A new catalytic route for the oxidative halogenation of cyclic enol ethers using tungstate exchanged on takovite

Article abstract of DOI:10.1002/adsc.200404138

An efficient and benign method for the regio- and stereoselective synthesis of halohydrins and β-halo ethers from dihydropyrans, dihydrofurans and anhydro sugars in the presence of a halide salt and hydrogen peroxide is presented with tungstate-exchanged takovite as oxidation catalyst.

Full text of DOI:10.1002/adsc.200404138

FULL PAPERS
A New Catalytic Route for the Oxidative Halogenation of Cyclic
Enol Ethers using Tungstate Exchanged on Takovite
B. Sels,a P. Levecque,a R. Brosius,a D. De Vos,a P. Jacobs,a,* D. W. Gammon,b
H. H. Kinfeb
a
Center for Surface Chemistry and Catalysis, Katholieke Universiteit Leuven, Kasteelpark Arenberg 23, 3001 Leuven,
Belgium
Fax: (þ32)-16-32-1998, e-mail: bert.sels@agr.kuleuven.ac.be, Pierre.Jacobs@agr.kuleuven.ac.be
b
Department of Chemistry, University of Cape Town, Rondebosch, 7701, South Africa
Received: May 17, 2004; Accepted: September 9, 2004
Abstract: An efficient and benign method for the re- Keywords: cyclic enol ethers; heterogeneous catalysis;
gio- and stereoselective synthesis of halohydrins and hydrogen peroxide; layered double hydroxide; oxida-
b-halo ethers from dihydropyrans, dihydrofurans tive halogenation; tungstate
and anhydro sugars in the presence of a halide salt
and hydrogen peroxide is presented with tungstate-
exchanged takovite as oxidation catalyst.
Introduction
enzymes, man-made analogues offer almost comparable
activities with improved long-term stabilities and this
Halogen-based oxidants such as elemental halogens, or- for an acceptable price. Recently, tungstate exchanged
ganic and inorganic hypohalites, hypervalent iodine(III) on naturally occurring minerals such as hydrotalcite-
and (V) reagents, dihalo-5,5’-dimethylhydantoins and and takovite-like materials has been demonstrated to
N-halosuccinimides are often used for the selective hal- be an excellent mimic for haloperoxidases.[6] Not only
ogenation of unsaturated hydrocarbons.[1,2] In particu- is the catalytic activity of the W-based catalyst close to
lar, the stereo- and regioselective halogenation of al- that of the crude enzyme mixture; the solid catalyst
kenes such as vinyl ethers finds wide application in or- also shows an excellent stability against oxidation in
ganic synthesis. However, most of the aforementioned contrast to the majority of the biocatalysts. Hydrotalcite
reagents are either highly toxic or expensive and pro- and takovite-like minerals, generally denoted as layered
duce stoichiometric amounts of waste.
double hydroxides, have been frequently applied as cat-
Todayꢀs increased environmental awareness prompts alyst support in other chemical transformations such as
chemists to search for clean and sustainable synthesis epoxidation, amine and thiol oxidation, hydroperoxida-
methodologies. In situ formation of reactive halogen tion and reductions.[7]
compounds is one of the most promising approaches
The catalytic oxyhalogenation cycle using the tung-
to overcome the safety and waste handling problems. state exchanged takovites has been fully elucidated
Electrochemical haloalkoxylation and halohydroxyla- and appears to be similar to that of the vanadium-con-
tion of alkenes using common halide salts have been em- taining haloperoxidases (VHPO).[5,6] The mechanism
ployed for the synthesis of various halogenated prod- behind the oxidative halogenation is illustrated in
ucts.[3] However, taking into account the costs and the Scheme 1. A key step is the oxidation of the halide to
apparatus needed with electrochemistry, reactive hal- the hypohalite anion by tungstate-activated peroxides
ides are better generated gradually in a chemical way. at the surface of the takovite mineral. The hypohalite
For instance, a reductive halogenation using NaBrO3 anion equilibrates with its conjugate acid and the corre-
or H5IO6 in the presence of NaHSO3 has been published sponding dihalide, the ratio depending on the pH, the
for the production of iodohydrins and bromohydrins.[4] halide concentration and the solvent. Subsequently,
The oxidative variant of in situ reactive halogen produc- the hypohalous acid rapidly reacts with the substrate
tion has been recently looked at more frequently. One producing halogenated hydrocarbons. Crucial in this
promising example of oxidative halogenation is illus- process is the availability of protons during the reaction
trated in nature, where haloperoxidases use H2O2 to ox- as one proton is consumed per cycle. In order to exclude
idize a halide to the halonium species, which in turn hal- corrosive conditions and to ensure product and catalyst
ogenates unsaturated hydrocarbons.[5] Instead of using stability, the protons are best delivered from weak acids
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DOI: 10.1002/adsc.200404138
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Scheme 1.
