A study of the Heck reaction in non-polar hydrocarbon solvents and in supercritical carbon dioxide

Article abstract of DOI:10.1071/CH07160

The effects of electronic and steric properties of phosphorus ligands on Heck reactions in supercritical CO₂ and non-polar hydrocarbon solvents were studied. In Heck reactions between iodobenzene and butyl acrylate, higher yields were obtained with less electron-rich phosphine ligands. This trend was also observed with the electron-poor triphenyl phosphite. A range of sterically demanding phosphites were then investigated. Biphenyl-containing phosphites 8 and 13 were found to be highly effective. In the Heck reaction between the less-reactive bromobenzene and butyl acrylate, the bulky, electron-rich tri-tert-butylphosphine ligand produced the best yield. These results emphasize the importance of both electronic and steric properties of phosphorus ligands in the Heck reaction in non-polar solvents. CSIRO 2007.

Full text of DOI:10.1071/CH07160

Full Paper
CSIRO PUBLISHING
Aust. J. Chem. 2007, 60, 566–571
www.publish.csiro.au/journals/ajc
A Study of the Heck Reaction in Non-Polar Hydrocarbon
Solvents and in Supercritical Carbon Dioxide
Jin-Kyun Lee,A,B Rachel M. Williamson, Andrew B. Holmes,
C
A,C,E
D
D
Edward J. Bush, and Ian F. McConvey
AMelville Laboratory for Polymer Synthesis, Department of Chemistry, University of Cambridge,
Lensfield Road, Cambridge CB2 1EW, UK.
B
Department of Materials Science and Engineering, Cornell University, Ithaca, NY 14853, USA.
School of Chemistry, Bio21 Institute, University of Melbourne, VIC 3010, Australia.
Process R&D, AstraZeneca Pharmaceuticals, Silk Road Business Park, Macclesfield,
C
D
Cheshire SK10 2NA, UK.
Corresponding author. Email: aholmes@unimelb.edu.au
E
The effects of electronic and steric properties of phosphorus ligands on Heck reactions in supercritical CO2 and non-polar
hydrocarbon solvents were studied. In Heck reactions between iodobenzene and butyl acrylate, higher yields were obtained
with less electron-rich phosphine ligands.This trend was also observed with the electron-poor triphenyl phosphite.A range
of sterically demanding phosphites were then investigated. Biphenyl-containing phosphites 8 and 13 were found to be
highly effective. In the Heck reaction between the less-reactive bromobenzene and butyl acrylate, the bulky, electron-rich
tri-tert-butylphosphine ligand produced the best yield. These results emphasize the importance of both electronic and
steric properties of phosphorus ligands in the Heck reaction in non-polar solvents.
Manuscript received: 18 May 2007.
Final version: 28 June 2007.
Introduction
accompanied by ongoing research into the complicated reaction
mechanism.[
12,15,16]
Organic solvents constitute the major proportion of the chemi-
cals required in chemical processes, particularly in the produc-
Most studies of the Heck reaction in scCO2 have focused on
adapting catalyst systems already established in polar organic
solvents, for example, by modifying the structure of phosphine
ligands and Pd precursors to increase their solubility in non-
polar scCO2. It was demonstrated that the Heck reaction could
be accomplished in scCO2 by appending perfluoroalkyl or short
poly(dimethylsiloxane) chains to the phosphine ligands.[
Alkylphosphines and phosphites that improve the solubility of
[
1]
tion of fine chemicals and pharmaceuticals. These solvents
are toxic, flammable, environmentally damaging, and difficult
[
2]
to recycle. To address this issue, research has been pursued in
two directions: the development of solvent-free processes,[
and replacement of hazardous solvents with environmentally
3,4]
17–19]
benign alternatives, such as water, ionic liquids, and supercritical
carbon dioxide (scCO2).[
2,5,6]
Solvent replacement is the pre-
ferred option because of the important role solvents play, e.g.,
improving mass and heat transfer during reaction and dissolving
unwanted substances in purification stages.
Pd complexes in scCO2 have also been reported to catalyze
the Heck reaction.[
20,21]
In addition to ligand modification,
it was shown that the solubility of Pd–phosphine complexes
could be enhanced by exploiting perfluoroalkyl-containing Pd
precursors.[
Supercritical carbon dioxide is defined as the state of CO2
above its critical pressure (Pc 7.38 MPa) and temperature (Tc
22]
◦
[7]
3
1.1 C). The non-toxic and non-flammable characteristics of
Although solubility of the Pd catalyst in scCO2 is impor-
tant, the electronic and steric properties of the ligand also have
an impact on the Heck reaction and these have received less
attention to date. In polar aprotic solvents the Pd catalyst can
be stabilized by solvent molecules; however, in scCO2 or non-
polar hydrocarbon solvents, the reaction is dependent on the
ligand for stabilization and activation of the catalyst. This means
the properties of the ligand required in Heck reactions in non-
polar solvents are different from those required in polar organic
solvents.
scCO2 along with its ready availability and inexpensive price
make it a strong alternative to conventional organic solvents.
Like a liquid, scCO2 displays substantial dissolution power that
can be manipulated for specific requirements, for example,
extraction or chromatography.[ Like a gas, it has very low vis-
cosity and high diffusivity, which enable effective mass and heat
8]
[
8,9]
transfer.
