Microwave accelerated, Ni/C-catalyzed cross-couplings of in situ-derived zirconocenes

Article abstract of DOI:10.1016/j.tet.2003.10.029

Both vinyl and alkyl zirconocenes undergo rapid couplings with aryl halides under heterogeneous conditions in a microwave reactor using Ni/C as catalyst. Ligand variations both in type and stoichiometry play major roles in the extent of conversion.

Full text of DOI:10.1016/j.tet.2003.10.029

Tetrahedron 60 (2004) 1309–1316
Microwave accelerated, Ni/C-catalyzed cross-couplings
of in situ-derived zirconocenes
*
Bruce H. Lipshutz and Bryan Frieman
Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA 93106-9510, USA
Received 4 August 2003; revised 1 October 2003; accepted 11 October 2003
Abstract—Both vinyl and alkyl zirconocenes undergo rapid couplings with aryl halides under heterogeneous conditions in a microwave
reactor using Ni/C as catalyst. Ligand variations both in type and stoichiometry play major roles in the extent of conversion.
q 2003 Elsevier Ltd. All rights reserved.
7
1. Introduction
from hydrozirconations, e.g. 1), we have returned to the
2
3
basic concept of utilizing sp - and sp -C–Zr bonds directly.
That is, how can vinyl and alkyl zirconocenes be employed
more effectively without recourse to zinc salt additives and
which rely on a base metal like nickel, rather than
palladium? Our focus has also included a shift to a more
environmentally benign, inexpensive, and recyclable
heterogeneous approach to catalysis, in particular using
As amply documented by the very recent monograph on
Titanium and Zirconium in Organic Synthesis’, edited by
‘
1
Ilan Marek, use of zirconocene intermediates in a wide
range of synthetic situations continues to blossom. One of
the more fundamental processes associated with organo-
zirconium chemistry is generally regarded as cross-coupling
2
8
reactions, or the zirconium version of ‘Negishi couplings’.
3
As originally disclosed in the mid-to-late 1970’s, diene or
nickel-on-charcoal (Ni/C). Since the combination of less
reactive ziconocenes (e.g. vs the corresponding zinc
species) together with catalyst heterogeneity would be
expected to depress reaction rates of the desired Negishi
styrene formation could be achieved via treatment of an in
situ generated vinyl zirconocene with a vinyl or aryl halide,
respectively (Scheme 1). Nickel(0) was the catalyst
9
–11
couplings, microwave irradiation
was postulated as a
3
a
employed at first, although palladium is now regarded in
4
most circles as more broadly applicable. While these
potential means of reaction acceleration. Although such
reactions of Ni/C under the influence of microwaves had not
been studied previously, there was evidence in the literature
seminal studies offered new inroads to valued C–C bond
constructions, the relatively low electronegativity (1.2–1.4)
of Zr and unreactive nature of the C–Zr bond toward
carbon-based electrophiles oftentimes necessitates trans-
metalations, thereby significantly expanding the scope of
zirconocene-based couplings. In the specific case of Negishi
1
2
that Pd/C could function in a related capacity. Thus, in this
report we describe the remarkable effect that microwave
irradiation exerts on various types of cross-couplings of
organozirconium species catalyzed by heterogeneous Ni/C
(Scheme 2).
couplings, addition of a zinc salt (e.g. ZnCl ) results in a
2
marked rate acceleration leading to extremely valuable
5
technology, especially in light of the many alternatives for
6
2. Results and discussion
preparing (functionalized) organozinc reagents. Notwith-
standing these developments, which greatly enhance the
utility of zirconocene derivatives (especially those resulting
Reactions of vinyl zirconocenes, prepared in the usual
7
fashion from terminal alkynes with Cp Zr(H)Cl, were
2
Scheme 1.
Keywords: Microwave; Negishi couplings; Nickel-on-charcoal; Alkyl/vinyl zirconocenes.
*
Corresponding author. Tel.: þ1-805-893-2521; fax: þ1-805-893-8265; e-mail address: lipshutz@chem.ucsb.edu
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.10.029

1310
B. H. Lipshutz, B. Frieman / Tetrahedron 60 (2004) 1309–1316
absence of phosphines, 2 was converted to 3 within
0 minutes in high yield.
1
As illustrated in Table 1 (entries 1 and 2), couplings of
representative vinyl zirconocenes under these phosphine-
free conditions on both an electron-rich and electron-poor
substrate proceed with equal facility. In the case of aryl
bromides, 2 equiv. of PPh were required (relative to the %
3
Scheme 2.
Ni/C present) for total conversion (entries 3 and 4).
Noteworthy are the cases of aryl chlorides (entries 5 and
6), which are notoriously unreactive toward vinyl zircono-
initially surveyed in combination with aryl halides in the
presence of Ni/C. Unlike the related Suzuki-like couplings
mediated by this catalyst, complete consumption of
starting material (initially on activated iodide 2, Scheme
3
cenes even with Ni(0) in solution. Reaction of highly
1
3
electron-rich chloride 4 was unexceptional under the
standard conditions employed, reaching completion within
40 min. However, in going from bromides to chlorides,
3
(
) could not be accomplished even under reflux conditions
THF) after 24 h. Conversions below 70% were observed
4 equiv. of Ph
bromides and 0 equiv. of PPh
P (as opposed to 2 equiv. of PPh
with
3
3
when room temperature conditions were applied. Interest-
ingly, while these early trials were mainly unsuccessful, the
importance of phosphine concentrations became apparent,
as the greatest extent of conversion was noted in the absence
of Ph P (rt: 4 Ph P, ,5%; 2 Ph P, 20%; no PPh , 40%
3
with iodides) were needed to
fully consume the aryl halide.
