A single precatalyst tandem RCM-allylic oxidation sequence

Article abstract of DOI:10.1039/c1cc11347j

Ring closing metathesis of allyloxy styrenes and a subsequent Ru-catalyzed allylic oxidation can be combined to a tandem sequence that makes coumarins accessible using less active but more conveniently available first generation catalysts.

Full text of DOI:10.1039/c1cc11347j

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A single precatalyst tandem RCM–allylic oxidation sequencew
Bernd Schmidt* and Stefan Krehl
Received 8th March 2011, Accepted 6th April 2011
DOI: 10.1039/c1cc11347j
Ring closing metathesis of allyloxy styrenes and a subsequent
Ru-catalyzed allylic oxidation can be combined to a tandem
sequence that makes coumarins accessible using less active but
more conveniently available first generation catalysts.
Fig. 1 Catalysts for olefin metathesis reactions.
Assisted tandem catalytic reactions have been defined as
catalyzed reaction sequences proceeding via more than one
mechanism, but with just one precatalyst.1 In these reactions,
Table 1 Attempted RCM of 1a using first generation catalyst A
the catalyst of the first cycle is transformed into the catalyst of
the second cycle by a chemical trigger, for instance an additive
which induces an organometallic transformation in situ.2 Over
the past decade, several reaction sequences consisting of an olefin
metathesis step and a subsequent non-metathesis transformation
of the newly generated CQC-double bond were developed. For
instance, by in situ conversion of the Ru–carbene into a Ru–
hydride,3 olefin metathesis can be coupled with hydrogenation4
or double bond isomerization.5,6 Oxidative transformations that
can be combined with olefin metathesis reactions include atom
transfer radical additions,7,8 dihydroxylation,9–12 and keto-
hydroxylation.12,13 In contrast, Ru-catalyzed olefin metathesis
and allylic oxidations have, to the best of our knowledge, never
been conducted as an assisted tandem catalysis. Such a method
might be useful in the synthesis of a,b-unsaturated lactones
and lactams and could evolve as an attractive alternative to
the RCM of acrylates or acrylamides. This type of RCM is often
associated with tremendous difficulties, such as limited stability
of the metathesis precursors, the necessity to apply high dilution
conditions14 and to use expensive second generation catalysts.
Occasionally, these drawbacks appear to be so serious that a two
step procedure of RCM and allylic oxidation using stoichio-
metric amounts of CrO3 is preferred.15
Entry c/mol LÀ1 Catalyst (mol %) Product Conversiona Yield
d
1
2
3
4
1.00b
1.00b
0.10c
0.01c
A (5)
3
3
2a
2a
—
12%
65%
n.d.
PCy3 (5)
A (5)
A (5)
Quant.
8%d
15%d
n.d.
Determined by 1H-NMR spectroscopy of the crude reaction
a
b
c
d
mixture. Benzene, 40 1C, 19 h. Toluene, 80 1C, 2 h. Remaining
amount was 1a.
supplement the established ones.22 A literature search revealed
that surprisingly few examples for the synthesis of coumarins
by RCM of styrenyl acrylates have been described so far, and
that the use of second generation catalysts such as C23 (Fig. 1)
appears to be mandatory.24–26 The initial substrate concentra-
tion should be as low as 0.01 M, although examples for a
successful conversion at 0.5 M have been reported.26 The high
costs associated with the use of second generation catalysts
and the practical inconveniences of high dilution prompted us
to search for different conditions. First, we decided to check
the alleged unsatisfactory performance of first generation
catalysts for the example of 1a (Table 1).
We considered the development of a tandem RCM–allylic
oxidation sequence in the course of a project directed at
the metathesis based synthesis of coumarins. Coumarins are
ubiquitious in nature16,17 and numerous interesting biological
activities, such as DNA gyrase inhibition,18 cytotoxicity19 or
platelet aggregation inhibition20 were reported for these hetero-
cycles. Consequently, there is a continuous interest in the
development of new synthetic methods in this field21 to
At high initial substrate concentrations (Table 1, entry 1)
the expected RCM product 2a was not detected. Instead, the
dimer 3 could be isolated in 12% yield. We suspected that
3 was formed via a Rauhut–Currier reaction,27 promoted
by dissociated phosphine ligand, and not via a Ru-catalyzed
non-metathesis reaction28 of A. Indeed, a catalytic amount of
PCy3 in the absence of any Ru-species efficiently catalyzes the
dimerization of 1a to 3, which was isolated in 65% yield (entry 2).
At lower initial substrate concentrations (entries 3 and 4) a
poor conversion to the RCM product 2a was observed. In
contrast to acrylates 1, the analogous allyl ethers 4 undergo
RCM to the corresponding 2H-chromenes 5 rapidly, even with
the less reactive first generation catalyst A.29,30 Examples for
Universitaet Potsdam, Institut fuer Chemie,
Organische Synthesechemie, Karl-Liebknecht-Straße 24-25,
D-14476 Potsdam-Golm, Germany.
E-mail: bernd.schmidt@uni-potsdam.de
w Electronic supplementary information (ESI) available: Experimental
details for all new compounds and copies of 1H- and 13C-NMR
spectra. See DOI: 10.1039/c1cc11347j
c
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Chem. Commun., 2011, 47, 5879–5881 5879