The palladium-mediated alkenylation reaction has received
much attention since its discovery by Heck in the late 1960s.[
As one of the most convenient methods to prepare substi-
10]
Herein we describe studies into the impact of electronic prop-
erties of phosphine ligands on a Heck reaction carried out in
non-polar hydrocarbon solvents and in scCO2. These studies are
then followed by an investigation into steric effects.
tuted olefins, the Heck reaction has been extensively studied
in industry as well as in academia.[
11–14]
More efficient reaction
conditions are continually being developed. These have been
©
CSIRO 2007
10.1071/CH07160
0004-9425/07/080566

Heck Reaction in Non-Polar Hydrocarbon Solvents
567
Ar-X
χi
Table 2. Results of the Heck reaction using (PhO)3P, the bulky phos-
phites 8 and 9, bulky phosphines, and phosphoramidite 10 (Scheme 1)
X ϭ OCH3
X ϭ H
X ϭ F
3.4
4.3
5.0
6.4
EntryA
SolventB
Ligand
Yield (GC)
[%]
X ϭ CF3
X
P
1
2
3
4
5
6
7
8
9
Heptane
Heptane
Heptane
Heptane
Heptane
Heptane
scCO2
scCO2
scCO2
scCO2
scCO2
(PhO)3P
8
9
76
82
<1
7
36
<1
50
87
9
1
2
3
4
(X ϭ OCH3)
(X ϭ H)
(X ϭ F)
(X ϭ CF3)
Cy P
3
t
(Bu )3P
10
(PhO)3P
8
9
X
X
Fig. 1. Influence of the 4-substituent on χi values in selected
10
11
14
Cy3P
45
72
3
triphenylphosphines.
t
(Bu )3P
scCO2
10
O
A
B
I
O
Reaction conditions as in Scheme 1.
In both scCO2 and heptane the reaction mixture was initially homo-
(
a)
OBu
ϩ
OBu
geneous.After a short time a solid (presumably triethylamine hydrochloride)
precipitated from the solution; at the end of the reaction in scCO2 a separate
liquid phase mixed with solid was observed. This was presumed to be butyl
cinnamate and triethylamine hydrochloride.
5
6
7
Scheme 1. (a) 2.45 mmol 5, 2.94 mmol 6, 2.70 mmol Et3N, 0.0245 mmol
Pd(OAc)2, 0.0490 mmol phosphine ligand, scCO2 (∼21 MPa) or heptane (in
◦
3
a sealed tube), 110 C, 16 h, 10 cm reaction vessel.
Comparing the results obtained in heptane, it was observed
that the yield increased as a function of the increasing electron-
withdrawing power of the aromatic substituent. The CF3-
substituted phosphine 4 exhibited the highest yield, while
methoxy-substituted 1 afforded the lowest. A similar trend was
observedinreactionsperformedinscCO2 withtheleastelectron-
rich phosphine 4, which gave the highest yield. An exception
was the most electron-rich ligand 1, which gave a higher yield
than the phosphine 3 in scCO2. Although the mechanism is not
identical, a similar observation was reported in a study of hydro-
formylation reactions carried out in scCO2.[ The activity of
Rh–ligand complexes increases as the electron density of the
phosphorus nuclei of the phosphine ligands decreases.
Table 1. Summary of Heck reactions in the presence of phosphine
ligands 1–4 (Scheme 1)
Entry
Solvent
Ligand
Yield (GC)A
%]
[
1
2
3
4
5
6
7
8
9
Heptane
Heptane
Heptane
Heptane
Heptane
scCO2
–
1
2
3
4
–
1
2
3
4
16
15
35
42
54
21
44
27
34
54
26]
We were interested in investigating if the trend observed
in Table 1 was applicable to the electron-poor triphenyl phos-
scCO2
scCO2
scCO2
scCO2
phite ligand [(PhO)3P], where χi of OPh = 9.7 and the cone
◦ [24]
angle = 128 ,
which has been used in previous studies of
1
0
[21,27]
the Heck reaction.
In heptane, the use of (PhO)3P gave a
AYields were calculated from the peak area of 7 on a GC chromatogram by
comparing it with an internal standard (mesitylene).
76% yield, considerably higher than the 54% yield obtained with
phosphine 4 (Table 2). The performance of (PhO)3P in scCO2
was comparable to that of the phosphine ligand 4.
Attention was then directed to studying the steric properties
of triaryl phosphites. Triphenyl phosphite has a relatively small
Results and Discussion
[24,28]
steric bulk.
It was decided to investigate the relationship
To examine the contribution of the electronic properties of the
phosphine ligands to the outcome of the Heck reaction in non-
polar solvents, triphenylphosphine 2, and three derivatives 1, 3,
between increasing structural bulk and reaction yields in a range
of phosphites. Phosphite ligands 8[ and 9 were synthesized
28]
[29]
(Fig. 2). Phosphite 8 is bulkier than (PhO)3P but is less bulky
and 4 were chosen as model ligands (Fig. 1).[ Phosphines
23]
◦ [24]
than compound 9, which has a cone angle of 175 .
