PdCl2-catalyzed efficient allylation and benzylation of heteroarenes under ligand, base/acid, and additive-free conditions

Article abstract of DOI:10.1039/c1cc10953g

We present a PdCl₂-catalyzed protocol for highly efficient allylation and benzylation of a rich variety of N-, O-, and S-containing heteroarenes under base/acid, additive, and ligand-free conditions. The method represents the very few examples

Full text of DOI:10.1039/c1cc10953g

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COMMUNICATION
PdCl2-catalyzed efficient allylation and benzylation of heteroarenes under
ligand, base/acid, and additive-free conditionsw
Feng-Quan Yuan,ab Lian-Xun Gaoa and Fu-She Han*ac
Received 18th February 2011, Accepted 14th March 2011
DOI: 10.1039/c1cc10953g
We present a PdCl2-catalyzed protocol for highly efficient allyl-
ation and benzylation of a rich variety of N-, O-, and S-containing
heteroarenes under base/acid, additive, and ligand-free conditions.
The method represents the very few examples for simple, univer-
sally applicable, clean, and atom-efficient functionalization of
heteroarenes.
Thus, the development of an efficient protocol that allows
for highly yielding and selective, generally applicable, green,
and atom-efficient allylation of various heteroarenes is highly
desirable.8 With our longstanding interest in transition-metal-
catalyzed synthesis of functionalized heteroarenes,9 herein, we
disclose that PdCl2 is a highly efficient catalyst to fulfill such a
goal. Namely, a rich range of N-, O- and S-based heteroarenes
can be allylated successfully with an equimolar or a slightly
excess of allylic acetate just in the presence of 2 mol% of PdCl2
as a catalyst under refluxed CH2Cl2 or (CH2)2Cl2,10 without
the need of any external bases/acids, additives, and ligands.
Moreover, only non-toxic acetic acid is generated as the
by-product in the transformation.
The N-, O-, and S-containing heteroarenes such as pyrrole, furan,
and thiophene-based derivatives are fundamental structural motifs
in numerous natural products, bioactive compounds, and
materials science.1 Therefore, methods for effective and straight-
forward functionalization of this class of molecules would be of
great interest. Allylic substitution represents one of the most
appealing reactions because the incorporated olefin may serve as
a latent group for versatile functionalization. So far, the Brønsted2
or Lewis acid,3 and iodine-catalyzed4 Friedel–Crafts (F–C) reac-
tion of an allylic alcohol (or its acetate) and heteroarene has been
frequently investigated which allows the reaction to proceed
cleanly with water or acetic acid as the only by-product. However,
the substrate scope of many of these pathways is limited.
ð1Þ
During the search of such a simple and efficient procedure, we
assumed that, based on the Tsuji–Trost or F–C reaction
mechanism (eqn (1)), the key to achieve this challenging goal
relies on the discovery of an appropriate metal catalyst whose
p-allylmetal complex A is sufficiently electrophilic to various
heteroarenes (Nuꢀ). Accordingly, an extensive screening of
catalyst was carried out by employing simple furan (1a) and
allylic acetate (2) as a model reaction (Table 1). Initial screening
revealed that various copper and nickel catalysts were inefficient.
However, the use of Pd(OAc)2 coupled with the presence of
20 mol% of PCy3 as a supporting ligand afforded the desired
3a in 10% yield (entry 1). Replacement of PCy3 by PPh3 led to
only a trace amount of 3a (entry 2). Surprisingly, the yield of
3a was increased significantly to 45% when the reaction was
performed in the absence of phosphine ligands (entry 3).
However, palladium black was observed in the reaction system
which should be the reason for incomplete conversion. From
these results, we proposed that although the addition of a
phosphine ligand may be acting to stabilize Pd(0), the nucleo-
philic substitution of heteroarenes is hampered by the steric or
electronic effect of the ligand. On the other hand, Pd(OAc)2
might be sufficiently active in the absence of an external ligand,
the reaction efficiency is lowered by the formation of Pd black.
