Page 3 of 5
ChemComm
(cyclohexylmethyl)styrene as the major isomer with 11:1
(dppf)Pd(0)
(L = dppf)
base
X
selectivity. A conjugated diene, 1,3-cyclohexadiene also coupled
in reasonable yield with 3:1 selectivity of 1-alkyl-1,3-
cyclohexadiene versus other isomers. Unfortunately, methyl
acrylate, 1-octene and n-butyl vinyl ether failed to couple.
DOI: 10.1039/C4CC00297K
(L)Pd(II)(H)X
5
(L)Pd(I)X
.
To confirm the involvement of alkyl radicals in our Heck
reaction, we included 1 equiv of TEMPO, a radical trap in the
model Heck reaction. No Heck product was detected and N-
cyclohexyl-TEMPO a was formed in 2:1 molar ratio to Pd0
Ar
Ph
Pd(L)X
Ar
+ (L)Pd(I)X
.
10 catalyst (Fig. 5a). Therefore, it is possible that during oxidative
addition of (dppf)Pd0, two consecutive single electron transfer
events occurred to generate two alkyl radials and (dppf)PdI2.
In another trapping experiment, the alkyl radical from N-Cbz-
Ar
Fig. 6 A possible catalytic cycle for Heck reaction of alkyl halides.
4-iodopiperidine
b
was partially intercepted by 1,4-
35
A tentative catalytic cycle is proposed in Fig 6. It starts from
single electron transfer from (dppf)Pd0 to alkyl halide, followed
by alkyl radical addition to styrene. The rate of alkyl radical
addition to styrene in solution was estimated by Minisci et al. to
be around 105 M-1s-1.14 Recombination of the resulting benzylic
15 cyclohexadiene (5 equiv) via hydrogen atom abstraction (Fig.
5b).
In 2012, Jian et al. reported Pd/dppf-catalyzed intramolecular
cyclization of alkyl iodides and pedant olefins. Atom transfer
radical addition was proposed to account for the formation of
20 alkyl halide products after ring closure.13 We excluded a possible
sequence of atom transfer radical addition to from benzylic
halides, followed by base-assisted elimination to form olefin
products (Fig. 5c). When a model "intermediate" c was added to
an active Heck reaction of CyI and styrene, c was fully
25 consumed, but the expected elimination product from c was only
formed in moderate yield (41%). Homocoupling of the benzylic
radical derived from c was the main side reaction. Furthermore, c
interfered with the Heck reaction of CyI and the yield of Heck
product derived from CyI was reduced from >70% to 13%.
40 radical and (dppf)XPd(I) forms (alkyl)PdX which undergoes Pd-
assisted β-hydride elimination to afford the Heck product.
In conclusion, we disclose herein an efficient Pd-catalyzed
method for intermolecular Heck reaction of alkyl halides, which
was an unsolved problem for many years. The simple, easily
45 available Pd/dppf catalyst showed good reactivity. Our
mechanistic investigation points to single electron transfer from
(dppf)Pd0 to alkyl halides. Compared to Co-catalyzed method
reported by Oshima et al.,6 no Grignard reagents were used which
allowed base-sensitive functional groups to be present.
30
Pd(PPh3)4 x mol%
50 Notes and references
dppf 1.4x mol%
(a)
Ph
N
O
Heck product (0%)
N
O
I
Cy2NMe, PhCF3
110 oC, 12 h
Division of Chemistry and Biological Chemistry
School of Physical and Mathematical Sciences
c-Hex
a
(1 equiv)
Nanyang Technological University, 21 Nanyang Link, Singapore 637371
Fax: (+65) 67911961; E-mail: jrzhou@ntu.edu.sg
55 † We thank Singapore National Research Foundation (NRF–RF2008–10)
and Nanyang Technological University for financial support. We thank
Johnson Matthey for a gift of palladium salts. Electronic Supplementary
Pd cat. (x mol%)
a
(%)
10
20
50
20
41
100
Pd(PPh3)4 5 mol%
dppf 7 mol%
Information
(ESI)
available:
Experimental
procedures
and
Cbz
Cbz
N
Cbz
Cbz
N
N
characterization of new compounds. See DOI: 10.1039/b000000x/
N
Ph
(b)
Cy2NMe, PhCF3
110 oC, 12 h
H
H
60
65
70
75
I
Ph
b
(x equiv)
1
Reviews: (a) R. F. Heck, Acc. Chem. Res., 1979, 12, 146; (b) I. P.
Beletskaya and A. V. Cheprakov, Chem. Rev. 2000, 100, 3009; (c) K.
C. Nicolaou, P. G. Bulger and D. Sarlah, Angew. Chem., Int. Ed.,
2005, 44, 4442; (d) Bräse, S.; de Meijere A. In Metal-Catalyzed
Cross-coupling Reactions; de Meijere, A., Diederich, F., Eds.; Wiley-
VCH: Weinheim, 2004; pp 217-316; (e) G. Zeni and R. C. Larock,
Chem. Rev., 2006, 106, 4644; (f) M. Oestreich, Wiley, New York,
2009.
x = 0 equiv
5 equiv
91%
46%
1%
7%
26%
13%
I
base
Pd/dppf
(c)
R
R
RX
Ph
Ph
Ph
elimination?
atom transfer
radical addition?
Pd(PPh3)4 5 mol%
dppf 7 mol%
c-Hex
Ph
Ph
Ph
Ph
I
13%
(2 equiv)
2
3
Examples: (a) R. F. Heck and J. P. Nolley, J. Org. Chem., 1972, 37,
2320; (b) S. A. Lebedev, V. S. Lopatina, E. S. Petrov and I. P.
Beletskaya, J. Organomet. Chem., 1988, 344, 253; (c) T. Mizoroki,
K. Mori and A. Ozaki, Bull. Chem. Soc. Jpn., 1971, 44, 581.
Examples: (a) S. Bräse, B. Waegell and A. de Meijere, Synthesis,
1998, 148; (b) Y. Xie, J. Hu, Y. Wang, C. Xia and H. Huang, J. Am.
Chem. Soc., 2012, 134, 20613; (c) Z. Yang and J. Zhou, J. Am. Chem.
Soc., 2012, 134, 11833; (d) G. Z. Wu, F. Lamaty and E. Negishi, J.
Org. Chem., 1989, 54, 2507; (e) K. Higuchi, K. Sawada, H. Nambu,
T. Shogaki and Y. Kita, Org. Lett., 2003, 5, 3703; (f) R. Matsubara,
A. C. Gutierrez and T. F. Jamison, J. Am. Chem. Soc., 2011, 133,
Cy2NMe, PhCF3
110 oC, 12 h
I
Me
Me
Ph
Me
Ph
41%
<5%
c (1 equiv)
Fig. 5 Mechanistic studies.
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 3