A user-friendly, all-purpose Pd-NHC (NHC = N-heterocyclic carbene) precatalyst for the Negishi reaction: A step towards a universal cross-coupling catalyst

Article abstract of DOI:10.1002/chem.200600206

We have developed the first user-friendly Negishi protocol capable of routinely cross-coupling all combinations of alkyl and aryl centers. The use of an easily synthesized, air stable, highly active, well-defined precatalyst PEPPSI-IPr (1; PEPPSI = pyridine-enhanced precatalyst preparation, stabilization and initiation; IPr = diisopropyl-phenylimidazolium derivative) substantially increases the scope, reliability, and ease-of-use of the Negishi reaction. All organohalides and routinely used pseudohalides were excellent coupling partners, with the use of chlorides, bromides, iodides, triflates, tosylates, and mesylates resulting in high yield of the coupled product. Furthermore, all reactions were performed by using general laboratory techniques, with no glove box necessary as the precatalyst was weighed and stored in air. Utilization of this methodology allowed for the easy synthesis of an assortment of sterically encumbered biaryls and druglike heteroaromatics, demonstrating the value of the PEPPSI-IPr system. Furthermore, this is also the first time Pd-NHC (NHC = N-heterocyclic carbene) methodology has surpassed the related phosphine-ligated Negishi processes both in activity and use.

Full text of DOI:10.1002/chem.200600206

FULL PAPER
DOI: 10.1002/chem.200600206
A User-Friendly, All-Purpose Pd–NHC (NHC=N-Heterocyclic Carbene)
Precatalyst for the Negishi Reaction: A Step Towards a Universal Cross-
Coupling Catalyst
Michael G. Organ,* Stephanie Avola, Igor Dubovyk, Niloufar Hadei,
[
a]
Eric Assen B. Kantchev, Christopher J. OꢀBrien, and Cory Valente
Abstract: We have developed the first
user-friendly Negishi protocol capable
of routinely cross-coupling all combina-
tions of alkyl and aryl centers. The use
of an easily synthesized, air stable,
highly active, well-defined precatalyst
PEPPSI-IPr (1; PEPPSI=pyridine-en-
hanced precatalyst preparation, stabili-
zation and initiation; IPr=diisopropyl-
phenylimidazolium derivative) substan-
tially increases the scope, reliability,
and ease-of-use of the Negishi reaction.
All organohalides and routinely used
pseudohalides were excellent coupling
partners, with the use of chlorides, bro-
mides, iodides, triflates, tosylates, and
mesylates resulting in high yield of the
coupled product. Furthermore, all reac-
tions were performed by using general
laboratory techniques, with no glove-
box necessary as the precatalyst was
weighed and stored in air. Utilization
of this methodology allowed for the
easy synthesis of an assortment of steri-
cally encumbered biaryls and druglike
heteroaromatics, demonstrating the
value of the PEPPSI-IPr system. Fur-
thermore, this is also the first time Pd–
NHC (NHC=N-heterocyclic carbene)
methodology has surpassed the related
phosphine-ligated Negishi processes
both in activity and use.
Keywords: alkanes · biaryls · CÀC
coupling · heterocycles · palladium
Introduction
still rely on the reasonably versatile [Pd
thesized by Malatesta and Angoletta in 1957.
nately, [Pd(PPh ) ]is very unstable and has modest reactivi-
ty. Recently the groups of Beller, Herrmann, Nolan,
A
H
R
U
G
[
10]
Unfortu-
Over the last 30 years, the development of transition-metal-
catalyzed cross-coupling reactions transformed the way
ACHTREUNG
3
4
[11]
[12]
[13]
[1]
[14]
carbon–carbon bonds are created. Within the current ar-
senal of transition-metal-catalyzed cross-coupling protocols,
palladium processes are amongst the most widely employed
and Sigman
have made significant progress towards the
development NHC-based palladium catalysts or precata-
[15]
lysts; however, their synthesis is still unattractive. There-
fore, it became clear to us that the development of an easily
prepared single Pd–NHC precatalyst for routine and ad-
vanced cross-coupling reactions would be a significant
breakthrough.
[
2]
[3]
[4]
[5]
and include Hiyama, Kumada, Negishi, Suzuki, and
[6]
Stille reactions. Central to the success of these transforma-
tions are palladium metal centers ligated most often with
tertiary phosphines or, recently, N-heterocyclic carbenes
[7]
(
NHC). Although yearly improvements to these support-
Working towards this goal, we recently detailed the syn-
thesis of a new Pd–NHC complex (1; Figure 1) and demon-
strated the complexꢀs superiority to catalysts generated in
situ from the corresponding imidazolium salt and a common
[
8]
[8,9]
ing ligands are made, advanced ligands
are still under-
used, mainly due to sensitivity, difficulty-of-use, limited
availability, and expense. Indeed, most synthetic chemists
Pd source ([Pd (dba) ]) in alkyl–alkyl cross-coupling reac-
A
H
R
U
2 3
[16]
tions. Here, we now report a comprehensive evaluation of
complex in the Negishi cross-coupling reaction
(Scheme 1). The Negishi reaction
tility to the excellent functional group tolerance and high re-
activity of organozinc reagents. However, for any Negishi
cross-coupling protocol to be employed widely it must fulfil
two main criteria: 1) the reaction must be conducted easily
and require no special handling, for example, use of a glove
[
a]Prof. M. G. Organ, S. Avola, I. Dubovyk, N. Hadei,
Dr. E. A. B. Kantchev, Dr. C. J. OꢀBrien, C. Valente
Chemistry Department, York University
1
[1,4]
owes much of it versa-
4
700 Keele Street, Toronto, M3J 1P3 (Canada)
[17]
Fax : (+1)416-736-5956
E-mail: organ@yorku.ca
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
Chem. Eur. J. 2006, 12, 4749 – 4755
ꢁ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4749

[18]
produced under conditions developed by Rieke et al.
However, the use of Rieke zinc to generate organozinc hal-
[
19]
ides can be problematic.
