Use of InCl3 as a cocatalyst and a Cl2Pd(DPEphos)- P(2-Furyl)3 catalyst system for one-pot hydrometalation-cross- coupling and carbometalation-cross-coupling tandem processes

Article abstract of DOI:10.1021/ol049716f

One-pot conversion of alkynes to regio- and stereodefined alkenylmetals containing Al and Zr via hydrometalation or carbometalation followed by their Pd-catalyzed cross-coupling with (E)-ICH=CHBr or (E)-ICH=CHCl proceeds cleanly and selectively to give the corresponding 1-halo1,3-dienes in excellent yields using a catalyst system consisting of Cl₂Pd(DPEphos), DIBAL-H, and TFP (catalyst A) with InCl₃ as a cocatalyst.

Full text of DOI:10.1021/ol049716f

ORGANIC
LETTERS
2004
Vol. 6, No. 10
1531-1534
Use of InCl3 as a Cocatalyst and a
Cl2Pd(DPEphos)−P(2-Furyl)3 Catalyst
System for One-Pot
Hydrometalation−Cross-Coupling and
Carbometalation−Cross-Coupling
Tandem Processes
Mingxing Qian, Zhihong Huang, and Ei-ichi Negishi*
Herbert C. Brown Laboratories of Chemistry, Purdue UniVersity, 560 OVal DriVe,
West Lafayette, Indiana 47907-2084
negishi@purdue.edu
Received February 17, 2004
ABSTRACT
One-pot conversion of alkynes to regio- and stereodefined alkenylmetals containing Al and Zr via hydrometalation or carbometalation followed
by their Pd-catalyzed cross-coupling with (E)-ICHdCHBr or (E)-ICHdCHCl proceeds cleanly and selectively to give the corresponding 1-halo-
1,3-dienes in excellent yields using a catalyst system consisting of Cl2Pd(DPEphos), DIBAL-H, and TFP (catalyst A) with InCl3 as a cocatalyst.
The one-pot synthesis of conjugated dienes via hydrometa-
lation involving Al1 and Zr2 hydrides followed by Pd-
catalyzed cross-coupling, as well as via Zr-catalyzed carbo-
alumination and Pd-catalyzed cross-coupling,3 was originally
reported during between 1976 and 1978. In many cases,
however, it was not only desirable but necessary to use either
cocatalysts or stoichiometric promoters, and none have been
superior to ZnCl2 or ZnBr2 as a cocatalyst for these
processes.3,4 Even so, these one-pot processes have still been
inferior, in some highly demanding cases,4f,5 to the process
involving (i) hydrometalation or carbometalation, (ii) iodin-
olysis followed by isolation and purification of alkenyl
iodides, (iii) lithiation with 2 equiv of t-BuLi in ether, (iv)
transmetalation with dry ZnCl2 or ZnBr2 to generate pre-
formed alkenylzinc derivatives, and (v) Pd-catalyzed cross-
coupling.
In our recent attempts to improve the synthetic usefulness
of the above-mentioned tandem processes for the syntheses
of dienes and polyenes further, Pd-catalyzed cross-coupling
reactions of (E)-ICHdCHBr4d,f,g,6,7 and (E)-ICHdCHCl7 have
(4) For representative examples of the use of Pd-Zn double-metal
catalysis, see: (a) Panek, J. S.; Hu, T. J. Org. Chem. 1997, 62, 4912; 4914.
(b) Hu, T.; Panek, J. S. J. Org. Chem. 1999, 64, 3000; J. Am. Chem. Soc.
2002, 124, 11368. (c) Drouet, K. E.; Theodorakis, E. A. J. Am. Chem. Soc.
1999, 121, 456; Chem. Eur. J. 2000, 1987. (d) Negishi, E.; Alimardanov,
A.; Xu, C. Org. Lett. 2000, 2, 65. (e) Thompson, C. F.; Jamison, T. F.;
Jacobson, E. N. J. Am. Chem. Soc. 2000, 122, 10482; J. Am. Chem. Soc.
2001, 123, 9974. (f) Zeng, F.; Negishi, E. Org. Lett. 2001, 3, 719. (g) Zeng,
F.; Negishi, E. Org. Lett. 2002, 4, 703.
(5) Negishi, E.; Owczarczyk, Z. Tetrahedron Lett. 1991, 32, 6682.
(6) Available from Aldrich Chemical Co.
(7) (a) Negishi, E.; Okukado, N.; Lovich, S. F.; Luo, F. T. J. Org. Chem.
1984, 49, 2629. (b) Negishi, E.; Hata, M.; Xu, C. Org. Lett. 2000, 2, 3687.
(c) Negishi, E.; Qian, M.; Zeng, F.; Anastasia, L.; Babinski, D. Org. Lett.
2003, 5, 1597.
(1) Baba, S.; Negishi, E. J. Am. Chem. Soc. 1976, 98, 6729. See also:
Negishi, E.; Baba, S. J. Chem. Soc., Chem. Commun. 1976, 596.
(2) Okukado, N.; Van Horn, D. E.; Klima, W. L.; Negishi, E. Tetrahedron
Lett. 1978, 1027. See also: Negishi, E.; Van Horn, D. E. J. Am. Chem.
Soc. 1977, 99, 3168.
(3) Negishi, E.; Okukado, N.; King, A. O.; Van Horn, D. E.; Spiegel, B.
I. J. Am. Chem. Soc. 1978, 100, 2254.
10.1021/ol049716f CCC: $27.50 © 2004 American Chemical Society
Published on Web 04/09/2004

