Re2O7-catalyzed reaction of hemiacetals and aldehydes with O-, S-, and C-nucleophiles

Article abstract of DOI:10.3762/bjoc.9.174

Re(VII) oxides catalyze the acetalization, monoperoxyacetalization, monothioacetalization and allylation of hemiacetals. The reactions, which take place under mild conditions and at low catalyst loadings, can be conducted using hemiacetals, the corresponding O-silyl ethers, and, in some cases, the acetal dimers. Aldehydes react under similar conditions to furnish good yields of dithioacetals. Reactions of hemiacetals with nitrogen nucleophiles are unsuccessful. 1,2-Dioxolan-3-ols (peroxyhemiacetals) undergo Re(VII)-promoted etherification but not allylation. Hydroperoxyacetals (1-alkoxyhydroperoxides) undergo selective exchange of the alkoxide group in the presence of either Re₂O₇ or a Bronsted acid.

Full text of DOI:10.3762/bjoc.9.174

Re2O7-catalyzed reaction of hemiacetals and
aldehydes with O-, S-, and C-nucleophiles
Wantanee Sittiwong, Michael W. Richardson, Charles E. Schiaffo,
Thomas J. Fisher and Patrick H. Dussault*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2013, 9, 1526–1532.
Department of Chemistry, University of Nebraska-Lincoln, Lincoln, NE
68588-0304, USA
doi:10.3762/bjoc.9.174
Received: 09 May 2013
Accepted: 08 July 2013
Published: 30 July 2013
Email:
Patrick H. Dussault* - pdussault1@unl.edu
* Corresponding author
Associate Editor: M. Rueping
Keywords:
© 2013 Sittiwong et al; licensee Beilstein-Institut.
License and terms: see end of document.
allylation; hemiacetal; O,O-acetal; O,S-thioacetal; peroxyacetal;
Re2O7; S,S-acetal
Abstract
Re(VII) oxides catalyze the acetalization, monoperoxyacetalization, monothioacetalization and allylation of hemiacetals. The
reactions, which take place under mild conditions and at low catalyst loadings, can be conducted using hemiacetals, the corres-
ponding O-silyl ethers, and, in some cases, the acetal dimers. Aldehydes react under similar conditions to furnish good yields of
dithioacetals. Reactions of hemiacetals with nitrogen nucleophiles are unsuccessful. 1,2-Dioxolan-3-ols (peroxyhemiacetals)
undergo Re(VII)-promoted etherification but not allylation. Hydroperoxyacetals (1-alkoxyhydroperoxides) undergo selective
exchange of the alkoxide group in the presence of either Re2O7 or a Brønsted acid.
Introduction
The synthetically important conversions of hemiacetals to synthesis of homoallylated amines from condensation of car-
acetals, thioacetals, or homoallyl ethers are typically achieved bonyl groups with an electron-poor amine in the presence of
through activation of the substrate with a strong Brønsted or allyltrimethylsilane [15]. We now describe the Re2O7-promoted
Lewis acid, or by conversion to an activated intermediate such reactions of peroxyhemiacetals, hemiacetals, and alkoxyhy-
as a haloacetal [1]. Perrhenates, best known as catalysts for droperoxides with O-, S- and C-nucleophiles.
large-scale alkene metathesis [2] and isomerization of allylic
alcohols [3-10], have been shown to promote condensation of Results
carbonyls with hydrogen peroxide or hydroperoxides [11,12], In the course of investigations into potential antischistosomal
intramolecular displacements of reversibly formed hemiacetals and antimalarial agents [16,17], we needed to prepare a number
and allylic alcohols [8,13], displacement of resonance-activated of 3-alkoxy-1,2-dioxolanes. Brønsted acid-promoted etherifica-
alcohols with electron-poor nitrogen nucleophiles [14], and a tion of hemiacetals (1,2-dioxolan-3-ols) required harsh condi-
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tions and proceeded in good yields only for unhindered alco- reactions were subsequently found to proceed efficiently at only
hols [18]. We were curious whether Re2O7, a catalyst known to 1% catalyst loading. Neither catalyst allowed etherification with
activate alcohols via a reversibly formed Re(VII) ester [19,20], a tertiary alcohol.
