Carbon-carbon bond formation through double sp2 C-H activations: Synthesis of ferrocenyl oxazoline derivatives

Article abstract of DOI:10.1021/om700806e

Direct arylation of simple arenes with ferrocenyl oxazolines was achieved in the presence of a stoichiometric amount of Pd(OAc)₂ or a catalytic amount of palladium with excess oxidant such as Cu(OAc)₂. This double sp² C-H activation process provides a unique access to the aryl-substituted ferrocene derivatives, even in the enantiopure form of planar chirality, in a few steps from readily available starting materials.

Full text of DOI:10.1021/om700806e

Organometallics 2007, 26, 4869-4871
4869
Carbon-Carbon Bond Formation through Double sp2 C-H
Activations: Synthesis of Ferrocenyl Oxazoline Derivatives
Ji-Bao Xia and Shu-Li You*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, People’s Republic of China
ReceiVed August 7, 2007
Summary: Direct arylation of simple arenes with ferrocenyl
oxazolines was achieVed in the presence of a stoichiometric
amount of Pd(OAc)2 or a catalytic amount of palladium with
excess oxidant such as Cu(OAc)2. This double sp2 C-H
actiVation process proVides a unique access to the aryl-
substituted ferrocene deriVatiVes, eVen in the enantiopure form
of planar chirality, in a few steps from readily aVailable starting
materials.
tives have been extensively applied in homogeneous catalysis,
organic synthesis, materials science, etc., and facile syntheses
of ferrocene derivatives, especially with intriguing planar
chirality, are in great demand.6
Synthesis of biaryl compounds and their heteroaromatic
analogues represents one of the most intense research areas in
chemistry due to their abundance among biologically active and
functional molecules.1 The classical coupling methods such as
Suzuki coupling require stoichiometric amounts of organome-
tallic aryl compounds and aryl halides.2 The synthesis of these
activated coupling precursors usually requires multistep syn-
theses, and a stoichiometric amount of undesired organometallic
byproducts is also produced from the coupling reaction.
Consequently, the direct arylation of C-H bonds via C-H
activation for the biaryl synthesis, potentially the solution to
the above problems, has received great attention and witnessed
significant progress in the past decade.3 However, most of the
processes still use either stoichiometric amounts of organome-
tallic aryl compounds or aryl halides.4 Synthesis of the unsym-
metrical biaryls through double sp2 C-H activation remains rare
but certainly extremely desirable.5 In addition, ferrocene deriva-
We envisaged that a directing group introduced to the
ferrocene would afford preferentially a proximal C-H activation
on the Cp ring to initiate the coupling process and possibly
reduce the homocoupling side product of the other arene (eq
1). An oxazoline is used for this purpose and also because of
its potentially wide applications in asymmetric catalysis.7,8 In
this paper, we report the synthesis of aryl-substituted ferro-
cenyl oxazolines through double C-H activations with either
stoichiometric or catalytic palladium catalyst.9 This approach
is also applicable to the highly diastereoselective synthesis of
planar chiral ferrocenyl oxazoline derivatives.
We began our studies by using ferrocenyl oxazoline 1 and
benzene as substrates in the presence of a stoichiometric amount
of Pd(OAc)2 to promote the coupling reaction. Refluxing 1 and
Pd(OAc)2 (1 equiv) in benzene without base did not lead to
any observable coupling products. When the reaction was carried
out by adding K3PO4 at the beginning, an 8% yield of 2a was
isolated. If the same base was added after refluxing 1 and
Pd(OAc)2 (1 equiv) in benzene for 3 h, forming the dimer I,10
* Corresponding author. E-mail: slyou@mail.sioc.ac.cn.
(1) (a) Hassan, J.; Se´vignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M.
Chem. ReV. 2002, 102, 1359. (b) Horton, D. A.; Bourne, G. T.; Smythe,
M. L. Chem. ReV. 2003, 103, 893. (c) Bringmann, G.; Gu¨nther, C.; Ochse,
M.; Schupp, O.; Tasler, S. Biaryls in Nature: A Multi-Facetted Class of
Stereochemically, Biosynthetically, and Pharmacologically Intriguing Sec-
ondary Metabolites. In Progress in the Chemistry of Organic Natural
Products; Herz, W., Falk, H., Kirby, G. W., Moore, R. E., Eds.; Springer-
Verlag: New York, 2001; Vol. 82.