Subsequently, Hou disclosed a
[20]
more convenient route to alkylzinc reagents
by heating
zinc metal (dust, powder, granule, or shot) and the required
bromoalkane in polar aprotic solvents, such as N,N-dimeth-
AHCTREUNG
Figure 1. Pyridine-enhanced precatalyst preparation, stabilization and ini-
tiation (PEPPSI) precatalyst family. The most active and versatile cata-
lyst, 1 (PEPPSI-IPr), bearing 2,6-diisopropylphenyl substituents at the N
atom of the carbene ring is shown.
col, in 1,3-dimethyl-2-imidazolidinone (DMI), complete re-
covery of the starting alkyl bromide resulted. We reasoned
that the lithium halide, formed as a byproduct in the Rieke
[18]
protocol, was responsible for the activation of the alkyl-
[21]
zinc reagent, possibly through formation of a lithium zinc-
ate. Indeed, upon addition of two equivalents of LiBr to
AHCTREUNG
nBuZnBr prepared under Houꢀs conditions, quantitative
conversion to heptylbenzene was achieved (Scheme 2). This
information enabled us to couple alkyl chlorides and sulfo-
nates by simply adding LiBr (2 equiv) to the reaction
medium. Accordingly, alkyl bromides were successfully cou-
pled in THF/N-methylpyrolidinone (NMP) 2:1 or THF/DMI
2
:1, whereas alkyl chlorides, mesylates, and tosylates re-
quired a solvent ratio of 1:3 in order to achieve high yields.
These results invitingly suggest the exciting possibility to se-
lectively couple an alkyl bromide in the presence of an alkyl
chloride followed by coupling the chloride in sequential cou-
[22]
pling reactions. Intriguingly, alkyl tosylates and mesylates
were coupled in high yield (Table 1, entries 4, 5, 15, and 16),
Table 1. Evaluation of PEPPSI complex 1 in the Negishi reaction.
Scheme 1. General, simplified mechanism for Negishi cross-coupling re-
actions catalyzed by PEPPSI complex 1.
1
2
[a]
Entry
R
X
R
Yield [%]
[
[
[
[
[
c]
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
n-heptyl
n-heptyl
n-heptyl
n-heptyl
n-heptyl
p-tolyl
A
T
E
N
2
)
2
)
2
)
2
)
2
)
3
3
3
3
3
Cl
Br
I
OTs
OMs
Cl
Br
I
OTf
OMs
OTs
Cl
Br
I
OTs
OMs
Cl
Br
I
nBu
nBu
nBu
nBu
nBu
n-heptyl
n-heptyl
n-heptyl
n-heptyl
n-heptyl
n-heptyl
88
100
68
100
100
100
100
95
b,g]
c]
c]
box; and 2) the protocol must be applicable to a large array
of substrates.
c]
[d]
[
[
[
[
[
b]
d]
d]
d]
d]
100
0
0
Results and Discussion
10
11
12
We previously reported the rapid cross coupling (30 minutes
at room temperature) of n-butylzinc bromide (nBuZnBr)
with 1-bromo-3-phenylpropane promoted by 1 (1 mol%;
[f]
Ph
70
[
[
[
[
e]
f]
f]
f]
13
Ph
Ph
Ph
Ph
p-MeOC
p-MeOC
p-MeOC
p-MeOC
p-MeOC
p-MeOC
100
100
90
87
80
88
73
71
0
1
4
[16]
15
Scheme 2). These studies were performed using nBuZnBr
16
17
18
19
20
21
22
[
[
[
[
[
[
e]
e]
e]
e]
e]
e]
6
6
6
6
6
6
H
H
H
H
H
H
4
4
4
4
4
4
p-tolyl
p-tolyl
p-tolyl
p-tolyl
OTf
OMs
OTs
p-tolyl
0
Scheme 2. PEPPSI complex 1 submitted to Negishi cross-coupling reac-
tions: a) THF/NMP, 2:1, nBuZnBr prepared from Rieke zinc; b) THF/
DMI, 2:1, nBuZnBr produced using Houꢀs protocol; c) THF/DMI, 2:1,
nBuZnBr produced using Houꢀs protocol with addition of two equiva-
lents of LiBr.
[a]GC yield against calibrated internal standard (undecane) performed
in duplicate. [b]THF/DMI, 2:1. [c]THF/DMI, 1:3. [d]THF/DMI, 1:2.
[e]THF/NMP, 2:1, no LiCl/Br. [f]THF/NMP, 1:2, no LiCl/Br. [g]Yielded
63% after 24 h with a catalyst loading of 0.1 mol%.
4750
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Chem. Eur. J. 2006, 12, 4749 – 4755

Cross-Coupling Reactions
FULL PAPER
in contrast to the corresponding aryl analogues (Table 1, en-
tries 10, 11, 21, and 22). This differing reactivity is unlikely
to be due to a more facile oxidative addition in the case of
the alkyl tosylate with respect to the aryl tosylate. Rather,
[23]
an alkyl halide is formed in situ. In contrast, the coupling
of aryl zinc reagents with aromatic halides and pseudoha-
lides did not require any additive (Table 1, entries 17–22).
Arylhalides and triflates also participated in cross-coupling
with alkylzinc reagents in excellent yields (Table 1, en-
tries 6–9). As a whole, the results presented in Table 1 dem-
onstrate that the pyridine-enhanced precatalyst preparation,
stabilization and initiation (PEPPSI) complex 1 (PEPPSI-
IPr; IPr=diisopropylphenylimidazolium derivative) is able
to catalyze the cross-coupling of organochlorides,
and -iodides; aryl triflates; and alkyl tosylates and mesylates
in all possible pairings in high yield at room temperature
Table 1, entries 1–3, 6–8, 12–14, and 17–19). To the best of
A
H
R
U
G
ACHTREUNG
(
our knowledge, this is the broadest substrate range ever
achieved with a single catalytic protocol.
