Access to Functionalized 3,5-Disubstituted 1,2-Dioxolanes under Mild Conditions through Indium(III) Chloride/Trimethylsilyl Chloride or Scandium(III) Triflate Catalysis

Article abstract of DOI:10.1002/adsc.201901145

Herein we report the use of catalytic amount of scandium(III) triflate or indium(III) chloride (with trimethylsilyl chloride) for the functionalization of endoperoxyacetals through Sakurai or Mukaiyama reactions. These catalysts allow milder and more practical conditions than those previously reported with improvements in scope and reproducibility. This method allows a full catalytic sequence from cyclopropanols to produce desired functionalized 1,2-dioxolanes. (Figure presented.).

Full text of DOI:10.1002/adsc.201901145

Title: Access to Functionalized 3,5-Disubstituted 1,2-Dioxolanes
under Mild Conditions through Indium(III) Chloride/Trimethylsilyl
Chloride or Scandium(III) Triflate Catalysis
Authors: Alexis Pinet, Bruno Figadère, and Laurent Ferrié
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201901145
Link to VoR: http://dx.doi.org/10.1002/adsc.201901145

10.1002/adsc.201901145
Advanced Synthesis & Catalysis
UPDATE
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Access to Functionalized 3,5-Disubstituted 1,2-Dioxolanes under
Mild Conditions through Indium(III) Chloride/Trimethylsilyl
Chloride or Scandium(III) Triflate Catalysis
Alexis Pineta, Bruno Figadèrea and Laurent Ferrié*a
a
BioCIS, Université Paris-Sud, CNRS, Université Paris-Saclay, Châtenay-Malabry 92290, France
E-mail : laurent.ferrie@u-psud.fr
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
stoichiometry can lead to more degradation products
(if in excess) or a worse conversion in desired
product (if in deficiency), which gives sometimes
difficulties to reproduce the experiments.[3] Thus, the
utilization of a mild Lewis acid under catalytic
amount at room temperature would be highly
desirable to circumvent the degradations products and
the utilization of sub-stoichiometric amount of Lewis
acid under low temperature conditions.
Abstract. Herein we report the use of catalytic amount of
scandium(III) triflate or indium(III) chloride (with
trimethylsilyl chloride) for the functionalization of
endoperoxyacetals through Sakurai or Mukaiyama
reactions. These catalysts allow milder and more practical
conditions than those previously reported with
improvements in scope and reproducibility. This method
allows a full catalytic sequence from cyclopropanols to
produce desired functionalized 1,2-dioxolanes.
Keywords: Peroxides; Peroxycarbenium; Acetal; Rare-
earths; Indium
Endoperoxides are a rich source of natural or
unnatural bioactive products, leading to the
development of important anti-malarial drugs such as
Artemisinin or Arterolane. We were involved these
last years in a scientific program towards the total
synthesis of mycangimycin, a fatty acid containing a
1,2-dioxolane pattern (Figure 1).[1][2]
Scheme 1. Previous work about the synthesis of
disubstituted 1,2-dioxolanes.
Figure 1. Artemisinin, Arterolan and Mycangimycin.
In order to prepare the dioxolanyl acetate, we
transformed some cyclopropanols 1a-g (obtained
either from Kulinkovich reaction[5] or chromium (II)
mediated cyclization of β-methylene aldehydes[6])
with two catalytic transformations. Firstly
cyclopropanols 1a-g were oxidized to peroxy-
hemiacetals 2a-g through the formation of a hydroxyl
radical mediated by Mn(acac)3, followed by
cyclopropyl opening and trapping of intermediate
radical with triplet oxygen.[7] Peroxy-hemiacetals 2a-
g were then acetylated with acetic anhydride in the
presence of 10 mol% of Yb(OTf)3 to give
acetoxyendoperoxyacetals 3a-g in overall good yields
(Scheme 2). Noteworthy is that only 0.5 mol% of
Yb(OTf)3 was found, more recently, to be enough for
the transformation. The use of a Lewis acid catalysed
Thereafter, we described a methodology[3] to build
disubstituted 1,2-dioxolanes through Lewis acid
activation of 1,2-dioxolanyl acetates with TiCl4 or
SnCl4 at low temperature. The corresponding
peroxycarbenium species[4] was then trapped with a
neutral nucleophile such as an allylsilane or silyl enol
ether. We also highlighted the fact that the 1,2-
dioxolane moiety undergoes two paths of
degradation/rearrangement due to activation by
strong Lewis acids (mainly TiCl4), leading to lower
yields but often higher diastereoselectivities.[3]
Moreover, this methodology tends to be difficult to
control since a slight modification of the Lewis acid
1
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10.1002/adsc.201901145
Advanced Synthesis & Catalysis
acetylation[8] was crucial to the success of this
transformation since organic peroxides are reacting
with amines, which are used in more common
protocols. Both reactions are safe and multi-gram
scalable and require low amounts of inexpensive
catalysts.