would enable displacement under milder conditions, potentially
allowing access to a broader range of alkoxydioxolanes. As Acetal formation
shown in Table 1, the use of Re2O7 or p-toluenesulfonic acid As illustrated in Table 2, we next investigated acetalization of
monohydrate (PTSA) as catalysts provided comparable yields tetrahydrofuranol 3, tetrahydropyranol 4a and the O-t-butyl-
in the etherification of dioxolanol 1a or the corresponding dimethylsilyl ether of the latter (4b). While good yields of
O-trimethylsilyl ether 1b with an unhindered alcohol, although acetals were obtained from the reaction with primary or second-
the perrhenate-catalyzed reaction proceeded much more rapidly. ary alcohols, or t-butyl hydroperoxide, acetalization with phenol
In the case of a neopentyl alcohol nucleophile, the perrhenate- proceeded in poor yield. Attempted acetalizations of 2,3,4,6-
catalyzed process was clearly superior, proceeding more rapidly tetrabenzylglucose, the corresponding tetraacetate, or their 1-O-
and furnishing a higher yield of acetal. The Re2O7-promoted silyl derivatives, were unsuccessful (not shown).
Table 1: Acetalization of hydroxy- and silyloxydioxolanes.
R
substrate
product
catalyst (equiv)
Re2O7 (0.1)
PTSA (0.1)
Re2O7 (0.01)
yield (reaction time)
1a
1b
1a
1a
1b
2a
2a
2b
—
—
73% (3 h)
75% (1 h)
—
83% (1 h)
81% (2 h)
78% (2 h)
0%
Ph(CH2)2
1-AdCH2a
Ada
—
33% (12 h)
74% (1 h)
0%
0%
—
—
0%
aAd = adamantyl.
Table 2: Transetherification of hemiacetals.
substrate
n
X
R
equiv
product
yielda
3
1
1
2
2
2
2
2
2
OH
Ph(CH2)2
2
2
5
2
2
2
2
1
5
83%
3
OH
t-BuO (t-BuOOH)
Ph(CH2)2
Ph(CH2)2
t-BuO
6
68–77%
89%
4a
4b
4a
4a
4a
4b
OH
7
OTBS
OH
7
82%
8
71–80%
70–90%
7%
OH
2-octyl
9
OH
Ph
10
10
OTBS
Ph
44%b
aDuplicate values; range given in case of variance. bIncludes some inseparable impurities.
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Resubmission of purified acetal 7 to typical reaction conditions In fact, the reaction of phenethyl alcohol (1.0 equiv) with only
in the presence of a slight excess of water did not result in the 0.5 equivalent of the oxybisacetal dimer proceeded rapidly to
reformation of 4a. However, we did observe rapid transacetali- furnish high yields of 7 (not shown).
zation when 7 was resubmitted to reaction conditions in the
presence of methanol (Scheme 1).
Monothioacetal formation
We next turned our attention to the synthesis of monothio-
After TLC monitoring of reactions revealed the build-up of an acetals, a functionality important for carbonyl protection and as
unknown intermediate, we conducted control reactions in the a precursor for oxycarbenium ions [21,22]. As illustrated in
absence of a nucleophile. These revealed a rapid Re2O7- Table 5, tetrahydrofuranol and tetrahydropyranol both undergo
promoted condensation of the hemiacetals to dimeric oxybis- condensation with a simple thiol in the presence of Re2O7 to
acetals (Table 3). As will be described later, these apparent provide the monothioacetal in good yield; only traces of the S,S-
byproducts proved to be competent substrates for acetal forma- dithioacetal were observed. The same reaction, when catalyzed
tion.
by a Brønsted acid, required a higher catalyst loading and
provided a lower yield of product accompanied by a greater
We next attempted to maximize the yield of acetal based upon amount of dithioacetal. Re(VII)-promoted reaction with
alcohol (Table 4). Good yields were obtained at a 1:1 ratio of thioacetic acid proceeded in much lower yield.
alcohol to hemiacetal and yields did not vary significantly with
the rate of addition of hemiacetal. This latter observation was As illustrated in Scheme 2, Re2O7 also promotes the reaction of
initially surprising given the rapidity of hemiacetal dimeriza- an aldehyde with a thiol or a dithiol to furnish a dithioacetal or a
tion (vide supra). However, we soon realized that the bisacetal 1,3-dithiane. A ketone substrate did not react under these condi-
ether 11 (Table 4, entry 4) was a remarkably effective substrate. tions (not shown).