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Table 2 Optimization of conditions for RCM–allylic oxidation sequencea
Entry
Solvent
c/mol LÀ1
Catalyst (mol %)
Oxidant
Ratiob 2a : 6a
Yield of 2a (%)
1
2
3
4
5
6
7
8
CH2Cl2
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
—
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.5
0.5
1.0
1.0
1.0
A (5.0)
A (5.0)
A (5.0)
A (5.0)
A (5.0)
A (5.0)
A (5.0)
A (5.0)
A (5.0)
A (5.0)
A (5.0)
A (5.0)
A (5.0)
A (5.0)
A (5.0)
A (2.5)
A (7.5)
A (5.0)
A (5.0)
A (5.0)
A (5.0)
B (5.0)
tBuOOHc
tBuOOHc
tBuOOHc
tBuOOHc
tBuOOHc
tBuOOHc
tBuOOHc
tBuOOHc
tBuOOHc
tBuOOHc
H2O2 (aq)
H2O2/urea
tBuOOtBu
(CumO)2
CumOOH
tBuOOHc
tBuOOHc
tBuOOHc
tBuOOHf
tBuOOHc
tBuOOHf
tBuOOHc
>19 : 1
>19 : 1
14 : 1
8 : 1
9 : 1
>19 : 1
2.6 : 1
3 : 1
—
>19 : 1
—
—
—
—
4 : 1
6 : 1
8 : 1
>19 : 1
>19 : 1
>19 : 1
n.d.
23
43
52
38
51
45
30
14
ClCH2CH2Cl
Benzene
Toluene
Ethyl acetate
—
d
Hexane/ethyl acetate (9 : 1)
Dioxane/ethyl acetate (9 : 1)
Acetic acid/ethyl acetate (1 : 1)
9
o5
e
10
11
12
13
14
15
16
17
18
19
20
21
22
—
—
57
d
o5
o5
o5
o5
42
42
50
55
54
d
—
Ethyl acetate
Ethyl acetate
Ethyl acetate
Ethyl acetate
Ethyl acetate
Benzene
Benzene
Benzene
Benzene
Benzene
58
51
59
>19 : 1
a
Catalyst A or B were added to a solution of 4a at 40 1C and stirred until 4a was fully converted to 5a (TLC, ca. 2 hours); then the oxidant
(4.0 equiv.) was added via a syringe pump over a period of 15 min and stirring was continued at 40 1C until intermediate 5a was fully consumed
(TLC, ca. 3 hours). Determined by 1H-NMR spectroscopy of the crude reaction mixture. Apart from 2a and 6a the mixture contains minor
b
c
d
amounts of unidentified by-products which are removed by column chromatography. 5.5 M solution in decane. Ethyl acetate/CH3CN/water
e
(6 : 6 : 1); RCM in ethyl acetate, CH3CN and water were added after RCM was complete. Solvent (CH2Cl2) was removed after RCM and
f
oxidation was conducted neat. 70 wt% in water.
allylic oxidations of 2H-chromenes to coumarins are scarce. We
are aware of one example for the synthesis of 2a from 5a in low
yield using a soil bacterium.31 The same transformation was
achieved with a Mn–salene catalyst and bleach as the oxidant.32
A number of different metal catalyzed allylic oxidations using
Fe(III),33 Rh(II),34 Mn(III),35 Pd(II),36 or Ru(IV)-catalysts37 and
alkyl hydroperoxides as oxidants have been reported. Ru-based
catalysts in combination with periodates have preferentially
been used for benzylic oxidations,38 e.g. in the synthesis of
bergenins.39 When we planned the Ru-catalyzed tandem
RCM–allylic oxidation sequence, periodates were ruled out as
potential oxidants because a dihydroxylation10,12,13 or oxidative
cleavage of the CQC-double bond had to be expected. Instead,
tert-BuOOH was first tested in various solvents (Table 2).
Initially, we tested solvents that are commonly used in olefin
metathesis reactions (entries 1–4) with an initial substrate concen-
tration of 0.1 M. Benzene emerged as the best solvent from these
experiments, whereas toluene gave a significantly lower yield of 2a.
Another disadvantage of toluene is the formation of benzopyrone
6a in notable amounts. In other solvents, such as hexane/ethyl
acetate or dioxane/ethyl acetate, regioselectivities as low as 3 : 1
were observed (entries 7 and 8). A promising result was obtained
when the allylic oxidation step was conducted without solvent
(entry 10). Unfortunately, the RCM of neat 4a did not proceed
satisfactorily, and we therefore conducted the metathesis reaction
in dichloromethane and removed the solvent prior to addition of
the oxidant. Under these conditions, the ratio of regioisomers
was >19 : 1 in favor of 2a, which was isolated in 57% yield. This
observation prompted us to investigate higher initial substrate
concentrations (entries 18–22) and to use benzene as a solvent,
which is well suited for both the RCM step and the allylic
oxidation. In these experiments, 2a was reproducibly obtained in