Encouraged by the results in Table 1, we examined addi-
tional substrates to evaluate the functional group and steric
tolerance, such as might be seen in the synthesis of materials
or biologically active systems. We were delighted to find
that functionalization of the reactants did not diminish the
3
3
3
generality of this protocol, with sp (RX)–sp (RZnX), sp –
A
H
R
U
G
2
2
3
2
2
sp , sp –sp , and sp –sp cross-coupling reactions (Scheme 3)
easily accomplished with 1 mol% of PEPPSI-IPr (1). Cou-
pling of a range of alkyl bromides, chlorides, and tosylates
was achieved at room temperature (Scheme 3, compounds
2
–7). Remarkably, by careful choice of reaction conditions it
was possible to selectively couple a bromide in the presence
of a chloride (Scheme 3, compound 2). An array of function-
ality was tolerated including esters, nitriles, amides, and ace-
tals (Scheme 3, 2–5). Noteworthy examples are the coupling
of (S)-citronellyl bromide in high yield (Scheme 3, com-
pound 8) and the stability of the TMS group in the reaction
conditions (Scheme 3, compounds 6, 9, and 10). The cou-
pling of alkylzinc reagents with aryl halides or aryl triflates
occurred in high yield with no transmetalation to the aryl-
zinc observed (Scheme 3, compounds 12–15). Aryl halides,
as expected, provided excellent coupling partners. Accord-
ingly, the facile synthesis of a range of druglike heteroaro-
matics and sterically congested biaryls was accomplished in
high yield (Scheme 3, compounds 16–22). A significant entry
is the coupling of o-chlorotoluene and 2,4,6-triisopropylphe-
nylzinc chloride at 608C—the lowest temperature this has
[8]
been accomplished with any protocol (Scheme 3, com-
pound 16). N-Boc-protected indole (Boc=tert-butyloxycar-
bonyl), pyridine, and multiple heteroatom-containing het-
erocycles were well tolerated (Scheme 3, compounds 12, 13,
1
5, 18, 20–22) Finally, the cross-coupling of a chiral zinc re-
Scheme 3. Complex substrate evaluation: all yields are of isolated prod-
uct and reactions were performed in duplicate. See the Experimental
Section for detailed reaction conditions.
agent with an acyl chloride (Scheme 3, compound 14) pro-
ceeded without concomitant decarbonylation, demonstrating
the mildness of this protocol.
Chem. Eur. J. 2006, 12, 4749 – 4755
ꢁ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4751

M. G. Organ et al.
Conclusion
124.3, 124.1, 28.7, 26.3, 23.2 ppm; elemental analysis calcd (%) for
C H40Cl N Pd: C 56.57, H 5.93, N 6.18; found: C 56.90, H 5.99, N 6.52.
32 3 3
Cross-coupling procedures (Scheme 3): All cross-coupling reactions were
run with a final solvent volume of 2.4 mL. The specific solvent ratio for
each reaction is listed within the experimental results for each compound
following the general procedures.
We have developed the first user-friendly Negishi protocol
capable of routinely cross-coupling all combinations of alkyl
and aryl partners. The use of an easily synthesized, air
stable, highly active, well-defined precatalyst 1 substantially
increases the scope, reliability and ease-of-use of the Negishi
reaction. Additionally, all reactions were performed by
using general laboratory techniques, with no glove-box nec-
essary as the precatalyst was weighed and stored in air. This
methodology also allowed for the easy synthesis of sterically
encumbered biaryls and druglike heteroaromatics, demon-
strating the usefulness of the PEPPSI-IPr system. Further-
more, this is also the first time Pd–NHC methodology has
surpassed the related phosphine-ligated Negishi processes
3
3
General procedure A (sp –sp ): In air, a vial was charged with 1 (3.4 mg,
1 mol%) and under an inert atmosphere LiBr (139.0 mg, 0.8 mmol) and
a stirrer bar were added. The vial was then sealed with a septum and
purged with argon after which THF (x mL) and DMI (x mL) or NMP
(
x mL) were added and the suspension was stirred until the solids dis-
solved. After this time, the organozinc (0.8 mL, 1.0m in DMI or NMP,
.8 mmol) and the organohalide or pseudohalide (0.5 mmol) were added.
0
ꢂ
The septum was replaced with a Teflon -lined screw cap under an inert
atmosphere and the reaction stirred for 2 h. After this time, the mixture
was diluted with diethyl ether (15 mL) and washed successively with
Na
tic acid) and 3 equiv of NaOH], water, and brine. After drying (anhy-
drous MgSO ) the solution was filtered, the solvent removed in vacuo,
and the residue purified by flash chromatography.
3
EDTA solution [1m; prepared from EDTA (ethylenediaminetetraace-
[8]
both in activity and use. The benefits of this protocol as
summarized above beckon wide adoption of the PEPPSI-IPr
precatalyst in research laboratories and chemical industries.
4
3
2
General procedure B (sp –sp ): In air, a vial was charged with 1 (3.4 mg,
mol%) and under an inert atmosphere ZnCl (107 mg, 0.8 mmol) and a
1
2
stirrer bar were added. The vial was then sealed with a septum and
purged with argon. THF (x mL) was added followed by the requisite
Grignard reagent (0.8 mL, 1.0m in THF, 0.8 mmol) and stirring continued
for 15 minutes at which time a white precipitate formed. Under an inert
atmosphere, LiBr (139.0 mg, 1.6 mmol), NMP (x mL) or DMI (x mL)
and the organohalide or pseudohalide (0.5 mmol) were added. The
Experimental Section
General: All reagents were purchased from commercial sources and
were used without further purification, unless indicated otherwise. Dry 1-
methyl-2-pyrrolidinone (NMP) and 1,3-dimethyl-2-imidazolidinone
ꢂ
septum was replaced with a Teflon -lined screw cap under an inert at-
(
DMI) were purchased from Fluka, stored over 4 Š molecular sieves,
mosphere and the reaction stirred for 2 h. After this time, the mixture
was diluted with diethyl ether (15 mL) and washed successively with
and handled under argon. Tetrahydrofuran (THF) was distilled from
sodium/benzophenone prior to use. All reaction vials (screw-cap thread-
ed, caps attached, 17”60 mm) were purchased from Fischer Scientific.
Na
3
EDTA solution (1m prepared from EDTA and 3 equiv of NaOH),
) the solution was fil-
water, and brine. After drying (anhydrous MgSO
4
CDCl
3
was purchased from Cambridge Isotopes. Thin-layer chromatogra-
tered, the solvent removed in vacuo, and the residue purified by flash
chromatography.
phy (TLC) was performed on Whattman 60 F254 glass plates and were vi-
sualized by using UV light (254 nm), potassium permanganate, or phos-
phomolybdic acid stains. Column chromatography purification was car-
ried out by using the flash technique on Silicycle silica gel 60 (230–
2
3
General procedure C (sp –sp ): In air, a vial was charged with 1 (3.4 mg,
mol%) and under an inert atmosphere LiBr (139.0 mg, 1.6 mmol) and
1
a stirrer bar were added. The vial was then sealed with a septum and
purged with argon. THF (x mL) and DMI (x mL), or NMP (x mL) were
then added and the suspension stirred until the solids had dissolved.