Scheme 2.
such as NH4þ. If the oxidative halogenation is not buf- between the two phases may be of interest in case of bro-
fered properly, the equilibrium shifts toward hypohalite mohydroxylation of more polar substrates such as dihy-
anions which rapidly react with H2O2 to form dioxygen drofurans.
in its singlet state and water. Obviously, this unproduc-
tive decomposition of H2O2 should be avoided as focussed on the yield based on oxidant efficiency. The
much as possible. bromohydroxylation proceeds more efficiently with re-
Further improvement of the bromination procedure
Herein, we report on the oxidative halogenation of cy- spect to the oxidant consumption in presence of an ap-
clic enol ethers into halo alcohols and ethers with ammo- propriate NH4Br concentration. For instance, when us-
nium halide salts and hydrogen peroxide using tungstate ing the same amount of hydrogen peroxide, the olefinic
anions exchanged on a synthetic takovite-like mineral as substrate was completely converted in the presence of
catalyst.
0.8 M NH4Br, whereas the conversion was only 66%
with 0.4 M NH4Br (entries 2 and 3). The more efficient
use of the oxidant is due to an increased HOBr/BrOꢀ ra-
tio, so that bromination is preferred over singlet oxygen
formation (Scheme 1). Interestingly, even with the high
Results and Discussion
Initially, we studied the catalyzed oxidative bromination initial Brꢀ concentration, hardly any dibromide is
of 2,3-dihydro-4H-pyran (DHP) in aqueous solvent con- formed. Replacement of NH4Br by HBr as source of
ditions. As can be deduced from Table 1, the experi- Brꢀ and Hþ appeared to be unsuccessful as the reaction
ments resulted in an efficient procedure for the transfor- was completely non-selective (entry 16). The by-prod-
mation of the alkene to the expected bromohydrin in ex- ucts in this reaction were not further investigated.
cellent yield (Scheme 2, 90–97%).
Variation in the total amount of H2O2 revealed that
Several general features are apparent in the reaction 1.2–1.4 equivalents of oxidant, i.e., 5–6 aliquots of
with DHP (Table 1). First, the composition of the aque- H2O2 (22 mmol) are sufficient to fully convert the pyran
ous organic solvent mixture plays an important role in selectively into the desired bromohydrin (entries 3, 5–
the bromohydrin selectivity (compare entries 1 and 2). 9). The time between consecutive additions of aliquots
When the bromination is carried out in one liquid phase, of H2O2 seems to be crucial. It was indeed established
e.g., by using water and CH3CN in a volume ratio of 2 to that the catalytic bromination system efficiently deals
3, the bromohydrin is formed in 29% yield, whereas in a with up to 22 mM of oxidant per 2 mM of W catalyst ev-
two liquid phase system, e.g., with 20 vol % CH3CN in ery 2.5 minutes at room temperature (entries 12 and 13).
