Synthesis of (all-rac)-α-tocopherol in supercritical carbon dioxide: Tuning of the product selectivity in batch and continuous-flow reactors

Article abstract of DOI:10.1002/adsc.200404312

α-Tocopherol was synthesized using a condensation reaction of 2,3,6-trimethylhydroquinone with isophytol in supercritical CO₂ using batch and continuous-flow reactors. In the batch reaction catalyzed by a fluorinated molecular catalyst bearing strong Bronsted acidity, C ₆F₅CHTf₂ (Tf=SO₂CF₃), an increase in the CO₂ pressure causes a marked increase in the product selectivity for α-tocopherol, albeit with a slight decrease in the product yield. The solubility measurements by extraction experiments and the supercritical fluid NMR (scNMR) indicate that the homogeneous and non-polar reaction phase in scCO₂ is crucial to obtain α-tocopherol with high selectivity. A continuous flow scCO₂ process for the condensation reaction can be performed with a strong acid resin, Amberlyst 15, as a solid acid catalyst to give the desired product with high selectivity.

Full text of DOI:10.1002/adsc.200404312

COMMUNICATIONS
Synthesis of (all-rac)-a-Tocopherol in Supercritical Carbon
Dioxide: Tuning of the Product Selectivity in Batch and
Continuous-Flow Reactors
a
b
a
b
Yoshiaki Kokubo, Aiko Hasegawa, Shigeki Kuwata, Kazuaki Ishihara,
c
a,
Hisashi Yamamoto, Takao Ikariya *
Graduate School of Science and Engineering and Frontier Collaborative Research Center, Tokyo Institute of Technology,
O-okayama, Meguro-ku, Tokyo 152-8552, Japan
a
Fax: (þ81)-3-5734-2637, e-mail: tikariya@apc.titech.ac.jp
b
c
Department of Biotechnology, Graduate School of Engineering, Nagoya University, Furo-cho, Chikusa-ku, Nagoya
464-8603, Japan
Department of Chemistry, The University of Chicago, 5735 South Ellis Avenue, Chicago, IL 60637, USA
Received: October 11, 2004; Accepted: December 12, 2004
Supporting Information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: a-Tocopherol was synthesized using a con-
densation reaction of 2,3,6-trimethylhydroquinone
derivatives 4, which are difficult to separate from the de-
[2]
sired product 1.
with isophytol in supercritical CO using batch and
Supercritical carbon dioxide (scCO ) as a reaction me-
2
2
continuous–flow reactors. In the batch reaction cata-
lyzed by a fluorinated molecular catalyst bearing
strong Brønsted acidity, C F CHTf (Tf¼SO CF ),
dium is an attractive alternative to organic solvents be-
cause of its low toxicity and ease of separation from
the product and catalyst. In addition to these environ-
[
11]
6
5
2
2
3
an increase in the CO pressure causes a marked in-
mental benefits, scCO has the pressure-tunable physi-
2
2
crease in the product selectivity for a-tocopherol, al-
beit with a slight decrease in the product yield. The
solubility measurements by extraction experiments
and the supercritical fluid NMR (scNMR) indicate
that the homogeneous and non-polar reaction phase
cal properties as a reaction medium such as the solubiliz-
ing ability, which would affect the outcome of reactions
in terms of the reactivity and selectivity. Since the con-
densation of 2 and 3 to 1 possibly proceeds through Frie-
[
4,7,8,10a,12]
del–Crafts alkylation-cyclization
or an ortho-
in scCO is crucial to obtain a-tocopherol with high
Claisen rearrangement of an intermediary allyl es-
2
[
13,14]
selectivity. A continuous flow scCO process for the
ter,
the use of non-polar reaction media would sup-
2
condensation reaction can be performed with a
strong acid resin, Amberlyst 15, as a solid acid cata-
lyst to give the desired product with high selectivity.
press the formation of the secondary cation from 3, to
minimize the formation of the undesired five-mem-
bered by–products 4. In fact, it has been reported that
the selectivity of 1 attained in a non-polar solvent, hep-
[
2]
Keywords: fluorinated catalyst; solid acid catalyst;
supercritical carbon dioxide; a-tocopherol
tane, is markedly improved, while the chemical yield
[
4,10a]
of 1 is maximized in polar aprotic solvents.