In all of the above cases, Ph P was the ligand used. To
quickly ascertain the importance of this reaction parameter,
four other phosphines were screened: another monodentate
3
3
3
3
3
product 3). Thus, under microwave irradiation and in the
Scheme 3.
Table 1. ‘Negishl couplings’ of vinyl zirconocenes with aryl halides catalyzed by Ni/C under microwave irradiation at 200 8C in THF
a
Entry
Vinyl zirconocene
Aryl halide
Time (min)
Yield (%)
b
83
1
10
b
2
3
15
15
83
c
86
c
4
5
20
77
d
30
40
76
d
6
75
a
Isolated, chromatographically purified material.
Reaction performed using 5% Ni/C and 0% PPh
Reaction performed using 5% Ni/C and 10% PPh
Reaction performed using 5% Ni/C and 20% PPh
b
c
d
3
relative to aryl iodide.
relative to aryl bromide.
relative to aryl chloride.
3
3

B. H. Lipshutz, B. Frieman / Tetrahedron 60 (2004) 1309–1316
1311
Table 2. Effect of ligands on cross-couplings of vinyl zirconcenes
Several additional types of substrates were examined under
these microwave enhanced, Ni/C-catalyzed conditions
without success. Thus, nonaflate 13 and vinyl iodide 14
each led to many unidentified side products in reactions with
a vinyl zirconocene. Each was also found to be sluggish,
with considerable amounts of starting material remaining.
1
4
Likewise, benzylic chloride 15, which couples at room
1
5
temperature with vinyl alanes under Ni/C catalysis, led to
no reaction even at 180 8C for 10 min. It was also
disappointing to observe even a simple vinyl zirconocene
derived from octyne could not be induced to add in a
4
1
6
conjugate fashion to cyclohexenone under microwave
irradiation at 200 8C in THF (10 min).
Phosphine ligand
Cy
dppe
rac BINAP
dppf
Ligand (equiv) vs Ni/C
Conversion (%)
3
P
4
2
2
2
4
5
9
11
18
95
Ph
3
P
Finally, we have questioned the extent of leaching of nickel
from the Ni/C used in these studies, as done in all previous
1
7
uses of this heterogeneous support. A quantitative ICP
species (Cy P), and three of the bidentate variety: dppe,
3
1
8
AES determination was made based on the reaction
mixture associated with entry 1 in Table 1. The data
indicated that 2.86% of the 5% Ni/C present (or 2.86% of
the 2.18 mg nickel for the amount of catalyst used) in the
reaction mixture could be detected. This figure corresponds
to 62.36 mg of nickel in solution, or the presence of
1.25 ppm.
racemic BINAP, and dppf (Table 2). Our findings, based on
the coupling of chloride 4 with vinyl zirconocene 5 to afford
6
, clearly indicate that Ph P is the only ligand in this group
3
capable of assisting in the oxidative addition step; the
recovered mass was the starting chloride.
3
The corresponding coupling using an sp -based C–Zr bond,
from hydrozirconation of an alkene, was also tested under
microwaves conditions. The combination of alkyl zircono-
cene 7 and aryl halide 8 led to a smooth conversion to
adduct 9 (Eq. (1)).
3
. Summary and conclusions
This study suggests that Ni/C is a viable catalyst for
mediating cross-coupling reactions between organozirco-
nium intermediates and aryl halides under microwave
irradiation. Aromatic iodides, bromides, and in some cases
even chlorides are amenable to these conditions. Microwave
accelerated couplings related to these zirconium-based
Negishi couplings, for example, involving aryl halides and
boronic acids or amines, are also underway and will be
reported in due course, as will our study on the use of CuCl
as a trivial means of sequestering mono- and bidentate
ð1Þ
mW
1
9
phosphines as used in some of the workups herein.
A more highly conjugated skeleton could be fashioned by
hydrozirconation of enyne 10, followed by Ni/C-catalyzed
coupling with aryl bromide 11. As previously observed for
such educts, 2 equiv. of triphenylphosphine (i.e. 8 mol%)
led to the desired dienic product 12 in good yield (Eq. (2)).
4. Experimental
4.1. General
Reactions were performed in oven-dried glassware under an
argon atmosphere containing a Teflon coated stir bar and
dry septum. THF was freshly distilled from Na/benzo-
phenone ketyl prior to use. Ni/C was stored and weighed out
as a black powder in a glove box. All commercially
ð2Þ
available reagents were distilled either from CaH or
2
molecular sieves under an inert atmosphere before use.
Schwartz’s reagent, Cp Zr(H)Cl, was prepared using the
2
2
0
standard procedure and titrated using octyne and then
analyzed by GC in triplicate and found to be .99% pure.
1
-Octyne, 5-hexyn-1-ol, 3-butyn-1-ol, 2-iodoanisole,

1312
B. H. Lipshutz, B. Frieman / Tetrahedron 60 (2004) 1309–1316
5-chloro-1,3-benzodioxole, CuCl, and NaOMe were pur-
chased from Aldrich. 1-Bromo-3,5-dimethylbenzene and
(259 mg, 99% pure, 1.00 mmol). THF (2.0 mL) was added
followed by 1-octyne (149 mL, 1.00 mmol) via syringe.