Scheme 1
been investigated. While their Pd-catalyzed cross-coupling
synthetically beneficial effects of double-phosphine catalyst
systems appear to be unprecedented. Although InBr3 was as
effective as InCl3, the latter was chosen, as it is less
expensive, especially on a molar basis.
Representative experimental results are summarized in
Scheme 1. For comparison, the results observed in the
with alkynylzincs4d,7 has been shown to be widely applicable
and generally satisfactory, their Pd-catalyzed reactions with
alkenyl,- aryl,- and alkylmetals containing Al, Zr, and others
have proved to be much more demanding, and satisfactory
results have, in the past, been obtained only in those cases
where â,â-dialkyl-substituted alkenylalanes generated by Zr-
catalyzed carboalumination were employed.4f Extensive
screening and optimization of Pd catalysts and cocatalysts,
as well as other parameters such as solvents, have therefore
been conducted, and a system consisting of Cl2Pd(DPEphos)8
[typically 1 mol %, DPEphos ) bis(2-diphenylphosphino-
phenyl)ether], tris(2-furyl)phosphine9 (TFP) (typically 2 mol
%), and InCl3, but not ZnCl2 or ZnBr2, as a cocatalyst has
proved to be uniquely satisfactory and distinctly superior to
any of the previously developed protocols and all of the other
procedures that have been examined in this study. Both the
(10) For the stoichiometric use of InCl3 in the Pd-catalyzed cross-
coupling, see: (a) Pe´rez, I.; Sestelo, J. P.; Sarandeses, L. A. Org. lett. 1999,
121, 1267. J. Am. Chem. Soc. 2001, 123, 4155. (b) Pena, M. A.; Pe´rez, I.;
Sestelo, J. P.; Sarandeses, L. A. Chem. Commun. 2002, 2246. (c) Rodriguez,
D.; Sestelo, J. P.; Saradeses, L. A. J. Org. Chem. 2003, 68, 2518. (d)
Gelman, D.; Schumann, H.; Blum, J. Tetrahedron Lett. 2000, 41, 7555. (e)
Shenglof, M.; Gelman, D.; Heymer, B.; Schumann, H.; Molander, G. A.;
Blum, J. Synthesis 2003, 302. (f) Jaber, N.; Schumann, H.; Blum, J. J.
Heterocycl. Chem. 2003, 40, 565. (g) Takami, K.; Yorimitsu, H.; Shinokubo,
H.; Matsubara, S.; Oshima, K. Org. Lett. 2001, 3, 1997. (h) Takami, K.;
Yorimitsu, H.; Oshima, K. Org. Lett. 2002, 4, 2993. (i) Nakamura, T.;
Kinoshita, H.; Shinokubo, H.; Oshima, K. Org. Lett. 2002, 4, 3165. (j)
Takami, K.; Mikami, S.; Yorimitsu, H.; Shinokubo, H.; Oshima, K. J. Org.
Chem. 2003, 68, 6627. (k) Lee, P. H.; Sung, S.; Lee, K. Org. Lett. 2001, 3,
3201. (l) Lee, K.; Lee, J.; Lee, P. H. J. Org. Chem. 2002, 67, 8265. (m)
Lee, K.; Seomoon, D.; Lee, P. H.; Angew. Chem., Int. Ed. 2002, 41, 3901.
(n) Lee, P. H.; Lee, S. W.; Lee, K. Org. Lett. 2003, 5, 1103. (o) Lee, P. H.;
Lee, S. W.; Seomoon, D. Org. Lett. 2003, 5, 4963. (p) Legros, J. Y.;
Promault, G.; Fiaud, J. C. Tetrahedron 2001, 57, 2507. (q) Lehmann, U.;
Awasthi, S.; Minehan, T. Org. Lett. 2003, 5, 2405.
10
use of InCl3 as a cocatalyst11 and the demonstration of
(8) Kranenburg, M.; Kamer, P. C. J.; Van Leeuwen, P. W. N. M. Eur.
J. Inorg. Chem. 1998, 155.
(9) Farina, V.; Krishnan, B. J. Am. Chem. Soc. 1991, 113, 9585.
1532
Org. Lett., Vol. 6, No. 10, 2004