Thus,
the reaction chemistry of the condensation to 1 in
a-Tocopherol (1) with the highest biological activity
[
1]
among the lipid-soluble antioxidant vitamins E, is
now industrially produced by the acid-catalyzed con-
densation of 2,3,6-trimethylhydroquinone (2) with iso-
phytol (3) or its derivatives (Scheme 1). In order to effi-
ciently and economically access this important com-
pound, a number of catalytic synthetic procedures using
[4]
[
2,3]
polymer-supported catalysts and solid acid catalysts
as well as unorthodox reaction media such as supercrit-
[5]
[2–10a]
ical fluids, have been examined.
main serious drawbacks including the low catalytic ac-
tivities and the formation of by-products, benzofuran Scheme 1.
There still re-
220
ꢀ 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/adsc.200404312
Adv. Synth. Catal. 2005, 347, 220–224

Synthesis of (all-rac)-a-Tocopherol in Supercritical Carbon Dioxide
COMMUNICATIONS
scCO requires a trade-off between activity and selectiv-
2
ity in order to attain the best reaction performance, and
the fine-tuning of the reaction conditions, including the
phase behavior and the polarity of reaction media by
changing the CO pressure and temperature, is also nec-
2
essary. We now describe the controlled condensation of
2
and 3 with the recently developed scCO -soluble, flu-
2
orinated Brønsted acids, C F CHTf (5a: Tf¼
6
5
2
[
15]
SO CF ) and CF (CF ) CH OC F CHTf (5b: n¼8,
2
3
3
2
n
2
6
4
2
[16]
5
c: n¼12) in a batch system, giving the desired prod-
uct 1 with good to excellent selectivity. An increase in
the CO pressure caused a significant improvement in
2
the product selectivity. The reactions in a continuous-
flow reactor were also examined, leading to an increase
in the productivity of 1.
We first measured the solubility of the fluorinated cat-
Figure 1. Pressure effect on the condensation of 2 with 3 in
alyst 5a as well as the substrates 2 and 3 in scCO . The
2
scCO catalyzed by 5a. Solid circles and open triangles repre-
2
catalyst 5a proved to be fairly soluble in scCO ; the sol-
2
sent the yield and selectivity, respectively. Reaction condi-
tions: 2 and 3 0.5 mmol, 5a 0.05 mmol, 1008C, reaction time
19
ubility was estimated to be 5.0 mmol/L by F NMR
[17]
spectroscopy
under supercritical conditions, 408C
1
6 h.
and 8.5 MPa. Extraction experiments at 1008C and
2
0 MPa revealed that the solubilities of the substrates
and 3 are 3.5 and 51 mmol/L, respectively, under these the liquid phase, in which a neat reaction took place to
give the undesired benzofuran derivatives 4 due to the
2
conditions (see Supporting Information).
The condensation reaction of 2 with 3 catalyzed by the higher polarity of the liquid phase formed during the re-
fluorinated molecular catalyst 5a (2 and 3: 0.5 mmol, 5a: action. The high selectivity attained in scCO may be ex-
2
[
11b, d]
0
.05 mmol ) in scCO was examined using the batch sys- plained by the solvent effect
rather than the dilu-
2
tem. The reaction in the homogeneous scCO phase at tion effect because simple dilution to the corresponding
2
35 MPa, 1008C, proceeded to give the desired product concentration (0.01 mol/L) in heptane resulted in lower-
1
in 31% yield with 97% selectivity, in addition to the ing of the selectivity of the product to 72% (entry 8). The
five-membered by-products 4 (1.1% yield) and the de- present results markedly contrast with the reported ones
composition products, trimethylquinone or dehydration obtained from the same reaction in scN O, in which no
2
[4]
products, derived from 2 and 3 under the reaction con- significant influence of the total pressure on the reactiv-
ditions. The outcome of the reaction was delicatelyinflu- ity and selectivity was observed. The reaction, howev-
[
5a]
enced by the CO pressure as shown in Figure 1. A de- er, seems to proceed totally in the liquid phase of the
2
crease in the CO pressure to 10 through 20 MPa result- substrates due to the much higher concentration of the
2
ed in an increase in the product yield although with a substrates (0.24–0.40 mol/L).