(2) (a) Miyaura, N.; Yamada, K.; Suzuki, A. Tetrahedron Lett. 1979,
20, 3437. (b) Miyaura, N.; Suzuki, A. J. Chem. Soc., Chem. Commun. 1979,
866. (c) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457. (d) Suzuki,
A. J. Organomet. Chem. 1999, 576, 147.
(3) For reviews: (a) Dyker, G. Angew. Chem., Int. Ed. 1999, 38, 1698.
(b) Campeau, L.-C.; Fagnou, K. Chem. Commun. 2006, 1253. (c) Godula,
K.; Sames, D. Science 2007, 312, 67. (d) Alberico, D.; Scott, M. E.; Lautens,
M. Chem. ReV. 2007, 107, 174. (e) Campeau, L.-C.; Stuart, D. R.; Fagnou,
K. Aldrichim. Acta 2007, 40, 35.
(4) For selected recent examples: (a) Chiong, H. A.; Daugulis, O. Org.
Lett. 2007, 9, 1449. (b) Giri, R.; Maugel, N.; Li, J.-J.; Wang, D.-H.;
Breazzano, S. P.; Saunders, L. B.; Yu, J.-Q. J. Am. Chem. Soc. 2007, 129,
3510. (c) Yang, S.; Li, B.; Wan, X.; Shi, Z. J. Am. Chem. Soc. 2007, 129,
6066. (d) Garc´ıa-Cuadrado, D.; de Mendoza, P.; Braga, A. A. C.; Maseras,
F.; Echavarren, A. M. J. Am. Chem. Soc. 2007, 129, 6880. (e) Wang, X.;
Gribkov, D. V.; Sames, D. J. Org. Chem. 2007, 72, 1476. (f) Battace, A.;
Lemhadri, M.; Zair, T.; Doucet, H.; Santelli, M. Organometallics 2007,
26, 472. (g) Proch, S.; Kempe, R. Angew. Chem., Int. Ed. 2007, 46, 3135.
(h) Shi, Z.; Li, B.; Wan, X.; Cheng, J.; Fang, Z.; Cao, B.; Qin, C.; Wang,
Y. Angew. Chem., Int. Ed. 2007, 46, 5554. (i) Chiong, H. A.; Pharm, Q.-
N.; Daugulis, O. J. Am. Chem. Soc. 2007, 129, 9879.
(6) (a) Hayashi, T., Togni, A., Eds. Ferrocenes; VCH: Weinheim, 1995.
(b) Richards, C. J.; Locke, A. J. Tetrahedron: Asymmetry 1998, 9, 2377.
(c) Dai, L.-X.; Tu, T.; You, S.-L.; Deng, W.-P.; Hou, X.-L. Acc. Chem.
Res. 2003, 36, 659. (d) Colacot, T. J. Chem. ReV. 2003, 103, 3101. (e)
Arraya´s, R. G.; Adrio, J.; Carretero, J. C. Angew. Chem., Int. Ed. 2006, 45,
7674.
(7) For utilization of oxazoline as a directing group in C-H activation,
see: (a) Giri, R.; Chen, X.; Yu, J.-Q. Angew. Chem., Int. Ed. 2005, 44,
2112. (b) Giri, R.; Chen, X.; Hao, X.-S.; Li, J.-J.; Liang, J.; Fan, Z.-P.; Yu,
J.-Q. Tetrahedron: Asymmetry 2005, 16, 3502. (c) Chen, X.; Li, J.-J.; Hao,
X.-S.; Goodhue, C. E.; Yu, J.-Q. J. Am. Chem. Soc. 2006, 128, 78.
(8) Selected examples for applications of ferrocenyl oxazolines: (a) Bolm,
C.; Mun˜iz-Ferna´ndez, K.; Seger, A.; Raabe, G.; Gu¨nther, K. J. Org. Chem.
1998, 63, 7860. (b) Donde, Y.; Overman, L. E. J. Am. Chem. Soc. 1999,
121, 2933. (c) You, S.-L.; Hou, X.-L.; Dai, L.-X.; Yu, Y.-H.; Xia, W. J.
Org. Chem. 2002, 67, 4684. (d) Rudolph, J.; Bolm, C.; Norrby, P.-O. J.
Am. Chem. Soc. 2005, 127, 1548. (e) Anderson, C. E.; Donde, Y.; Douglas,
C. J.; Overman, L. E. J. Org. Chem. 2005, 70, 648. (f) Yan, X.-X.; Peng,
Q.; Zhang, Y.; Zhang, K.; Hong, W.; Hou, X.-L.; Wu, Y.-D. Angew. Chem.,
Int. Ed. 2006, 45, 1979. (g) Onodera, G.; Nishibayashi, Y.; Uemura, S.
