Enhanced product selectivity in continuous N-methylation of amino alcohols over solid acid-base catalysts with supercritical methanol

Article abstract of DOI:10.1002/1521-3773(20020916)41:18<3476::AID-ANIE3476>3.0.CO;2-5

The unique properties of supercritical fluids can be exploited for fine-tuning product selectivity. Under the conditions listed for the N-methylation of amino alcohols (see scheme) over solid acid-base bifunctional catalysts, the total yield and product selectivity could be improved. Enhanced product selectivity might be attributed to the milder reaction conditions possible with supercritical methanol, as well as the increased concentration of methanol on the catalyst.

Full text of DOI:10.1002/1521-3773(20020916)41:18<3476::AID-ANIE3476>3.0.CO;2-5

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CH3
N
Enhanced Product Selectivity in Continuous
N-Methylation of Amino Alcohols over
Solid Acid Base Catalysts with
H
N
CH3
N
+
CH3
OH
H
OH
H
OH
scCH3OH
1
2
3
Supercritical Methanol
Tomoharu Oku and Takao Ikariya*
RN
NR
N
N
NH
Supercritical fluids (SCFs) used as reaction media for
homogeneous molecular catalysis or as compressed carriers
4
5
6
gas or liquid phase
4]
for heterogeneous catalysis[1 have great potential for the
manipulation of catalytic reactions. We have demonstrated
that the pressure-tunable, unique properties of SCFs can
remarkably enhance the reactivities and selectivities of
molecular catalysts.[1] Besides these benefits for homogenous
catalysis, when heterogeneously catalyzed reactions are
performed over solid catalysts under supercritical conditions,
the pressure-tunable, liquidlike solubility and gaslike diffu-
sivity of the SCFs can significantly enhance the selectivity of
the reactions if the unique properties of SCFs favor one of the
reactions. Rapid deactivation of the catalyst resulting from
coke formation on the surface can also be suppressed.
Furthermore, applications of SCFs as a reactant and carrier
medium can influence the outcome of the reaction owing to
an increase in the concentration of the reactant on the catalyst
surface. In fact, Baiker et al. reported that the selectivity of
the amination of alkanediols or alkanolamines to give
diamines conducted with scNH3 over a Co Fe catalyst
increased remarkably when the pressure of the scNH3 was
changed.[3] Thus, heterogeneous catalysis in SCF media has
received considerable attention as researchers have tried to
manipulate the catalyst performance in terms of the selectiv-
ity.[3,4] However, fine-tuning the product selectivity of super-
critical-phase reactions over solid catalysts has remained
largely unexplored. Here we report the successful chemo-
selective alkylation of functionalized amines such as 2-
aminoethanol (1) over solid acid or acid base bifunctional
catalysts with supercritical methanol (scCH3OH, Pc ¼
8.1 MPa, Tc ¼ 239.58C). A significant increase in the selectiv-
ity of N-alkylation was achieved by using scCH3OH as a
reactant and carrier medium for continuous-flow reactions.
For the reaction of 1 with CH3OH to provide industrially
useful chemicals,[5] the product distribution is highly influ-
enced by the reaction phase as well as by the catalyst
(Scheme 1). For example, the vapor-phase reaction of 1 over
conventional solid acid catalysts such as H-b zeolites[6]
provides predominantly the products of intermolecular dehy-
dration, piperazine (5) and triethylenediamine (6), in addition
to N-methylated products, N-methylaminoethanol (2) and
N,N-dimethylaminoethanol (3). Alkaline earth metal silicon
Scheme 1. The reaction of 1 with methanol.
or alkali metal–phosphorus silicon oxides in the gas phase
selectively afford the product of intramolecular dehydration,
ethyleneimine (4), at higher temperatures instead of 5 and 6.[7]
Therefore, in general, the N-alkylation of 1 with methanol
under such severe conditions proceeds in a nonselective
manner and leads to various side reactions, cyclization,
À
oligomerization, and decomposition through C N bond
cleavage.