Thus, the search of a Pd catalyst bearing an appropriate anion
and/or a ligand as well as a suitable solvent is crucial because these
factors have been shown to influence dramatically the redox
property and affinity of the metal ion, and thereby, affecting the
Alternatively, the Pd(0)-catalyzed allylation of heteroarenes
with alcohol derivatives via the Tsuji–Trost-type reaction has
been extensively investigated.5 In addition, sporadic examples
by using Ru6 and Ni7 catalysts have also been reported.
However, it is rather surprising that the pathways focused
overwhelmingly on the indole derivatives. Application to other
types of heteroarenes such as O- and S-based, and N-function-
alized indole derivatives has been sparsely investigated.
Moreover, the methods are less atom-efficient, and environ-
mentally and ecologically less compatible because smooth
transformation often necessitates the use of external ligands,
as well as a large amount of activators such as base/acid,
trialkyl boranes, and BSA. In addition, the formation of regio-
isomers such as N- and 3-allylindoles, and N,3-diallylindole is
also an important concern.5a,b
a Changchun Institute of Applied Chemistry,
Chinese Academy of Sciences, 5625 Renmin Street,
Changchun 130022, Jilin, China. E-mail: fshan@ciac.jl.cn;
Tel: +86-431-8526-2936
b Graduate School of Chinese Academy of Sciences,
Beijing, 100864, China
c State Key Laboratory of Fine Chemicals, Dalian 116024, China
w Electronic supplementary information (ESI) available: Experimental
procedures, characterization data, and 1H- and 13C-NMR spectra. See
DOI: 10.1039/c1cc10953g
c
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Chem. Commun., 2011, 47, 5289–5291 5289

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Table 2 Allylation of heteroarenes (1) with allylic acetate (2)a
Table 1 Optimization of the reaction conditionsa
Entry Heteroarene
T/h Product
Yieldb (%)
3a 72c
1
2
1a R = H
1b R = Me
2
5
3b 92c
3c 88
3d 93
Entry Equiv. of 1a Pd cat. (mol%)
Solvent T/h Yieldb (%)
1
2
3
4
5
6
7
8
20
20
20
20
20
20
20
20
10
10
5
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
CH2Cl2 24
CH2Cl2 24
CH2Cl2 24
10c
Traced
45
20
30
50
70
75
72
73
71
72
72
3
1c
1d
10
THF
Toluene 24
24
Pd(dppf)Cl2 (10) CH2Cl2 24
4
2
Pd(cod)Cl2 (10) CH2Cl2
PdCl2 (10)
PdCl2 (10)
Pd(cod)Cl2 (10) CH2Cl2
Pd(cod)Cl2 (10) CH2Cl2
2
2
2
2
2
4
2
CH2Cl2
CH2Cl2
5
6
7
8
1e R = H
8
3
6
8
3e 94
3f 86
3g 87
3h 88
9
1f R = Me
1g R = Bu
1h R = Boc
10
11
12
13
5
5
Pd(cod)Cl2 (2)
PdCl2 (2)
CH2Cl2
CH2Cl2
9
10
1i R = H
1j R = Me
10
8
3i 29c
3j 96
a
Unless otherwise noted, allylic acetate 2 (100 mg, 0.4 mmol, 1.0 equiv.)
and solvent (1.5 mL) under reflux were employed for reaction develop-
b
ment. Isolated yield. 20 mol% of PCy3 was used as a supporting
d
ligand. 20 mol% of PPh3 was used as a supporting ligand.
