Petasis olefination in a continuous-flow microwave reactor: Exo-glycals from sugar lactones

Article abstract of DOI:10.1055/s-0030-1261163

An efficient Petasis olefination of sugar lactones under continuous-flow microwave conditions was developed. Their conversion into exo-glycals can be steered by adjusting the residence time and the concentration of the solution within the reactor. Applying a continuous-flow procedure, the reaction time can be shortened to less than three minutes, several hundred times shorter compared to values given in the literature for batch procedures. This setup is utilizable for a gram-scale synthesis of enol ethers and exo-glycals, in particular, such ones containing potentially (Lewis) acid sensitive acetalic protecting groups. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1261163

1978
LETTER
Petasis Olefination in a Continuous-Flow Microwave Reactor: exo-Glycals
from Sugar Lactones
exo-Glycals
fr
t
S
ug
e
ar
L
actone
f
s
an Koch, Holger Löwe, Horst Kunz*
Institut für Organische Chemie, Johannes Gutenberg-Universität Mainz, Duesbergweg 10-14, 55128 Mainz, Germany
Fax +49(6131)3924786; E-mail: hokunz@uni-mainz.de
Received 11 January 2011
O
Δ
CH3
CH3
Abstract: An efficient Petasis olefination of sugar lactones under
continuous-flow microwave conditions was developed. Their con-
version into exo-glycals can be steered by adjusting the residence
time and the concentration of the solution within the reactor. Apply-
ing a continuous-flow procedure, the reaction time can be shortened
to less than three minutes, several hundred times shorter compared
to values given in the literature for batch procedures. This setup is
utilizable for a gram-scale synthesis of enol ethers and exo-glycals,
in particular, such ones containing potentially (Lewis) acid sensitive
acetalic protecting groups.
Cp2Ti CH2
Cp2Ti
R1
R2
– CH4
1
2
CH2
Cp2Ti CH2
R2
O
–
Cp2Ti
O
R1
R2
R1
3
Scheme 1 Proposed mechanism of the Petasis olefination
heating the reaction mixture in a sealed glass tube in a
microwave oven accompanied by an increased pressure
inside.
Key words: Petasis olefination, continuous-flow reactions, exo-
glycals, sugar lactones, microwave support
Petasis olefinations accelerated by this means have been
reported by Ley et al. for a complex ketone,8 by Hartley
for imino esters,9 by Gallagher et al. for the olefination of
oxalates10 and, very recently, of sugar lactones.2
Owing to their distinct nucleophilic reactivity, enol ethers
and, in particular, exo-glycals are considered interesting
synthons for further conversion, as for example to
spiroketals1 or C-glycosides.2 Commonly applied olefina-
tion reactions, for example, Wittig, Horner, Julia, or
Peterson olefination,3 require basic reaction conditions
not applicable to the conversion of carboxylic esters into
enol ethers. The Tebbe olefination4 is useful for the syn-
thesis of enol ethers from esters. However, the required
reagent is very sensitive to moisture. In contrast, the
Petasis olefination5 of esters not only provides nonbasic
conditions, the reagent dimethyltitanocene (1, Scheme 1)
dissolved in toluene–THF also is stable towards moisture
and air. It can be stored at +4 °C over a longer period with-
out decomposition.6 Upon heating the molecule elimi-
nates methane and forms the active titan carbenoide
species 2, which can react with the carbonyl compound in
a cycloaddition reaction to form the more or less stable ti-
tanacycle 3. After cycloreversion the olefinated product is
released.
The latter observation and the limited reaction volume in
a microwave glass tube prompted us to perform the reac-
tion under continuous-flow conditions, as previously de-
scribed for various other reactions.11
We now accomplished the first Petasis olefination under
continuous-flow conditions combined with microwave ir-
radiation. The experimental setup shown in Figure 1 con-
sists of an HPLC pump for delivering solvents and the
reaction mixture, capillaries (PTFE, 3.2 mm OD, 1.6 mm
ID) used as both, sample loop (total volume: 6 mL) and
flow reactor (total volume: 8.5 mL), a microwave oven for
heating the reaction mixture in the reactor followed by a
pressure relief valve to ensure the appropriate pressure.
Under commonly applied batch conditions substrate and
reagent are dissolved in toluene–THF and heated in the
dark under inert atmosphere at 65–80 °C for several hours
to afford a complete conversion.5 It is assumed that the
methane elimination to form the reactive species starts at
about 65 °C and is the rate-limiting step.7
Figure 1 Continuous-flow reactor setup: For the optimization pro-
cedure the sample is injected by a syringe into the sample loop outside
Consequently, elevating the temperature should strongly
enhance the reaction rate, which, however, is limited by the microwave oven. For the preparative use, the sample loop is remo-
ved, and the reaction mixture is introduced directly by the HPLC
pump
the low boiling point of THF of 66 °C under atmospheric
pressure. The temperature limitation can be overcome by
With this setup the crucial parameters of increased tem-
perature and pressure as well as an efficient heat transfer
to the reaction mixture can be adjusted.
SYNLETT 2011, No. 14, pp 1978–1982
Advanced online publication: 10.08.2011
DOI: 10.1055/s-0030-1261163; Art ID: B01011ST
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.2
0
1
1