After this time, the organozinc (0.8 mL, 1.0m in DMI or NMP, 0.8 mmol)
and the organohalide or pseudo halide (0.5 mmol) were added. The
4
00 mesh). NMR spectra were recorded on a Bruker 400AV spectrome-
ter or a Bruker 300AV spectrometer, as indicated. The chemical shifts
1
(
d) for H are given in ppm referenced to the residual proton signal of
1
3
the deuterated solvent. The chemical shifts (d) for C are referenced rel-
ative to the signal from the carbon of the deuterated solvent. Gas chro-
matography was performed on Varian Series GC/MS/MS 4000 System.
Optical rotations were measured on a Perkin–Elmer Model 241 polarim-
eter by using 10 cm cells and the sodium D line at ambient temperature
in the solvent specified (concentration c is given as g per 100 mL).
ꢂ
septum was replaced with a Teflon -lined screw cap under an inert at-
mosphere and the reaction stirred for 2 h. After this time, the mixture
was diluted with diethyl ether (15 mL) and washed successively with
Na
3
EDTA solution (1m; prepared from EDTA and 3 equiv of NaOH),
), the solution was fil-
water, and brine. After drying (anhydrous MgSO
4
Synthesis of the PEPPSI-IPr complex (1)—medium-scale synthesis: In
tered, the solvent removed in vacuo, and the residue purified by flash
chromatography.
air a 250 mL beaker was charged with PdCl
24.5 g, 57.6 mmol), Cs CO (98.2 g, 300 mmol) and a stirrer bar. 3-Chlo-
ropyridine (150 mL) was added; the beaker was covered with aluminum
2
(9.82 g, 55.4 mmol), IPr·HCl
(
2
3
2
2
General procedure D(sp –sp ): In air, a vial was charged with 1 (3.4 mg,
mol%) and under an inert atmosphere ZnCl (0.8 mmol) and a stirrer
ACHTREUNG
1
2
foil (to prevent solvent evaporation) and heated with vigorous stirring
for 16 h at 808C directly on the stirrer hotplate. After cooling to RT, the
bar were added. The vial was then sealed with a septum and purged with
argon. THF (x mL) was then added followed by the requisite Grignard
reagent (0.8 mL, 1.0m in THF, 0.8 mmol) and stirring continued for
reaction mixture was diluted with CH
of silica gel covered with a pad of Celite eluting with CH
product was completely recovered. Most of the CH Cl was removed
rotary evaporator) at RT, and the 3-chloropyridine was recovered for
2
Cl
2
and passed through a short pad
2
2
Cl until the
1
5 minutes, at which time a white precipitate formed. NMP (x mL) was
2
2
then added followed by the organohalide or pseudo halide (0.5 mmol).
(
ꢂ
The septum was replaced with a Teflon -lined screw cap under an inert
reuse by vacuum distillation (water aspirator vacuum). Complex 1 was
isolated after triturating with pentane, decanting the supernatant, and
drying in high vacuum. trans-Dichloro(1,3-bis-(2,6-diisopropylphenyl)imi-
dazolylidinium)(3-chloro-pyridine)palladium(ii) (1; 35 g, 93%) was ob-
tained as a yellow solid after triturating with pentane, decanting the su-
pernatant, and drying under high vacuum. M.p. 2408C (decomp);
NMR (400 MHz, CDCl
atmosphere and the reaction stirred for 2 h. After this time, the reaction
mixture was diluted with diethyl ether (15 mL) and washed successively
A
H
R
U
G
with Na
3
EDTA solution (1m; prepared from EDTA and 3 equiv of
) the solution
NaOH), water, and brine. After drying (anhydrous MgSO
4
1
was filtered, the solvent removed in vacuo, and the residue purified by
flash chromatography.
H
3
): d=8.62 (d, J=1.6 Hz, 1H), 8.54 (d, J=5.6 Hz,
1
4
H), 7.57 (d, J=8.2 Hz, 1H), 7.52 (t, J=7.7 Hz, 2H), 7.37 (d, J=7.7 Hz,
H), 7.16 (s, 2H), 7.09 (dd, J=8.0 Hz, 5.7 Hz, 1H), 3.18 (m, 4H), 1.50 (d,
Data for compound 2: Following general procedure A (THF/DMI, 2:1),
13-chloro-2,2-dimethyltridecanenitrile (104 mg, 81% yield) was isolated
1
3
1
13
J=6.7 Hz, 12H), 1.14 ppm (d, J=6.8 Hz, 12H); C NMR (100 MHz,
CDCl ): d=153.5, 150.5, 149.4, 146.7, 137.4, 135.0, 132.0, 130.3, 125.1,
(R
f
=0.18, 3 vol% diethyl ether in pentane) as a clear oil. The H and C
[
8d]
3
NMR spectra were identical to those previously described.
4752
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ꢁ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 4749 – 4755

Cross-Coupling Reactions
FULL PAPER
Data for compound 3: Following general procedure A (THF/DMI, 2:1),
Data for compound 10: Following general procedure B (THF/NMP, 1:2),
2
-(5-cyclohexylpentyl)isoindole-1,3-dione (115 mg, 80% yield) was isolat-
ed (R =0.40, 20 vol% diethyl ether in pentane) as a white solid (m.p.
4–758C). The alkylzinc bromide reagent was purchased from Aldrich.
[5-(2-methoxyphenyl)pent-1-ynyl]trimethylsilane (113 mg, 92% yield)
was isolated (R
f
=0.30, 5 vol% diethyl ether in pentane) as a clear vis-
cous oil. H NMR (400 MHz, CDCl ): d=7.23–7.15 (m, 2H), 6.96–6.85
(m, 2H), 3.84 (s, 3H), 2.74 (t, J=7.5 Hz, 2H), 2.27 (t, J=7.4 Hz, 2H),
f
1
7
3
1
H NMR (300 MHz, CDCl
3
): d=7.86–7.80 (m, 2H), 7.75–7.67 (m, 2H),
1
3
3
.68 (t, J=7.2 Hz, 2H), 1.80–1.65 (m, 7H), 1.36–1.27 (m, 4H), 1.25–1.10
1.84 (quint, J=7.7 Hz, 2H), 0.19 ppm (s, 9H); C NMR (100 MHz,
CDCl ): d=157.5, 130.1, 130.0, 127.2, 120.3, 110.2, 107.7, 84.6, 55.2, 29.4,
1
3
(
m, 6H), 0.97–0.85 ppm (m, 2H); C NMR (100 MHz, CDCl
3
): d=168.4,
3
1
13
1
33.8, 132.2, 123.1, 38.0, 37.5, 37.3, 33.3, 28.6, 27.1, 26.7, 26.4 ppm; ele-
28.8, 19.6, 0.2 ppm. H and C NMR spectra have been provided in the
Supporting Information to attest purity.
mental analysis calcd (%) for C19
C 76.49, H 8.42, N 5.08.