c
11
1k
10
3k 86
activity of the catalyst.11,5b A brief examination of the solvents
showed that CH2Cl2 was a suitable solvent (entries 3 vs. 4 and 5),
which was selected for further optimization of the catalysts. After
numerous trials, we eventually found that both PdCl2 and
Pd(cod)Cl2 are competent catalysts, affording the desired product
3a in over 70% yield (entries 7 and 8). Further optimization
revealed that the reaction could proceed smoothly by decreasing
1a to 5.0 equivalents with the catalyst loading as low as 2 mol%
(entries 12 and 13). Here, PdCl2 appeared to be superior to
Pd(cod)Cl2 in terms of stability and availability. Thus, the finally
optimized conditions for the highly selective C-2 allylation of furan
are: allylic acetate 2 (1.0 equiv.), furan 1a (5.0 equiv.), and PdCl2
(2 mol%) in CH2Cl2 under reflux. Under these simple conditions,
3a could be obtained in 72% isolated yield in 2 h (entry 13).12 It
should be mentioned that, although a detailed mechanism deserves
further investigation, the formation of Pd black implies that the
allylation proceeds more possibly via the Pd(0)-catalyzed Tsuji–
Trost pathway rather than the Pd(II)-catalyzed F–C reaction.
With the optimized conditions available, we then examined
the generality of this methodology by varying the structures of
heteroarenes. The results showed that a rich range of hetero-
arenes can be allylated very efficiently in the presence of
equimolar allylic acetate 2 in excellent yield and regio-
selectivity. As summarized in Table 2, the O-based heteroarenes
such as methylfuran (1b) and benzofuran (1c) underwent
smooth coupling to afford the C-2 allylated products 3b and
3c in 92% and 88% yields, respectively (entries 2 and 3). A
range of N-based heteroarenes such as the free N–H pyrrole
(entry 4, 1d) and indole (entry 5, 1e), as well as the N-protected
derivatives either with an electron-rich alkyl (entries 6 and 7, 1f
and 1g) or with an electron-deficient Boc group (entry 8, 1h)
also exhibit excellent compatibility to the reaction conditions.
No N-allylated regioisomers were isolated for the free N–H
pyrrole and indole. Here, pyrrole afforded the C-2 allylated
product (entry 4), whereas indole derivatives formed the C-3
functionalized products (entries 5–8). This is attributed to the
different nucleophilicity between pyrrole and indole scaffolds.3e
a
Unless otherwise noted, the reaction conditions are: heteroarenes 1
(0.4 mmol, 1.0 equiv.), allylic acetate 2 (0.4 mmol, 1.0 equiv.), PdCl2
b
c
(2 mol%) in CH2Cl2 (1.5 mL) under reflux. Isolated yield. 5.0 equiv.
of heteroarenes was used due to their volatile property.
Finally, the S-containing heteroarenes such as methylthiophene
(entry 10, 1j) and thianaphthene (entry 11, 1k) also react
uneventfully to give the C-2 allylated products in very high
yields, although the reaction of thiophene appeared aberrant
(entry 9, 1i). Possibly, the 2,5-diallylated thiophene is the major
product for this particular substrate.13
To further probe the general feasibility of this technology,
the less commonly studied benzylic acetate 4 was subjected to
reaction with a range of heteroarenes (Table 3). Initial trials
revealed that the benzylation was rather sluggish under the
optimized conditions due to the disrupted aromaticity of the
p-benzylpalladium species.14 However, to our delight, efficient
conversion as well as excellent selectivity was observed for a
diverse class of heteroarenes just by means of elevating the
temperature to ca. 80 1C by using ClCH2CH2Cl instead of
CH2Cl2 as a solvent. As shown in Table 3, furan derivatives
underwent smooth coupling to provide the C-2 functionalized
products in excellent yields (entries 1ꢀ3, 5a–c). Several indole
derivatives such as free N–H indole 1e (entry 4), the electron-rich
N-alkylindoles 1f and 1g (entries 5 and 6), and the electron-
deficient N-carbonyl derivatives 1h and 1l (entries 7 and 8)
are also viable substrates, affording the corresponding C-3
functionalized products in high to excellent yields. In addition,
the reaction conditions are also tolerant of thiophene derivatives
to give the C-2 benzylated products very efficiently (entries 9ꢀ11,
1j–k). It should be mentioned that in contrast to the less effective
reaction of thiophene and allylic acetate 2 (Table 2, entry 9),
benzylic acetate 4 could react smoothly with thiophene 1i
(Table 3, entry 9).