LETTER
exo-Glycals from Sugar Lactones
1979
The pressure inside the system was adjusted to 8 bar by a
pressure relief valve at the outlet. If the back pressure is
too low, uncontrolled evaporation of solvent resulting in
gas bubbles within the reaction zone would occur.
Ph
O
Ph
O
O
O
O
O
BnO
O
BnO
CH2
The increasing gas volume would push the sample solu-
tion out of the reactor faster than desired and result in an
undefined short residence time and a decreased conver-
sion. On the other hand, too high pressure in addition to
increased temperature can possibly lead to a burst of the
teflon tubes employed.
OBn
OBn
5
4
BnO
BnO
O
O
O
O
Ph
Ph
O
O
O
CH2
As model substrates, six sugar-derived lactones with dif-
ferent protecting-group patterns were chosen (Scheme 2).
The olefination of these substances can be monitored by
NMR after each run as is illustrated for the galactose-de-
rived substrate 6 in Figure 2.
OBn
OBn
6
7
BnO
BnO
O
O
O
O
O
Ph
Ph
O
O
CH2
OBn
O
OBn
O
8
9
O
O
Ph
Ph
O
O
O
CH2
BnO
10
BnO
O
OBn
OBn
11
Ph
O
Ph
O
O
O
O
BnO
O
BnO
CH2
OBn
OBn
13
12
CH3
CH3
BnO
BnO
BnO
BnO
O
O
O
CH2
OBn
14
OBn
15
Figure 2 NMR monitoring of the olefination of 6. a: Substrate; b:
1.5 mL/min; c: 1.0 mL/min; d: 0.75 mL/min; e: 0.5 mL/min; f: 0.35
mL/min; g: 0.25 mL/min; h: product. Decreasing the flow rate sub-
stantially increases the amount of product
Scheme 2 Conversion of the sugar lactones into exo-glycals
For the optimization of the reaction conditions, model ex-
periments with small quantities of the substrates were per-
formed. In order to inject the reaction mixture as a single
plug, the sample was not directly introduced by the HPLC
pump. Instead, a sample loop – the capillary outside of the
reaction zone – was used. This capillary was emptied
completely by applying a stream of dry N2 gas, before the
reaction mixture, the solution of lactone and Petasis re-
agent, was filled in by a syringe.
First experiments showed that especially at low flow rates
dilution effects at the interface of the sample plug and the
pure solvent occur, even though the sample is initially in-
troduced as a single plug. This resulted in drastic lowering
of the reaction rate in the diluted areas and an incomplete
conversion with regard to the sample collected at the end
of the run. As a consequence, additional plugs of the re-
agent solution were placed in front and behind the sub-
When running the reaction, the HPLC pump delivers pure strate–reagent mixture inside the sample loop, in order to
solvent (toluene–THF = 1:1) with a constant flow rate, eliminate this effect.
which moves the reaction mixture continuously through
Depending on the flow rate and therewith on the residence
the reaction zone. The capillary inside the microwave
time within the reaction zone, the conversion of the sub-
oven (CEM discover), the actual continuous-flow reactor,
strate 6 into the product 7 changes in a systematic manner
(see Figure 2 and Figure 3). For example, at a residence
is isolated with glass wool in order to minimize thermal
losses over the large outer tube surface. Therefore, an ex-
time of 5.67 min (flow rate: 1.5 mL/min) the substrate can
act temperature control directly at the Teflon reactor tubes
still be observed (47% remaining), whereas the conver-
via an IR sensor is not possible. The reaction is performed
sion can be judged complete after prolongation of the
with a constant microwave power of 50 W.
reaction time to 42.5 min (flow rate: 0.2 mL/min).
Synlett 2011, No. 14, 1978–1982 © Thieme Stuttgart · New York