H2O, a yield as high as 63% was detected. The yield im- According to this most efficient procedure the catalyst
provement is the result of increased bromohydrin selec- runs with a maximum of 275 cycles per hour at room
tivity rather than rate acceleration. The increase in se- temperature of which 85% produces the desired bromi-
lectivity likely results from the protective role of the or- nated compound. Faster addition of the oxidant leads to
ganic phase taking into account the instability of the bro- a pressure build-up in the reaction vessel as a result of
minated tetrahydropyran. The nature of the organic sol- the competitive decomposition of H2O2. The loss of ox-
vent is not crucial as acetonitrile can be replaced by idant is clearly reflected in the moderate yields, as ob-
similarly polar solvents such as methyltetrahydrofuran, tained in entries 10 and 11 (58% and 84%, respectively).
tetrahydrofuran and dioxane without considerably af- Despite the lower oxidant efficiency, the oxidative bro-
fecting the catalytic results (compare for instance en- minationremains selective, hence showing that the high-
try 3 with 4). Although not always necessary, small ly reactive singlet oxygen does not influence the product
amounts of ethyl acetate, toluene, dichloromethane or outcome in the case of cyclic enol ether bromination.
benzonitrile may be added in order to ensure the protec-
The oxidative bromination system is not only selective
tion of the bromohydrin. Increased polarity differences and efficient; it also shows a high productivity. In entry
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Table 1. Oxidative hydrohalogenation (Br or I) of 2,3-dihydro-4H-pyran under various conditions catalyzed by WO42ꢀ
exchanged on takovite.
Entry
[DHP],
mM
[WO24ꢀ],
mM
[NH4Br],
mM
[H2O2],
mM
Time
[min]
Selectivity
[%][a]
Conversion
[%]
Productivity
[mmol product·gꢀ1 ·hꢀ1
]
1[b]
2
90
90
90
90
90
90
90
90
90
90
90
90
90
180
360
360
360
360
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
2.0
2.0
2.0
2.0
2.0
4.0
4.0
4.0
1.0
400
400
800
800
800
800
800
800
800
800
800
800
800
800
800
330
400
400
176
176
176
176
132
110
66
40
40
40
40
30
25
15
10
5
7.5
10
12
25
25
25
25
10
23
29
96
92
94
97
97
96
100
95
98
99
99
96
93
93
100
66
100
100
100
92
51
35
14
59
84
97
96
99
96
100
99
20
43
61
63
87
96
88
95
70
104
112
104
50
93
96
–
246
450
3
4[c]
5
6
7
8
9
10
11
12
13
14
15
16[d]
17[f]
18[g]
44
22
110
110
110
110
220
440
440
440
506
[e]
–
93
99
97
Standard reaction conditions: 2 mL CH3CN, 8 mL H2O, 2,3-dihydro-4H-pyran, NH4Br, WO24ꢀ on takovite, H2O2 (aqueous 35
wt %) in portions of 0.22 mmol, ambient conditions, 1000 rpm stirring.
[a]
3-Bromo-2-hydroxy product.
In 6 mL CH3CN and 4 mL H2O.
In 2 mL THF and 8 mL H2O.
HBr instead of NH4Br.
Completely non-selective.
At 358C.
NH4I instead of NH4Br at 358C.
[b]
[c]
[d]
[e]
[f]
[g]
15 for instance, DHP (0.36 M) is almost quantitatively suspension as a result of the slight molar excess of the io-
converted into the 3-bromo-2-hydroxytetrahydropyran dide salt initially available with respect to the substrate.
in the presence of the heterogeneous W catalyst When new substrate is added to the coloured solution,
(4 mM) at ambient temperature using only 1.2 equiva- the solution turns colourless again, thus showing that re-
lents of oxidant. This result corresponds to a productiv- actions can be carried out with high atom efficiency in
ity of almost 100 mmol bromohydrin per gram of cata- the halogen.
lyst and per hour. The production can rise to
250 mmol·gꢀ1 ·hꢀ1 (or 45 g·gꢀ1 ·hꢀ1) by raising the re- methanol the alkene was selectively transformed into
action temperature by 108C (entry 17). the 3-bromo-2-methoxy ether (Scheme 3). Although
When the oxidative bromination was carried out in
According to a similar procedure, iodohydrin is syn- the bromination in methanol requires somewhat more
thesized in yields up to 96% by replacing NH4Br for oxidant in order to ensure full conversion, the bromo-
NH4I. The lower reduction potential of iodide in com- methoxylation yields and productivities remain excel-
parison with that of bromide allows lower catalyst con- lent (Table 2). For instance, DHP (0.36 M) on treatment
centrations. In the optimal conditions 450 mmol or with NH4Br (0.40 M) and 1.7 equivalents H2O2 in meth-
94 g of 2-hydroxy-3-iodotetrahydropyran were pro- anol in the presence of 4 mM WO24ꢀ exchanged on syn-
duced at 358C using 1 g of catalyst within one hour reac- thetic takovite gave the 3-bromo-2-methoxy adduct in
tion time (entry 18).