Angew. Chem., Int. Ed. 2006, 45, 3819. (h) Weiss, M. E.; Fischer, D. F.;
Xin, Z.-Q.; Jautze, S.; Schweizer, W. B.; Peters, R. Angew. Chem., Int. Ed.
2006, 45, 5694.
(9) During the preparation of the manuscript, two reports on the Pd-
catalyzed C-C bond formation via double C-H activations appeared; see:
(a) Stuart, D. R.; Fagnou, K. Science 2007, 316, 1172. (b) Dwight, T. A.;
Rue, N. R.; Charyk, D.; Josselyn, R.; DeBoef, B. Org. Lett. 2007, 9, 3137.
(10) For details, see the Supporting Information.
(5) (a) Itahara, T. J. Chem. Soc., Chem. Commun. 1981, 254. (b) Li, R.;
Jiang, L.; Lu, W. Organometallics 2006, 25, 5973, and references therein.
10.1021/om700806e CCC: $37.00 © 2007 American Chemical Society
Publication on Web 08/25/2007

4870 Organometallics, Vol. 26, No. 20, 2007
Communications
Table 1. Optimization of the Reaction Conditionsa
Table 1). Noticeably, a 64% yield of 2a was obtained when the
isolated dimer I was used (entry 10, Table 1).
entry
base
time (h)
yield (%)b
1
48
24
24
48
30
11
11
72
48
24
NR
8
2c
3
K3PO4
K3PO4
Na2CO3
KOtBu
Cs2CO3
K2CO3
Et3N
Under these optimized conditions, several other arenes have
also been tested in the cross-coupling reaction with 1. When
toluene was used, 2b was isolated in 44% yield (m/p: 2.7:1)
together with 1% of 3b. When the isolated palladium dimer
was used, an identical result, isolation of 2b in 47% yield
(m/p: 2.6:1), was obtained. Fluorobenzene was also suitable
for the cross-coupling reaction; 2c was afforded in 63% yield
as a mixture of three regioisomers (o/m/p: 13.3:9:1). When 1
was reacted with tert-butylbenzene, a 32% yield of 2d (m/p:
1.7:1) and 3% of bis-coupled product 3d were obtained. The
lack of ortho product here, as well as in the case of toluene, is
probably due to the steric bulkiness of the tert-butyl or methyl
group. To avoid the regioisomer, symmetrical substrates such
as 1,4-dimethoxybenzene were used, and 26% of 2e was
obtained. Interestingly, heterocyclic arenes such as 2,3-benzo-
furan could also undergo the cross-coupling reaction at the
2-position of 2,3-benzofuran to afford 2f (37%). No reaction
occurred when mesitylene was used, probably due to steric
congestion. Cross-coupling of 1 with pentafluorobenzene led
to a complex mixture.
An intriguing feature of ferrocene derivatives is the introduc-
tion of planar chirality when two different groups are installed
on the same Cp ring. Under the optimized reaction conditions,
we have checked the possibility to synthesize planar chiral
ferrocene derivatives by utilizing the enantiopure ferrocenyl
oxazoline. As shown in Scheme 1, starting from ferrocenyl
oxazoline 4, 5 (24%) was obtained as a single diastereomer when
the dimer was formed in situ. Interestingly, palladium dimer II
was easily formed and the structure was confirmed by an X-ray
analysis.10,11 When the isolated dimer II was further refluxed
in benzene in the presence of K2CO3 (2.3 equiv), a 69% yield
of 5 resulted. To obtain the diastereomer of 5, 6 was subjected
to the coupling conditions, and cross-coupled product 7 was
obtained in 54% yield. Removal of the trimethylsilyl group by
refluxing 7 in a solution of TBAF in THF led to 8 (76%), a
diastereomer of 5. Therefore, compounds 5 and 8, having the
same central chirality but different planar chirality, could be
synthesized conveniently with excellent diastereoselectivity.