Scheme 1: Transacetalization of acetal 7.
Table 3: Dimerization of hemiacetals.
entry
X
n
reaction time (h) conditionsa
bisacetal (%)
aldehyde (%)
1
2
3
4
5
6
7
4a
4a
4a
4a
3
2
2
2
2
1
2
2
0.1
0.1
0.5
2
a
11 (57%)
11 (59%)
11 (12%)
NR
12 (5%)
12 (3%)
trace
b
a,d
a,e
a
NR
0.1
0.1
0.5
13 (37%)
11 (30%)
11 (62%)
14 (28%)
12 (2%)
12 (4%)
4a
4a
a
c
aa:1% Re2O7; b: 2% Re2O7; c:10% PTSA; d: with 3 Å mol sieves (powdered); e: with 4 Å mol sieves (powdered).
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Beilstein J. Org. Chem. 2013, 9, 1526–1532.
Table 4: Optimization of acetalization conditions.
entry
substrate rate of 4a addition (equiv/min)
reaction time (h)
additives
7 (%)
1
2
3
4
5
6
7
4a
4a
4a
11
4a
4a
4a
0.1
1
—
—
—
—
—
93
94
87
87
89
0.04
1
0.01
2
all at once
all at once
0.02
0.5
1
1
3 Å mol sieves (powder)
4 Å mol sieves (powder)
NR
NR
0.02
2
Table 5: Synthesis of monothioacetals.
substrate
catalyst
n
R
acetals
O,S (%)
S,S (%)
3
Re2O7
Re2O7
Re2O7
PTSA
1
2
2
2
pentyl
pentyl
acetyl
pentyl
15 (71–80%)
16 (78–88%)
18 (10%)
(traces)
17 (2%)
—
4a
4a
4a
16 (62%)
17 (8%)
Scheme 2: Thioacetalization of hexanal with Re2O7.
The mono- and dithioacetalization reactions were visibly gradually becomes translucent but remains very dark (Figure
different from the O-acetalizations described above. Whereas S2, Supporting Information File 1).
addition of Re2O7 to a hemiacetal in the presence of an alcohol
generates a transparent light yellow solution (Figure S1, Attempted reaction with nitrogen nucleophiles
Supporting Information File 1), addition of thiol to a mixture of Perrhenate proved ineffective for catalyzing the formation of
Re2O7 and hemiacetal produces an opaque, black, solution that N,O-acetals (Table 6). Although these investigations were
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Beilstein J. Org. Chem. 2013, 9, 1526–1532.
complicated by the limited solubility of some of the nucleo-
philes in dichloromethane, similar results were obtained in
acetonitrile, where solubility was less of an issue.
Table 7: Allylation of hemiacetals.
Table 6: Attempted synthesis of N,O-acetals.
substrate
product
NR
yield
NR
1a
substrate
Nu
X
product
(yield)
3
33%b
23a
4a
benzamide
benzamide
acetamide
BzNH
BzNH
AcNH
21 (10%)
4b
—
—
—
—
4a
11
41%b
53%c
4a or 4b
4a or 4b
4a or 4b
24a
24a
benzylamine BnNH
morpholine morpholino
90%c
The poor results with N-nucleophiles led us to reinvestigate a
proven reaction in the presence of amines. The previously
successful condensation of 4a with phenethyl alcohol (see
Table 2) failed completely in the presence of added morpholine
or pyridine (not shown).
22
25
aVolatile product. bIsolated yield. cGC yield (toluene standard).
Allylation of hemiacetals
Transetherification of hydroperoxyacetals
Re2O7 has been successfully applied to intramolecular Prins We were curious about the interactions of Re(VII) oxides with
reactions of alkenes with reversibly generated hemiacetals [13], hydroperoxyacetals (1-alkoxyhydroperoxides), versatile
and we were curious about the potential for applications to intermediates available from ozonolysis of alkenes in
intermolecular allylations. As illustrated in Table 7, tetra- alcoholic solvents [23,24]. As can be seen in Table 8, Re2O7,
hydrofuranol 3, tetrahydropyranol 4a, bisacetal 11, and Me3SiOReO3 and PTSA all catalyze alkoxide metathesis to
oxadadamantyl hemiacetal 22 all underwent allylation in the furnish a moderate yield of a new hydroperoxyacetal. The
presence of stoichiometric allyltrimethylsilane and 1% of exchange reaction was observed in several solvents (e.g.,
Re2O7. The isolated yields of 23 and 24 may be artificially low CH2Cl2, 1,2-dichloroethane) but was most efficient in acetoni-
due to product volatility. Peroxyhemiacetal (dioxolanol 1a) trile. The alkoxide exchange was accompanied by much slower
failed to react under these conditions.