almost quantitative yield (entry 2, 98%) corresponding
Reactions with iodide are easy to follow in contrast to to a productivity of 62 mmol 3-bromo-2-methoxy ether
reactions with bromide. After addition of H2O2 to the re- per hour and per gram catalyst. Again, the productivity
action mixture containing iodide, the reaction immedi- can be doubled by increasing the reaction temperature
ately turns yellow-brown due to I2 accumulation. The re- by 108C (entry 3, 130 mmol·gꢀ1 ·hꢀ1). A similar iodo-
action mixture fades to colourless within a couple of mi- methoxylation using NH4I gives the corresponding
nutes as the iodination of DHP proceeds. At this time a product in almost quantitative yields (entry 4, 96%).
new shot of H2O2 may be added. Reaction completeness
Table 3 shows the general applicability of the halogen-
is evidenced by a stable yellow-brown coloration of the ation using various alcohols including primary, secon-
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Table 2. Oxidative methoxy(iodination)bromination of 2,3-dihydro-4H-pyran at various conditions catalyzed by WO24ꢀ ex-
changed on takovite.
Entry
[DHP],
mM
[WO24ꢀ],
mM
[NH4Br],
mM
[H2O2],
mM
Time [min]
Selectivity
[%][a]
Conversion
[%]
Productivity
[mmol product·gꢀ1 ·hꢀ1
]
1
90
2.0
4.0
4.0
1.0
400
400
400
400
154
616
616
550
35
42
20
25
93
98
99
97
100
99
100
99
35
62
130
415
2
360
360
360
3[b]
4c
Standard reaction conditions: 10 mL CH3OH, 2,3-dihydro-4H-pyran, NH4Br, WO24ꢀ on Takovite, H2O2 (aqueous 35 wt %) in
portions of 0.22 mmol, ambient conditions, 1000 rpm stirring.
[a]
3-Bromo-2-methoxy product.
At 358C.
With NH4I instead of NH4Br at 358C.
[b]
[c]
Table 3. Synthesis of various 2-alkoxy-3-bromo adducts of 2,3-dihydro-4H-pyran.
Entry
ROH
Selectivity
[%]
Conversion
[%]
Productivity
trans/cis[a]
[mmol·gꢀ1 ·hꢀ1
]
1
2
3
4
5
6
7
8
MeOH
EtOH
n-PrOH
n-BuOH
CH2(OCH3)CH2OH
CF3CH2OH
i-PrOH
i-BuOH
i-BuOH
99
99
84
85
95
73
94
91
92
10
94
100
99
65
64
52
48
61
26
63
49
57
3
8.5 (9)[b]
10
11
12
10
12
12
13
13
–
97
92[c]
100
55
100
84[c]
97[c]
40[c]
67
d
9
10
11
t-BuOH
1,2-Propanediol
41
9 (4[e]
)
Standard reaction conditions: 10 mL CH3OH, 3.6 mmol 2,3-dihydro-4H-pyran, 4 mmol NH4Br, 3,6 mM WO24ꢀ on Takovite
(80 mg), 1.7 equivs. H2O2 (aqueous 35 wt%) in portions of 0.22 mmol every 1.5 minutes, ambient conditions , 1000 rpm stirring.
[a]
Stereochemistry: molar ratio of trans/cis isomer calculated based on the GC areas.
Molar ratio calculated based on H NMR.
NH4Br not completely solubilized.
2.0 equivs. instead of 1.7 equivs. H2O2 (aqueous 35 wt %).