The cross-coupling reactions with catalytic palladium acetate
(10 mol %) and an extra oxidant have also been explored by
using ferrocenyl oxazoline 1 as the substrate.10 Several oxidants
such as benzoquinone, Cu(OAc)2, molecular oxygen, and
different additives were tested, and Cu(OAc)2 was found to be
30(4)
29(19)
36(7)
63(18)
70(16)
<5
4
5
6
7
8
9c
10d
K2CO3
K2CO3
42(17)
64(9)
a Reaction conditions: 1 (0.3 mmol) and Pd(OAc)2 (0.3 mmol) in benzene
(1.5 mL) were refluxed for 3 h, then base (0.69 mmol) was added. Isolated
b
yield of 2a based on 1. The number in parentheses indicates the yield of
c
d
the recovered 1. Base was added at the beginning. Isolated dimer I was
used.
Table 2. Cross-Coupling Reactions of 1 with Arenesa
temp
time
(h)
entry
arene
benzene
method
(°C)b
yield (%)c
70 (2a)
44 (2b, m/p:
2.7:1):1 (3b)
47 (2b, m/p:
2.6:1)
63 (2c, o/m/p:
13.3:9:1)
32 (2d, m/p:
1.7:1):3 (3d)
26 (2e)
1
2
A
A
100
100
11
24
toluene
3d
4
toluene
100
100
100
120
8
24
48
82
fluorobenzene
tert-butylbenzene
A
C
C
5
6
1,4-dimethoxy-
benzene
7
2,3-benzofuran
mesitylene
pentafluoro-
benzene
B
C
C
100
120
120
51
120
40
37 (2f)
NR
complicated
8
9e
a Methods: A: 1 (0.3 mmol) and Pd(OAc)2 (0.3 mmol) in arene (1.5
mL) were heated for 3 h, then K2CO3 (0.69 mmol) was added. B: 1 and
Pd(OAc)2 in CH2Cl2 were refluxed for 3 h; after removal of CH2Cl2, K2CO3
and arene was added and heated. C: 1, Pd(OAc)2, and K2CO3 were heated
b
c
d
in arene. The temperature of oil bath. Isolated yield based on 1. Isolated
e
dimer I was used. A complex mixture was given.
the yield of 2a was improved to 30% (entry 3, Table 1). Various
bases were tested in the reaction, and all of them led to the
formation of 2a except organic base such as Et3N. An optimal
yield of 70% was obtained when K2CO3 was used (entry 7,
Scheme 1. Synthesis of Planar Chiral Ferrocenyl Oxazolines

Communications
Scheme 2. Catalytic Cross-Coupling Reactions
Organometallics, Vol. 26, No. 20, 2007 4871
Scheme 3. Isotope Effects in the Cross-Coupling Reaction
In summary, we have found that ferrocenyl oxazoline, where
the oxazoline was employed as a directing group, could react
with simple arenes via double sp2 C-H activations. Excellent
diastereoselectivities were obtained in the cross-coupling reac-
tions when chiral ferrocenyl oxazolines were used, providing a
facile method to synthesize planar chiral aryl-substituted fer-
rocenyl oxazolines. A catalytic process has also been realized,
but the catalytic efficiency needs further improvement. Further
mechanistic investigations and development of a more efficient
catalytic system are currently underway.
optimal. In the presence of 10 mol % of Pd(OAc)2, 2 equiv of
Cu(OAc)2, and 2.3 equiv of K2CO3, the reaction was carried
out at 120 °C in a sealed tube to give a complete conversion of
1; 4% of 2a and 39% of 3a were isolated (Scheme 2). However,
further application of these catalytic conditions to other
substrates proved less successful. For instance, coupling of 1
with 2,3-benzofuran under the catalytic conditions gave only
17% of 2f and 6% of 3f.
To determine the intermolecular isotope effects in this cross-
coupling reaction, palladium dimer I was subjected to the
reaction conditions utilizing equimolar benzene and benzene-
d6. As shown in Scheme 3, 2a and the coupling product from
benzene-d6 were obtained in a ratio of 1.8:1 (kH/kD), suggesting
the involvement of the C-H cleavage in the rate-limiting
step.4h,7a
Acknowledgment. We thank the Chinese Academy of
Sciences and the National Natural Science Foundation of China
for financial support.
Supporting Information Available: Experimental procedures
and analysis data for new compounds, CIF file of II (CCDC
643978). This material is available free of charge via the Internet
at http://pubs.acs.org.
(11) For 4-ferrocenyl-1,3-oxazoline, a different palladium complex,
palladation on a different Cp ring, is formed; see: Moyano, A.; Rosol, M.;
Moreno, R. M.; Lo´pez, C.; Maestro, M. A. Angew. Chem., Int. Ed. 2005,
44, 1865.
OM700806E