Thus, it is evident that the method presented herein is
extremely efficient for the allylation and benzylation of a wide
c
5290 Chem. Commun., 2011, 47, 5289–5291
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Table 3 Benzylation of heteroarenes (1) with benzylic acetate (4)a
materials. In addition, the results presented herein would have
further implications beyond this work and would promote the
investigation and development of more efficient processes
for other transition-metal-catalyzed reactions. These works
along with mechanistic studies are currently underway in our
laboratory.
Entry Heteroarene
T/h Product
Yieldb (%)
5a 86c
Financial support from Hundred Talent Program of CAS
and State Key Laboratory of Fine Chemicals (KF1008) is
acknowledged.
1
2
1a R = H
20
1b R = Me 10
5b 91c
3
1c
30
26
5c 80
Notes and references
4
5
6
7
1e R = H
5d 84
5e 90
5f 92
5g 81
1 (a) S. Cacchi and G. Fabrizi, Chem. Rev., 2005, 105, 2873; and
references cited therein; (b) T. Eicher and S. Hauptmann, The
chemistry of heterocycles, Wiley-VCH, Weinheim, 2003.
2 For example: (a) R. Sanz, A. Martınez, D. Miguel, J. M. Alvarez-
Gutierrez and F. Rodrıguez, Adv. Synth. Catal., 2006, 348, 1841;
(b) K. Motokura, N. Nakagiri, T. Mizugaki, K. Ebitani and
K. Kaneda, J. Org. Chem., 2007, 72, 6006; (c) J. L. Bras and
J. Muzart, Tetrahedron, 2007, 63, 7942; (d) Y.-L. Liu, L. Liu,
Y.-L. Wang, Y.-C. Han, D. Wang and Y.-J. Chen, Green Chem.,
2008, 10, 635; (e) J. A. McCubbin and O. V. Krokhin, Tetrahedron
Lett., 2010, 51, 2447.
1f R = Me 15
1g R = Bu 12
1h R = Boc 40
8
1l R = Ac 35
5h 85
9
10
1i R = H 20
1j R = Me 14
5i 85c
5j 91
11
1k
36
5k 83
3 For In(III)-catalyzed allylations, see: (a) M. Yasuda, T. Somyo and
A. Baba, Angew. Chem., Int. Ed., 2006, 45, 793; (b) J. S. Yadav,
B. V. S. Reddy, K. V. Rao, P. P. Rao, K. S. Raj, A. R. Prasad,
A. Prabhakar and B. Jagadeesh, Synlett, 2006, 3447;
(c) J. S. Yadav, B. V. S. Reddy, A. K. Basak, A. V. Narsaiah,
A. Prabhakar and B. Jagadeesh, Tetrahedron Lett., 2005, 46, 639;
For AuCl3-catalyzed reactions, see: (d) W. Rao and P. W. H.
Chan, Org. Biomol. Chem., 2008, 6, 2426; For Mo(II)-catalyzed
reactions, see: (e) A. V. Malkov, S. L. Davis, I. R. Baxendale,
W. L. Mitchell and P. Kocovsky, J. Org. Chem., 1999, 64, 2751;
For Ca(II)-catalyzed reaction, see: (f) M. Niggemann and
M. J. Meel, Angew. Chem., Int. Ed., 2010, 49, 3684.
a
Unless otherwise noted, the reaction conditions are: heteroarenes 1
(0.4 mmol, 1.0 equiv.), benzylic acetate 4 (0.4 mmol, 1.0 equiv.), PdCl2
b
(2 mol%) in 1,2-dichloroethane (1.5 mL) under reflux. Isolated yield.
c
5.0 equiv. of heteroarene was used due to their volatile property.
range of heteroarenes. As a general observation in these
transformations, the electron-rich heteroarenes react more
rapidly than the electron-deficient congeners as a parallel
comparison of the results both in Tables 2 and 3 shows. For
instance, conversion of furan, pyrrole, and thiophene can be
completed in a shorter time than the more delocalized benzo-
furan, indole, and thianaphthene, respectively. Similarly, the
N-substituted indoles with an electron-donating group react
more rapidly than those with an electron-withdrawing group.