6
InCl3/TMSCl 0.005/2
13 h
64%
80:20
[a] Isolated yield.
[b] Diastereomeric ratios were determined by 1H NMR.
In parallel to our studies of InCl3/TMSCl as a
potent mild Lewis acid system, rare-earth metal
triflates or more generally metallic triflate of type
“M(OTf)3” were also promising species since they
were reported in catalytic version of Mukaiyama
aldol reaction but also for Sakurai allylation.[10] Thus,
with these elements in hands, an investigation of
metallic triflate was also conducted on peroxyacetal
3a in a Sakurai reaction with allytrimethylsilane 5.
Post-transition metal triflates such as indium(III)
or bismuth(III) revealed to be poorly effective as
Lewis acid in our reaction (Table 2, entries 1 and 2).
In particular, bismuth(III) led to the formation of
many degradation products in a very short time, while
reactions employing In(OTf)3 proceeded slowly and
extended reaction times brought many side-products
without improving the yield of dioxolane 4a. Some
popular rare-earth metal triflates in catalysis were
also screened at 10% mol.[10a] Reaction employing
triflates of Yb(III), Y(III), and La(III) proceeded very
slowly (6-48 h) giving modest yields of compound
4a, resulting again in a bad conversion/ degradation
ratio (Table 2, entries 5,6 and 7). In contrast,
scandium(III) gave interesting results, comparable to
those obtained with InCl3/TMSCl (Table 2, entry 3).
Decreasing the amount of catalyst by half did not
modify the results (Table 2, entry 4). The improved
reactivity of Sc(OTf)3 towards other tested metal
rare-earth triflates is not surprising since Sc(OTf)3 is
known to possess a higher oxophilicity.[11]
Scheme 2. Synthesis of 1,2-dioxolanyl acetates 3a-g
Then,
our
attention
focused
on
the
functionalization of endoperoxyacetals 3a-g under
catalytic conditions. Considering the literature about
catalytic Sakurai reactions combining InCl3 and
TMSCl,[9] these reagents were chosen as a starting
point. In the Sakurai reaction between peroxyacetal
3a and allyl-trimethylsilane 5, InCl3 or TMSCl were
alone unable to catalyse the reaction (Table 1 entries
1 and 2). However, when the experiment was run
with 10 mol% of InCl3 and TMSCl (Table 1 entry 3),
we obtained expected product 4a in less than 30 min.
The amount of both TMSCl and InCl3 was then
reduced gradually until reaching 0.5 mol% of InCl3
(entry 6). The less the amount of InCl3 was used, the
more the reaction time increased, but this shows the
possibility to decrease sensibly the amount of catalyst
(entries 5 and 6). Optimal conditions were identified
for 5 mol% of InCl3 and 2.5 equivalent of TMSCl
(entry 4). This last result was comparable in term of
yield and diastereoselectivity with the use of sub-
stoechiometric amount of SnCl4 at –40 °C (81% vs
80% and 70:30 vs 65:35).[3]
Table 2. Sakurai reaction study with various metal (III)
triflates as catalyst on peroxyacetal 3a.
Stoichio-
Entry[a] Conditions metry
(equiv)
Reaction
Time
dr[b]
trans:cis
Yield[a]
Table 1. Sakurai reaction study with InCl3/TMSCl as
catalyst couple on peroxyacetal 3a.
1
2
3
4
5
6
7
Bi(OTf)3 0.1
In(OTf)3 0.1
Sc(OTf)3 0.1
Sc(OTf)3 0.05
Yb(OTf)3 0.1
30 min
60 min
30 min
30 min 78% 67:33
6 h
21% 80:20
31% 68:32
82% 67:33
49% 83:17
34% 86:14
31% 78:22
Y(OTf)3
0.1
48 h
19 h
Stoichio-
metry
(equiv)
Reaction
Time
dr[b]
trans:cis
La(OTf)3 0.1
Entry[a] Conditions
Yield[a]
[a] Isolated yield.
[b] Diastereomeric ratios were determined by 1H NMR.
1
2
3
4
5
InCl3
TMSCl
InCl3/TMSCl 0.1/5
InCl3/TMSCl 0.05/2.5
InCl3/TMSCl 0.01/2
0.1
5
3 h
3 h
n.r.
n.r.