We screened various solid acid catalysts for the reaction of 1
with scCH3OH by using a continuous-flow fixed-bed tubular
reactor at 250 3008C and a pressure range of 0.1 to 15 MPa
(contact time of amine to catalyst, W/F ¼ 55 111 g-cath/mol-
amine, amine/CH3OH molar ratio ¼ 1/10.8 ). The catalysts
tested–H-mordenite,[8] H-b zeolite,[6] amorphous silica-alu-
mina,[9] g-alumina,[10] and the Cs-P-Si mixed oxide–effected
N-methylation under supercritical conditions to give predom-
inantly N-methylation products 2 and 3 in good to excellent
yields. Compounds 4, 5, and 6 were also obtained as minor
products as listed in Table 1. A visual inspection of the inside
of a 10-mL high-pressure vessel equipped with sapphire
windows confirmed that the reactants and expected products
are all dissolved into scCH3OH to make a single supercritical
phase under the reaction conditions examined here. Obvi-
ously, application of supercritical conditions improves the
conversion of amine as well as the selectivity for N-methy-
lated products in comparison to gas-phase reactions which
give only low conversion.[11]
Among the most efficient catalysts in scCH3OH are
combined ternary mixed-oxide catalysts, M-P-Si (M ¼ alkali
metal), which have both very weak acidic and basic sites. The
product selectivity is delicately influenced by the alkali metal
components in these catalysts and by the reaction conditions.
A Cs-P-Si mixed-oxide catalyst effected the efficient N-
methylation of 1 at 3008C and under otherwise the same
conditions as described in Table 1 to give the desired products
2 and 3 in 67% yield (71% conversion and 94% cumulated
selectivity). When the reaction was performed with a W/F
value of 133 ghmolÀ1 and an amine/CH3OH ratio of 1/20
under otherwise identical conditions, the yield of the desired
products increased to 81% (86% conversion and 94%
selectivity). An increase in the temperature from 300 to
4008C caused a serious drop in the selectivity to 25%,
although the conversion of 1 increased, as shown in Figure 1.
At the higher reaction temperature of 4008C, the super-
critical-phase reaction gave a complicated mixture of 4,
methoxyethylamine, and some other degradation compounds.
In contrast to the scCH3OH phase, the gas-phase reaction
[*] Prof. T. Ikariya
Graduate School of Science and Engineering
Tokyo Institute of Technology
2-12-1 O-okayama, Meguro-ku, Tokyo 152-8552 (Japan)
Fax : (þ 81)3-5734-2637
E-mail: tikariya@o.cc.titech.ac.jp
T. Oku
Joint Research Center for Supercritical Fluids
Japan Chemical Innovation Institute (JCII)
3476
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Table 1. Reaction of 1 with methanol over various solid catalysts in both gas and supercritical phases.[a]
Entry
Catalyst
T[8C]/P [MPa]
W/F [ghmolÀ1
]
Conv. [%]
Yield [%]
Selectivity [%]
2
3
2 þ 3
4
5 þ 6
1
2
3
4H-
5
6
7
8
9
10
11
12
13
H-mordenite
H-mordenite
H-b zeolite
b zeolite
SiO2 Al2O3
SiO2 Al2O3
SiO2 Al2O3
g-Al2O3
g-Al2O3
g-Al2O3
Na-P-Si oxide
K-P-Si oxide
Cs-P-Si oxide
300/0.1
300/15
250/0.1
250/15
300/0.1
300/8.2
300/15
300/0.1
300/8.2
300/15
270/8.2
300/8.2
300/0.1
111
111
55
55
66
66
66
79
79
79
55
55
55
0
26
18
32
347
77
81
21
48
48
0
12
2
12
2
15
15
12
24
26
1
0
461
1
8
26
10
13
3
9
10
36
0
0
0
0
0
17
63
0
32
35
71
69
75
37
0
0
0
46
0
0
0
0
tr
0
0
0
10
8
9
3
1
100
7435
12
16
12
6
604
1
58
37
4
14Cs-P-Si oxide
300/8.2
55
71
51
16
940
1
15
16
Cs-P-Si oxide
Cs-P-Si oxide
300/8.2
300/8.2[b]
133
133
79
86
48
48
24
33
91
94
0
0
0
0
[a] Conditions: The reaction was conducted in a fixed-bed, tubular reactor with an amine/CH3OH molar ratio of 1/10.8 and W/F ¼ 55 133 ghmolÀ1. The
product ratio was determined by GC after the reaction conditions had been at steady state for 6 h. [b] Amine/CH3OH ¼ 1/20.