1
–4 have comparable steric bulk about the phosphorus nuclei
The incorporation of the bulky, biphenyl-containing phos-
phite 8 significantly improved the yields of the Heck reaction
both in scCO2 and heptane (Table 2). This is believed to be a
result of the combination of the steric bulk and electron-poor
properties of the ligand. Interestingly, the bulkiest phosphite lig-
and 9 did not catalyze the reaction effectively. In this case, in
heptane (and in toluene) there appeared to be no visible change
in the appearance of the reaction solution, and the precipitation
of black Pd particles was not observed. In scCO2 only a very
◦
[24,25]
(
cone angle 145 ),
but contain different substituents at the
para-position to the phosphorus atom. The phosphorus atom of
phosphine 4 has the lowest electron density based on the highest
χi value of Ar–CF3,[ whereas that of phosphine 1 has the
highest electron density (Fig. 1).
The Heck coupling between iodobenzene and butyl acrylate
in heptane and scCO2 was selected as a suitable test reaction,
and was examined in the presence of 1 mol-% Pd(OAc)2 and
24]
0
2
mol-% phosphine ligand (Scheme 1). The results of the test
low yield was observed (9%). Presumably, Pd was excessively
reactions, with and without ligand, are summarized in Table 1.
stabilized by the bulkiest phosphite 9 and thus did not participate

5
68
J.-K. Lee et al.
O
O
O
O
O
O
P
O
P
P N
O
8
9
10
Fig. 2. Structures of sterically bulky phosphites 8, 9, and phosphoramidite 10.
O
O
O
P
O
P O
O
(b)
(a)
4
6%
4
2%
12
O
O
13
P
Cl
(
d)
(c)
17%
33%
O
O
O
O
P
O
11
P O
15
14
Scheme 2. Reagents and conditions: (a) 1.68 mmol 2,4-di-tert-butylphenol, 1.68 mmol 11, 1.68 mmol
n
◦
n
Bu Li, THF, −78 C to room temp., 1 h; (b) 4.21 mmol hexan-1-ol, 4.21 mmol 11, 4.63 mmol Bu Li, Et2O,
◦
−
78 C to room temp., 1 h; (c) 2.53 mmol cyclohexanol, 2.53 mmol 11, 0.253 mmol 12-crown-4, 2.53 mmol
n
◦
t
Bu Li, THF, −78 C to room temp., 1 h; (d) 2.53 mmol 11, 2.53 mmol KO(Bu ), 0.253 mmol 18-crown-6,
◦
THF, −78 C to room temp., 1 h.
Table 3. Results of Heck reactions using structurally modified phos-
phites 12–15 (Scheme 1)
Table 4. Results of Heck reactions between bromobenzene and butyl
acrylate in octane and scCO2
O
Br
O
EntryA
(a)
Solvent
Ligand
Yield (GC)
%]
OBu
ϩ
[
OBu
1
2
3
4
5
6
7
8
Heptane
Heptane
Heptane
Heptane
scCO2
scCO2
scCO2
scCO2
12
13
14
15
12
13
14
15
<1
90
81
68
37
70
39
17
16
6
7
EntryA
Solvent
Ligand
Yield (GC)
[
%]
1
2
3
4
5
6
7
Octane
Octane
Octane
Octane
scCO2
scCO2
scCO2
—
8
8
7
28
80
2
13
(Bu )3P
—
t
AReaction conditions as in Scheme 1.
13
(Bu )3P
12
24
t
in the catalytic cycle.An alternative explanation is the formation
AReagents and conditions: 2.45 mmol 16, 2.94 mmol 6, 2.70 mmol Et3N,
.0245 mmol Pd(OAc)2, 0.0490 mmol phosphine or phosphite ligand, octane
of an ortho-palladated triarylphosphite species; this is known to
0
◦
[30]
be stable up to 140 C in N,N-dimethylformamide (DMF).
◦
3
(
in a sealed tube) or scCO2 (∼21 MPa), 130 C, 16 h, 10 cm vessel.
The performance of the electron-poor, bulky phosphite lig-
and 8 in the Heck reaction was compared to that of the
highly electron-rich bulky phosphines, Cy3P (χi of Cy = 0.1
interesting that highly electron-rich phosphines, which include
the arylphosphine 1 (entry 7 in Table 1), showed better yields
in scCO2 than in heptane. A more detailed study is needed
to elucidate this phenomenon. The performance of the phos-
phoramidite 10, a close analogue of which has been reported
◦
t
t
and cone angle = 170 ) and (Bu )3P (χi of Bu = 0 and cone
◦
[24]
angle = 182 ). Thesephosphinesdidnotexhibitgoodactivity
t
in heptane (entries 4 and 5 in Table 2). Only (Bu )3P performed
well in scCO2, as was previously reported by Early et al.[ It is
20]

Heck Reaction in Non-Polar Hydrocarbon Solvents
569
to be highly active in polar aprotic solvent conditions,[28] was
also compared with that of phosphite 8. However, the phospho-
ramidite 10 showed poor performance in both solvents: heptane
and scCO2.
chemical shift of a residual protic solvent (CHCl3 at δ 7.28 or
dimethyl sulfoxide (DMSO) at δ 2.50) as an internal reference.