2
H25NO : C 76.22, H 8.42, N 4.68; found:
Data for compound 11: Following general procedure B (THF/NMP, 1:2),
3
-phenyl-1-(4-fluorophenyl)propane (97 mg, 91% yield) was isolated
Data for compound 4: Following general procedure A (THF/NMP, 2:1),
1
(
R
f
=0.40, pentane) as a clear viscous oil. H NMR (400 MHz, CDCl
3
):
2
0
-(5-phenylpentyl)
.20, 5 vol% diethyl ether in pentane) as a clear oil. H NMR (300 MHz,
): d=7.29 (t, J=7.2 Hz, 2H), 7.19 (d, J=7.3 Hz, 3H), 4.52 (t, J=
.8 Hz, 1H), 4.12 (dd, J=11.7, 4.8 Hz, 2H), 3.76 (dt, J=12.6, 2.4 Hz,
H), 2.63 (t, J=7.5 Hz, 2H), 2.17–2.00 (m, 1H), 1.74–1.55 (m, 4H), 1.50–
A
C
H
T
R
E
U
N
G
f
[1,3]dioxane (107 mg, 86% yield) was isolated (R =
1
d=7.31 (t, J=8.0 Hz, 2H), 7.22 (t, J=8.0 Hz, 3H), 7.18–7.12 (m, 2H),
6
7
1
.99 (t, J=8.4 Hz, 2H), 2.66 (q, J=7.6 Hz, 4H), 1.96 ppm (quint, J=
CDCl
3
1
3
1
ACHTREUNG
.6 Hz, 2H); C NMR (100 MHz, CDCl
3
): d=161.2 ( J
(C,F)=242 Hz),
4
2
1
1
4
3
ACHTREUNG
42.1, 137.8 ( J
A
H
R
U
G
(C,F)=8 Hz), 128.4, 128.3, 125.8,
2
1
13
1
3
115.0 ( J
A
H
R
U
G
.28 ppm (m, 5H); C NMR (100 MHz, CDCl
25.5, 102.3, 66.9, 35.8, 35.1, 31.3, 29.1, 25.8, 23.8 ppm; elemental analysis
: C 76.88, H 9.46; found: C 76.57, H 9.85.
Data for compound 5: Following general procedure A (THF/DMI, 2:1),
9S,13)-dimethyltetradec-12-enoic acid ethyl ester (123 mg, 87% yield)
was isolated (R =0.60, 5 vol% diethyl ether in pentane) as a clear vis-
3
): d=142.7, 128.4, 128.2,
have been provided in the Supporting Information to attest purity.
calcd (%) for C15
H
22
O
2
Data for compound 12: Following general procedure C (THF/DMI, 2:1),
6
-benzo
isolated (R
NMR (300 MHz, CDCl
(d, J=8.0 Hz, 1H), 5.94 (s, 2H), 2.58 (t, J=7.6 Hz, 2H), 1.67–1.59 (m,
A
H
R
U
G
1
(
3
): d=6.74 (d, J=8.0 Hz, 1H), 6.69 (s, 1H), 6.63
f
2
D
3
1
cous oil. [a] =+0.84 (c=2.5 in CH
2
Cl
2 3
); H NMR (300 MHz, CDCl ):
13
2
H), 1.57–1.50 (m, 4H), 1.35 ppm (s, 6H); C NMR (100 MHz, CDCl
3
):
d=5.11 (t, J=6.0 Hz, 1H), 4.13 (q, J=7.1 Hz, 2H), 2.30 (t, J=7.4 Hz,
d=147.5, 145.6, 136.0, 125.2, 121.0, 108.7, 108.1, 100.7, 40.9, 35.4, 32.4,
31.7, 26.7, 24.8 ppm; H and C NMR spectra have been provided in the
Supporting Information to attest purity.
2
1
H), 2.05–1.90 (m, 2H), 1.75–1.58 (m, 8H), 1.45–1.20 (m, 14H), 1.20–
.05 (m, 2H), 0.86 ppm (d, J=6.3 Hz, 3H); C NMR (100 MHz, CDCl ):
3
1
13
1
3
d=173.9, 130.9, 125.0, 60.1, 37.1, 36.9, 34.4, 32.4, 29.8, 29.3, 29.1, 26.9,
5.7, 25.5, 25.0, 19.5, 17.6, 14.2 ppm; elemental analysis calcd (%) for
: C 76.54, H 12.13; found: C 76.08, H 12.48.
Data for compound 6: Following general procedure A (THF/NMP, 1:2),
,2-dimethyl-1-trimethylsilanylundec-10-ynenitrile (97 mg, 74% yield)
was isolated (R =0.50, 5 vol% diethyl ether in pentane) as a clear oil
after removing volatile impurities under reduced pressure for 12 h.
NMR (300 MHz, CDCl
Data for compound 13: Following general procedure C (THF/DMI, 2:1),
6
ed (R
2
-pyridine-2-yl-hexanoic acid ethyl ester (108 mg, 98% yield) was isolat-
18 34 2
C H O
1
f
=0.10, 30 vol% diethyl ether in pentane) as a clear oil. H NMR
(
300 MHz, CDCl ): d=8.50 (dd, J=4.2, 0.6 Hz, 1H), 7.56 (dt, J=7.2,
3
2
1
7
2
1
1
.8 Hz, 1H), 7.14–7.03 (m, 2H), 4.10 (q, J=7.2 Hz, 2H), 2.77 (t, J=
f
.5 Hz, 2H), 2.28 (t, J=7.5 Hz, 2H), 1.82–1.60 (m, 4H), 1.48–1.30 (m,
1
H
13
H), 1.21 ppm (t, J=7.1 Hz, 3H); C NMR (100 MHz, CDCl
3
): d=
3
): d=2.22 (t, J=7.2 Hz, 2H), 1.60–1.45 (m, 6H),
73.7, 162.1, 149.2, 136.2, 122.7, 120.9, 60.1, 38.2, 34.2, 29.5, 28.8, 24.8,
4.2 ppm. elemental analysis calcd (%) for C13 : C 70.56, H 8.65;
1
3
1
1
0
.45–1.30 (m, 12H), 0.15 ppm (s, 9H); C NMR (100 MHz, CDCl
3
): d=
H
19NO
2
25.2, 107.5, 84.3, 41.1, 32.3, 29.4, 28.8, 28.6, 28.5, 26.7, 25.2, 19.8,
.1 ppm; elemental analysis calcd (%) for C16 29NSi: C 72.93, H 11.09;
found: C 70.67, H 8.95.