Table 2. N-Methylation of various amines over the Cs-P-Si catalyst in
scCH3OH.[a]
100
80
Entry Amine
Conv. [%] Sel. 2 þ 3 [%] Sel. 4 þ 5 þ 6 [%]
60
40
20
1
2
3
HO(CH2)2NH2
HO(CH2)3NH2
HO(CH2)4NH2
90
81
87
51
71
76
45
2478
18
15
16
11
941
93
12
80
87
88
82
x/%
1
87
20
13
0.1
0.5
4HO(CH
2)5NH2
0
5
7
8
HO(CH2)2O(CH2)2NH2
HO(CH2)2NHCH3
HO(CH2)2NHC2H5
HO(CH2)2NHCH(CH3)2
n-C4H9NH2
C6H5NH2
2-pyrrolidone
C2H5O(CH2)2NH2
100
80
60
40
20
0
9
1
10
11
12
13
94
94
88
98
y/%
[a] Conditions: The reaction was conducted over the Cs-P-Si catalyst at
300
330
360
400
3008C in a fixed-bed tubular reactor with an amine/CH3OH molar ratio of
1/20 and W/F ¼ 140 ghmolÀ1
T/ °C
.
Figure 1. The effect of temperature on the conversion of 1 (x) and
selectivity for N-methylated products (y) in the gas phase (white bars) and
the supercritical phase, P ¼ 8.2 MPa, (black bars) in the methylation of 1
over the Cs-P-Si catalyst. Conditions: W/F ¼ 25 ghmolÀ1, CH3OH/amine ¼
10.8/1.
the reaction. The reactivity decreases in the order of 2-
aminoethanol > 3-aminopropanol > 5-aminopentanol, al-
though 4-aminobutanol gave predominantly the cyclization
product, pyrrolidine, in 87% selectivity, possibly because of
thermodynamic reasons. Diglycolamine with a structural
similarity to 5-aminopentanol provided N-methylated prod-
ucts along with morpholine as a byproduct. Unlike bifunc-
tionalized amines, simple amines including n-butylamine,
aniline, and 2-pyrrolidone were far less reactive regardless of
their structures; the conversion of the amines ranged from 10
to 20% with high selectivity for N-methylation. The hydroxy
group on the other terminus in the functionalized amines is a
crucial structural factor in achieving high reactivity, possibly
because of the anchoring effect of the hydroxy group on the
catalyst surface. In fact, ethoxyethylamine bearing no hydroxy
group was far less reactive than 1.
under otherwise identical conditions at 3008C exhibited
unsatisfactory productivity, 12% conversion, and 58% selec-
tivity. The reaction at the higher reaction temperature of
4008C afforded 4 with 72% selectivity as the major product.
Thus, the use of scCH3OH as a carrier medium and reactant
improved the productivity of N-methylation significantly over
that of the gas-phase reaction. The change in the selectivities
might be attributed to the milder reaction conditions possible
with scCH3OH, as well as the increased concentration of
CH3OH on the catalyst surface.
The scope and limitation of this N-methylation over the Cs-
P-Si mixed-oxide catalyst in scCH3OH was investigated at
3008C and 8.2 MPa with an amine/CH3OH molar ratio of
1/20. N-Methylation of various functionalized amines pro-
ceeded smoothly to provide the corresponding N-methylated
products with a high selectivity (Table 2). Noticeably, the
structures of the amino alcohols influenced the outcome of
Although the mechanism of the reaction on the catalyst
surface is not clear yet, valuable information was provided by
the N-methylation of N-alkylaminoethanols with scCH3OH
under conditions similar to those described in Table 2. The
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molar ratio ¼ 10.8/1 or 20/1 and the LHSV (mL-liquid/mL-cath), which is
the space velocity as normal liquid flow rate of the mixed solution of
reactants, is 5 hÀ1).
reaction gave only N,N-alkylmethylaminoethanols without
formation of any disproportionation products under these
conditions. Substituents on the nitrogen atom of N-alkylami-
noethanols affect the reactivity with scCH3OH mainly be-
cause of steric and electronic factors; the reactivity decreased
in the substituent order of H > CH3 > C2H5 > CH(CH3)2.