Table 1. Pd- and In-Cocatalyzed Hydrometalation-Cross-Coupling and Carbometalation-Cross-Coupling Tandem Processes for
One-Pot Conversion of Alkynes into Stereo- and Regiodefined 1-Halo-1,3-dienes
yield,a
dimer
%
entry
R1CtCZ
nHexCtCH
R2MLn
ICHdCHX
mol % InCl3
time, h
product
monomer
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
HAliBu2
ICHdCHBr
ICHdCHBr
ICHdCHBr
ICHdCHCl
ICHdCHCl
ICHdCHBr
ICHdCHBr
ICHdCHBr
ICHdCHBr
ICHdCHBr
ICHdCHBr
ICHdCHBr
ICHdCHBr
ICHdCHCl
ICHdCHBr
34
10
7
34
10
34
10
7
34
34
34
10
7
4
8
10
4
8
4
8
10
4
4
4
85 (81b)
82
76
87 (85b)
80
77
76
70
89 (84b)
86 (82b)
91 (87b)
85
77
95 (93b)
80 (70b)
<1
2
4
<1
<1
1
3
6
<1
<1
2
5
7
15
4
11
12
13
19
5
c
6
10
12
<1
c
nHexCtCH
nHexCtCH
nHexCtCH
nHexCtCH
nHexCtCH
nHexCtCH
nHexCtCH
PhCtCH
HAliBu2
HAliBu2
HAliBu2
HAliBu2
HZrCp2Cl
HZrCp2Cl
HZrCp2Cl
HZrCp2Cl
EtCtCEt
HZrCp2Cl
nHexCtCH
nHexCtCH
nHexCtCH
nHexCtCH
HOCH2CH2CtCH
Me3Al-Cl2ZrCp2
Me3Al-Cl2ZrCp2
Me3Al-Cl2ZrCp2
Me3Al-Cl2ZrCp2
Me3Al-Cl2ZrCp2
8
10
4
3
8
<1
<1
34
34
10
a Yield by GLC. b Isolated yield. c Not readily detected by GLC.
corresponding reactions of preformed (E)-1-octenylzinc
bromide and tris[(E)-1-octenyl]indium are also shown in eq
4 in Scheme 1. These results indicate the following: (1) In
none of the tandem reactions shown in eqs 1-3 were the
previously developed Pd-Zn double-metal-catalyzed pro-
cedures satisfactory, even in cases where the optimized
catalyst system (catalyst A) consisting of 1 mol %
Cl2Pd(DPEphos), 2 mol % TFP, and 2 mol % DIBAL-H for
reduction of Cl2Pd(DPEphos) (vide infra) was used. (2) In
contrast, the Pd-In double-metal-catalyzed process employ-
ing catalyst A has been highly and uniquely satisfactory. (3)
And yet, In is not superior to Zn in the corresponding
stoichiometric reactions of alkenylmetals containing Zn and
In. Furthermore, the Pd-In cocatalysis is superior to either
of the reactions represented by eq 4 in Scheme 1, pointing
to favorable synergistic effects associated with Al-In and
Zr-In combinations. Irrespective of the precise mechanistic
interpretation, the Pd-In double-metal-catalyzed protocol
presented in eqs 1-3 of Scheme 1 has provided a one-pot
tandem procedure that is far superior to any previously
developed ones for the indicated transformations.
a cosolvent for the synthesis of unsymmetrical carotenoids.
The use of THF as a solvent led to very low product yields.
It was also necessary to evaporate CH2Cl2 used for Zr-
catalyzed methylalumination before the addition of DMF and/
or THF. More critically, even this procedure was found to
be rather unsatisfactory in cases where â-monosubstituted
alkenylmetals containing Al or Zr were used. The procedure
reported herein has solved all of the problems mentioned
above and appears to be widely applicable and generally
dependable, as indicated by the results summarized in Table
1. All of the isolated products were of g98% isomeric purity
1
by H and 13C NMR spectroscopy and GLC analysis.
It may be worth describing in some detail how uniquely
advantageous catalyst A consisting of Cl2Pd(DPEPhos) and
TFP is, even though no persuasive rationalization can be
presented at this time. In view of multistage nature of Pd-
catalyzed cross-coupling, it was envisioned that optimal Pd
catalysts for two or more microsteps may be different from
one another. On this basis, various two-phosphine catalyst
systems were screened initially for the reaction of preformed
(E)-1-octenylzinc bromide with (E)-ICHdCHBr (1.2 equiv)
at 23 °C in THF, and the combination of Cl2Pd(DPEphos)
and TFP, i.e., catalyst A, has been found to be distinctly
superior to any others. Specifically, the use of one-phosphine
Pd catalyst systems (5 mol % in Pd) such as Pd(PPh3)4
(18%), Pd(t-Bu3P)2 (12%), Pd2(dba)3-2TFP (24%),
Cl2Pd(dppf)-2DIBAL-H (40%), and Cl2Pd(DPEphos)-
2DIBAL-H (43%) all led to the disappointingly low yields
indicated in parentheses. Various binary combinations of the
As indicated earlier, one of our recent papers4f described
a satisfactory one-pot conversion of terminal alkynes into
(E,E)-1-bromo-4-methyl-1,3-dienes via (i) carboalumination
with Me3Al-Cl2ZrCp2 and (ii) cross-coupling in the presence
of 5 mol % Pd(PPh3)4, 1 equiv of ZnBr2, and DMF used as
(11) For the use of InBr3 as a cocatalyst in the Pd-catalyzed cross-
coupling of terminal alkynes with aryl iodides, see: Sakai, N.; Annaka,
K.; Konakahara, T. Org. Lett. 2004, 6, 1527. We thank Prof. N. Sakai for
sharing their results with us before publication.
Org. Lett., Vol. 6, No. 10, 2004
1533