/
/
25 min 63%
35 min 81% 67:33
3 h 61% 80:20
70:30
Because InCl3/TMSCl and Sc(OTf)3 exhibited
similar results in term of reaction time, catalyst
loading, diastereoselectivities and yields, we chose to
2
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10.1002/adsc.201901145
Advanced Synthesis & Catalysis
further study these two catalytic systems under the
optimized selected conditions (Table 1, entry 4 and
Table 2, entry 4). The influence of lateral chain R1 at
position 3 of 1,2-dioxolanyl acetates 3b-g was
investigated in the Sakurai reaction with allylTMS
(Table 3). InCl3/TMSCl and Sc(OTf)3 behaved
similarly to furnish 1,2-dioxolanes 4b-g, giving same
selectivity. Only some differences appeared on the
yield with sometimes a significant improvement with
InCl3/TMSCl compared to Sc(OTf)3 (Table 3, Entries
1 and 7).
When these results are compared to our previous
report involving SnCl4 or TiCl4 as Lewis acids,[3]
these two catalytic systems gave overall slightly
lower yields than sub-stoichiometric SnCl4 but it was
compensated by a higher selectivity toward trans
product.
giving dioxolane 18, but the yield was significantly
higher with Sc(OTf)3 (Table 4, entries 7-8).
Mukaiyama aldol reaction was also experienced
under our two selected conditions. Ketone derivatives
gave contrasted results; enol ether 10 from
acetophenone gave good conversion in compound 19,
in particular with Sc(OTf)3 (entry 10) but t-butyl
methyketone derivative 11 reacted sluggishly giving
poor yields (until 28 h) of t-butyl ketone 20 in both
cases (Table 4, entries 11-12); this poor yield could
be attributed to some steric hindrance in the
nucleophile. Silyl enol ether of esters and thioesters
proved to react similarly under the two tested
conditions affording ester 21, thioesters 22 and 23 in
nice yields (Table 4, entries 13-18). Thioesters 22
and 23 are particularly interesting, since some cross
coupling reactions could be applied [12] and because of
their ease of conversion into the corresponding
carboxylic acid. For example, we were able to
convert thioester 22 into the corresponding
carboxylic acid 24 with H2O2 and LiOH in aqueous
THF in 1h at rt in 99% yield.
Table 3. Sakurai reaction with InCl3/TMSCl or Sc(OTf)3
as catalysts on different substrates 3b-g.
Table 4. Addition of various nucleophiles to peroxyacetal
3a[a] under catalytic conditions.
[a] Reaction conditions: 3a (1 equiv.), InCl3/TMSCl (5/250
mol%) or Sc(OTf)3 (5 mol%), AllylTMS 5 (3 equiv.), 30-
60 min.
[b] Isolated yield.
[c] Diastereomeric ratios were determined by 1H NMR.
The nature of the nucleophile was also examined
on dioxolanyl acetate 3a for the two selected catalysts
(Table 4). Methyl allyltrimethylsilane 6 gave product
15 with similar results for both systems (Table 4,
entries 1-2), as well as TMS cyanide 7 and TMS
azide 8 (Table 4, entries 3-4 and 5-6), which
produced very efficiently compounds 16 and 17.
Triethylsilane 9 was able to reduce the acetal function
[a] Reaction conditions: 3a (1 equiv.), InCl3/TMSCl (5 /250
mol%) or Sc(OTf)3 (5 mol%), nucleophile 6-14 (3 equiv.),
30-60 min.
[b] Isolated yield.
3
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10.1002/adsc.201901145
Advanced Synthesis & Catalysis
[c] Diastereomeric ratios were determined by 1H NMR.
20h and 28h reaction time using respectively
InCl3/TMSCl and Sc(OTf)3.
To an ice-bath cooled solution of peroxy-hemiacetal 2a-g
(1 equiv.) in anhydride acetic (2 mL/mmol) was added
Yb(OTf)3 (10 mol%, but it can be lower to 0.5 mol% such
as with 3a; most rare-earth metal triflates are usable with
similar results in this reaction). Reaction was monitored by
TLC and when no starting material remains (usually 30
min-1 h) the reaction was quenched by pouring the
reaction mixture into a saturated solution of NaHCO3 at 0-
5 °C to be stirred 30 min at this temperature. The aqueous
phase was extracted with Et2O three times and organic
layer was washed with brine and dried over MgSO4.
Volatiles were removed under reduced pressure without
heating, and the residue was used in its state without
[d]
When these results are now compared to the sub-
stoichiometric utilization of SnCl4 as a Lewis acid,[3]
it can be observed that the yields were overall similar
and diastereoselectivities were slightly better towards
trans products by using the catalytic versions.
Nevertheless, there are some exceptions where strong
Lewis acids are superior, such as with t-butyl enol
ether 11, which seemed to react better with SnCl4 due
to higher reactivity of this later.[3] For the same
reason 1-bromo- and 1-chloro-trimethylsilanes were
completely inert by using our selected catalytic
systems due to a decreased nucleophilicity of these
allylsilanes. In contrast, InCl3/TMSCl and Sc(OTf)3
were far superior to SnCl4 (and TiCl4) in some cases.