Furthermore, the lack of formation of O-methylated products
in the reaction of 1 with CH3OH under supercritical
conditions may exclude the possibility of the intramolecular
dehydration producing ethyleneimine 4, which is a main
product in the gas-phase reaction over the Cs-P-Si mixed-
oxide catalysts. These experimental results as well as those
previously reported[7] suggest that the reaction proceeds by
means of selective adsorption of 1 through the hydroxy group
on the acid base pair site of the catalyst to lead to the b-
aminoethyl silylester or the b-aminoethyl phosphate species.[7]
CH3OH should form its methylester on the neighboring acidic
sites in a similar manner. After N-methylation on the amino
group with methyl moieties through deprotonation of the
amino groups by the basic sites, these N-methylated adsor-
bates may be effectively desorbed with the aid of scCH3OH.
In contrast to the reactivity of the Cs-P-Si mixed-oxide
catalyst, which has both acidic and basic sites on the surface,
b-zeolite or amorphous silica-alumina catalysts with relatively
strong acid sites exerted unsatisfactory selectivity, while the g-
alumina catalyst, which has both strong acid and base sites,
exhibited comparatively good reactivity and selectivity.
In summary, we have described the first examples of the
selective N-methylation of bifunctional amines over the solid
acid base bifunctional catalyst in scCH3OH as well as
enhanced product selectivity on changing the pressure of
CH3OH. The use of scCH3OH, which acts as a methylating
agent and a reaction medium, as well as adjustment of the
catalyst components results in the fine-tuning of the reaction
conditions and particularly the reaction temperature for
chemoselective methylation of the functionalized amines.
Further investigations of the detailed mechanism of the
methylation of the amines, the origin of the enhancement of
the selectivity in scCH3OH, and the effect of the cogenerated
water on the reactivity[12] are now in progress.
The reaction products were identified by GC-MS analysis (Agilent 5973N-
6890N, Agilent Technologies). The selectivity and chemical yield of the
products were determined by GC analysis (GC-17A, Shimadzu Co.; FID
detector and DB-1 capillary column, J&W)). Conversion of amines Xa,
yield Yn, and selectivity Sn of each of the methylated products 2, 3, and n
were defined as:
Xa ¼ ðFaðiniÞÀFaÞ=FaðiniÞ ꢀ 100 ð%Þ
Yn ¼ Fn=FaðiniÞ ꢀ 100 ð%Þ
Sn ¼ Yn=Xa ꢀ 100 ð%Þ
ð1Þ
ð2Þ
ð3Þ
Fa(ini) and Fa represent molar flow rates of reactant amine at the reactor inlet
and outlet, respectively, and Fn represents that of methylated product n at
the reactor outlet.
During the reaction, no degradation products of methanol such as
dimethylether, carbon monoxide, and methane were detected. Methanol
was only consumed as a reactant in the N-methylation reaction.
Received: May 16, 2002 [Z19317]
[1] a) P. G. Jessop, T. Ikariya, R. Noyori, Nature 1994, 368, 231 233;
b) P. G. Jessop, T. Ikariya, R. Noyori, Science 1995, 269, 1065 1069;
c) T. Ikariya, R. Noyori in Transition Metal Catalyzed Reactions (Eds.:
S.-I. Murahashi, S. G. Davies), IUPAC, Blackwell Science, New York,
1999, pp. 1 28; d) P. G. Jessop, T. Ikariya, R. Noyori, Chem. Rev.
1999, 99, 475 493; e) Chemical Synthesis Using Supercritical Fluids
(Eds.: P. G. Jessop, W. Leitner), Wiley-VCH, Weinheim, 1999; f) R.
Noyori, T. Ikariya in Stimulating Concepts in Chemistry, Wiley-VCH,
2000, pp. 13 24.