All shifts are quoted in parts per million (ppm) relative to CHCl3
or DMSO and coupling constants J are measured in Hz. 13
C
The effect of modifying the phosphite 8 was then examined
Table 3). By incorporating an ortho Bu group into 8, the more
sterically congested phosphite 12 was prepared (Scheme 2).
Alkyl–aryl mixed phosphites 13–15 were also synthesized. Eval-
uation reactions were then carried out under identical conditions
to those in Scheme 1.
NMR spectra were recorded on a Bruker DPX-400 (101 MHz)
spectrometer using the central resonance of the triplet of CDCl3
at δ 77.0 as an internal reference. 31P NMR (162 MHz) spectra
were recorded on a Bruker DPX-400 spectrometer with a QNP
probe using the chemical shift of H3PO4 at δ 0.0 as an internal
reference. Microanalyses were carried out by the Department of
Chemistry (University of Cambridge, UK). Mass spectra were
recorded by the EPSRC National Mass Spectrometry Service
Centre (Swansea, UK). All chemical ionization (CI) measure-
ments were performed with NH3 as the carrier gas. In cases
where reaction yields were estimated by gas chromatography,
the sample was injected with a known amount of internal stan-
dard (mesitylene). From the peak areas of the sample and internal
standard in the chromatogram, the yield was calculated using a
calibration curve.
t
(
The Heck reaction using the phosphite ligand 12 showed a
7% yield in scCO2, but the reaction did not proceed at all in
3
heptane (or in toluene). The alkyl–aryl phosphite 13 showed
good to high activities in both scCO2 and in heptane and was
found to be as active as the phosphite ligand 8. This result is
useful because alkyl chains may be exploited in immobilizing
phosphite ligands onto a solid support. As the steric bulk of the
substituents increased from n-hexyl to cyclohexyl and again to
tert-butyl, the yield of the Heck reaction decreased.
3
Having successfully developed ligands 8 and 13 for the Heck
reaction between iodobenzene and butyl acrylate, we were then
interested in applying the same catalyst system to reactions
involving a less reactive substrate, such as bromobenzene. The
Heck reaction between bromobenzene and butyl acrylate was
examined in both octane and scCO2 (Table 4). Reactions were
All scCO2 reactions were carried out in a 10 cm Hastelloy
reaction vessel equipped with a thermocouple, pressure trans-
ducer, sapphire window, and bursting disc. CO2 was passed
through an Oxisorb catalyst to remove traces of oxygen and was
delivered to the reaction vessel in a safety-glass cabinet, using a
Pickel PM101 N2-driven CO2 pump.[
31]
◦
t
carried out at 130 C with phosphites 8, 13, and (Bu )3P. The
higher boiling solvent octane was selected for these studies
owing to the higher reaction temperatures required.
Carbon dioxide (purity, 99.999% min.) was purchased from
Messer. Heptane (HPLC grade, Aldrich), octane (anhydrous,
Aldrich), and Pd(OAc)2 (Strem) were used as received. Tri-
phenylphosphine was used after recrystallization from EtOH.
The phosphites 8 and 13 were not effective ligands for
bromobenzene Heck couplings (Table 4). Although phosphite
Triphenylphosphine derivatives 1,[ 3,
32]
[32]
and 4
[33]
were pre-
1
3 performed better than 8, the yield observed was 28%. A
pared according to the literature procedures and recrystallized
synthetically useful yield (80%) was obtained with the bulky
electron-rich (Bu )3P. It is presumed that the higher yield using
from EtOH. Tris(2-tert-butylphenyl) phosphite 9 was prepared
according to the literature procedure, and recrystallized from
t
[29]
the solvent octane (Table 4, entry 4) compared with heptane
hexane.
(
Table 2, entry 5) is a consequence of the higher reaction temper-
t
ature employed. Phosphite 13 and (Bu )3P were then examined
Representative Procedure for the Heck
Reaction in scCO2
under the same conditions in scCO2 and gave yields of 12 and
2
4%, respectively. It is believed that, in scCO2, the catalytic
To a scCO2 reaction vessel were added Pd(OAc)2 (0.0055 g,
species was insufficiently soluble owing to the lower density of
CO2 at the higher operating temperatures. It is noted that the
higher temperature used here does not alter the phase behaviour.
0
.0245 mmol), a phosphine or phosphite ligand (0.0490 mmol),
iodobenzene (0.500 g, 2.45 mmol), butyl acrylate (0.377 g,
.94 mmol), and Et3N (0.273 g, 2.70 mmol). After purging with
2
N2, the reactor was sealed and filled to approximately half the
volume of the vessel with liquid CO2. The reaction mixture was
magnetically stirred and heated to 110 C. At this temperature
Conclusions
◦
In the Heck reaction between iodobenzene and butyl acrylate
in scCO2 and in heptane, less electron-rich phosphines resulted
in higher yields. This general result was then extended further
to the electron-poor ligand, (PhO)3P. The impact of steric bulk
of phosphite ligands was then investigated. Biphenyl-containing
phosphite ligands 8 and 13 resulted in high-yielding Heck reac-
tions. In the Heck reaction between the less-reactive bromo-
the internal pressure was around 21 MPa. After 16 h the mixture
was allowed to cool to ambient temperature and the CO vapour
2
was released by bubbling into a bottle that contained CH Cl
2
2
3
(40 cm ). The reactor was then rinsed with another portion of
CH Cl (20 cm ) and the wash solution was combined with the
3
2
2
vented solution. After mixing with a known amount of mesity-
benzene and butyl acrylate, the bulky, highly electron-rich
lene (∼0.058 g), an aliquot (0.2 µL) of the CH Cl solution was
2
2
t
(
Bu )3P gave the best yield, whereas the bulky phosphites 8 and
injected into the gas chromatograph. The yield was calculated
using a calibration curve. The chemical identity of butyl cin-
namate 7, isolated by preparative TLC, was confirmed by IR
spectroscopythroughcomparisonwiththeauthenticmaterial, R
1
3 were less effective. These results indicate the importance of
both electronic and steric properties of the phosphorus ligand in
Heck reactions in scCO2 and non-polar hydrocarbon solvents.
