Direct arylation of cyclic enamides via Pd(ii)-catalyzed C-H activation

Article abstract of DOI:10.1039/b903151k

A new direct coupling of cyclic enamides with aryl boronic acids via Pd(ii)-catalyzed C-H functionalization has been achieved with good yields (up to 90%).

Full text of DOI:10.1039/b903151k

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Direct arylation of cyclic enamides via Pd(II)-catalyzed C–H activationw
Hai Zhou, Wan-Jun Chung, Yun-He Xu and Teck-Peng Loh*
Received (in Cambridge, UK) 16th February 2009, Accepted 14th April 2009
First published as an Advance Article on the web 7th May 2009
DOI: 10.1039/b903151k
A new direct coupling of cyclic enamides with aryl boronic acids
via Pd(II)-catalyzed C–H functionalization has been achieved
with good yields (up to 90%).
reaction worked best in the presence of Cu(OTf)2 as the
oxidant, K2CO3 as the base and dioxane as the solvent.
With the optimized reaction conditions in hand, we
continued to explore the scope of this Pd(II)-catalyzed C–H
arylation process. Different aromatic boronic acids were next
examined (Table 2). This transformation was amenable to
various aromatic boronic acids possessing electron-donating
or electron-withdrawing groups, furnishing the products in
good to excellent yields. Electron-withdrawing groups, such as
nitro, on the phenyl ring of the boronic acid usually helped to
increase the ratio of 3 (3 : 4 = 95 : 5, Table 2, entry 8). In
addition, the position of the substituents on the aromatic ring
of the boronic acid also played a vital role in determining the
ratio. An ortho-methyl group provided a higher ratio of 3 than
did meta- and para-methyl groups, perhaps arising from steric
hindrance (Table 2, entry 3 vs. 4 and 5). A meta-methoxy
group afforded a higher ratio of 3 than a para-methoxy group
(Table 2, entry 9 vs. 10). This may have been due to electronic
effects. It should be noted herein that a meta-methoxy group
is electron-withdrawing, whereas a para-methoxy group is
electron-donating.
C–C bond formation is vital in organic chemistry. Among
the many known cross-coupling reactions, Suzuki–Miyaura
coupling is one of the most important C–C bond construction
protocols employed in the synthesis of commodity chemicals,
pharmaceutical compounds and biologically-active natural
products.1 One of the main drawbacks associated with this
classic Pd-catalyzed cross-coupling reaction is the need to use
organohalides or surrogates as substrates. Therefore, many
research groups have focused on C–H activation using simple
non-halogenated substrates.2 Recently, the formation of
C–C bonds through aromatic C–H activation via coupling
with organoboron reagents (Suzuki-type reaction), assisted by
a directing group, has been reported by several groups.3
However, as far as we know, the direct cross-coupling of
cyclic enamides via ortho C–H activation using a palladium
catalyst has not been reported. Herein, we report the highly
efficient direct cross-coupling reaction between cyclic enamides
and aryl boronic acids using catalytic amounts of palladium(II)
acetate.
Table 1 Screening conditions for the Pd(II)-catalyzed direct arylation
of 1a with phenylboronic acid (2a)a
To begin our study, a-tetralone-derived enamide 1a was
chosen to couple with phenylboronic acid (2a) in the presence
of Pd(OAc)2 as a catalyst under various reaction conditions
(Table 1). Firstly, using K2CO3 as the base and dioxane as the
solvent, we surveyed the effect of different oxidants. To our
delight, the desired product, 3a, was obtained, along with
aromatized coupling product 4a (92 : 8) in low to excellent
yield (Table 1, entries 1–6). However, Cu(OTf)2 was found to
be the most efficient oxidant for this coupling reaction,
yielding the product in 80% yield (Table 1, entry 6). It is
worthwhile noting that the presence of base is critical to this
coupling reaction. Reactions without the use of base lead to
intractable mixtures of products. Furthermore, the substrate
readily decomposes under acidic conditions. Among the
various bases screened (Table 1, entries 13–17), stronger bases
gave higher ratios of 3a, but in lower yields. For instance,
t-BuOK afforded the highest ratio (96 : 4), albeit with a low
yield (23%) (Table 1, entry 16). Solvents also have a strong
influence on the yield of the product. As shown in Table 1, the
Yield (%)b
(3a : 4a)c
Entry
Oxidant
Base
Solvent
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Ag2O
AgF
AgOAc
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
KOAc
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
DCE
CH3CN
tBuOH
DMSO
DMF
Toluene
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
39
32
34
30
38
80
52
0
Ag2CO3
Cu(OAc)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
0
0
29 (50 : 50)
39 (41 : 59)
64 (77 : 23)
54 (74 : 26)
37 (91 : 9)
23 (96 : 4)
76 (90 : 10)