slight decrease in the selectivity, reaching up to 62%
The low yield of 1 in scCO is at least partly ascribed to
2
yield and 94% selectivity at 20 MPa. The reactivity the side reaction of 3 to give dehydration products such
[
4]
and selectivity markedly decreased below 10 MPa, and as phytadienes, which can be suppressed by slow addi-
[
2,5]
in the absence of CO under neat conditions, resulted tion of 3. Indeed, addition of 3 at a rate of 2 mmol/h
2
in product 1 in only 19% yield with 93% selectivity.
using a sample injector to the reaction mixture markedly
A visual inspection as well as the solubility test men- improved the yield and selectivity as shown in entry 9,
tioned above revealed that above 20 MPa at 1008C, the yield of 1 reaching 69% while maintaining the purity
the compound 3 and the catalyst 5a are all miscible in (97%) at 20 MPa. Similarly, the strong acid catalysts in-
CO , while the solid compound 2 (0.5 mmol) is not com- cluding perfluorinated catalysts 5b and 5c as well as solid
2
pletely soluble in CO based on the solubility test strong acid catalysts were found to effect the condensa-
2
(
3.5 mmol/L at 20 MPa; 17 mmol/L at 35 MPa). As tion reaction under the optimized conditions described
shown in Figure 1 and Table 1, significant changes in in Table 2 to give the desired product with high selectiv-
yield and selectivity were observed around the satura- ity. Again, the CO single phase including reactants 2
2
tion concentration of 2 in scCO . These results indicate and 3 over the solid catalyst is crucial to attaining high
2
that the single homogeneous phase of scCO is crucial catalyst performance in terms of selectivity and reactiv-
2
[
18]
to attaining high product selectivity. In fact, under high ity.
dilution conditions, the reaction gave the desired prod-
The utilization of a continuous–flow fixed-bed reactor
uct, although the yield was low (entry 1). In the reaction for the condensation of 2 with 3 over the solid catalyst,
under higher concentration and lower CO pressure Amberlyst 15, caused a marked improvement in the ef-
2
conditions, the reactants 2 and 3 precipitate to form ficiency of the reaction. The apparatus for the continu-
Adv. Synth. Catal. 2005, 347, 220–224
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ꢀ 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
221

COMMUNICATIONS
Yoshiaki Kokubo et al.
[a]
Table 1. Effect of the reaction conditions on the yield and selectivity of 1 in the batch reaction.
[
b]
[c]
Entry
Solvent, MPa
2 and 3 [mmol]
5a [mmol]
Yield [%]
Selectivity [%]
1
4
1
2
3
4
5
6
7
CO , 20
0.1
0.5
1.0
3.0
0.5
1.0
3.0
0.5
0.5
0.01
0.05
0.1
0.3
0.05
0.1
0.3
0.05
0.05
9
62
70
67
31
48
59
33
69
<0.1
4.1
4.7
7.2
1.1
1.4
4.3
13
>99
94
94
90
97
97
93
72
97
2
CO , 20
2
CO , 20
2
CO , 20
2
CO , 35
2
CO , 35
2
CO , 35
2
[
[
d]
e]
8
9
heptane
CO , 20
1.9
2
[a]
[b]
[c]
[d]
[e]
Conditions: 1008C, 16 h in a 50-mL autoclave.
Determined by GC.
Defined as 1/(1þ4).
[2]
A solution of 3 in heptane was added dropwise over 15 min under azeotropic reflux with removal of water.
Compound 3 was added to the reactor at a rate of 2 mmol/h with a sample injector.
Table 2. Effect of the catalyst used for the condensation of 2
[a]
with 3 in scCO2.
[
b]
[c]
Entry Catalyst
Yield [%]
Selectivity [%]
1
4
[
d]
1
2
3
4
5
6
5a
69
48
49
73
73
74
1.9
1.6
1.3
2.5
7.6
4.6
97
97
97
97
90
94
[
d]
5b[
d]
5c
[
e]
6
[
e]
Amberlyst 15[
e]
Nafion NR50
[
a]
Conditions: 2 and 3 were 0.5 mmol each, CO 20 MPa,
2
1
008C, 16 h in a 50-mL autoclave. Compound 3 was added
Figure 2. Experimental apparatus for the continuous-flow re-
action.
to the reactor at a rate of 2 mmol/h with a sample injector.
Determined by GC.
[
[
[
[
b]
c]
d]
e]
Defined as 1/(1þ4).
0
5
.05 mmol.