F
−
1
0
.35 (1/5, EtOAc/hexane). νmax (film)/cm 3058, 3027, 2958,
Experimental
2870, 1709, 1637, 1454, 1309, 1274, 1166, 980, 766, 709, 684.
General
ꢀ
ꢀ
ꢀ
3
,3 ,5,5 -Tetra(tert-butyl)-2,2 -bisphenol
Phosphorochloridite 11
To a magnetically stirred solution of 3,3 ,5,5 -tetra(tert-
Caution! All high-pressure scCO2 reactions should be carried
out with adequate containment and with extreme caution.
1
ꢀ
ꢀ
H NMR spectra were recorded on a Bruker DPX-400
ꢀ
[34]
(
400 MHz) or DRX-500 (500 MHz) spectrometer, using the
butyl)-2,2 -bisphenol
(10.2 g, 24.8 mmol) and PCl3 (6.82 g,

5
70
J.-K. Lee et al.
3
−1
4
9.7 mmol) in toluene (150 cm ) was added a catalytic amount
(solid)/cm 2958, 2870, 1459, 1436, 1396, 1361, 1279, 1231,
1197, 1168, 1118, 1091, 1020, 971, 857, 842, 774, 761, 687.
δH (400 MHz, CDCl3) 7.42 (2H, d, J 2.5, ArH), 7.16 (2H, d, J
2.5, ArH), 3.45–3.36 (2H, m, NCH), 1.52 (18H, s, C(CH3)3),
1.37 (18H, s, C(CH3)3), 1.2–0.7 (12H, br s, NCH(CH3)2). δC
(101 MHz, CDCl3) 148.0 (d, JCP 6.5), 145.2, 139.7, 132.4 (d, JCP
3), 126.3, 123.8, 47.3–43.9 (br s), 35.3, 34.5, 31.5, 31.4, 27.6–
25.3 (br s), 23.6–21.2 (br s). δP (162 MHz, CDCl3) 154.2. m/z
of 4-dimethylaminopyridine (0.152 g, 1.24 mmol) at ambient
temperature under a N2 atmosphere. After the solution was
heated to reflux, N2 was bubbled into the solution to expel
the HCl gas generated from the reaction. After 2 h, the mix-
ture was cooled to ambient temperature while maintaining the
N2 bubbling and then concentrated under reduced pressure. The
resulting yellow coloured solid was purified by recrystalliza-
3
+
+
tion from 1,2-dichloroethane/MeCN (1/2, 105 cm ) to give the
phosphorochloridite 11 as colourless crystals (10.1 g, 86%), mp
(ES ) 540.3962 [(M + H) , C34H55NO2P requires 540.3965],
+
539 (EI, M , 12%), 524 (12), 496 (16), 482 (10), 439 (36), 377
◦
[35]
◦
−1
1
2
1
7
84–186 C (lit.
183–186 C). νmax (solid)/cm 2958, 2905,
(8), 132 (13).
870, 1468, 1436, 1397, 1363, 1295, 1223, 1203, 1168, 1117,
084, 1019, 978, 929, 877, 854, 781, 704. δH (400 MHz, CDCl3)
.50 (2H, d, J 2.5, ArH), 7.21 (2H, d, J 2.5, ArH), 1.51 (18H, s,
C(CH3)3), 1.39 (18H, s, C(CH3)3). δC (101 MHz, CDCl3) 147.6,
45.5 (d, JCP 6), 140.4, 132.6 (d, JCP 4), 126.7, 124.9, 35.5, 34.7,
1.5, 30.9. δP (162 MHz, CDCl3) 172.2. The δH and δP data are
ꢀ
ꢀ
ꢀ
ꢀ
3,3 ,5,5 -Tetra(tert-butyl)-1,1 -biphenyl-2,2 -diyl
2,4-Di(tert-butyl)phenyl Phosphite 12
The crude product was purified by flash column chromatography
petroleum spirits (40–60 C)] and crystallized fromTHF/MeCN
1
3
◦
[
to give the phosphite 12 as colourless crystals (0.455 g, 42%),
[36]
in agreement with literature values.