Regiochemistry: ratio of the 2-OH-n-propoxy vs. 2-OH-isopropoxy ethers.
[b]
[c]
[d]
[e]
1
amount of ammonium bromide, such as for methanol,
ethanol and isopropyl alcohol (entries 1–2, 7). The lim-
ited solubility of the bromide salt is the reason for the
moderate conversions obtained in n-butanol and isobu-
tyl alcohol (entries 4 and 8). As incomplete conversions
were anticipated, more oxidant was added to drive the
reactions to completion without losing selectivity (com-
pare entry 8 with 9). In this way, the 3-bromo-2-i-butoxy
ether is synthesized with 92% selectivity at 89% yield.
Apart from brominated ethers, some bromohydrins
are formed. Hence, despite their low concentration, wa-
ter molecules may act as competitive nucleophiles, espe-
cially when the bromination is carried out in the pres-
Scheme 3.
dary and tertiary alcohols. Whereas tertiary alcohols are ence of sterically encumbered alcohols (compare entries
difficult to introduce in the final product (entry 10), the 1 and 2 with 7 and 8). When a primary and secondary al-
reactions proceed remarkably well with the other alco- cohol are present in the same molecule such as in 1,2-
hols as long as these alcohols solubilize an appropriate propanediol, the 3-bromo ether derived from the pri-
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Halohydrins, for instance, are easily dehalogenated or
transformed, e.g., into the epoxides, the stereoselectivity
of which is highly dependent on the dehydrohalogena-
tion procedure applied.[8f] As an example, the dehydro-
halogenation of glucal iodohydrin with NaH in THF at
58C selectively leads to the b-epoxide. Note that the
stereoisomeric a-epoxide is typically formed via direct
epoxidation procedures.[9]
As can be seen from Table 4, the W-catalyzed oxida-
tive halogenation method appears to be quite general
for the production of 3-iodo- and 3-bromo-2-hydroxy-
lated and alkoxylated cyclic ethers 8–41. The addition
to the cyclic enol ethers clearly occurs completely regio-
selectively in a Markovnikov fashion. This regiocontrol
of the halonium attack on the b-carbon has been ration-
alized by the stabilizing effect of the oxygen atom.
Steric effects play an important role in the stereo-
chemistry of the products. As can be extracted from Ta-
ble 3, formation of the cis isomer appears to be more
pronounced in the case of smaller alcohol nucleophiles.
For instance, in the reaction with DHP in methanol, the
trans to cis molar ratio of the 2-methoxy-3-bromo prod-
ucts 10 and 11 is 8.5, whereas it is 13 when the nucleo-
Figure 1. Filtrate test for the bromoethoxylation of DHP in
ethanol. Reaction conditions of Table 2.
mary alcohol is preferably formed (entry 11). Ethanol phile is isobutyl alcohol (entries 1 and 8, Table 3).
captures the bromonium intermediate more efficiently Substituents on the substrate direct the stereoselectiv-
than trifluoroethanol (entry 6). Here, the low nucleophi- ity more strongly than the nature of the alcoholic nucle-
licity of trifluoroethanol likely results in a slow reaction ophile. In the bromomethoxylation of 2-methoxy-3,4-di-
with the bromonium intermediate.
hydro-2H-pyran 2, for instance, a considerable amount
Whereas a wide variety of solvent nucleophiles can be of cis product 15 was analyzed, whereas the cis isomer
incorporated in the product, several attempts to intro- is only a minor by-product for the unsubstituted pyran
duce Clꢀ, Fꢀ, or N3ꢀ in the final product by means of ad- (compare entry 5 with entry 2, Table 4). A similar cis:
dition of their respective ammonium or sodium salts trans isomer distribution of 2:3 was found earlier by
failed.