0 mg.
reaction conditions. An excess of the reactant 3 was nec-
essary to achieve the high yield of 1 (entry 2–6), proba-
bly because of the dehydrative self-condensation of 3 as
ous reaction is shown in Figure 2. To minimize the neat a side reaction. Again, the CO pressure also affected
2
reaction and the dehydration of 3, both 2 and 3 were in- the yield and selectivity of 1; the yield reached up to
troduced into the reactor as solutes of scCO . The flow 80%, with 96% selectivity under the optimized condi-
2
rates were determined by separate extraction measure- tions as shown in Table 3 (entry 5). This improvement
ments so that both of the substrates were supplied to the may be explained by rapid removal of the coproduct wa-
reactor in the required molar ratio. Ethyl acetate was ter, which enhances the polarity of the reaction phase
added to the product flow to prevent the choking of and often deactivates the acid catalyst, from the flow re-
the highly viscid 1. The reaction using the polystyrene- actor.
[
16]
bound fluorous acid 6 as a solid catalyst was hampered
In summary, this paper describes the controlled con-
by swelling of the catalyst in the reactor, while the solid densation of 2 with 3 to (all-rac)-a-tocopherol with flu-
acid catalyst, Amberlyst 15, was found to work well in orinated strong acids in scCO in good selectivity and
2
scCO in both the batch and continuous-flow reactors. moderate yield. The outcome of the reaction was appre-
2
The results are summarized in Table 3. Although the ciably influenced by the phase behavior and the polarity
yield and selectivity in the Amberlyst-catalyzed batch of the reaction mixture, which can be tuned by changing
reaction were unsatisfactory (entry 1), those in the con- the pressure of CO . The productivity in the Amberlyst-
2
tinuous-flow reaction are significantly increased. The catalyzed continuous-flow reaction was improved com-
outcome of the reaction is delicately influenced by the pared to the batch reaction.
222
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Adv. Synth. Catal. 2005, 347, 220–224

Synthesis of (all-rac)-a-Tocopherol in Supercritical Carbon Dioxide
COMMUNICATIONS
[a]
Table 3. Effect of CO pressure and molar ratio of 2 to 3 on the yield and selectivity of 1 in the flow reaction.
2
[
b]
[c]
Entry
MPa
Molar ratio (3/2)
Flow rate of CO to extract 3 [mL/min]
Yield [%]
Selectivity [%]
2
1
4
[
d]
1
2
3
4
5
6
20
25
25
25
25
25
1.0
0.9
1.7
4.3
6.0
7.8
–
73
15
56
70
79
66
7.6
2.9
9.5
6.9
3.4
4.1
90
84
86
91
96
94
0.01
0.02
0.04
0.07
0.09
[
a]
Conditions: 1008C, 4 mm diameter and 50 mm height tubular reactor, 200 mg of Amberlyst 15, flow rate of the HPLC pump
2
to extract 2 is 0.4 mL/min, W/F¼6.8ꢁ10 [cat.-g/(mol/h)].
[
[
[
b]
c]
d]
Determined by GC.
Defined as 1/(1þ4).
Batch reaction (0.5 mmol of 2 and 3, 50 mg of Amberlyst 15, 16 h in a 50-mL autoclave).
Experimental Section
Standard Procedure for the Batch Reaction
Safety warning: Operators of high-pressure equipment should
take proper precautions to minimize the risk of personal injury.
The fluorous catalysts 5 and the polymer-supported catalyst
Trimethylhydroquinone 2 was charged in a 50-mL autoclave
equipped with a magnetic stirrer. The catalyst was placed in-
side a separate glass tube in the autoclave to avoid a neat reac-
[15,16]
6
were prepared according to the literature,
berlyst 15, and Nafion NR50 were used as received. The
scNMR spectra were recorded on a JEOL LA-300 spectrome-
while 2, 3, Am-
tion in neat 3 prior to CO introduction. After the autoclave
2
1
9
F
had been evacuated and flushed with argon repeatedly, 3 was
added to the autoclave with a syringe. The autoclave was
[17a]
ter using a zirconia cell;
dimethyl sulfoxide-d in a sealed
warmed to 1008C, and then CO was introduced. After stirring
6
2
Pyrex tube was used as the deuterium lock. The chemical shifts
are referenced to the signal of trifluorotoluene in (CD ) SO at
for 16 h, the reactor was cooled with a dry ice–methanol bath,
3
2
and CO was released from the reactor. The reactor was slowly
2
ꢀ
64.0 ppm. The GC analyses were performed on a GL Science
GC353B equipped with a DB-1 column.
warmed to room temperature, and the product was analyzed by
GC. The yield was determined using squalane as an internal
standard. The results are summarized in Table S2 (see Support-
ing Information).