Data for compound 14: Following general procedure C (THF/DMI, 2:1),
-(4-fluorophenyl)-(4S,8)-dimethylnon-7-en-1-one (114 mg, 87% yield)
was isolated (R =0.40, 3 vol% diethyl ether in pentane) as a clear vis-
H
found: C 72.58, H 11.42.
1
Data for compound 7: Following general procedure A (THF/NMP, 1:2),
f
2
,2-dimethyl-9-phenylnonanenitrile (85 mg, 70% yield) was isolated (R
f
=
23
1
cous oil. [a]D =+1.07 (c=1.68 in CH
d=8.01 (m, 2H), 7.14 (t, J=8.6 Hz, 2H), 5.11 (t, J=5.9 Hz, 1H), 3.00–
2
1
NMR (100 MHz, CDCl
1
3
2 2 3
Cl ); H NMR (300 MHz, CDCl ):
0
.50, 5 vol% diethyl ether in pentane) as a clear oil after removing vola-
1
tile impurities under reduced pressure for 12 h. H NMR (400 MHz,
CDCl ): d=7.29 (t, J=6.8 Hz 2H), 7.21 (d, J=6.4 Hz, 3H), 2.64 (t, J=
.6 Hz, 2H), 1.70–1.60 (m, 2H), 1.58–1.45 (m, 4H), 1.40–1.30 ppm (m,
.87 (m, 2H), 2.07–1.95 (m, 2H), 1.90–1.65 (m, 4H), 1.60–1.48 (m, 5H),
13
3
.47–1.30 (m, 1H), 1.25–1.13 (m, 1H), 0.95 ppm (d, J=6.3 Hz, 3H);
C
7
1
4
1
ACHTREUNG
3
): d=199.1, 167.2 ( J
1
3
2H); C NMR (100 MHz, CDCl
1.1, 35.9, 32.4, 31.5, 29.5, 29.3, 29.2, 26.7, 25.3 ppm. H and C NMR
3
): ?142.8, 128.4, 128.3, 125.6, 125.3,
3
2
ACHTREUNG
30.7 ( J
A
H
R
U
G
1
13
spectra have been provided in the Supporting Information to attest
purity.
17 23
C H FO: C 77.82, H 8.84; found: C 78.07, H 9.05.
Data for compound 15: Following general procedure C (THF/DMI, 2:1),
6-(N-boc-indol-5-yl)hexanoic acid ethyl ester (149 mg, 83% yield) was
Data for compound 8: Following general procedure B (THF/NMP, 2:1),
of 1-[(3S,7)-dimethyloct-6-enyl]-2-methoxybenzene (107 mg, 87% yield)
isolated (R =0.15, 3 vol% diethyl ether in pentane) as a clear viscous oil.
f
1
was isolated (R
f
=0.40, 5 vol% diethyl ether in pentane) as a clear vis-
H NMR (400 MHz, CDCl ): d=8.04 (d, J=8.1 Hz, 1H), 7.60 (d, J=
3
2
3
1
cous oil. [a] =+8.55 (c=2.29 in CH
2
Cl
2
); H NMR (400 MHz, CDCl
3
):
3.4 Hz, 1H), 7.38 (s, 1H), 7.16 (d, J=8.5 Hz, 1H), 6.54 (d, J=3.4 Hz,
1H), 4.15 (q, J=7.2 Hz, 2H), 2.73 (t, J=7.5 Hz, 2H), 2.32 (t, J=7.5 Hz,
2H), 1.75–1.65 (m, 13H), 1.44–1.35 (m, 2H), 1.28 ppm (t, J=7.1 Hz,
D
d=7.25–7.15 (m, 2H), 6.93 (t, J=7.6 Hz, 1H), 6.88 (d, J=8.1 Hz, 1H),
5
2
6
1
1
.17 (t, J=6.9 Hz, 1H), 3.87 (s, 3H), 2.72–2.58 (m, 2H), 2.11–1.97 (m,
H), 1.74 (s, 3H), 1.65–1.40 (m, 7H), 1.30–1.17 (m, 1H), 1.00 ppm (d, J=
1
3
3H); C NMR (100 MHz, CDCl
3
): d=173.8, 149.8, 136.9, 133.6, 130.8,
1
3
.2 Hz, 3H); C NMR (100 MHz, CDCl
26.7, 125.1, 120.4, 110.2, 55.3, 37.1, 37.0, 32.5, 27.7, 25.8, 25.5, 19.6,
7.7 ppm; elemental analysis calcd (%) for C17 26O: C 82.87, H 10.64;
3
): d=157.4, 131.6, 131.0, 129.7,
125.9, 125.0, 120.3, 114.9, 107.2, 83.4, 60.2, 35.6, 34.3, 31.6, 28.7, 28.2, 24.9,
4
14.3 ppm; elemental analysis calcd (%) for C21H29NO : C 70.17, H 8.13;
H
found: C 70.49, H 8.39.
found: C 83.02, H 10.92.
Data for compound 9: Following general procedure B (THF/NMP, 1:2),
trimethyl-[5-(2,4,6-trimethylphenyl)pent-1-ynyl]silane (115 mg, 89%
=0.80, pentane) as a clear oil. H NMR (300 MHz,
): d=6.88 (s, 2H), 2.80–2.72 (m, 2H), 2.39 (t, J=6.8 Hz, 2H), 2.30
Data for compound 16: This reaction was carried out at 608C. Following
general procedure D (THF/NMP, 1:1), 2,4,6-triisopropyl-2’-methylbiphen-
f
yl (133 mg, 90% yield) was isolated (R =0.50, hexanes) as a white solid
1
1
13
yield) was isolated (R
CDCl
f
(m.p. 94–958C). The melting point, H and C NMR spectra were identi-
[
24]
cal to those previously described.
3
1
3
(
s, 6H), 2.26 (s, 3H), 1.75–1.66 (m, 2H), 0.22 ppm (s, 9H); C NMR
100 MHz, CDCl ): d=136.1, 135.6, 135.1, 128.9, 107.3, 85.0, 28.5, 28.1,
0.8, 20.3, 19.7, 0.2 ppm. elemental analysis calcd (%) for C17 26Si: C
9.00, H 10.14; found: C 78.69, H 10.42.