K3PO4
Cs2CO3
t-BuOK
Na2CO3
Division of Chemistry and Biological Chemistry, School of Physical
and Mathematical Sciences, Nanyang Technological University,
21 Nanyang Link, SPMS-04-01, Singapore 637371.
E-mail: teckpeng@ntu.edu.sg; Fax: +65 6515 8229;
Tel: +65 6513 8203
w Electronic supplementary information (ESI) available: Detailed
experimental procedures, 1H and 13C NMR spectra, and analytical
data for all compounds. See DOI: 10.1039/b903151k
a
Conditions: 10 mol% Pd(OAc)2, 2 equiv. of 2a, 2 equiv. of oxidant,
b
c
2 equiv. of base, 80 1C, 16 h. Yields of isolated products. Ratios in
parentheses are the ratios of 3a and 4a (inseparable), which were
calculated by 1H NMR analysis; the other ratios were 92 : 8.
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Table 2 The Pd-catalyzed direct arylation of 1a with various boronic
acids 2a
Table 3 The Pd-catalyzed direct arylation of various cyclic enamides
1 with 2aa
Entry
1
2
3 : 4b
Yield (%)c
80
Entry
1
1
3 : 4b
Yield (%)c
82
92 : 8
86 : 14
2
3
82 : 18
95 : 5
60
75
2
3
4
5
75 : 25
86 : 14
96 : 4
63
65
69
74
4
5
6
7
80 : 20
80 : 20
86 : 14
90 : 10
67
70
57
67
100 : 0
6
7
100 : 0
100 : 0
71
70
8
9
95 : 5
64
68
68
88 : 12
71 : 29
10
8
100 : 0
100 : 0
57
90
a
Conditions: 10 mol% Pd(OAc)2, 2 equiv. of 2, 2 equiv. of Cu(OTf)2,
b
2 equiv. of K2CO3, dioxane, 80 1C, 16 h. The ratios of 3 and 4
(inseparable) were calculated by 1H NMR analysis. Yields of
isolated products.
c
9
a
Conditions: 10 mol% Pd(OAc)2, 2 equiv. of 2a, 2 equiv. of Cu(OTf)2,
b
Various cyclic enamides were next investigated (Table 3).4
This direct arylation could tolerate both mono- and
di-substitution on either the phenyl or aliphatic ring of
a-tetralone-derived enamides (Table 3, entries 1–4). Substitution
of the aliphatic ring produced a very high ratio of the
coupling product (Table 3, entry 4). In the case of
4-chromanone-derived enamides, this coupling reaction also
worked well with various substituents (for substrates 1f–1j) on
either the phenyl or aliphatic ring, providing only product 3.
No aromatized products were observed in all of these cases
(Table 3, entries 5–9).
2 equiv. of K2CO3, dioxane, 80 1C, 16 h. The ratios of 3 and 4
(inseparable) were calculated by 1H NMR analysis. Yields of
isolated products.
c
The other possibility is that starting material 1 is first oxidized
to aromatic acetamide 7, followed by aromatic C–H activation
and C–C coupling via palladacycle 8 to provide de-hydrogenated
product 4 (path b).8 Similar aromatic C–H activation has been
reported by the groups of Inoue7 and Shi.3d
In summary, we have developed a new direct coupling
method to access various cyclic enamide derivatives9 from
cyclic enamides and aryl boronic acids via Pd(II)-mediated
direct C–H functionalization. Further investigations to expand
the scope of the substrates and to further understand the
mechanism of this coupling reaction are in progress.
We gratefully acknowledge the Nanyang Technological
University and the Singapore Ministry of Education Academic
Research Fund Tier 2 (T206B1221; T207B1220RS) for their
financial support of this research.
A mechanism of the coupling reaction is proposed, as shown
in Scheme 1. With the assistance of the acetamino group,
six-membered palladacycle 5 is formed, which transmetallates
with 2a. Subsequent reductive elimination leads to product 3
and Pd(0). The Pd(0) species is re-oxidized to Pd(II) by Cu(II) to
complete the catalytic cycle (path a). Side coupling product 4
may well be reached through two possible paths (b and c).5
Product 3 may be oxidized by the oxidant to give 4 (path c).6
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J. Am. Chem. Soc., 2006, 128, 5033; (l) J. H. Chu, C. C. Chen and
M. J. Wu, Organometallics, 2008, 27, 5173; (m) H. Ge,
M. J. Niphakis and G. I. Georg, J. Am. Chem. Soc., 2008, 130,
3708; (n) H. Kawai, Y. Kobayashi, S. Oi and Y. Inoue, Chem.
Commun., 2008, 1464.
3 (a) X. Chen, J. J. Li, X. S. Hao, C. E. Goodhue and J. Q. Yu, J. Am.