◦
◦
mp 202–205 C. RF 0.33 [petroleum spirits (40–60 C)] (Found:
C 77.9, H 9.6. C42H61O3P requires C 78.2, H 9.5%). νmax
ꢀ
ꢀ
ꢀ
ꢀ
−1
3
4
,3 ,5,5 -Tetra(tert-butyl)-1,1 -biphenyl-2,2 -diyl
-(tert-Butyl)phenyl Phosphite 8
(solid)/cm 2958, 2906, 2869, 1464, 1396, 1361, 1198, 1169,
1122, 1086, 913, 851, 783, 693. δ (500 MHz, CDCl ) 7.44 (2H,
H
3
d, J 2.5, ArH), 7.33 (1H, d, J 2.5, ArH), 7.25 (2H, d, J 2.5, ArH),
.07 (1H, dd, J 2.5 and 8.5, ArH), 7.02 (1H, dd, J 2.5 and 8.5,
ArH), 1.42 (18H, s, C(CH3)3), 1.39 (18H, s, C(CH3)3), 1.31
9H, s, C(CH3)3), 1.24 (9H, s, C(CH3)3). δC (101 MHz, CDCl3)
To a magnetically stirred solution of 11 (2.00 g, 4.21 mmol)
in Et2O (20 cm ) was added a solution of 4-tert-butylphenol
3
7
(
(
0.664 g, 4.42 mmol) and Et3N (0.490 g, 4.84 mmol) in Et2O
20 cm ) dropwise at ambient temperature under a N2 atmos-
3
(
1
1
3
1
6
48.9 (d, JCP 6), 146.5, 146.0 (d, JCP 6), 145.1, 140.1 (d, JCP 1.5),
38.9, 132.8 (d, JCP 4), 126.5, 124.2, 123.1, 119.3, 119.1, 35.4,
4.8, 34.7, 34.4, 31.5, 31.1, 31.0, 30.0. δP (162 MHz, CDCl3)
phere. The solution was then stirred for 1 h at ambient tem-
perature and concentrated under reduced pressure. The crude
product containing Et3N·HCl was purified by flash column chro-
matography (1/20, EtOAc/hexane), where the adsorbent (silica
gel) was first treated by flushing successively with Et2O and
+
+
42.6. m/z (ES ) 645.4432 [(M + H) , C42H62O3P requires
+
45.4431], 646 [CI, (M + H) , 100%], 457 (31), 441 (91), 429
◦
(32), 413 (31), 226 (19), 206 (48), 191 (67).
petroleum spirits (40–60 C). The resulting viscous liquid crys-
tallized from MeCN to give phosphite 8 as colourless crystals
◦
ꢀ
ꢀ
ꢀ
ꢀ
(
(
1.82 g, 73%), mp 168–169 C. RF 0.74 (1/10, EtOAc/hexane).
3,3 ,5,5 -Tetra(tert-butyl)-1,1 -biphenyl-2,2 -diyl
Hexyl Phosphite 13
Found: C 77.55, H 9.2. C38H53O3P requires C 77.5, H 9.1%.)
−1
νmax (solid)/cm 2960, 2906, 2869, 1502, 1462, 1435, 1396,
361, 1231, 1201, 1166, 1122, 1088, 870, 844, 782, 756, 705.
The crude product was purified by flash column chromato-
graphy [petroleum spirits (40–60 C)] in which the adsorbent
silica gel) was first treated by flushing with Et2O. The purified
product crystallized from CH2Cl2/MeCN to give the phos-
phite 13 as colourless crystals (1.05 g, 46%), mp 121–123 C.
RF 0.25 [petroleum spirits (40–60 C)] (Found: C 75.4, H 9.9.
C34H53O3P requires C 75.5, H 9.9%). νmax (solid)/cm 2954,
868, 1469, 1437, 1394, 1361, 1229, 1201, 1123, 1090, 992,
64, 848, 781, 765, 694. δH (400 MHz, CDCl3) 7.45 (2H, d, J
.5, ArH), 7.19 (2H, d, J 2.5, ArH), 3.79 (2H, q, J 7.0, OCH2),
.60–1.54 (2H, m, CH2), 1.52 (18H, s, C(CH3)3), 1.38 (18H, s,
◦
1
δH (500 MHz, CDCl3) 7.48 (2H, d, J 2.5, ArH), 7.31 (2H, d,
J 8.5, ArH), 7.22 (2H, d, J 2.5, ArH), 7.02 (2H, d, J 8.5, ArH),
(
◦
1
.54 (18H, s, C(CH3)3), 1.39 (18H, s, C(CH3)3), 1.32 (9H, s,
◦
C(CH3)3). δC (101 MHz, CDCl3) 150.2 (d, JCP 7), 146.9 (d,
JCP 2.5), 145.7 (d, JCP 6), 140.4 (d, JCP 1.5), 133.1 (d, JCP 3.5),
−
1
1
3
26.9, 126.7, 124.6, 120.1 (d, JCP 8), 35.7, 34.9, 34.6, 31.8, 31.7,
2
8
2
1
+
1.6, 31.5. δP (162 MHz, CDCl3) 139.7. m/z (ES ) 589.3805
+
+
[
(M + H) , C38H54O3P requires 589.3805], 589 [CI, (M + H) ,
1
00%], 471 (18), 456 (29), 441 (50), 428 (26), 412 (13), 135 (23).