These results imply that the nucleophilicities of the heteroarenes
are affected by their electronic properties.
4 Z. Liu, L. Liu, Z. Shafiq, Y.-C. Wu, D. Wang and Y.-J. Chen,
Tetrahedron Lett., 2007, 48, 3963.
5 (a) W. E. Billups, R. S. Erkes and L. E. Reed, Synth. Commun.,
1980, 10, 147; (b) M. Bandini, A. Melloni and A. Umani-Ronchi,
Org. Lett., 2004, 6, 3199; (c) M. Kimura, M. Futamata, R. Mukai
and Y. Tamaru, J. Am. Chem. Soc., 2005, 127, 4592; (d) S. Ma,
S. Yu, Z. Peng and H. Guo, J. Org. Chem., 2006, 71, 9865;
(e) B. M. Trost and J. Quancard, J. Am. Chem. Soc., 2006,
128, 6314; (f) M. Bandini, A. Melloni, F. Piccinelli, R. Sinisi,
S. Tommasi and A. Umani-Ronchi, J. Am. Chem. Soc., 2006,
128, 1424; (g) H. Y. Cheung, W.-Y. Yu, F. L. Lam, T. T.-L.
Au-Yeung, Z. Zhou, T. K. Chan and A. S. C. Chan, Org. Lett.,
2007, 9, 4295.
6 G. Onodera, H. Imajima, M. Yamanashi, Y. Nishibayashi,
M. Hidai and S. Uemura, Organometallics, 2004, 23, 5841.
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S. R. Piettre, J.-H. Sheu and C. S. Swindell, J. Org. Chem., 1986,
51, 2343.
Finally, we briefly examined the reaction of several hetero-
arenes with an unsymmetric allylic acetate 6 (Scheme 1). High
yields paired with modest to high regioselectivity (relative to
allylic acetate 6) were obtained under the identical conditions
to react with allylic acetate 2 (Table 2).
In conclusion, we have developed a very simple, broadly
applicable, clean, and atom-efficient protocol for the allylation
and benzylation of furan, pyrrole, and thiophene-based hetero-
arenes via the PdCl2-catalyzed Tsuji–Trost strategy. The method
represents the very few examples for highly efficient function-
alization of heteroarenes under base/acid, additive, and ligand-
free conditions, and therefore, should find practical applications
in the synthesis of natural products, pharmaceuticals, and
8 (a) B. M. Trost, Science, 1991, 254, 1471; (b) B. M. Trost, Science,
1983, 219, 245; (c) B. M. Trost and G. Dong, Nature, 2008, 456, 485.
9 (a) F. S. Han, M. Higuchi and D. G. Kurth, Org. Lett., 2007,
9, 559; (b) F. S. Han, M. Higuchi and D. G. Kurth, Tetrahedron,
2008, 64, 9108.
10 For furan, pyrrole and thiophene heteroarenes, 5.0 equiv. was used
due to their volatile nature.
11 M. Kalek, M. Jezowska and J. Stawinski, Adv. Synth. Catal., 2009,
351, 3207; and references cited therein.
12 The structures of 3a and some representative N- and S-containing
products were carefully confirmed by 1H-, 13C-NMR and 1H–1H
COSY spectra. See ESIw.
13 The structure of the diallylated product deserves a detailed analysis
since, although the integration areas and the number of peaks are
consistent with the proposed structure in 1H-NMR, the coupling
constants of the related peaks did not match each other.
14 (a) B. M. Trost and L. C. Czabaniuk, J. Am. Chem. Soc., 2010,
132, 15534; (b) R. Kuwano, Y. Kondo and Y. Matsuyama, J. Am.
Chem. Soc., 2003, 125, 12104.
Scheme 1 Allylation of heteroarenes with unsymmetric allylic acetate.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 5289–5291 5291