After 30 min, the hydrozirconation was complete by GC.
4
1
-chlorobenzotrifluoride were purchased from Lancaster.
-Hexene, 4-iodobenzotrifluoride, and 4-bromofluoro-
benzene were purchased from Acros. 3,4-Dimethoxy-6-
methyl-2-toluene-sulfonyloxybenzyl chloride was obtained
from Optima. All microwave experiments were performed
using an Emrys Optimizer in 2–5 mL pyrex reaction vessels
which were flame dried under an argon atmosphere. Each
contained a Teflon stir bar and Teflon coated reaction vessel
cap. ICP-AES analyses was performed on a Thermo Jarrell
Ash IRIS plasma spectrometer. GC analyses were carried
out using an HP-5 capillary column (0.25 mm£30 m; cross-
linked 5% PH ME siloxane) and a time program beginning
with 5 min at 50 8C followed by 20 8C/min ramp to 280 8C,
then 20 min at this temp. Column chromatography was
performed using Davisil Grade 633 Type 60A silica gel.
TLC analyses were performed on commercial Kieselgel 60
F254 silica gel plates. NMR spectra were obtained on Varian
Nickel-on-charcoal catalyzed coupling. To an Emrys
Optimizer 2–5 mL pyrex reaction vessel was added Ni/C
(67.3 mg, 0.04 mmol) under argon at rt. THF (1 mL) was
added followed by BuLi (31 mL, 2.55 M in hexanes,
0.08 mmol). The solution was allowed to stir at rt for
5 min after which 4-iodobenzotrifluoride (117 mL,
0.80 mmol) was added dropwise at rt and the mixture
allowed to stir for 5 min. The vinyl zirconocene was then
transferred via cannula to the Ni/C mixture at rt. The
reaction vessel was placed in the Emrys Optimizer and
exposed to microwave irradiation according to the follow-
ing specifications: temperature: 200 8C, time: 600 s, fixed
hold time: on, sample absorption: normal, pre-stirring: 30 s.
After cooling to room temperature, the crude reaction
mixture was filtered through a glass frit containing Fullers
Earth to remove the Ni/C and the zirconium salts, and the
filter cake was further washed with ether and hexanes. The
filtrate was collected, solvents were removed on a rotary
evaporator, and the crude mixture was purified by flash
chromatography on silica gel with pet ether. The title
compound was obtained (244 mg; 95%) as a clear, viscous
Inova systems using CDCl as solvent, with proton and
3
carbon resonances at 400 and 100 MHz, respectively. FTIR
spectra were obtained on an ATI Mattson Infinity series
spectrometer neat on NaCl plates and are reported in cm2
1
.
Mass spectral data were acquired on a VF Autospec or an
analytical VG-70-250 HF instrument.
oil; R 0.80 (pet ether).
f
4
.2. Preparation of Ni(II)/C
IR (neat): 2929, 2858, 2254, 1916, 1616, 1466, 1413, 1324,
21
w
1
Darco KB (5.00 g, 100 mesh) activated carbon (25% H O
2
1127, 1068, 1017, 909, 731 cm . H NMR (400 MHz,
CDCl ): d 7.58–7.53 (m, 2H), 7.47–7.42 (m, 2H), 6.43 (d,
content) was added to a 100 mL round bottom flask
containing a stir bar. A solution of 727 mg (Aldrich,
4,407-4, Ni content by ICP determination: 92%;
.30 mmol) Ni(NO ) ·6H O in 35 mL deionized H O was
3
J¼16.1 Hz, 1H), 6.36 (dt, J¼6.1, 16.1 Hz, 1H), 2.26
2
2
(apparent quartet, J¼7.4 Hz, 2H), 1.56–1.46 (m, 2H),
1
3
1.44–1.27 (m, 8H), (0.93, t, J¼7.1 Hz, 3H). C NMR
3
2
2
2
added to the activated carbon and 40 mL of deionized H O
2
(100 MHz, CDCl ): d 141.66, 138.25, 134.34, 128.77,
3
was added to wash down the sides of the flask. The flask was
purged under argon and stirred vigorously for 1 min. The
flask was submerged in an ultrasonic bath under a positive
argon flow for 30 min. The flask was attached to an
argon purged distillation setup and placed in a pre-heated
126.22, 125.69, 125.65, 125.61, 125.57, 33.33, 31.96, 29.36,
29.15, 22.86, 14.31. MS (EI): m/z (relative %) 256 (16), 185
(29), 172 (100), 165 (12), 115 (19), 55 (10), 43 (13).
HREIMS: m/z calcd for C H F 256.1433; found
1
5
19 3
256.1438.
175–180 8C sand bath with stir plate. As the distillation
ended, the flask temperature rises automatically but should
be held below 210 8C for an additional 15 min. Upon
cooling to rt, the black solid was washed with H O
2
(
course fritted funnel. The 100 mL of H O used to wash the
2£50 mL) under argon into a pre-dried in vacuo 150 mL
4.3.2. Table 1, entry 1. E-Triisopropyl-[6-(4-trifluoro-
methylphenyl)-hex-5-enyloxy]-silane. TIPS protected 5-
2
Ni/C was rotavaped and analyzed for any remaining nickel.
The fritted funnel was turned upside down under vacuum for
hexynol (254 mg, 1 mmol), Cp Zr(H)Cl (259 mg, 99%
2
pure, 1.00 mmol) and THF (2.0 mL) were added to a
10 mL flasked protected from light using aluminum foil.