Data for compound 17: The organozinc reagent was prepared through di-
(
3
rected ortholithiation followed by transmetalation to ZnCl following a
2
[8f]
2
7
H
literature procedure. The cross coupling was carried out at 608C. Fol-
lowing general procedure D (THF/NMP, 1:2), of 2,6-dimethoxy-2’,6’-di-
Chem. Eur. J. 2006, 12, 4749 – 4755
ꢁ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4753

M. G. Organ et al.
methylbiphenyl (108 mg, 89% yield) was isolated (R
ethyl ether in pentane) as a white solid (m.p. 104–1058C) after removing
volatile impurities under reduced pressure for 12 h. The melting point,
f
=0.15, 3 vol% di-
C. Fang, Tetrahedron 2005, 61, 9723; d) N. Hadei, E. A. B. Kantchev,
C. J. OꢀBrien, M. G. Organ, J. Org. Chem. 2005, 70, 8503; e) N.
Hadei, E. A. B. Kantchev, C. J. OꢀBrien, M. G. Organ, Org. Lett.
2005, 7, 3805; f) J. E. Milne, S. L. Buchwald, J. Am. Chem. Soc.
1
13
[24]
H and C NMR spectra were identical to those previously described.
Data for compound 18: Following general procedure D (THF/NMP, 1:1),
-phenyl-6-thiophen-2-ylpyridazine (114 mg, 96% yield) was isolated
=0.48, 33 vol% ethyl acetate in hexanes) as pale yellow crystals (m.p.
2
004, 126, 13028; g) T. Brenstrum, D. A. Gerristma, G. M. Adja-
beng, C. S. Frampton, J. Britten, A. J. Robertson, J. McNulty, A.
Capretta, J. Org. Chem. 2004, 69, 7635; h) T. Brenstrum, D. A. Ger-
ristma, G. M. Adjabeng, C. S. Frampton, J. Britten, A. J. Robertson,
J. McNulty, A. Capretta, J. Org. Chem. 2004, 69, 7635; i) J. H.
Kirchhoff, C. Dai, G. C. Fu, Angew. Chem. 2002, 114, 2025; Angew.
Chem. Int. Ed. 2002, 41, 1945; j) M. R. Netherton, G. C. Fu, Angew.
Chem. 2002, 114, 4066; Angew. Chem. Int. Ed. 2002, 41, 3910;
k) G. A. Grasa, M. S. Viciu, J. Huang, C. Zhang, M. L. Trudell, S. P.
Nolan, Organometallics 2002, 21, 2866; l) M. R. Netherton, C. Dai,
K. Neuschütz, G. C. Fu, J. Am. Chem. Soc. 2001, 123, 10099, and
references there in.
3
(
1
2
7
1
R
f
1
61–1628C). H NMR (300 MHz, CDCl
H), 7.87 (q, J=4.8 Hz, 2H), 7.76–7.70 (m, 1H), 7.58–7.47 (m, 4H),
.24–7.15 ppm (m, 1H); C NMR (100 MHz, CDCl
40.7, 136.0, 130.0, 129.2, 129.0, 128.1, 126.7, 126.1, 124.0, 122.6 ppm.
3
): d=8.16 (dd, J=3.9, 1.5 Hz,
1
3
3
): d=157.4, 153.5,
Spectral data is provided as it is more detailed with respect to the litera-
[
25]
ture values.
Data for compound 19: Following general procedure D (THF/NMP, 1:1),
-mesitylnaphthalene (118 mg, 96% yield) was isolated (R =0.65, pen-
tane) as a colorless, viscous oil. The H and C NMR spectra were identi-
1
f
1
13
[
26]
[9]A. C. Frisch, M. Beller, Angew. Chem. 2005, 117, 680; Angew.
Chem. Int. Ed. 2005, 44, 674.
10]L. Malatesta, M. Angoletta, J. Chem. Soc. 1957, 1186.
11]a) R. Jackstell, M. G. Andreu, A. C. Frisch, K. Selvakumar, A. Zapf,
H. Klein, A. Spannenberg, D. Rçttger, O. Briel, R. Karch, M.
Beller, Angew. Chem. 2002, 114, 1028; Angew. Chem. Int. Ed. 2002,
cal to those previously described.
Data for compound 20: Following general procedure D (THF/NMP, 2:1),
-(2,4,6-trimethylphenyl)benzo[1,2,5]thiadiazole (114 mg, 90% yield) was
isolated (R =0.26, 2 vol% diethyl ether in pentane) as yellow crystals
[
[
5
ACHTREUNG
f
1
(
m.p. 54–558C). H NMR (300 MHz, CDCl
3
): d=8.07 (d, J=9.0 Hz, 1H),
7
2
1
.81 (s, 1H), 7.42 (dd, J=4.5, 1.5 Hz, 1H), 7.02 (s, 2H), 2.39 (s, 3H),
4
1, 986; b) A. C. Frisch, F. Rataboul, A. Zapf, M. Beller, J. Organo-
1
3
.08 ppm (s, 6H); C NMR (100 MHz, CDCl
37.5, 137.3, 135.7, 132.4, 128.4, 121.2, 21.1, 20.8 ppm (one carbon signal
S: C 70.83, H 5.55, N
3
): d=155.3, 154.0, 142.8,
met. Chem. 2003, 687, 403.
[
12]a) G. D. Frey, J. Schütz, E. Herdtweck, W. A. Herrmann, Organome-
tallics 2005, 24, 4416; b) C. W. K. Gstçttmayr, V. P. W. Bçhm, E.
Herdtweck, M. Grosche, W. A. Herrmann, Angew. Chem. 2002, 114,
missing); elemental analysis calcd (%) for C15
1.01; found: C 70.61, H 5.92, N 11.06.
Data for compound 21: Following general procedure D (THF/NMP, 2:1),
-(4-fluorophenyl)benzo[1,3]dioxole (106 mg, 98% yield) was isolated
=0.60, 5 vol% diethyl ether in pentane) as a white solid (m.p. 42–
14 2
H N
1
1
421; Angew. Chem. Int. Ed. 2002, 41, 1363; c) W. A. Herrmann, C.-
5
ACHTREUNG
P. Reisinger, M. Spiegler, J. Organomet. Chem. 1998, 557, 93.
13]a) O. Navarro, N. Marion, N. M. Scott, J. Gonzalez, D. Amoroso, A.
Bell, S. P. Nolan, Tetrahedron 2005, 61, 9716; b) R. Singh, M. S.
