A R T I C L E S
Zhou and Fu
Table 1. Effect of Various Reaction Parameters on the Efficiency
of a Negishi Cross-Coupling
strated that nickel complexes can catalyze Negishi reactions of
primary alkyl bromides and iodides with a range of organozinc
reagents.11,12
Motivated by our early success in applying Pd/PR3-based
catalysts (PR3 ) a bulky, electron-rich trialkylphosphine) to
Suzuki reactions of alkyl electrophiles, we decided to initiate
an investigation of the utility of these catalysts in the Negishi
cross-coupling, a process of particular interest due to its high
functional-group tolerance and the ready availability of orga-
nozinc reagents.13 We set as our objective the development of
a method that is effective for a wide range of unactivated alkyl
electrophiles (iodides, bromides, chlorides, and tosylates). In
this article, we describe our progress toward achieving that goal,
specifically, a single catalyst system that can cross-couple a
spectrum of substrates (eq 1).14
entry
change from the standard conditions
yield (%)a
1
2
3
4
5
6
7
8
none
70
0
0
54
48
43
55
65
without 2% Pd2(dba)3
without 8% PCyp3
without NMI
without NMP
at 30 °C
with 4% PCyp3
with 1% Pd2(dba)3, 4% PCyp3
a Yield according to GC, versus a calibrated internal standard.
Table 2. Effect of the Ligand on the Efficiency of a Negishi
Cross-Coupling
Results and Discussion
entry
ligand
yield (%)a
For our initial studies, we chose to explore couplings of
alkylzinc halides, due to their availability from commercial
suppliers and from the reaction of zinc with alkyl halides.15
Knochel has noted that, with his catalyst system, alkylzinc
halides are significantly less reactive than diorganozinc reagents,
therefore requiring the presence of Bu4NI (3 equiv) in order to
achieve efficient cross-coupling.11 With regard to the alkyl
electrophile, we decided to focus on alkyl bromides.
After exploring a variety of reaction parameters, we deter-
mined that 2% Pd2(dba)3/8% PCyp3/NMI in THF/NMP at 80
°C can effect the cross-coupling of an alkyl bromide with an
organozinc halide in fairly good yield (70%; Table 1, entry 1;
dba ) dibenzylideneacetone, Cyp ) cyclopentyl, NMI )
N-methylimidazole). An illustrative sampling of the impact of
various parameters on the course of the reaction is provided in
Table 1.
1
2
3
4
5
6
7
8
PCyp3
PCy3
70
65
59
55
3
9
5
1
0
P(i-Pr)3
P(t-Bu)2Me
P(t-Bu)3
P(n-Bu)3
PPh3
P(o-tol)3
P(2,4,6-trimethoxyphenyl)3
P(2-furyl)3
Cy2P(CH2)2PCy2
1,3-bis(mesityl)-4,5-dihydroimidazolium
tetrafluoroborate
P(OPh)3
9
10
11
12
2
0b
4
13
0
a Yield according to GC, versus a calibrated internal standard. b Ligand
loading: 4%.
toward transmetalation.16,17 From an extensive survey of
solvents, a 2:1 mixture of THF and NMP emerged as the best;
for example, the cross-coupling is significantly less efficient in
THF alone (entry 1 vs entry 5). The Negishi reaction does
proceed at lower temperature, albeit in lower yield (entry 1 vs
entry 6). A decrease in the phosphine:Pd ratio (2:1 in entry 1
vs 1:1 in entry 7) also results in a decreased yield of the desired
compound (70% vs 55%). Finally, a reduced catalyst loading
(2% palladium) can be employed, at the cost of just a small
loss in cross-coupling efficiency (entry 1 vs entry 8).
Not surprisingly, the choice of ligand has a substantial impact
on the course of the reaction (Table 2). As we have observed
for other cross-couplings of alkyl electrophiles,4,5,9,10 among the
ligands that we have investigated, only trialkylphosphines of
the appropriate size furnish active catalysts for this Negishi
coupling. PCyp3, which is commercially available, provides the
In the absence of Pd2(dba)3 or PCyp3, none of the desired
product is generated (Table 1, entries 2 and 3, respectively).
The presence of NMI leads to a somewhat improved yield (entry
1 vs entry 4), perhaps through activation of the organozinc halide
(11) (a) Devasagayaraj, A.; Stu¨demann, T.; Knochel, P. Angew. Chem., Int. Ed.
Engl. 1995, 34, 2723-2725. (b) Giovannini, R.; Stu¨demann, T.; Dussin,
G.; Knochel, P. Angew. Chem., Int. Ed. 1998, 37, 2387-2390. (c)
Giovannini, R.; Knochel, P. J. Am. Chem. Soc. 1998, 120, 11186-11187.
(d) Giovannini, R.; Stu¨demann, T.; Devasagayaraj, A.; Dussin, G.; Knochel,
P. J. Org. Chem. 1999, 64, 3544-3553. (e) Piber, M.; Jensen, A. E.;
Rottla¨nder, M.; Knochel, P. Org. Lett. 1999, 1, 1323-1326. (f) Jensen, A.
E.; Knochel, P. J. Org. Chem. 2002, 67, 79-85.
(12) For reviews of Negishi cross-couplings of organozinc reagents, see ref 1.
(13) For reviews and leading references, see: (a) Organozinc Reagents, A
Practical Approach; Knochel, P., Jones, P., Eds.; Oxford: New York, 1999.
(b) Erdik, E. Organozinc Reagents in Organic Synthesis; CRC Press:
Boston, 1996. (c) Boudier, A.; Bromm, L. O.; Lotz, M.; Knochel, P. Angew.
Chem., Int. Ed. 2000, 39, 4414-4435.
(14) As our study was nearing completion, Beller parenthetically described a
Pd/PCy3-catalyzed Negishi cross-coupling of 1-chlorohexane with PhZnBr
that proceeds in 41% yield: Reference 7.
(16) For a report of enhanced reactivity of an alkylzinc reagent in the presence
of NMI, see: Inoue, S.; Yokoo, Y. J. Organomet. Chem. 1972, 39, 11-
16.
(17) The addition of a styrene derivative (3-trifluoromethylstyrene) or n-Bu4-
NI, which can be critical for efficient coupling with Knochel’s nickel-
based catalyst (ref 11), has no effect on the Pd2(dba)3/PCyp3-based catalyst.
(15) (a) For reviews and leading references, see: Rieke, R. D.; Hanson, M. V.
In Organozinc Reagents, A Practical Approach; Knochel, P., Jones, P.,
Eds.; Oxford: New York, 1999; pp 23-36. Rieke, R. D.; Hanson, M. V.
Tetrahedron 1997, 53, 1925-1956. (b) For a recent report, see: Hou, S.
Org. Lett. 2003, 5, 423-425.
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12528 J. AM. CHEM. SOC. VOL. 125, NO. 41, 2003