After 60 min, the hydrozirconation was complete by GC. A
mixture containing Ni/C (67.3 mg, 0.04 mmol), THF
(1 mL), n-BuLi (31 mL, 2.55 M in hexanes, 0.08 mmol),
and 4-iodobenzotrifluoride (117 mL, 0.80 mmol) was pre-
pared using the typical procedure above, followed by the
cross-coupling reaction using the following conditions:
temperature: 200 8C, time: 900 s, fixed hold time: on,
sample absorption: normal, pre-stirring: 30 s. After a
standard workup, chromatography of the residue on silica
gel with pet ether afforded 333 mg (83%) of the title
3
h until the Ni/C falls from the frit into the collection flask.
The collection flask is then dried in vacuo at 100 8C for 18 h.
Using these specific amounts, all of the nickel is mounted on
the support, which corresponds to 0.552 mmol Ni(II)/g
catalyst, or 3.2% Ni/catalyst by weight.
4.3. General procedure for Ni/C-catalyzed cross-
couplings of vinyl zirconocenes with aryl halides
compound as a clear oil; R 0.38 (pet ether).
f
4.3.1. E-1-Octenyl-4-trifluoromethylbenzene (3). Hydro-
zirconation. To a 10 mL round-bottom flask wrapped in
IR (neat): 2941, 2865, 1616, 1462, 1325, 1165, 1126, 1068,
1015, 967, 882, 680 cm2 . H NMR (400 MHz, CDCl ): d
1 1
3
aluminum foil and under argon was added Cp Zr(H)Cl
2
7.58–7.52 (m, 2H), 7.46–7.41 (m, 2H), 6.44 (d, J¼16.0 Hz,

B. H. Lipshutz, B. Frieman / Tetrahedron 60 (2004) 1309–1316
1313
1
2
2
1
1
1
H), 6.28 (dt, J¼7.1, 16.0 Hz, 1H), 3.75 (t, J¼6.8 Hz, 2H),
silica gel with pentane afforded 277 mg (86%) of the title
compound as a clear oil; R 0.36 (pentane).
.29 (apparent q, 2H), 1.69–1.54 (m, 4H), 1.16–1.08 (m,
1H). C NMR (100 MHz, CDCl ): d 141.59, 134.09,
f
1
3
3
28.96, 128.68, 126.24, 125.90, 125.67, 125.63, 125.60,
25.56, 123.20, 63.39, 33.10, 32.74, 25.69, 18.25, 18.17,
2.23. MS (EI): m/z (relative %) 357 (100), 207 (18), 185
IR (neat): 2942, 2865, 1602, 1508, 1463, 1382, 1230, 1157,
1104, 1013, 964, 882, 850, 774, 733, 680 cm2 . H NMR
1 1
(400 MHz, CDCl ): d 7.34–7.29 (m, 2H), 7.03–6.97 (m,
3
(
6
(
10), 179 (24), 159 (11), 153 (10), 127 (13), 83 (17), 75 (20),
1 (14), 43 (10). HREIMS: m/z calcd for C H F OSi
2H), 6.43 (d, J¼16.0 Hz, 1H), 6.19 (dt, J¼7.1, 16.0 Hz, 1H),
13
3.82 (t, J¼6.8 Hz, 2H), 2.47 (ddt, J¼1.2, 6.8, 6.8 Hz, 2H),
2
2 35 3
þ
M 2C H ) 357.1853; found 357.1861.
3
1.13–1.08 (m, 21H). C NMR (100 MHz, CDCl ): d
7
3
1
1
63.38, 160.93, 134.14, 134.10, 130.54, 127.61, 127.53,
27.33, 127.31, 115.63, 115.41, 63.42, 36.98, 18.23, 12.21.
MS (EI): m/z (relative %) 332 (1), 303 (2), 289 (100), 159
(54), 145 (34), 129 (30), 115 (23), 103 (20), 75 (35), 59 (33),
þ
4
3 (31). HREIMS: m/z calcd for C H FOSi (M 2C H )
1
9
31
3 7
279.1575; found 279.1580.
4
.3.3. Table 1, entry 2. Et-Butyl-[6-(2-methoxyphenyl)-
TBDMS protected
-hexyn-1-ol (212 mg, 1 mmol), Cp Zr(H)Cl (259 mg,
hex-5-enyloxy]-dimethylsilane.
5
9
2
9% pure, 1.00 mmol) and 2.0 mL of THF were added to
a 10 mL flask and protected from light using aluminum foil.
After 60 min, the hydrozirconation was complete by GC. A
mixture containing Ni/C (67.3 mg, 0.04 mmol), THF
4
.3.5. Table 1, entry 4. E-[4-(3,5-Dimethylphenyl)-but-3-
(
2
1 mL), BuLi (31 mL, 2.55 M in hexanes, 0.08 mmol), and
-iodoanisole (104 mL, 0.80 mmol) was prepared using the
enyloxy]-triisopropylsilane. TIPS protected 3-butyn-1-ol
226 mg, 1 mmol), Cp Zr(H)Cl (259 mg, 99% pure,
(
typical procedure above followed by the cross-coupling
reaction using the following conditions: temperature:
2
1
.00 mmol) and 2.0 mL of THF were added to a 10 mL
flask and protected from light using aluminum foil. After
0 min, the hydrozirconation was complete by GC. Ni/C
2
00 8C, time: 900 s, fixed hold time: on, sample absorption:
6
normal, pre-stirring: 30 s. After a standard workup,
chromatography of the residue on silica gel with pet
ether–methylene chloride (95:5) afforded 212 mg (83%)
(67.3 mg, 0.04 mmol), PPh3 (21 mg, 0.08 mmol), THF
(1 mL), n-BuLi (31 mL, 2.55 M in hexanes, 0.08 mmol),
and 5-bromo-2,3-dimethylbenzene (109 mL, 0.8 mmol)
were used according to the typical procedure, followed by
the cross-coupling reaction using the following conditions:
temperature: 200 8C, time: 1200 s, fixed hold time: on,
sample absorption: normal, pre-stirring: 30 s. After standard
workup, chromatography of the residue on silica gel with
petroleum ether afforded 204 mg (77%) of the title
of the title compound as a clear oil; R 0.08 (pet ether–
f
methylene chloride).