[2] As reviews: a) P. E. Savage, S. Gopalan, T. I. Mizan, C. J. Martino,
E. E. Brock, AIChE J. 1995, 41, 1723 1778; b) P. E. Savage in
Handbook of Heterogeneous Catalysis, Vol. 4 (Eds.: G. Ertl, H.
Knˆzinger, J. Weitkamp), Wiley-VCH, Weinheim, 1997, pp. 1339
1347; c) A. Baiker, Chem. Rev. 1999, 99, 453 473; d) L. Fan, K.
Fujimoto in Chemical Synthesis Using Supercritical Fluids (Eds.: P. G.
Jessop, W. Leitner), Wiley-VCH, Weinheim, 1999, pp. 388 413; e) R.
Wandeler, A. Baiker, CATTECH 2000, 4, 34 50; f) J. R. Hyde, P.
Licence, D. Carter, M. Poliakoff, Appl. Catal. A 2001, 222, 119 131;
g) B. Subramaniam, C. J. Lyon, V. Arunajatesan, Appl. Catal. B 2002,
37, 279 292; h) B. Subramaniam, Appl. Catal. A 2001, 212, 199 213;
i) B. Subramaniam, M. A. McHugh, Ind. Eng. Chem. Process Des.
Dev. 1986, 25, 1 12.
[3] a) G. Jenzer, T. Mallat, A. Baiker, Catal. Lett. 1999, 61, 111 114; b) A.
Fischer, M. Maciejewski, T. B¸rgi, T. Mallat, A. Baiker, J. Catal. 1999,
183, 373 383; c) A. Fisher, T. Mallat, A. Baiker, J. Catal. 1999, 182,
289 291; d) A. Fischer, T. Mallat, A. Baiker, J. Mol. Catal. A 1999,
149, 197 204; e) A. Fischer, T. Mallat, A. Baiker, Angew. Chem. 1999,
111, 362 365; Angew. Chem. Int. Ed. 1999, 38, 351 354.
Experimental Section
The Cs-P-Si mixed-oxide catalyst was prepared by the following procedure:
Silica beads of 10 to 20 mesh size (CARiACT Q-30, Fuji Silysia Chemical
Co. LTD.) were impregnated with an aqueous solution of cesium nitrate
and ammonium dihydrogenphosphate. The crude mixture was then dried at
1208C and calcined at 5008C for 2 h in air. The Cs/P/Si atomic ratio in the
catalyst was 1/0.8/5 and the specific surface area was 7 m2 gÀ1. The acid and
base strength measured by the Hammet indicator method was weaker than
H0 ¼ þ6.3 and HÀ ¼ þ8.3, respectively. Chemisorption of NH3 and CO2 at
room temperature from the vapor phase did not occur in temperature-
programmed desorption (TPD) analysis.
[4] a) W. K. Gray, F. R. Smail, M. G. Hitzler, S. K. Ross, M. Poliakoff, J.
Am. Chem. Soc. 1999, 121, 10711 10718; b) M. G. Hitzler, F. R.
Smail, S. K. Ross, M. Poliakoff, Chem. Commun. 1998, 359 360;
c) M. G. Hitzler, F. R. Smail, S. K. Ross, M. Poliakoff, Org. Process
Res. Dev. 1998, 2, 137 146; d) M. G. Hitzler, M. Poliakoff, Chem.
Commun. 1997, 1667 1668; e) U. R. Pillai, E. Sahle-Demessie, Chem.
Commun. 2002, 422 423; f) R. J. Bonilla, P. G. Jessop, B. R. James,
Chem. Commun. 2000, 941 942; g) R. Wandeler, N. Kunzle, M. S.
Schneider, T. Mallat, A. Baiker, Chem. Commun. 2001, 673 674.
[5] a) M. R. Edens, J. F. Lochary in Kirk-Othmar Encyclopedia of
Chemical Technology, Vol. 2, 4th ed. (Eds.: J. I. Kroschwitz, M.
Howe-Grant), Wiley, New York, 1991, pp. 1 26; b) Electronic
Release, ™Ethanolamines and Propanolamines∫: H. Hammer, W.