Solubility Measurements of the Substrates and
Catalyst
The solubilities of 2 and 3 in scCO were measured by extrac-
2
tion experiments. The apparatus is shown in Figure S1 (see
Supporting Information). An excess of 2 or 3 (ca. 50 mmol)
in a 50-mL autoclave was warmed to 1008C in an oven with a
stirrer. Carbon dioxide was introduced into the autoclave
with the total pressure kept constant by an automatic back
pressure regulator attached to the outlet. To avoid the precip-
itation of the extract in the tube, ethyl acetate was mixed into
the extract solution. The extracted substrate was collected
Procedure for the Continuous-Flow Reaction
The apparatus for the reaction is shown in Figure 2. The tubu-
lar reactor (4 mm diameter and 50 mm height) loaded with a
catalyst (200 mg), was set in an oven. An excess of 2 and 3
(ca. 50 mmol each) was charged under argon in two autoclaves
placed in the same oven, from which these substrates were sup-
plied to the reactor as solutes in scCO
Prior to the continuous–flow reactions, the amounts of 2 ex-
tracted by scCO from the autoclave had been measured at a
fixed flow rate (0.4 mL/min) and various CO pressures by sep-
.
2
with a gas–liquid separator. The flow rate of CO was moni-
2
tored by a soap-film flow meter. The solubilities of 2 and 3 at
various pressures are listed in Table S1 (see Supporting Infor-
mation).
2
2
arate extraction experiments with the apparatus shown in Fig-
ure S1 (see Supporting Information). Then, the flow rate for
The solubility of the fluorous catalyst 5a in the scCO phase
2
was estimated by integration of the signals of 5a and the inter-
the extraction of 3 at each CO pressure was determined by
2
1
9
nal standard (CF C H , 0.75 mL, 6.2 mmol) in the F scNMR
similar extraction measurements to realize the required molar
ratio of 3 to 2 in the reactor.
3
6
5
spectra. The spectrum obtained at 84 atm and 408C indicated
that the solubility of 5a in scCO under these conditions is
After both the reactor and autoclaves were warmed to
2
5
.0 mmol/L.
1008C for 30 min and the reactor was purged with CO , 2 and
2
19
Catalyst 5a: F NMR (282 MHz, scCO ): d¼ ꢀ157.9,
3 in scCO were introduced to the reactor. The product was col-
2
2
ꢀ
156.8, ꢀ142.6, ꢀ140.3, ꢀ127.7 (s, 1F each, C F ), ꢀ75.2
lected by a gas–liquid separator, and the yield and selectivity of
1 were determined as described above.
6
5
(s, 6F, CF ).
3
Adv. Synth. Catal. 2005, 347, 220–224
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ꢀ 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
223

COMMUNICATIONS
Yoshiaki Kokubo et al.
Supporting Information Available
2002, 344, 37–39; b) T. Netscher, W. Bonrath, A. Haas,
E. Hoppmann, H. Pauling, Chimia 2004, 58, 153–155.
11] a) P. G. Jessop, T. Ikariya, R. Noyori, Science 1995, 269,
Experimental apparatus for the extraction of 2 and 3, extrac-
[
tion experiments of 2 and 3 by scCO , and effects of solvent
2
1
065–1069; b) P. G. Jessop, T. Ikariya, R. Noyori,
and concentration of the yield and selectivity of 1 in the batch
reaction.
Chem. Rev. 1999, 99, 475–493; c) A. Baiker, Chem.
Rev.1999, 99, 453–473; d) P. G. Jessop, W. Leitner,
(
Eds.), Chemical Synthesis Using Supercritical Fluids, Wi-
ley-VCH: Weinheim, 1999; e) J. R. Hyde, P. Licence, D.