IR (neat): 2959, 2252, 1701, 1459, 1367, 1148, 1013, 911,
7
33, 647 cm2 . H NMR (400 MHz, CDCl ): d 7.46–7.42
1
1
3
(
m, 1H), 7.23–7.17 (m, 1H), 6.96–6.85 (m, 2H), 6.73 (d,
J¼16.0 Hz, 1H), 6.23 (dt, J¼7.0, 16.0 Hz, 1H), 3.86 (s, 3H),
compound as a clear oil; R 0.22 (pet. ether).
f
3
1
.66 (t, J¼6.5 Hz, 2H), 2.27 (ddt, J¼1.2, 7.0, 7.0 Hz, 2H),
1
3
.65–1.50 (m, 4H), 0.92 (s, 9H), 0.08 (s, 6H). C NMR
IR (neat): 2865, 2728, 2248, 1602, 1464, 1382, 1248, 1202,
1
(
1
2
100 MHz, CDCl ): d 156.43, 131.82, 128.00, 127.13,
3
26.56, 124.62, 120.82, 110.94, 63.35, 55.62, 33.46, 32.64,
6.20, 25.96, 18.59, 25.05. MS (EI): m/z (relative %) 263
1
109, 1013, 996, 965, 909, 883, 851, 793, 734, 681 cm2
H NMR (400 MHz, CDCl ): d 7.02 (apparent s, 2H), 6.89
.
1
3
(
1
6
apparent s, 1H), 6.43 (d, J¼16.0 Hz, 1H), 6.28 (dt, J¼7.1,
(100), 147 (10), 121 (38), 91 (12), 75 (31), 73 (14).
þ
HREIMS: m/z calcd for C H O Si (M 2C H ) 263.1460;
found 263.1467.
6.0 Hz, 1H), 3.84 (t, J¼6.8 Hz, 2H), 2.51 (ddt, J¼1.2, 6.8,
1
9
32
2
4 9
1
3
.8 Hz, 2H), 2.34 (s, 6H), 1.16–1.10 (m, 21H). C NMR
(100 MHz, CDCl ): d 138.05, 137.86, 131.84, 128.87,
3
1
27.00, 124.12, 63.57, 37.11, 21.48, 18.24, 12.23. MS (EI):
m/z (%) 332 (1), 303 (2), 289 (100), 159 (54), 145 (34), 129
30), 115 (23), 103 (20), 75 (35), 59 (33), 43 (31). HREIMS:
m/z calcd for C H OSi 332.2547; found 332.2535.
(
2
1 36
4
.3.4. Table 1, entry 3. E-[4-(4-Fluorophenyl)-but-3-
enyloxy]-triisopropylsilane. TIPS protected 3-butyn-1-ol
226 mg, 1 mmol), Cp Zr(H)Cl (259 mg, 99% pure,
(
2
1
.00 mmol) and 2.0 mL of THF were added to a 10 mL
flask and protected from light using aluminum foil. After
0 min, the hydrozirconation was complete by GC. A
mixture containing Ni/C (67.3 mg, 0.04 mmol), PPh3
21 mg, 0.08 mmol), THF (1 mL), n-BuLi (31 mL, 2.55 M
in hexanes, 0.08 mmol), and 4-bromofluorobenzene (88 mL,
.8 mmol) was prepared using the typical procedure above,
followed by the cross-coupling reaction using the following
conditions: temperature: 200 8C, time: 900 s, fixed hold
time: on, sample absorption: normal, pre-stirring: 30 s.
After standard workup, chromatography of the residue on
6
4.3.6. Table 1, entry 5. E-Triisopropyl-[4-(4-trifluoro-
methylphenyl)-but-3-enyloxy]-silane. The TIPS protected
3-butyn-1-ol (226 mg, 1 mmol), Cp Zr(H)Cl (259 mg, 99%
2
pure, 1.00 mmol) and 2.0 mL of THF was added and
protected from light using aluminum foil. After 60 min, the
hydrozirconation was complete by GC. Ni/C (67.3 mg,
0.04 mmol), PPh (42 mg, 0.16 mmol), THF (1 mL), BuLi
3
(31 mL, 2.55 M in hexanes, 0.08 mmol), and 4-chloro-
benzotrifluoride (107 mL, 0.8 mmol) were prepared using
(
0

1314
B. H. Lipshutz, B. Frieman / Tetrahedron 60 (2004) 1309–1316
the typical procedure followed by the cross-coupling
reaction using the following conditions: temperature:
n-BuLi (31 mL, 2.55 M in hexanes, 0.08 mmol), and 4-
chloro-1,3-benzodioxole (93 mL, 0.8 mmol) were used
according to the typical procedure, followed by the cross-
coupling reaction using the following conditions: tempera-
ture: 200 8C, time: 2400 s, fixed hold time: on, sample
absorption: normal, pre-stirring: 30 s. After standard
workup, GC of the title compound indicated 5% conversion.