Duggan and Hall using t-butyl hypobromite in metha-
In order to demonstrate the stabilityof the catalyst, re- nol.[2c] The crucial factor in the substituent-dependent
actions were subjected to the classic filtrate tests (Fig- stereocontrol is the favourable axial orientation of the
ure 1). For instance, in the case of the bromoethoxyla- 6-methoxy group as a result of the anomeric stabilizing
tion of DHP, a first experiment was performed accord- effect. So, while the nucleophilic attack of the alcohol
ing to the standard procedure (see entry 1, Table 2) ex- is normally trans to the halide in the absence of steric
cept that only 88 mM H2O2 were added instead of hindrance, the formation of the cis product becomes
154 mM. Analysis of the reaction mixture shows a 3-bro- more competitive when an axial substituent is located
mo-2-ethoxylated ether yield of 68%. Subsequently, the at the 6 position as a consequence of a 1,3-diaxial con-
solid catalyst was removed by centrifugation and the straint in the molecule.
centrifugate was contacted 3 times with 22 mM H2O2 ev-
The product stereochemistry is not only directed by
ery 2.5 minutes. Analysis of the reaction solution re- steric factors but also by the nature of the activated hal-
vealed that no active tungsten was found as the yield ide. In the iodination, the stereochemistry of addition is
of the bromoethoxylated product was unaltered. More- almost exclusively trans. However, when the electro-
over, when the removed catalyst was reused in the clas- phile is Br-based, the stereochemistry remains predom-
sic conditions of entry 1 (run 2), similar results were ob- inantly trans, but with considerable cis formation (com-
tained as with a fresh catalyst (run 1) pointing to a real pare entry 2 with 4, entry 8 with 10). This halide-depend-
recyclability of the catalyst.
ent stereochemistry agrees well with earlier work on hal-
In order to explore the scope of the reactions several oalkoxylation of dihydropyrans and has been rational-
substituted and non-substituted cyclic enol ethers (1– ized in terms of either a bridged halonium with the
7) were selected including the glycals 6a, 6b and 7 (Ta- charge located at the halide or a carbocation-like inter-
ble 4). Halogenation forms one of the major routes to- mediate bearing the charge at the carbon atom.[1c,2g,10] In
ward the stereoselective functionalization of glycals the iodonium case, only the bridged intermediate is
and is reported in literature with N-bromoacetamide, formed giving trans addition almost exclusively. In the
N-bromosuccinimide, N-iodosuccinimide and Br2.[8] bromination the intermediate bridged cation is not as
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stable as with I; some carbocation is formed which af-
fords the cis next to the trans isomer.
The higher reactivity of benzylated than acetylated
glycals is consistent with the electron-donating and elec-
tron-withdrawing characters of the respective protect-
ing groups. The particular role of the C-6 substituent
has been discussed previously[8b] in the context of studies
on the bromination of benzylated or acetylated glycals,
with the postulate that interaction of this with the non-
bonding electron pairs on the ring oxygen will affect
their stabilizing role on the intermediate carbocation
Which of these intermediates are formed, is also at C-1.
strongly related to the nature of the solvent. While the
When the reactions were carried out in acetonitrile,
haloalkoxylation in alcohols mainly gives trans product, bromo- or iodohydrins were formed in excellent yields
the halohydroxylation in water yields about an equimo- (entries 13, 15 and 17). In all cases the manno-products
lar stereoisomeric mixture of cis and trans products (en- predominated, i.e., those resulting from top- or b-face
tries 1 and 3). So, probably due to its better ion solvation addition of the halogen. This selectivity was lowest in
power, water exerts a stabilizing effect on the carboca- the case of benzylated galactal (entry 17), reflecting
tion intermediate leading to an almost equimolar isomer the influence of the pseudo-axial C-4 substituent which
production. By comparison of entry 1 with 3, it is clear presumably alters the conformation of the dihydropyran
that the stabilizing effect of the solvent on the intermedi- ring and the orientation of its dipole, thereby influencing
ate states exceeds the influence of the halide.