C(CH3)3), 1.32–1.22 (6H, m, CH2), 0.88 (3H, t, J 7.0, CH2CH3).
δC (101 MHz, CDCl3) 146.3 (d, JCP 6), 146.2, 139.8, 132.7 (d,
JCP 3.5), 126.5, 124.1, 65.0 (d, JCP 4), 35.3, 34.6, 31.5, 31.4 (d,
JCP 5.5), 31.1 (d, JCP 2.5), 30.9, 25.3, 22.5, 14.0. δP (162 MHz,
ꢀ ꢀ ꢀ ꢀ
,3 ,5,5 -Tetra(tert-butyl)-1,1 -biphenyl-2,2 -diyl
N,N-Diisopropylphosphoramidite 10
3
To a magnetically stirred solution of diisopropylamine (0.234,
+
+
3
n
CDCl3) 137.9. m/z (ES ) 541.3804 [(M + H) , C34H54O3P
2
(
.31 mmol) in tetrahydrofuran (THF, 5 cm ) was added Bu Li
+
3
requires 541.3805], 542 [ES, (M + H) , 46%], 524 (24), 502
1.6 M solution in hexane, 1.64 cm , 2.63 mmol) at ambient
(16), 475 (53), 457 (13), 314 (48), 292 (47), 273 (42), 268 (38),
temperature under a N2 atmosphere. The solution was stirred
◦
251 (100), 208 (23), 167 (22).
for 10 min and cooled to −78 C. A solution of 11 (1.00 g,
3
2
.10 mmol) in THF (10 cm ) was subsequently added and the
ꢀ ꢀ ꢀ ꢀ
,3 ,5,5 -Tetra(tert-butyl)-1,1 -biphenyl-2,2 -diyl
3
resulting mixture was allowed to warm to ambient temperature.
After the solution was stirred overnight, it was concentrated
under reduced pressure. The crude product was purified by
Cyclohexyl Phosphite 14
The crude product was purified by flash column chromato-
◦
◦
flashcolumn chromatography [petroleum spirits(40–60 C)]and
graphy [petroleum spirits (40–60 C)], where the adsorbent (sil-
crystallized from CH2Cl2/MeCN to give the phosphoramidite
ica gel) was first treated by flushing with Et2O. The purified
product crystallized from CH2Cl2/MeCN to give the phosphite
14 as colourless crystals (0.450 g, 33%), mp 182–183 C. RF
◦
1
0 as colourless crystals (0.224 g, 20%), mp 184–185 C. RF
◦
◦
0
.23 [petroleum spirits (40–60 C)] (Found: C 75.7, H 10.1,
N 2.6. C34H54NO2P requires C 75.65, H 10.1, N 2.6%). νmax
0.74 (1/10, EtOAc/hexane) (Found: C 75.7, H 9.4. C34H51O3P

Heck Reaction in Non-Polar Hydrocarbon Solvents
571
requires C 75.8, H 9.5%). νmax (solid)/cm 1 2960, 2930, 2865,
1
8
−
[7] P. G. Jessop, W. Leitner, in Chemical Synthesis Using Supercritical
Fluids 1999 (Wiley-VCH: Weinheim).
442, 1396, 1361, 1283, 1226, 1202, 1122, 1089, 955, 875,
39, 778, 759, 700. δH (400 MHz, CDCl3) 7.43 (2H, d, J 2.5,
ArH), 7.18 (2H, d, J 2.5, ArH), 4.29–4.20 (1H, m, OCH), 1.91–
.87 (2H, m, CH2), 1.74–1.71 (2H, m, CH2), 1.55–1.48 (21H, s,
C(CH3)3 and CH2), 1.37 (18H, s, C(CH3)3), 1.24–1.18 (3H, m,
CH2). δC (101 MHz, CDCl3) 146.1, 146.0 (d, J 6.5), 140.0 (d, JCP
.5), 132.8 (d, JCP 4), 126.5, 124.0, 75.3 (d, JCP 12), 35.3, 34.6,
4.5 (d, JCP 4), 31.5, 31.2, 25.2, 24.2. δP (162 MHz, CDCl3)
[
8] R. S. Oakes,A.A. Clifford, C. M. Rayner, J. Chem. Soc., PerkinTrans.
2001, 917. doi:10.1039/B101219N
9] E. J. Beckman, J. Supercrit. Fluid 2004, 28, 121. doi:10.1016/S0896-
446(03)00029-9
1
[
1
8
[
10] R. F. Heck, J. Am. Chem. Soc. 1968, 90, 5518. doi:10.1021/
JA01022A034
11] R. F. Heck, Org. React. 1982, 27, 345.
12] I. P. Beletskaya, A. V. Cheprakov, Chem. Rev. 2000, 100, 3009.
doi:10.1021/CR9903048
1
3
1
5
4
[
[
+
+
45.9. m/z (ES ) 539.3649 [(M + H) , C34H52O3P requires
+
39.3649], 539 (EI, M , 12%), 524 (12), 496 (16), 482 (10),
[13] J. G. de Vries, Can. J. Chem. 2001, 79, 1086. doi:10.1139/CJC-79-5-
39 (36), 377 (8), 132 (13).