2
00 8C, time: 1800 s, fixed hold time: on, sample absorption:
normal, pre-stirring: 30 s. After standard workup, followed
by evaporation of most of the solvent, CuCl (5.3 mg,
0
.053 mmol) was added and swirled for 10 min to sequester
the triphenylphosphine. Chromatography of the residue on
silica gel with petroleum ether afforded 227 mg (76%) of the
title compound as a clear oil; R 0.35 (pet. ether).
4.3.9. Table 2; dppe. TIPS protected 3-butyn-1-ol (226 mg,
1
f
mmol), Cp Zr(H)Cl (259 mg, 99% pure, 1.00 mmol) and
2
IR (neat): 2943, 2866, 1503, 1465, 1325, 1165, 1125, 1067,
9
2.0 mL of THF were added to a 10 mL flask and protected
from light using aluminum foil. After 60 min, the
hydrozirconation was complete by GC. Ni/C (67.3 mg,
0.04 mmol), dppe (31.8 mg, 0.08 mmol), THF (1 mL),
n-BuLi (31 mL, 2.55 M in hexanes, 0.08 mmol), and
4-chloro-1,3-benzodioxole (93 mL, 0.8 mmol) were used
according to the typical procedure, followed by the cross-
coupling reaction using the following conditions: tempera-
ture: 200 8C, time: 2400 s, fixed hold time: on, sample
absorption: normal, pre-stirring: 30 s. Upon standard
workup, GC of the title compound indicated 9% conversion.
08, 736 cm2 . H NMR (400 MHz, CDCl ): d 6.91–6.90
1
1
3
(
(
m, 1H), 6.79–6.73 (m, 2H), 6.37 (d, J¼15.7 Hz, 1H), 6.28
dt J¼7.1, 15.7 Hz, 1H), 3.80 (t, J¼6.8 Hz, 2H), 2.51 (ddt,
1
3
J¼1.2, 6.8, 6.8 Hz, 2H), 1.12–1.07 (m, 21H). C NMR
(
100 MHz, CDCl ): d 141.45, 130.68, 130.52, 129.10,
3
1
1
26.29, 125.70, 125.66, 125.63, 125.59, 63.15, 37.01, 18.22,
2.21. MS (EI): m/z (%) 329 (100), 198 (11), 128 (14), 120
(
for C H F OSi M 2(C H ) 329.1550; found 329.1549.
45), 92 (15), 74 (11), 58 (10), 42 (28). HREIMS: m/z calcd
þ
2
0
31
3
3 7
4.3.10. Table 2; BINAP. TIPS protected 3-butyn-1-ol
(226 mg, 1 mmol), Cp Zr(H)Cl (259 mg, 99% pure,
2
1.00 mmol) and 2.0 mL of THF were added to a 10 mL
4
.3.7. Table 1, entry 6. E-(4-Benzo[1,3]dioxol-5-yl-but-3-
enyloxy)-triisopropylsilane. TIPS protected 3-butyn-1-ol
226 mg, 1 mmol), Cp Zr(H)Cl (259 mg, 99% pure,
flask and protected from light using aluminum foil. After
60 min, the hydrozirconation was complete by GC. Ni/C
(67.3 mg, 0.04 mmol), (R)-BINAP (49.8 mg, 0.08 mmol),
THF (1 mL), n-BuLi (31 mL, 2.55 M in hexanes,
0.08 mmol), and 4-chloro-1,3-benzodioxole (93 mL,
0.8 mmol) were used according to the typical procedure,
followed by the cross-coupling reaction using the following
conditions: temperature: 200 8C, time: 2400 s, fixed hold
time: on, sample absorption: normal, pre-stirring: 30 s.
Upon standard workup, GC of the title compound indicated
11% conversion.
(
2
1
.00 mmol) and 2.0 mL of THF were added to a 10 mL
flask and protected from light using aluminum foil. After
0 min, the hydrozirconation was complete by GC. Ni/C
6
(
(
67.3 mg, 0.04 mmol), PPh3 (42 mg, 0.16 mmol), THF
1 mL), n-BuLi (31 mL, 2.55 M in hexanes, 0.08 mmol),
and 4-chloro-1,3-benzodioxole (93 mL, 0.8 mmol) were
used according to the typical procedure, followed by the
cross-coupling reaction using the following conditions:
temperature: 200 8C, time: 2400 s, fixed hold time: on,
sample absorption: normal, pre-stirring: 30 s. After standard
workup followed by evaporation of most of the solvent,
CuCl (5.3 mg, 0.053 mmol) was added and the mixture
swirled for 10 min to sequester the triphenylphosphine.