TMSCN 7 and TMSN3 8 gave significant higher
yields with both catalytic systems. More importantly,
enol ether of ester 12 and thioesters 13 and 14 were
completely unreactive with SnCl4 and TiCl4, whereas
compounds 21, 22, 23 were very efficiently obtained
with the catalytic methods, expanding the initial
scope of our reaction.
In conclusion, we developed a new catalytic
protocol of functionalization for 1,2-dioxolanyl
acetates, identifying two efficient systems, namely
InCl3/TMSCl and Sc(OTf)3. Overall the use of
InCl3/TMSCl or Sc(OTf)3 over SnCl4 (and TiCl4) is
justified by simpler experimental procedures (room
temperature versus -40°C, inert powders versus
fumigating and hazardous reagents), atom economy
and improvement of diastereoselectivity. Although
some poorly reactive species such as deactivated
allylsilanes, and hindered nucleophiles work better
with SnCl4 and TiCl4, the two new catalytic systems
also enlarge the reagents scope to ester and thioester
enol ether derivatives, which makes complementary
the catalytic and the stoichiometric versions of the
studied transformation.
further purification in case of good purity.
When
necessary, the residue could be purified on a silica gel flash
column chromatography.
General Procedures for the preparation of
functionalized 1,2-dioxolanes 4a-g and 15-23
under catalytic conditions:
Prior to use, catalysts were dried (if soggy or old), under
high vacuum (0.5 mmHg) and gentle warming with a heat-
gun.
Using InCl3 and TMSCl: To
a
solution of
acetoxyendoperoxyacetal 3a-g (1 equiv.) and desired
nucleophile (3 equiv.) in dry DCM (4 mL/mmol) was
added 5 mol% InCl3 and TMSCl (2.5 equiv.) sequentially.
After disappearance of starting material monitored on TLC
(usually 1 h), the reaction mixture was poured into a
saturated solution of NaHCO3. Aqueous phase was
extracted with Et2O three times and organic layer was
washed with brine and dried over MgSO4. Volatiles were
removed under reduced pressure and the crude residue was
purified by silica gel flash column chromatography to
afford the different 3,5-disubstituted 1,2 dioxolanes 4a-g
and 15-23.
Using Sc(OTf)3: To a solution of acetoxyendoperoxyacetal
3a-g (1 equiv.) and desired nucleophile (1.5-3 equiv.) in
dry DCM (4 mL/mmol) was added 5 mol% Sc(OTf)3.
After disappearance of starting material monitored on TLC
(usually 1 h), the reaction mixture was poured into a
saturated solution of NaHCO3. Aqueous phase was
extracted with Et2O three times and organic layer was
washed with brine and dried over MgSO4. Volatiles were
removed under reduced pressure and the crude residue was
purified by silica gel flash column chromatography to
afford the different 3,5-disubstituted 1,2 dioxolanes 4a-g
and 15-23.
Acknowledgements
A.P. thanks the MESRI for a PhD fellowship. We thank Karine
Leblanc and Jean-Christophe Jullian (BioCIS, Châtenay-
Malabry) for HRMS analysis and NMR services, respectively.
Experimental Section
General Procedure for the preparation of peroxy-
hemiacetals 2a-g:
References
To a solution of cyclopropanol 1a-g (1 equiv.) in THF (1
mL/mmol), was added Mn(acac)3 (0.5 mol%) and the
reaction mixture was then stirred under an atmosphere of
oxygen. After disappearance of starting material monitored
on TLC (usually from 1 to 2 h), pentane was added
precipitating most of the manganese salts. The solution
was filtrated on a silica pad and was rinsed with Et2O
several times. Volatiles were removed under reduced
pressure without heating to afford peroxy-hemiacetals 2a-
g. This procedure allows generally excellent yields with
sufficiently pure materials for further utilization. In some
cases, flash column chromatography might be needed, we
advise to perform it in isocratic gradient as fast as possible.
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10.1002/adsc.201901145
Advanced Synthesis & Catalysis
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5
This article is protected by copyright. All rights reserved.

10.1002/adsc.201901145
Advanced Synthesis & Catalysis
UPDATE
Access to Functionalized 3,5-Disubstituted 1,2-
Dioxolanes under Mild Conditions through
Indium(III) Chloride/Trimethylsilyl or
Scandium(III) Triflate Catalysis.
Adv. Synth. Catal. Year, Volume, Page – Page
Alexis Pinet, Bruno Figadère and Laurent Ferrié*
6
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