Kˆrnig, T. Weber, H. Kieczka in Ullmann©s Encyclopedia of Industrial
Chemistry, 6th ed., Wiley-VCH, Weinheim, 2001; c) Electronic
Release, ™Amines, Aliphatic∫: K. Eller, E. Henkes, R. Rossbacher,
H. Hˆke in Ullmann©s Encyclopedia of Industrial Chemistry, 6th ed.,
Wiley-VCH, Weinheim, 2001.
The N-methylation reaction of 1 in the gas or supercritical phase was
carried out isothermally in a continuous up-flow tubular reactor (SUS316
tubular reactor with a Swagelok VCR joint, 1/2 inch î 10 mm î 135 mm).
The reactor was loaded with catalyst particles and placed in an oven. A
mixture of amine and methanol was introduced into the reactor through the
preheating coil with an HPLC pump (PU1580, JASCO Co.). The pressure
in the reaction system was controlled by the automatic back-pressure
regulator (880-81, JASCO Co.) at 0.1 to 15 MPa. Standard reaction
conditions were used (5.0 mL catalyst, 3008C, 8.2 MPa, methanol/amine
3478
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the osmium center,[2] or chiral auxilliaries present in the
substrate.[3,4] Here we report a conceptually different ap-
proach to asymmetric dihydroxylation using permanganate in
the presence of a chiral phase-transfer reagent.[5,6]Recently,
we reported the asymmetric oxidative cyclization of 1,5-
dienes 1 by permanganate using a chiral phase-transfer
catalyst (Scheme 1).[5] Whereas the permanganate promoted
[6] H-b zeolite (CP811E-22, protonated form, ZEOLYST Int.; Si/Al
atomic ratio of 12/1) was used after it had been pelletized to 0.3
0.8 mm.
[7] a) H. Tsuneki, Appl. Catal. A 2001, 221, 209 217; b) M. Ueshima, H.
Tsuneki in Catalytic Science and Technology, Vol. 1 (Eds.: S. Yoshida,
N. Takezawa, T. Ono), Kodansha-VCH, Tokyo, 1991, pp. 357 360;
c) M. Ueshima, Y. Shimasaki, Y. Hino, H. Tsuneki in Acid-Base
Catalysis (Eds.: K. Tanabe, H. Hattori, T. Yamaguchi, T. Tanaka),
Kodansha, Tokyo, 1989, pp. 41 52; d) M. Ueshima, H. Yano, H.
Hattori, Sekiyu Gakkaishi 1992, 35, 362 365; e) H. Tsuneki, Y.
Shimasaki, K. Ariyoshi, Y. Morimoto, M. Ueshima, Nippon Kagaku
Kaishi 1993, 11, 1209 1216.
[8] H-Mordenite (HSZ640HOA, protonated form, Tosoh Co.; Si/Al
atomic ratio of 9/1) was used after it had been pelletized to 0.3
0.8 mm.
[9] Amorphous silica-alumina (N632L, Nikki Chemical Co.; SiO2/Al2O3
molar ratio of 11/1, specific surface area 400 m2 gÀ1) was used after it
had been pelletized to 0.3 0.8 mm.
O
a)
Ar
O
H
Ar
HO
H
Br
OH
2 (58–75% ee)
O
1
N
BnO
3
[10] g-Alumina (N612N, Nikki Chemical Co.; specific surface area
200 m2 gÀ1) was used after it had been pelletized to 0.3 0.8 mm.
[11] After 6 h reaction time under supercritical conditions the H-morden-
ite catalyst was still white and very active. In contrast, reaction in the
gas phase resulted in immediate blackening and deactivion of the
catalyst due to coking.
N
Scheme 1. Asymmetric oxidative cyclization of 1,5-dienes 1. a) KMnO4
(powder) (1.6 equiv), AcOH (6.5 equiv), 3 (0.1 equiv)/CH2Cl2, À308C.
oxidative cyclization reaction of 1,5-dienes and the formation
of a-ketols from olefins occur under slightly acidic conditions,
permanganate oxidations conducted under basic conditions
favor dihydroxylation.[7] Therefore, permanganate oxidations
using chiral phase-transfer agents in alkaline media should
provide a new approach to asymmetric dihydroxylation.