Chromatography of the residue on silica gel with petroleum
ether afforded 208 mg (75%) of the title compound as a
4.3.11. Table 2; dppf. TIPS protected 3-butyn-1-ol
(226 mg, 1 mmol), Cp Zr(H)Cl (259 mg, 99% pure,
2
1.00 mmol) and 2.0 mL of THF were added to a 10 mL
flask and protected from light using aluminum foil. After
60 min, the hydrozirconation was complete by GC. Ni/C
(67.3 mg, 0.04 mmol), dppf (44.4 mg, 0.08 mmol), THF
(1 mL), n-BuLi (31 mL, 2.55 M in hexanes, 0.08 mmol),
and 4-chloro-1,3-benzodioxole (93 mL, 0.8 mmol) were
used according to the typical procedure, followed by the
cross-coupling reaction using the following conditions:
temperature: 200 8C, time: 2400 s, fixed hold time: on,
sample absorption: normal, pre-stirring: 30 s. Upon
standard workup, GC of the title compound indicated 18%
conversion.
clear oil; R 0.10 (pet. ether).
f
IR (neat): 2943, 2866, 1503, 1490, 1250, 1104, 908, 734,
80, 650, 450 cm2 . H NMR (400 MHz, CDCl ): d 6.91–
1 1
6
6
6
3
.90 (m, 1H), 6.79–6.73 (m, 2H), 6.37 (d, J¼15.7 Hz, 1H),
.28 (dt, J¼7.1, 15.7 Hz, 1H), 3.80 (t, J¼6.8 Hz, 2H), 2.51
C
1
3
(
ddt, J¼1.3, 6.8, 6.8 Hz, 2H), 1.12–1.07 (m, 21H).
NMR (100 MHz, CDCl ): d 148.10, 146.85, 132.51, 131.25,
3
1
1
25.73, 120.55, 108.39, 105.58, 101.11, 63.51, 36.93, 18.22,
2.20. MS (EI): m/z (%) 348 (24), 305 (100), 174 (53), 156
(
(
53), 144 (86), 134 (34), 130 (32), 116 (68), 114 (50), 102
30), 86 (22), 74 (37), 58 (49), 44 (25). HREIMS: m/z calcd
for C H O Si 348.2129; found 348.2121.
0 32 3
2
4
1
2
.3.8. Table 2; Cy P. TIPS protected 3-butyn-1-ol (226 mg,
3
mmol), Cp Zr(H)Cl (259 mg, 99% pure, 1.00 mmol) and
2
.0 mL of THF were added to a 10 mL flask and protected
4.3.12. Eq. 1. 1-n-Hexyl-2-methoxybenzene (9). 1-Hexene
(124 mL, 1 mmol), Cp Zr(H)Cl (259 mg, 99% pure,
1.00 mmol) and THF (2.0 mL) were added to a 10 mL
flask and protected from light using aluminum foil. After
60 min, the hydrozirconation was complete by GC. Ni/C
(67.3 mg, 0.04 mmol), THF (1 mL), n-BuLi (31 mL, 2.55 M
2
from light using aluminum foil. After 60 min, the hydro-
zirconation was complete by GC. Ni/C (67.3 mg,
0
.04 mmol), Cy P (44.9 mg, 0.16 mmol) THF (1 mL),
3

B. H. Lipshutz, B. Frieman / Tetrahedron 60 (2004) 1309–1316
1315
in hexanes, 0.08 mmol), and 2-iodoanisole (104 mL,
.80 mmol) were used according to the typical procedure,
1.00 mmol) and THF (2.0 mL) were added to a 10 mL flask
and protected from light using aluminum foil. After 30 min,
the hydrozirconation was complete by GC. Ni/C (67.3 mg,
0.04 mmol), THF (1 mL), n-BuLi (31 mL, 2.55 M in
hexanes, 0.08 mmol), and 4-iodobenzotrifluoride (117 mL,
0.80 mmol) were used according to the typical procedure,
followed by the cross-coupling reaction using the following
conditions: temperature: 200 8C, time: 600 s, fixed hold
time: on, sample absorption: normal, pre-stirring: 30 s. The
reaction mixture was filtered using a 60 mL course filter
funnel after cooling to room temperature. The reaction
mixture was then washed through the funnel with ether
(3£20 mL). The filtrate was refilltered with ether washings
(3£10 mL). The solvent was evaporated and the crude
0
followed by the cross-coupling reaction using the following
conditions: temperature: 200 8C, time: 900 s, fixed hold
time: on, sample absorption: normal, pre-stirring: 30 s.
Upon standard workup, chromatography of the residue on
silica gel with hexanes afforded 131 mg (85%) of the title
compound as a clear oil; R 0.41 (hexanes).
f
IR (neat): 2926, 2856, 1729, 1601, 1493, 1464, 1377, 1289,
2
1
1
1
(
241, 1177, 1128, 1051, 1033, 751 cm
.
H NMR
400 MHz, CDCl ): d 7.20–7.12 (m, 2H), 6.91–6.83 (m,
3
2
H), 3.83 (s, 3H), 2.61 (apparent t, J¼7.7 Hz, 2H), 1.44–
1
3
1
CDCl ): d 157.63, 131.57, 129.93, 126.93, 120.49, 110.40,
.18 (m, 8H), 0.90 (t, J¼7.1 Hz, 3H). C NMR (100 MHz,
material digested with 10 mL of 20% HNO and 5 mL
3
3
5
5.46, 31.99, 30.36, 30.04, 29.53, 22.88, 14.35. MS (EI):
concentrated HCl at reflux for 8 h. Upon cooling and
dilution with H O (20 mL), the mixture was extracted with
m/z (%) 192 (21), 122 (12), 121 (100), 91 (44), 43 (19).
HREIMS: m/z calcd for C H O 192.1510; found
1
2
hexanes (10 mL) and CH Cl (2£10 mL) and the combined
1
3
20
2
2
92.1514.
organic layers washed with H O. The solvents were
2
removed from the combined aqueous phases and the
ICP-AES sample was prepared by adding 2% HCl in a
way that the final (estimated) nickel concentration was
between 1 and 35 ppm. The analytical sample prepared was
determined to have 1.25 ppm Ni in solution (2.86% Ni in
solution).