6-1086
[
14] F. Alonso, I. P. Beletskaya, M. Yus, Tetrahedron 2005, 61, 11771.
doi:10.1016/J.TET.2005.08.054
15] G. T. Crisp, Chem. Soc. Rev. 1998, 27, 427. doi:10.1039/A827427Z
16] C. Amatore, A. Jutand, J. Organomet. Chem. 1999, 576, 254.
doi:10.1016/S0022-328X(98)01063-8
ꢀ ꢀ ꢀ ꢀ
,3 ,5,5 -Tetra(tert-butyl)-1,1 -biphenyl-2,2 -diyl
3
[
[
tert-Butyl Phosphite 15
The crude product was purified by flash column chromatogra-
phy [petroleum spirits (40–60 C)], where the adsorbent (silica
gel) was first treated by flushing with Et2O. The purified prod-
◦
[17] M. A. Carroll, A. B. Holmes, Chem. Commun. 1998, 1395.
doi:10.1039/A802235F
uct crystallized from CH2Cl2/MeCN to give the phosphite
[18] D. K. Morita, D. R. Pesiri, S. A. David, W. H. Glaze, W. Tumas, Chem.
Commun. 1998, 1397. doi:10.1039/A802621A
◦
1
5 as colourless crystals (0.224 g, 17%), mp 151–153 C. RF
[
[
[
[
19] S. Saffarzadeh-Matin, C. J. Chuck, F. M. Kerton, C. M. Rayner,
Organometallics 2004, 23, 5176. doi:10.1021/OM0496277
20] T. R. Early, R. S. Gordon, M. A. Carroll, A. B. Holmes, R. E. Shute,
I. F. McConvey, Chem. Commun. 2001, 1966.
21] Y. Kayaki, Y. Noguchi, T. Ikariya, Chem. Commun. 2000, 2245.
doi:10.1039/B006846M
0
.70 (1/10, EtOAc/hexane) (Found: C 74.9, H 9.7. C32H49O3P
−
1
requires C 75.0, H 9.6%). νmax (solid)/cm 2960, 2869, 1464,
1434, 1394, 1363, 1230, 1168, 1125, 1090, 951, 940, 874, 848,
819, 780, 694. δH (400 MHz, CDCl3) 7.43 (2H, d, J 2.5, ArH),
7.17 (2H, d, J 2.5, ArH), 1.56 (9H, s, C(CH3)3), 1.52 (18H, s,
C(CH3)3), 1.36 (18H, s, C(CH3)3). δC (101 MHz, CDCl3) 145.9,
45.8, 140.0 (d, JCP 1.5), 133.0 (d, JCP 3.5), 126.5, 124.0, 79.1
d, JCP 10), 35.3, 34.6, 31.5, 31.2 (d, JCP 3), 31.1. δP (162 MHz,
22] N. Shezad, R. S. Oakes, A. A. Clifford, C. M. Rayner, Tetrahedron
Lett. 1999, 40, 2221. doi:10.1016/S0040-4039(99)00176-8
1
(
[23] M. Qadir, T. Mochel, K. K. Hii, Tetrahedron 2000, 56, 7975.
+
+
CDCl3)147.1. m/z (ES )530.3750[(M + NH4) , C32H53NO3P
doi:10.1016/S0040-4020(00)00703-1
[
[
24] C. A. Tolman, Chem. Rev. 1977, 77, 313. doi:10.1021/CR60307A002
25] P. B. Dias, M. E. M. Depiedade, J. A. M. Simoes, Coord. Chem. Rev.
requires 530.3758], 456 (EI, 20%), 441 (30), 423 (4), 385 (5),
3
67 (4).
1994, 135–136, 737. doi:10.1016/0010-8545(94)80082-0
[
26] D. R. Palo, C. Erkey, Organometallics 2000, 19, 81. doi:10.1021/
OM990560A
Acknowledgments
We thank AstraZeneca (UK), the Overseas Research Students Awards
Scheme (Universities UK), the Cambridge Overseas Trust, the Engineer-
ing and Physical Sciences Research Council (UK), the Australian Research
Council, VESKI, and CSIRO for generous financial support. This project
was carried out with partial support from the Materials World Network
[
[
27] M. Beller, A. Zapf, Synlett 1998, 792. doi:10.1055/S-1998-1760
28] G. P. F. van Strijdonck, M. D. K. Boele, P. C. J. Kamer, J. G. de Vries,
P. van Leeuwen, Eur. J. Inorg. Chem. 1999, 1073.
[
[
[
29] T. Jongsma, G. Challa, P. van Leeuwen, J. Organomet. Chem. 1991,
4
21, 121. doi:10.1016/0022-328X(91)86436-T
30] D. A. Albisson, R. B. Bedford, P. N. Scully, Tetrahedron Lett. 1998,
9, 9793. doi:10.1016/S0040-4039(98)02175-3
(
NSF/ARC). We thank Dr C. J. Smith, Dr M. W. S. Tsang, and Dr D. J.
Jones for their interest in this work. We also thank Dr U. Wille for assistance
with GC analyses.
3
31] W. P. Hems,T. M.Yong, J. L. M. vanNunen,A. I. Cooper,A. B. Holmes,
D. A. Griffin, J. Mater. Chem. 1999, 9, 1403. doi:10.1039/A901105F
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