above-mentioned phosphines were then screened, and catalyst
A was found to be by far the most satisfactory combination,
as shown in eq 4 in Scheme 1. On the other hand, all of the
others, including Cl2Pd(DPEphos)-dppf (31%), Cl2Pd-
(DPEphos)-2PPh3 (39%), Cl2Pd(dppf)-2TFP (51%),
Cl2Pd(dppf)-2PPh3 (44%), Cl2Pd(dppf)-DPEphos (38%),
Cl2Pd(PPh3)2-dppf (42%), Pd(t-Bu3P)2-dppf (38%),
Pd(t-Bu3P)2-2TFP (32%), Pd(t-Bu3P)2-DPEphos (17%),
and Pd(t-Bu3P)2-2PPh3 (21%), led to low product yields
accompanied by extensive formation of byproducts. In cases
where Pd(II) complexes were used, DIBAL-H was used as
an external reducing agent. Mysteriously, even Cl2Pd(TFP)2-
DPEphos (36%) and Pd2(dba)3-2DPEphos-4TFP (37%)
were distinctly and unmistakably inferior to catalyst A. At
present, the unique superiority of catalyst A over all of the
others tested remains as a mechanistic puzzle to be clarified.
Scheme 2
a Yield by GLC. bIsolated yield. c(p-MeOC6H4)3In used in place
of p-MeOC6H4ZnBr.
The superior catalytic activity of catalyst A extends beyond
the 1-halo-1,3-diene synthesis described above. Thus, it has
substantially improved the reaction of preformed arylzinc
derivatives with (E)-ICHdCHBr, as indicated in Scheme 2.
catalyst system consisting of Cl2Pd(DPEphos) and TFP has
been shown to be effective in selective monosubstitution of
1,2-dihaloethylenes.
Acknowledgment. We thank the National Science Foun-
dation (CHE-0309613), the National Institutes of Health (GM
36792), and Purdue University for support of this work. We
also thank Boulder Scientific Co. and FMC Corp. for their
assistance in the procurement of Zr and P reagents, respec-
tively.
It has become increasingly clear from this and other recent
works reported by us and others that selective Pd- or Ni-
catalyzed cross-coupling reactions involving 1,1-12 and 1,2-
dihaloalkenes7c tend to be considerably more capricious and
demanding but that satisfactory procedures may nevertheless
be developed through optimization of (i) catalysts, especially
ligands, (ii) cocatalysts, and (iii) solvents. In this paper, the
use of InCl3 as a cocatalyst and/or a double-phosphine
Supporting Information Available: Detailed experi-
mental procedures and compound characterization data. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(12) (a) Shi, J.; Zeng, X.; Negishi, E. Org. Lett. 2003, 5, 1825. (b) Zeng,
X.; Hu, Q.; Qian, M.; Negishi, E. J. Am. Chem. Soc. 2003, 125, 13636. (c)
Shi, J.; Negishi, E. J. Organomet. Chem. 2003, 687, 518. (d) Zeng, X.;
Qian, M.; Hu, Q.; Negishi, E. Angew. Chem., Int. Ed. 2004, in press.
OL049716F
1534
Org. Lett., Vol. 6, No. 10, 2004