Chem. Soc., 2006, 128, 78; (b) X. Chen, C. E. Goodhue and J. Q. Yu,
J. Am. Chem. Soc., 2006, 128, 12634; (c) R. Giri, N. Maugel, J. J. Li,
D. H. Wang, S. P. Breazzano, L. B. Saunders and J. Q. Yu, J. Am.
Chem. Soc., 2007, 129, 3510; (d) Z. J. Shi, B. J. Li, X. B. Wan,
Z. Fang, B. Cao, C. M. Qin and Y. Wang, Angew. Chem., Int. Ed.,
2007, 46, 5554.
4 Preliminary investigations using linear enamides proved futile.
5 (a) For aromatization, see: L. F. Silva, F. A. Siqueira Jr,
E. C. Pedrozo, F. Y. M. Vieira and A. C. Doriguetto, Org. Lett.,
2007, 9, 1433; (b) E. Nino, D. Avnir, M. S. Eisen and J. Blum,
J. Sol–Gel Sci. Technol., 2005, 35, 159; (c) W. K. Wong, X. P. Chen,
T. W. Chik, W. Y. Wong, J. P. Guo and F. W. Lee, Eur. J. Inorg.
Chem., 2003, 3539; (d) R. Neumann and M. Lissel, J. Org. Chem.,
1989, 54, 4607; (e) T. G. Back, J. H.-L. Chau and M. Parvez,
Synthesis, 1995, 162.
Scheme 1 A proposed mechanism for the direct arylation of cyclic
enamides.
Notes and references
1 (a) For reviews, see: H. Doucet, Eur. J. Org. Chem., 2008, 2013;
(b) N. Miyaura and A. Suzuki, Chem. Rev., 1995, 95, 2457;
(c) A. Suzuki, Pure Appl. Chem., 1991, 63, 419; (d) A. Suzuki,
J. Organomet. Chem., 1999, 576, 147; (e) S. Kotha, K. Lahiri and
D. Kashinath, Tetrahedron, 2002, 48, 9633.
6 An experiment to prove path c: the ratio of the coupling products in
Table 2, entry 5 (original ratio 80 : 20), under standard phenylation
reaction conditions for 16 h, changed to 25 : 75.
7 H. Horino and N. Inuoe, J. Org. Chem., 1981, 46, 4416.
8 Aromatic acetamide 7 was observed under the reaction conditions
of the direct arylation of 1 in the absence of organoboronic acid.
9 (a) For their importance and extensive application in asymmetric
catalytic hydrogenation, see: S. Enthaler, B. Hagemann, K. Junge,
G. Erre and M. Beller, Eur. J. Org. Chem., 2006, 2912;
(b) J. L. Renaud, P. Dupau, A.-E. Hay, M. Guingouain,
P. H. Dixneuf and C. Bruneau, Adv. Synth. Catal., 2003, 345, 230;
(c) Z. G. Zhang, G. X. Zhu, Q. Z. Jiang, D. M. Xiao and X. M. Zhang,
J. Org. Chem., 1999, 64, 1774; (d) M. Van den Berg, R. M. Haak,
A. J. Minnaard, A. H. M. De Vries, J. G. De Vries and B. L. Feringa,
Adv. Synth. Catal., 2002, 344, 1003; (e) M. J. Burk, G. Casy and
N. B. Johnson, J. Org. Chem., 1998, 63, 6084; (f) P. Dupau, P. Le
Gendre, C. Bruneau and P. H. Dixneuf, Synlett, 1999, 1832.
2 (a) For recent references, see: D. Alberico, M. E. Scott and
M. Lautens, Chem. Rev., 2007, 107, 174; (b) J. M. Lee, D. S. Ahn,
D. Y. Jung, J. Lee, Y. Do, S. K. Kim and S. Chang, J. Am. Chem.
Soc., 2006, 128, 12954; (c) S. H. Cho, S. J. Hwang and S. Chang,
J. Am. Chem. Soc., 2008, 130, 9254; (d) Y. Iwai, K. M. Gligorich
and M. S. Sigman, Angew. Chem., Int. Ed., 2008, 47, 3219; (e) C. Jia,
T. Kitamura and Y. Fujiwara, Acc. Chem. Res., 2001, 34, 633;
(f) A. E. Shilov, G. B. Shul and Pin, Chem. Rev., 1997, 97, 2879;
(g) J. H. Delcamp, A. P. Brucks and M. C. White, J. Am. Chem.
Soc., 2008, 130, 11270; (h) D. H. Wang, M. Wasa, R. Giri and
J. Q. Yu, J. Am. Chem. Soc., 2008, 130, 7190; (i) S. Yang, B. Li,
X. Wan and Z. Shi, J. Am. Chem. Soc., 2007, 129, 6066;
(j) Y. H. Xu, J. Lu and T. P. Loh, J. Am. Chem. Soc., 2009, 131,
1372; (k) D. J. Cardenas, B. Martin-Matute and A. M. Echavarren,
´
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This journal is The Royal Society of Chemistry 2009
3474 | Chem. Commun., 2009, 3472–3474