the preferred face of attack of the electrophile. With the
The stereochemical outcome of the haloethoxylation limited data available it is not possible to draw firm con-
of 2-methyl-4,5-dihydrofuran 4 and 2,3-dihydrofuran 5 clusions on the effects of protecting groups on the selec-
in ethanol supports the hypothesis of the existence of tivity in that the reactions of the acetylated glucals were
two intermediate states. According to the theory, one carried out at higher temperatures. However, in forma-
would expect a larger amount of cis isomer in the case tion of bromohydrins (products 31 and 35) from benzy-
of the substituted furan due to the electron-donating ef- lated and acetylated glucals, respectively, the manno:
fect of the methyl substituent at position 2. The predict- gluco ratio changes from 6:3 to 8:1, and the trans:cis ra-
ed stereochemistry is indeed reflected in the catalytic tio from 5:4 to 6:3. The selectivity towards the manno-
data showing a cis:trans ratio of 1:7 for the substituted configuration is most marked in the reactions using
dihydrofurans 22 and 23, where it is 1:25 for the unsub- NH4I (entry 13, products 32) with a manno:gluco ratio
stituted dihydrofuran 5 (compare entry 8 with 12).
of 14:1, and a surprisingly high ratio (8:6) of cis:trans.
Whereas the halogenation of 2-methyl-4,5-dihydro- This suggests that following the favoured b-face addi-
furan predominantly yields cyclic 3-halo-2-alkoxy com- tion of the iodonium ion, the oxocarbenium ion is
pounds when performed in alcohol, ring opening ap- strongly stabilized with assistance from the electron-do-
pears to be a major pathway in water giving the open- nating benzyl protecting group on C-6.
chain a-halo-w-hydroxy ketones 21 and 24 as the ulti-
When reactions were carried out in the polar, nucleo-
mate product (entries 7 and 9). In the case of the iodohy- philic solvent methanol, the methyl-2-deoxy-2-halo gly-
droxylation, the linear a-iodo-methyl ketone 24 was an- cosides were obtained in good to excellent yields (en-
alyzed as the sole product, whereas the cyclic bromohy- tries 14, 16 and 18), even in the case of the less reactive
droxy ethers 19 and 20 appear to be more stable in the acetylated glucal (entry 16). The reactions of benzylated
bromohydroxylation conditions. A 2:3 molar mixture or acetylated glucal using NH4I (entry 14, products 34
of bromohydrins (19 and 20) and bromomethyl ketone and entry 16, products 38) were highly stereoselective,
21 was analyzed by 1H NMR directly after full conver- yielding predominantly the a-mannosides.
sion of the methylfuran.
In all of the reactions involving glycals it was establish-
The methodology was successfully extended to the ed that reaction did not take place or took place very
halofunctionalization of protected glycals, which pro- slowly in the absence of the WO24ꢀ exchanged takovite.
ceeded in most cases in high yield and with some syn-
thetically useful stereoselectivities (Table 4, entries
13–18). The stereochemical outcomes were consistent Conclusions
with results reported for other methods,[12] and were de-
pendent to some extent on the halide used, the solvent To conclude, we have demonstrated that halohydrins
and the presence of ether or ester protecting groups, and halo ethers can be generated from cyclic enol ethers
while the latter factor had a significant effect on the via the oxidative halogenation with commercial hydro-
rate of reaction. Reactions of benzylated glucal or galac- gen peroxide in the presence of a WO24ꢀ exchanged syn-
tal proceeded to completion within 1.5 h at ambient thetic takovite under mild conditions. To the best of our
temperatures while acetylated glucal required 2.5–5 h knowledge, this is the first report on oxidative halogen-
at 608C, and in some cases did not go to completion.
ation of this type of molecules including the anhydro
102
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asc.wiley-vch.de
Adv. Synth. Catal. 2005, 347, 93–104

Oxidative Halogenation of Cyclic Enol Ethers
FULL PAPERS
(300 MHz): dC ¼99.3(C-2), 59.5(C-6), 55.8(C-8), 49.4(C-3),
sugars using a stable and easily recyclable solid catalyst.
Current efforts are focussed on the continued examina-
tion of these stereoselective reactions as well as on their
application in the synthesis of glycoconjugates and oli-
gosaccharides.
29.5(C-4), 27.0(C-5).