exchange of the peroxide; for example, prolonged reaction
Table 8: Alkoxide exchange within hydroperoxyacetals.
substrate
R1
R2
catalyst
reaction time (h) product
yield
26
26
26
27
26
28
Me
Me
Me
Et
Et
Re2O7
2
27
41%
41%
40%
43%
—
Et
Me3SiOReO3
PTSA
2
27
Et
5
27
Me
iPr
Me
Re2O7
2
26
Me
iPr
Re2O7
2–48
0.5
mixtures
26
Re2O7
42%
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Beilstein J. Org. Chem. 2013, 9, 1526–1532.
(>24 h) of acetal 26 in MeOH (solvent) in the presence of The results with peroxyhemiacetals are consistent with the
catalytic Re(VII) furnished a 40% yield of the dimethyl acetal known reactivity of bisperoxyacetals [26]. The hydroperoxy-
(not shown).
acetals showed no sign of electrophilic activation of the
hydroperoxide (which would presumably lead to heterolytic
fragmentation) and activation of the peroxide C–O was clearly
Discussion
All the reactions described appear to involve the intermediacy disfavored relative to activation of the alkoxide C–O bond.
of perrhenate esters. Previous investigators have hypothesized Rapid alkoxide metathesis was also observed in the presence of
that the barrier for Re2O7-promoted C–O ionization of a strong Brønsted acid. Our observations suggest that the
hemiacetals is relatively low [13]. The differences in reactivity seeming lack of reactivity of ozonolysis-derived 1-methoxyhy-
between hemiacetals of cyclic ethers (displaced by alcohols and droperoxides towards methanolic acid may mask a rapid degen-
allyltrimethylsilane) and those of cyclic peroxides (reactive erate exchange [27].
only towards alcohols) demonstrates that the extent of acti-
vation is dependent on the nature of the substrate, and that The failure of the perrhenate to catalyze formation of N,O-
different levels of activation are required for trapping by acetals was initially perplexing. However, reported perrhenate-
heteroatom versus carbon nucleophiles. Previous work estab- promoted dehydrations of amides and oximes require relatively
lished that the perrhenate-catalyzed isomerization of alcohols high temperatures [28-30]. Our results suggest that amines and
can also employ silyl ethers as substrates [25], and our work amides actively suppress the ability of Re(VII)-oxides to acti-
demonstrates that the same is true for the hemiacetals investi- vate alcohols. We note, however, a recent report by Ghorai
gated here. However, our work also demonstrates that oxybis- describing the allylation of iminium ions generated from alde-
acetals (for example, bis 2-tetrahydropyranyl ether) are highly hydes and sulfonamides in the presence of Re2O7 [15].
effective substrates for the Re-catalyzed processes.
Conclusion
The results are in keeping with the formation of perrhenate Perrhenates hold broad potential as catalysts for electrophilic
esters which can undergo displacement by nucleophiles. Our activation of hemiacetals. The ability to catalyze formation of
results suggest that in the case of etherifications with alcohols, O,O-, O,S-, and S,S-acetals under very mild conditions offers a
the intermediates can sometimes be regenerated from the prod- useful complement to traditional Brønsted acid catalysts.
uct acetals. Moreover, our results clearly demonstrate that
Re2O7 reversibly dimerizes hemiacetals in a reaction that is
Supporting Information
sufficiently rapid that it is possible that the oxybisacetal dimers
may be the predominant precursors of the perrhenate intermedi-
Experimental details and detailed information, including
ates and therefore the reaction products (Scheme 3).
references and spectral listings related to prepared
molecules, are provided in Supporting Information File 1.
Supporting Information File 1
Experimental details.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-9-174-S1.pdf]
Acknowledgements
Research was conducted with funding from the NSF (CHE-
1057982) in facilities remodeled with support from the NIH
(RR016544).
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