Carter, M. Poliakoff, Appl. Catal., A 2001, 222, 119–
Acknowledgements
1
31; f) B. Subramaniam, C. J. Lyon, V. Arunajatesan,
This work was supported by a Grant-in-Aid for Scientific Re-
search on Priority Areas (No. 14078209) from the Ministry of
Education, Culture, Sports, Science and Technology, Japan
and partially supported by the 21st century COE Program.
Appl. Catal., B 2002, 37, 279–292; g) W. Leitner, Acc.
Chem. Res. 2002, 35, 746; h) M. F. Sellin, I. Bach, J. M.
Webster, F. Montilla, V. Rosa, T. Aviles, M. Poliakoff,
D. J. Cole-Hamilton, J. Chem. Soc. Dalton Trans. 2002,
4
569–4576; i) J.-D. Grunwaldt, R. Wandeler, A. Baiker,
Catal. Rev. – Sci. Eng. 2003, 45, 1–96.
References and Notes
[
12] R. M. Parkhurst, W. A. Skinner, in: The Chemistry of
Heterocyclic Compounds, Vol. 36, (Eds.: G. P. Ellis,
I. M. Lockhart), John Wiley and Sons, New York,
[
1] K.-U. Baldenius, L. von dem Bussche-Hꢁnnefeld, E. Hil-
gemann, P. Hoppe, R. Stꢁrmer, in: Ullmannꢀs Encyclope-
dia of Industrial Chemistry, 6th edn., Vol. 38, Wiley-
VCH, Weinheim, 2003, pp. 109–294.
1
981, pp. 59–137.
ˇ
[
[
[
[
[
13] F. M. D. Ismail, M. J. Hilton, M. Stefinovi c´ , Tetrahedron
Lett. 1992, 33, 3795–3796.
14] U. Svanholm, V. D. Parker, J. Chem. Soc. Perkin Trans. 2
[2] A. Hasegawa, K. Ishihara, H. Yamamoto, Angew. Chem.
Int. Ed. 2003, 42, 5731–5733.
1
974, 169–173.
[3] M. Schneider, K. Zimmermann, F. Aquino, W. Bonrath,
Appl. Catal. A 2001, 220, 51–58.
15] K. Ishihara, A. Hasegawa, H. Yamamoto, Angew. Chem.
Int. Ed. 2001, 40, 4077–4079.
16] K. Ishihara, A. Hasegawa, H. Yamamoto, Synlett 2002,
[
[
4] F. Schager, W. Bonrath, J. Catal. 1999, 182, 282–284.
5] a) S. Wang, W. Bonrath, H. Pauling, F. Kienzle, J. Super-
crit. Fluids 2000, 17, 135–143; b) W. Bonrath, R. Karge,
in High Pressure Chemistry, (Eds.: R. V. Eldick, F.-G.
Klamer), Wiley-VCH, Weinheim, 2002.
1
299–1301.
17] a) Y. Kayaki, T. Suzuki, Y. Noguchi, S. Sakurai, M. Ima-
nari, T. Ikariya, Chem. Lett. 2002, 424–425; b) O. Ihata,
Y. Kayaki, T. Ikariya, Angew Chem. Int. Ed. 2004, 43,
[
[
[
[
6] M. Matsui, N. Karibe, K. Hayashi, H. Yamamoto, Bull.
Chem. Soc. Jpn. 1995, 68, 3569–3571.
7] M. Matsui, H. Yamamoto, Bull. Chem. Soc. Jpn. 1996, 69,
7
17–719; c) T. Tsukahara, Y. Kayaki, T. Ikariya, Y. Ike-
da, Angew Chem. Int. Ed. 2004, 43, 3719–3722.
18] In the Amberyst-catalyzed reaction carried out in much
higher concentrations of the substrates (0.29 mol/L), for
example, the yield of 1 was reported to be only 60.7%,
[
1
37–139.
8] K. Ishihara, M. Kubota, H. Yamamoto, Synlett 1996,
045–1046.
9] F. Schager, W. Bonrath, Appl. Catal. A 2000, 202, 117–
20.
1
[5]
and the selectivity was not discussed. See also: R. Low-
ack, J. Meyer, M. Eggersdorfer, P. Grafen, United States
Patent 5,523,420, 1996.
1
[10] a) W. Bonrath, A. Haas, E. Hoppmann, T. Netscher, H.
Pauling, F. Schager, A. Wildermann, Adv. Synth. Catal.
224
ꢀ 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
Adv. Synth. Catal. 2005, 347, 220–224