Typical Procedure for the Oxidative
Methoxyhalogenation of Glycals using WO24ꢀ-TV
Method (a): Benzylated glucal or galactal: To a mixture of
WO24ꢀ-TV (4 mg, 0.002 mmol W) and benzylated glycal 6a or
7 (100 mg, 0.24 mmol) in acetonitrile or methanol (3–5 mL)
containing ammonium bromide or ammonium iodide (1.5–6
equivs.) at room temperature, was added hydrogen peroxide
in portions of 0.22 mmol (or 20 mL of 35% aqueous solution)
every 5 minutes until complete conversion as judged by TLC.
The catalyst was then removed by filtration or centrifugation
and the filtrate partitioned between ice-water and diethyl
ether. The organic layer was separated, washed with water
and dried over MgSO4. After recording 1H and 13C NMR spec-
tra of the mixture of isomers these were separated on a column
of silica, eluting with mixtures of ethyl acetate and hexane.
Method (b): Acetylated glucal: To a mixture of WO24ꢀ-TV
(4 mg, 0,002 mmol W) and benzylated glycal 6b (100 mg,
0.368 mmol) in acetonitrile or methanol (3–5 mL) containing
ammonium bromide or ammonium iodide (1.5–6 equivs.) at
608C, was added hydrogen peroxide in portions of 0.22 mmol
(or 20 mL of 35% aqueous solution) every 5 minutes until com-
plete conversion as judged by TLC. The catalyst was then re-
moved by filtration or centrifugation and the filtrate parti-
tioned between ice-water and diethyl ether. The organic layer
was separated, washed with water and dried over MgSO4. After
recording 1H and 13C NMR spectra of the mixture of isomers
these were separated on a column of silica, eluting with mix-
tures of ethyl acetate and hexane.
Experimental Section
Preparation of the Tungstate-Exchanged Takovite
(WO24ꢀ-TV)
The synthetic takovite mineral with the formula
ꢀ
Ni0.63Al0.37(OH)2(NO3
)0.37 ·0.69 H2O wasprepared bythe con-
trolled hydrolysis of the Ni and Al nitrate salts in carbonate-
free conditions according to published procedures.[11] The salt
solutions were purged with N2 to avoid uptake of carbonate
by the precipitates. Under vigorous stirring, 120 mL of both
solutions were combined slowly in an N2 atmosphere at room
temperature at a rate of 60 mL·minꢀ1, while the pH was
kept constant at 8.5 by addition of NaOH (1 M). After addi-
tional stirring for 12 hours at the same temperature, the suspen-
sion was centrifuged and washed with deionized water in 3 cy-
cles, shock-frozen in liquid nitrogen and freeze-dried. For the
anion exchange of tungstate, air-dry takovite (1.5 g) was sus-
pended in an aqueous solution of Na2WO4 ·2 H2O (150 mL,
5 mM) at room temperature for 12 h under N2. The final
WO24ꢀ-TV catalyst was washed and dried as before.
Typical Procedure for the Oxidative
Methoxybromination of Cyclic Vinyl Ethers using
WO24ꢀ-TV
Acknowledgements
To a mixture of WO24ꢀ-TV (80 mg, 0.04 mmol W) and 3,4-dihy-
dro-2H-pyran (1; 0.3 g) in methanol containing ammonium
bromide (10 mL, 0.4 M) at room temperature, was added in
portions of 0.22 mmol hydrogen peroxide (or 20 mL of 35%
aqueous solution) every 2.5 minutes until complete conversion
of 1. The catalyst was then removed by filtration or centrifuga-
tion and the filtrate partitioned between ice-water and diethyl
ether. The organic layer was separated, washed with water and
dried over MgSO4. After sampling the dried solution for GC
and GC-MS analysis, the solvent was removed under vacuum
affording 0.65 g of a pale yellow oil, which was found to be a
The authors thank FWO-Vlaanderen (BFS) for a post-doctoral
fellowship, and Helen Schevernels for skilful technical assis-
tance. This work was performed in the frame of the IAP pro-
gram “Supramolecular Chemistry and Catalysis” of the Belgian
Federal government. This research is supported by the National
Foundation (South Africa) and the Flemish Government (Bilat-
eral Scientific Cooperation, BIL 02/37).
1
more or less pure mixture of cis and trans isomers by H and
References and Notes
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