4
.3.13. Eq. 2. E,E-Triisopropyl-[6-(4-propylphenyl)-
(12). Hex-3-en-5-ynyl-
(252 mg, 1 mmol), Cp Zr(H)Cl
hexa-3,5-dienyloxy]-silane
21
oxytriisopropylsilane
259 mg, 99% pure, 1.00 mmol) and THF (2.0 mL) were
added and protected from light using aluminum foil. After
0 min, the hydrozirconation was complete by TLC. Ni/C
2
(
Acknowledgements
9
(
(
67.3 mg, 0.04 mmol), PPh3 (21 mg, 0.08 mmol), THF
1 mL), n-BuLi (31 mL, 2.55 M in hexanes, 0.08 mmol),
Financial support provided by the NIH (GM 40287) is
warmly acknowledged with thanks. We are indebted to
Amgen, Inc., the NSF, and Dean M. Moskovits (UCSB) for
the funds needed to purchase the microwave reactor used in
this study and to Personal Chemistry for making the
Optimizer affordable to us.
and 1-bromo-4-n-propylbenzene (124 mL, 0.8 mmol) were
prepared using the typical procedure followed by the cross-
coupling reaction using the following conditions: tempera-
ture: 180 8C, time: 900 s, fixed hold time: on, sample
absorption: normal, pre-stirring: 30 s. The filtrate was
collected, most of the solvents were removed on a rotary
evaporator, and CuCl (2.7 mg, 0.026 mmol) was added and
the mixture swirled for 10 min to sequester the triphenyl-
phosphine. Chromatography of the residue on silica gel with
hexanes afforded 237 mg (80%) of the title compound as a
References and notes
1. Titanium and Zirconium in Organic Synthesis; Marek, I., Ed.;
Wiley-VCH: Weinheim, 2002.
clear oil; R 0.15 (hexanes).
f
2
. (a) Negishi, E.; Liu, F. In Metal-Catalyzed Cross-Coupling
Reactions; Diederich, F., Stang, P. J., Eds.; Wiley-VCH:
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Horn, D. E.; Okukado, N. J. Am. Chem. Soc. 1987, 109, 2393.
IR (neat): 3019, 2941, 2865, 1509, 1462, 1380, 1246, 1105,
1
1
070, 1013, 985, 931, 882, 779, 739, 681, 658 cm2 . H
NMR (400 MHz, CDCl ): d 7.34 (apparent d, 2H), 7.16
1
3
(
apparent d, 1H), 6.76 (dd, J¼15.7, 15.7 Hz, 1H) 6.48 (d,
3. (a) Negishi, E.; Van Horn, D. E. J. Am. Chem. Soc. 1977, 99,
3168. (b) Okukado, N.; Van Horn, D. E.; Klima, W. L.;
Negishi, E. Tetrahedron Lett. 1978, 1027.
J¼15.7 Hz, 1H), 6.30 (dd, J¼15.7, 15.7 Hz, 1H), 5.87 (dt,
J¼7.4, 15.7 Hz, 1H), 3.80 (t, J¼6.8 Hz, 2H), 2.61 (t,
J¼7.4 Hz, 2H), 2.44 (apparent q, 2H), 1.67 (qt, J¼7.4,
4. Handbook of Organopalladium Chemistry; Negishi, E., Ed.;
Wiley/Interscience: New York, 2002.
7
1
.4 Hz, 2H), 1.16–1.10 (m, 21H), 0.99 (t, J¼7.4 Hz, 3H).
3
C NMR (100 MHz, CDCl ): d 142.05, 135.26, 132.60,
3
5. (a) Negishi, E.; Owczarczyk, Z. Tetrahedron Lett. 1991, 32,
6683. (b) Negishi, E.; Okukado, N.; King, A. O.; Van Horn,
D. E.; Spiegel, B. I. J. Am. Chem. Soc. 1978, 100, 2254.
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Schlosser, M., Ed.; Wiley: Chichester, 2002.
1
2
31.38, 130.67, 128.87, 128.60, 126.29, 63.41, 37.99, 36.92,
4.72, 18.23, 14.04, 12.20. MS (EI): m/z (%) 372 (31), 329
(
(
(
100), 199 (26), 197 (38), 157 (63), 145 (71), 136 (33), 133
36), 131 (27), 129 (28), 122 (33), 115 (47), 103 (30), 75
22), 59 (31), 43 (32). HREIMS: m/z calcd for C H OSi
2
4 40
7. Schwartz, J.; Labinger, J. A. Angew. Chem., Int. Ed. Engl.
1976, 15, 333.
3
72.2847; found 372.2848.
8
. Lipshutz, B. H. Adv. Synth. Catal. 2001, 343, 313.
4
.4. Sample preparation for ICP-AES
9. Bose, A. K.; Manhas, M. S.; Ganguly, S. N.; Sharma, A. H.;
Banik, B. K. Synthesis 2002, 1578.
10. Stadler, A.; Kappe, C. O. Org. Lett. 2002, 4, 3541.
Octyne (149 mL, 1 mmol), Cp Zr(H)Cl (259 mg, 99% pure,
2

1316
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1
1
1
1
1
2. Olofsson, K. In Microwaves in Organic Synthesis; Loupy, A.,
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