very high regioselectivity and isolated yields exceeding 50%. It is
also possible to use an aqueous solution of tert-BuOOH instead of
the more expensive decane solution (entries 19, 21), with only a
small decrease in isolated yield. Finally, we could demonstrate
that the first generation Grubbs’ catalyst A and the Umicore
M1 catalyst (B) give virtually identical results in this sequence
(entries 20 vs. 22). Among other oxidants tested in this study, only
cumol hydroperoxide leads to the isolation of 2a in significant
amounts (entry 15), albeit in significantly lower yield compared
to tert-BuOOH under otherwise identical conditions (entry 5).
Hydrogen peroxide (entries 11, 12), bis-tert-butylperoxide and
bis-cumolperoxide (entries 13, 14) failed to give any allylic oxida-
tion product 2a. In these cases, the intermediate chromene 5a and
numerous unidentified byproducts were detected. Finally, we
tested whether or not the allylic oxidation step is actually
Ru-catalyzed by subjecting isolated and carefully purified 5a to
the same conditions as listed in Table 2, entry 5. After 72 hours,
a mixture of peroxide 7a (36%), coumarin 2a (14%) and
c
5880 Chem. Commun., 2011, 47, 5879–5881
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Table 3 RCM–allylic oxidation sequencea
Notes and references
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for A for B
(%) (%)
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R1
R2
R3
R4
R5
2
4a –H –H
4b –H –H
4c –H –H
4d –H –H
4e –H –H
4f –H –H
4g –H –H
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4i –H –H
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2b 56b
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–OMe –H
2e 40d
2f 63
2g 61
2h 52
2i 30
2j 30
2k 35
2l 50
2m 47
2n 39
–H
–H
–H
–H
–H
–H
–H
–H
–H
–H
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–H
–H
–H
–Me
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–Cl
4n –H –CHQCH–CHQCH– –H
a
Conversion of starting materials 4 and intermediates 5 were quantitative
b
in all cases. Yields are average values from two experiments. Inseparable
c
10 : 1 mixture of 2b and pyrone 6b. NEt3 (2.5 equiv.) was added after
3 hours, and the mixture was heated to 80 1C. c = 0.1 mol LÀ1
.
d
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Having identified optimized conditions for the RCM–allylic
oxidation sequence, we explored the scope of this transforma-
tion, using first generation catalysts A and B for each example
(Table 3). In most cases fair yields and very high coumarin to
pyron selectivities were observed. Noteworthy is the case of 4e,
where a lower initial substrate concentration is preferred. The
synthesis of 8-alkoxy coumarins 2c and 2d deserves a comment:
under the standard conditions, these products were isolated in
34% and 38% yield, respectively, along with 17% of peroxide
7c (Table 2, R = OMe) and 15% of 7d (Table 2, R = OEt),
respectively. It was previously described in the literature that
peroxides can be converted to the corresponding carbonyl
compounds by treatment with NEt3. Therefore, we repeated
this experiment and added NEt3 after completion of the allylic
oxidation step, which lead to significantly increased yields of 2c
and 2d. Peroxides such as 7c,d are most likely intermediates in
our tandem sequence, which would be in accord with mechan-
istic proposals by Murahashi et al.40 for the Ru-catalyzed
oxidation of alkanes proceeding via stabilized radicals.
In conclusion, we could demonstrate that Ru-catalyzed
RCM and allylic oxidation can be coupled in tandem. Further
investigations into the mechanism and the scope of this
method are currently under investigation.
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This work was generously supported by the DFG. We thank
Evonik Oxeno for generous donations of solvents, and
Umicore for generous donation of M1 catalyst.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 5879–5881 5881