Enones had been shown to undergo permanganate oxida-
tive cyclization reactions to afford tetrahydrofuran diols 2
with good levels of enantioselectivity (Scheme 1),[5,8] and were
therefore chosen as substrates for initial dihydroxylation
studies (Scheme 2). Oxidation of 4a under liquid liquid
achiral phase-transfer conditions gave racemic diol 5a as the
major isolated product in reasonable yield (entry 1, Table 1).
The majority of the remaining mass balance was accounted
[12] Effect of water: Water generated from methylation of 1 may possibly
inhibit the reaction by competitive adsorption with the reactants on
the catalyst surface. In fact, we found that the adsorption equilibrium
constants (K) of CH3OH and water are much larger than that of 1 by a
simulation in the reaction kinetics by Langmuir Hinshelwood mech-
anism, KCH OH/K1 ¼ 100, Kwater/K1 ¼ 3000. An increase in the portion of
3
scCH3OH by changing the molar ratio of CH3OH to 1 at the same
amine contact time (W/F) improved the reaction conversion and the
space time yields, which suggests that desorption of the generated
water from the catalyst surface could be promoted by scCH3OH.
An Asymmetric Phase-Transfer
Dihydroxylation Reaction**
Bu
Bu
OH
Riaz A. Bhunnoo, Yulai Hu, Dramane I. Lainÿ, and
Richard C. D. Brown*
a)
HO
Ph
Ph
O
O
4a
5a
Scheme 2. Phase-transfer promoted dihydroxylation of enone 4a. For
conditions and yields see Table 1.
The asymmetric dihydroxylation of olefins using osmium
tetraoxide is a powerful process that has found widespread
application in organic synthesis.[1] Systems developed to date
realize enantioinduction through the use of chiral ligands on
Table 1. Phase-transfer (PT) promoted dihydroxylation of enone 4a (see
Scheme 2).[a]
Entry Method[b] PT
[equiv]
Time Yield of 5a [%][c] ee[d]
[min] [BRSM [%]]
[%]
[*] Dr. R. C. D. Brown, R. A. Bhunnoo, Dr. Y. Hu
Department of Chemistry
University of Southampton
1
2
3
4
5
6
7[e]
A
A
B
B
B
B
B
Adogen 464 (1.0)
3 (1.0)
3 (1.0)
3 (1.0)
3 (1.0)
45
45
30
55
N/A
47
63
62
62
Highfield, Southampton SO17 1BJ (UK)
Fax : (þ 44)23-80596805
41 [45]
41 [96]
51 [87]
27 [40]
33 [64]
30 [42]
E-mail: rcb1@soton.ac.uk
60
180
420
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Dr. D. I. Lainÿ
GlaxoSmithKline
Medicines Research Centre
3 (0.2)
3 (3.0)
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Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY (UK)
[a] Reactions were conducted on a 0.37 mmol scale. [b] Method A: KMnO4
(s) (0.37 mmol), CH2Cl2 (16 mL), pH 9 buffer (8 mL), 08C. Method B:
KMnO4 (s) (1.5 equiv), CH2Cl2, À608C. [c] Yields represent analytically
pure isolated material. BRSM indicates the isolated yield based on recoved
[**] We acknowledge GlaxoSmithKline/EPSRC for
a CASE award
(R.A.B.), the Leverhulme Trust (Y.H.), and the Royal Society
(R.C.D.B.) for fellowships, Syngenta, AstraZeneca, and Merck Sharp
and Dohme for unrestricted grants. We also thank Dr Barry Lygo
(University of Nottingham) for helpful discussions.
enone. [d] Enantiomeric excess was determined by HPLC using
a
CHIRALCEL OD-H column, hexane/iPrOH (80:20) eluent. Rt ¼
5.28 min (major), Rt ¼ 6.24min (minor). [e] Reaction carried out with
three equivalents of KMnO4.
Supporting information for this article is available on the WWW under
http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2002, 41, No. 18
¹ 2002 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0044-8249/02/4118-3479 $ 20.00+.50/0
3479