Viciu, N. Kramareva, O. Navarro, S. P. Nolan, Org. Lett. 2005, 7,
(
R
f
[
1
4
9
2
1
1
3
38C). H NMR (400 MHz, CDCl ): d=7.52–7.48 (m, 2H), 7.13 (t, J=
.2 Hz 2H), 7.01 (d, J=9.2 Hz, 2H), 6.90 (d, J=8.0 Hz, 1H), 6.03 ppm (s,
1
3
1
H); C NMR (100 MHz, CDCl
3
): d=162.2 ( J
A
H
R
U
G
1
829; c) H. Lebel, M. K. Janes, A. B. Charette, S. P. Nolan, J. Am.
2
47.1, 137.1, 134.6, 128.4, 120.5, 115.6 ( J
01.2 ppm. H and C NMR spectra have been provided in the Support-
A
H
R
U
G
Chem. Soc. 2004, 126, 5046; d) M. S. Viciu, E. D. Stevens, J. L. Pe-
tersen, S. P. Nolan, Organometallics 2004, 23, 3752; e) M. S. Viciu, O.
Navarro, R. F. Germaneau, R. A. Kelly III, W. Sommer, N. Marion,
E. D. Stevens, C. Luigi, S. P. Nolan, Organometallics 2004, 23, 1629;
f) M. S. Viciu, R. A. Kelly III, E. D. Stevens, F. Naud, M. Studer,
S. P. Nolan, Org. Lett. 2003, 5, 1479.
1
13
ing Information to attest purity.
Data for compound 22: Following general procedure D (THF/NMP, 1:2),
2
-cyano-6-(2-methoxyphenyl)pyridine (95 mg, 90% yield) was isolated
(
1
R =0.30, 50 vol% diethyl ether in pentane) as white crystals (m.p. 109–
f
1
13
108C). The melting point, H and C NMR spectra were identical to
[
14]D. R. Jensen, M. J. Schultz, J. A. Mueller, M. S. Sigman, Angew.
Chem. 2003, 115, 3940; Angew. Chem. Int. Ed. 2003, 42, 3810.
15]Even though Pd–NHC complexes are air stable, their synthesis re-
quires rigorously anhydrous conditions and, in some cases, a glove-
box if free carbene is used. These factors make large-scale produc-
tion unattractive.
[
27]
those previously described.
[
Acknowledgement
[
16]a) Preceeding paper in this issue: C. J. OꢀBrien, E. A. B. Kantchev,
N. Hadei, C. Valente, G. A. Chass, A. Lough, A. C. Hopkinson,
M. G. Organ, Chem. Eur. J. 2006, 12, 4743; b) detailed in the above
paper are comparisons between the in situ protocol (see ref. [8d])
and the preformed precatalyst 1 (PEPPSI-IPr, see ref. [16a]). These
studies showed that the reaction depicted in Scheme 2 yielded 75%
after 6 h when employing the in situ protocol (at 4 mol% loading),
which compared to 93% in 15 minutes with precatalyst 1 (PEPPSI-
IPr, at 1 mol% loading). Furthermore, the apparent turnover
We wish to thank the ORDCF (Ontario) and NSERC (Canada) for fi-
nancial support.
[
1]a) Metal-Catalyzed Cross-Coupling Reactions, 2nd ed. (Eds.: A. de
Meijere, F. Diederich), Wiley-VCH, Weinheim, 2004; b) Handbook
of Organopalladium Chemistry for Organic Synthesis (Ed.: E. Ne-
gishi), Wiley, New York, 2002.
À1
[
[
2]Y. Hatanaka, T. Hiyama, J. Org. Chem. 1988, 53, 918.
3]K. Tamao, K. Sumitani, M. Kumada, J. Am. Chem. Soc. 1972, 94,
number (TON) h for the in situ process (4 mol% loading) was 7.5,
whereas it was 300 when utilizing 1 (PEPPSI-IPr at 0.1 mol% load-
ing). These results clearly demonstrate the superiority of the pre-
formed precatalyst 1 over in situ methodology.
4
374.
4]a) E. Negishi, A. O. King, N. Okukado, J. Org. Chem. 1977, 42,
821; b) A. O. King, N. Okukado, E. Negishi, J. Chem. Soc. Chem.
[
1
[17] Organozinc Reagents—A Practical Approach, (Eds.: P. Knochel, P.
Jones), Oxford University Press, Oxford (UK), 1999.
Commun. 1977, 683.
[
[
[
5]N. Miyaura, K. Yamada, A. Suzuki, Tetrahedron Lett. 1979, 20, 3437.
6]D. Milstein, J. K. Stille, J. Am. Chem. Soc. 1978, 100, 3636.
7]a) W. A. Herrmann, Angew. Chem. 2002, 114, 1342; Angew. Chem.
Int. Ed. 2002, 41, 1290; b) M. C. Perry, K. Burgess, Tetrahedron:
Asymmetry 2003, 14, 951.
[18]a) R. D. Rieke, M. V. Hanson, J. D. Brown, Q. J. Niu, J. Org. Chem.
1996, 61, 2726; b) L. Zhu, R. M. Wehmeyer, R. D. Rieke, J. Org.
Chem. 1991, 56, 1445.
[19]The rate of addition of the zinc halide to the lithium naphthalide
solution has a substantial affect on the activity of the Rieke zinc
produced. If the addition rate is rapid the Zn will fail to insert into
carbon–halide bond. This is especially pronounced if catalytic naph-
thalene is employed. See reference [18].
[
8]a) A. Zapf, M. Beller, Chem. Commun. 2005, 431; b) T. E. Barder,
S. D. Walker, J. R. Martinelli, S. L. Buchwald, J. Am. Chem. Soc.
2
005, 127, 4685; c) C. J. OꢀBrien, E. A. B. Kantchev, G. A. Chass, N.
Hadei, A. C. Hopkinson, M. G. Organ, D. H. Setiadi, T.-H. Tang, D.-
[20]S. Huo, Org. Lett. 2003, 5, 423.
4754
www.chemeurj.org
ꢁ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 4749 – 4755

Cross-Coupling Reactions
FULL PAPER
[
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[
22]These studies are ongoing and will be published in due course.
23]To illustrate the ease of alkyl halide formation under the reaction
conditions: Formation of 1-bromo-3-phenylpropane was found to be
rapid on addition of LiBr to a solution of 3-phenylpropyl tosylate
Received: February 14, 2006
Published online: March 28, 2006
(GC/MS).
Chem. Eur. J. 2006, 12, 4749 – 4755
ꢁ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4755