X
= Cl (entry 2), for which the first oxidative addition
probably occurs at the least sterically hindered C-Cl
Table 2. Double Intramolecular C(sp2)-H/C(sp3)-H Aryla-
tiona
entry
X
R
product
yield (%)b
drc
1
2
3
4
5
Br
Cl
H
7a
7a
7b
7c
7d
68
83
72
87
60
4.5:1
4.5:1
5:1
H
Br
Br
Br
F
CF3
OMe
5:1
5:1
A doubleintramolecular C(sp2)-H/C(sp3)-H arylation
was next investigated, and dihalogenated substrates 6,
synthesized in five steps from commercially available
a Reaction conditions: Pd(OAc)2 (5 mol %), P(Cyp)3•HBF4
(20 mol %), K2CO3 (2 equiv), DMF, 140 °C, 24-36 h. b Yield of the
isolated product. c Determined by 1H NMR analysis of the crude
reaction mixture.
(9) For similar conditions developed for intermolecular C-H aryla-
ꢀ
tions of heteroarenes: Liegault, B.; Lapointe, D.; Caron, L.; Vlassova,
(12) For similar conditions developed for intramolecular C(sp2)-H
arylations: (a) Campeau, L.-C.; Parisien, M.; Leblanc, M.; Fagnou, K.
J. Am. Chem. Soc. 2004, 126, 9186. (b) Campeau, L.-C.; Parisien, M.;
Jean, A.; Fagnou, K. J. Am. Chem. Soc. 2006, 128, 581.
A.; Fagnou, K. J. Org. Chem. 2009, 74, 1826.
(10) Lafrance, M.; Fagnou, K. J. Am. Chem. Soc. 2006, 128, 16496.
(11) Liegault, B.; Petrov, I.; Gorelsky, S. I.; Fagnou, K. J. Org. Chem.
ꢀ
2010, 75, 1047.
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Org. Lett., Vol. 13, No. 7, 2011

bond. This order of arylation events may explain why a
complete regioselectivity was observed for the intramole-
cular C(sp2)-H arylation, which occurred as expected at
the most sterically accessible C(sp2)-H bond para to the
quaternary benzylic carbon.12
Finally, we examined the feasibility of a double intra-
molecular C(sp3)-H/C(sp3)-H arylation under the same
guidelines.5b,c As in previous examples, the corresponding
individual C-H arylations are known,4f but we again
wondered if a single batch of catalyst could perform both
operations. To this purpose, we chose to study the reactiv-
ity of dichloride 8 (Scheme1), which was synthesizedin five
steps, 37% overall yield, from 2,4-dichloroacetophenone
10. We considered as well other dihalogenated substrates,
but 8 turned out to be the most accessible. Gratifyingly,
compound 8 furnished original fused tricyclic product 9 in
75% yield, under conditions previously optimized for
individual C-H arylations, i.e. with tricyclohexylphos-
phine as the Pd ligand, Cs2CO3/pivalic acid as the base/
additive, and mesitylene as the solvent.4f
In conclusion, we have synthesized original polycyclic
molecules in good yields and diastereoselectivities by
double C-H arylations mediated by a single palladium/
phosphine catalyst. Both double intermolecular/intramo-
lecular and intramolecular/intramolecular C-C couplings
were performed successfully, which indicates that this
concept may be broadly used for the rapid construction
of molecular complexity.
Scheme 1. Double Intramolecular C(sp3)-H/C(sp3)-H
Arylation
ꢁ
Acknowledgment. We thank Ministere de l’Enseigne-
ment Superieur et de la Recherche (fellowship to C.P.),
ꢀ
Agence Nationale de la Recherche, Institut Universitaire
de France, and Johnson Matthey PLC (loan of palladium
acetate). We are also grateful to E. Jeanneau, C. Toppan,
ꢀ
and D. Bouchu (Universite Claude Bernard Lyon 1) for
X-ray diffraction, NMR, and MS analyses, respectively,
and N. Martin for carefully reading the experimental part.
Supporting Information Available. Full characteriza-
tion of all new compounds, detailed experimental proce-
dures, copies of NMR spectra for target molecules, and
X-ray crystal structure data (CIF) for compound 3f. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Org. Lett., Vol. 13, No. 7, 2011
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