1980
S. Koch et al.
LETTER
Under the same conditions, the glucose-derived building
block 4 reacted remarkably faster, and complete conver-
sion was already reached after 5.67 min (at 1.5 mL/min,
Table 1).
Table 1 Comparison of the Conversion of Different Substrates
Using a 0.18 M Solution of Petasis Reagent in Toluene–THF
Entry Substrate
Residence time Conversion
(min)
(%)
BnO
O
O
1
2
3
5.67
11.33
34.00
53
68
93
O
Ph
O
OBn
6
Ph
O
O
O
4
5.67
>99
BnO
O
OBn
4
Figure 3 Correlation of residence time inside the microwave zone
and the conversion obtained for the olefination of 6 taken from the in-
tegration of the corresponding 1H NMR signals of substrate and pro-
duct shown in Figure 2
O
5
6
5.67
11.33
77
93
16
17
Logically, if the formation of the carbenoide species 2 by
a-elimination is complete after a short time in the experi-
ment using the gluconolactone 4, it should be just the
same in the presence of the galactonolactone 6. However,
the reaction rates for the conversion of 4 and 6 to give the
corresponding exo-glycals differ significantly. This leads
to the conclusion, that, in contrast to the batch reaction,
the elimination of methane is not the rate-limiting step un-
der the continuous-flow microwave conditions, but the re-
action of the carbenoide intermediate 2 with the substrate.
This result was confirmed when benzophenone and ben-
zyl benzoate were reacted under the same conditions.
Benzophenone reacts slightly faster than the galactono-
lactone 6, whereas the ester can only be olefinated to a low
extend even at long reaction times (Table 1), although
monitoring by NMR showed the complete disappearance
of the Petasis reagent.
O
7
8
11.33
34.00
8
17
O
cooling of the reaction tube12 with an air stream. In both
microwave-assisted reactions the reaction times are re-
markably shorter than under conventional flask condi-
tions. For example, the fucose derivative 14 is
conventionally olefinated at 70 °C within 16 hours with
an identical yield of 74%13 as in the continuous-flow reac-
tion in a residence time of 5.67 min (Table 2).
Table 2 Microwave-Assisted Petasis Olefination under Batch and
Flow Conditions Using a 0.46 M Solution of Petasis Reagent in
Toluene–THF
Assuming that the rate-determining step is a bimolecular
reaction, the reaction rate should be strongly dependent on
the total concentration of the two reaction partners within
the solution. Therefore, a further enhancement should be
possible by applying a higher concentration.
Entry Substrate Continuous flow
Batch reaction
Yield (%) Time (min) Yield (%) Time (min)
1
2
3
4
5
6
4
65
71
70
50
52
74
5.67
5.67
5.67
5.67
5.67
8.5
67
70
70
51
50
74
30
30
30
30
30
30
6
Indeed, the increase of the Petasis reagent concentration
from 0.18 M to 0.46 M resulted in a remarkably acceler-
ated conversion. For example, up to a flow rate of 3.0 mL/
min corresponding to a residence time of only 2.8 min, the
two lactones 4 and 6 as well as the diastereomeric mixture
of 10 can be olefinated with complete conversion.
8
10
12
14
After the reaction was complete, the crude product was
easily purified by flash chromatography, eluting first the
nonpolar impurities and subsequently the pure product.
The yields obtained by this method range from about 50%
to 74% and are in accordance with the respective yields
achieved in analogous batch reactions carried out at max-
imum 65 °C under microwave irradiation of 200 W and
An increased flow rate allows for a preparative applica-
tion of the continuous-flow reaction even on gram scale.
It is an important feature of the synthesis under flow con-
ditions that the scale-up of the reaction after optimization
with small quantities of the valuable substrate is done by
Synlett 2011, No. 14, 1978–1982 © Thieme Stuttgart · New York

LETTER
exo-Glycals from Sugar Lactones
1981
simply increasing the operation time of the reactor with- After HPLC separation of the two isomers of compound
out changes regarding conversion or yield. For example, 11 (Figure 6), the two were distinguished by the observed
2.0 g of the glucose-derived lactone 4 were converted into NOE contacts. Especially in the case of the S-isomer,
the corresponding exo-glycal 5 at a flow rate of 1.5 mL/ clear NOE crosspeaks exist for the interaction of the ace-
min in 30 minutes including conditioning of the flow sys- tal proton with H4 of the furanose ring and of the ortho
tem.
protons of the adjacent phenyl group with H5, which al-
lows an assignment of these groups to the two hemi-
spheres of the acetal ring.
All obtained olefination products were characterized by
1H and 13C NMR spectroscopy as well as COSY, HSQC,
and NOESY experiments if required for complete assign-
ment of the chemical shifts. Additionally, the conforma-
tions of the molecules were determined, facilitating the
interpretation of the stereochemical outcome of subse-
quent reactions of the exo-glycals, as for example, the
hydroboration of the products.14
Analysis of the coupling-constant patterns of compound
13 and 15 revealed that both molecules adopt the same
conformation as their non-olefinated precursors, namely
4C1 in the case of the galactose and 1C4 for the fucose de-
rivative (Figure 4). The latter nearly is a mirror image of
13.
Figure 6 Conformations of the R-isomer (left) and S-isomer (right)
of compounds 11
In conclusion, the olefination of complex sugar-derived
lactones to exo-glycals was achieved under continuous-
flow conditions. This procedure allowed an optimization
of the conversion by regulation of the residence time and
the concentration on milligram scale, before the ready
scale-up of the reaction to a gram-scale production. It can
be concluded from these results that micro reactors are
also efficient in preparative microwave-assisted conver-
sions of other sensitive carbonyl substrates under contin-
uous-flow conditions.
Figure 4 Conformations of compounds 13 (left) and 15 (right)
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Probably due to annulation of a second ring formed by the
benzylidene acetals in compounds 5, 7, and 9 (Figure 5),
these molecules all exist in a B2,5 boat conformation,
bringing the O-benzyl group in position 2 into an axial ori-
entation. The endo and exo orientation of the acetalic phe-
nyl ring derived from the NOESY spectrum and
confirmed by X-ray analysis of the exo isomer.
Acknowledgment
This work was supported by the Deutsche Forschungsgemeinschaft.
S.K. is grateful for a grant by the Studienstiftung des Deutschen
Volkes.
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