Catalyzed Claisen rearrangements of O-allyl kojates

Article abstract of DOI:10.1016/j.tetlet.2013.05.002

Allylic ethers of kojic acid undergo Claisen rearrangement with catalysis by zinc triflate to give the corresponding C-allylated kojic acids in moderate to good yields.

Full text of DOI:10.1016/j.tetlet.2013.05.002

Tetrahedron Letters 54 (2013) 3752–3754
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Catalyzed Claisen rearrangements of O-allyl kojates
⇑
Michael C. Pirrung , Jenifer N. Nalbandian
Department of Chemistry, University of California, Riverside, CA 92521, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Allylic ethers of kojic acid undergo Claisen rearrangement with catalysis by zinc triflate to give the cor-
responding C-allylated kojic acids in moderate to good yields.
Received 5 April 2013
Revised 26 April 2013
Accepted 2 May 2013
Available online 10 May 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Claisen rearrangement
Microwave-assisted synthesis
Lewis acid catalysis
Zinc triflate
The Claisen rearrangement of allylic ethers of the pyrone natu-
ral product kojic acid1 has provided access to interesting bioactive
compounds. Such reactions are key to the preparation of early
intermediates in syntheses of phorbol and related compounds,2
and our lab has used the aromatic version of this process to access
heterocyclic biaryls.3 Typical conditions for these Claisen rear-
rangements are demanding, requiring long reaction times or tem-
peratures exceeding 150 °C. The ability to catalyze them would
expand the range of functionalities that could be tolerated. In some
cases, these reactions create asymmetric centers, so the possibility
of chiral catalysis is also tantalizing.
There is a significant structural similarity between allylic ethers
of kojic acid and the (allyloxy)acrylates that have proved to be one
of the most successful reactants in catalyzed Claisen rearrange-
ments, including asymmetric versions.4 Further, kojates are locked
into a conformation that permits chelation between the two oxy-
gens (Chart 1); such a chelate is used as a model to explain asym-
metric catalysis in reactions of (allyloxy)acrylates, which by
contrast to kojates are conformationally flexible. We hypothesized
that it should be possible to promote the Claisen rearrangement of
O-allyl kojates using catalysts similar to those that succeed with
(allyloxy)acrylates. The range of catalysts examined here is wide,
including Lewis and Brønsted–Lowry acids as well as a hydrogen
bonding catalyst. We find that zinc triflate is the most efficient of
the catalysts examined for the Claisen rearrangement of a prenyl
kojate, and that classical metal box-based asymmetric catalysts
do not provide rate enhancement. The rate acceleration was deter-
mined and the scope of the reaction was examined.
To evaluate catalysts for the allyl kojate Claisen rearrangement,
starting with kojic acid (1) a prototype reactant 2 can be prepared
in 84% yield (Scheme 1). Its purely thermal rearrangement could be
conducted at 160 °C (neat, open flask, 1 h) to give product 3 in 94%
yield. Under conditions reported by Wender2b (78 °C, ethanol,
60 h), it is produced in 79% yield.
Catalysts for the rearrangement of 2 were screened at 10 mol%
under a standard set of conditions: 0.028 M in toluene, microwave
heating at 100 °C, 1 h. It is simple to determine reaction progress
by 1H NMR spectroscopy using the integration of the vinylic hydro-
gens in the crude reaction product. These reactions are clean and in
all cases the product was isolated in pure form. All reactions were
performed in duplicate, and the outcome of the study of a selection
of catalysts is summarized in Table 1.
For comparison to catalyzed processes, the thermal reaction
was conducted at 100 °C, where it gives very little product. The
conventional Lewis acid Claisen catalyst5 boron trifluoride etherate
gives only a trace of 3, and in fact is an inhibitor. Palladium(II)
Chart 1. Putative reactant–catalyst complexes for catalyzed Claisen rearrange-
ments of (allyloxy)acrylates and allyl kojates.
⇑
Corresponding author. Tel.: +1 951 827 2722; fax: +1 951 827 2749.
E-mail address: michael.pirrung@ucr.edu (M.C. Pirrung).
Scheme 1. Preparation of prenyl kojate 2.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.05.002

M. C. Pirrung, J. N. Nalbandian / Tetrahedron Letters 54 (2013) 3752–3754
3753
catalysis4d is likewise ineffective. While gold(I) catalysts have been
used for the aryl allyl Claisen rearrangement6 and the propargyl
Claisen rearrangement,7 neither gold catalyst that we examined
is effective for this reaction. Metal triflates have also been investi-
gated previously, Yb(III) and Cu(II) for the (allyloxy)acrylates4a and
Yb(III) for aryl allyl ethers.8 While complete conversion of 2 is seen
with both, the isolated yield of 3 is low. With a milder Lewis acid,
Ag(I), no catalysis is observed. Trost reported the use of lanthanide
NMR shift reagents to promote an aromatic Claisen rearrange-
ment,9 and this method was used in natural product synthesis
for the introduction of C-prenyl groups.10 The europium complex
was examined here, with the result that the rearrangement prod-
uct could be obtained only in low yield.
Jacobsen has reported hydrogen-bonding guanidinium catalysts
for Claisen rearrangements of (allyloxy)acrylates, including asym-
metric versions.11 In the case of 2, Jacobsen’s simple guanidinium
salt (Chart 2) results in no catalysis.
The best of these reactions are catalyzed with zinc triflate,
which completely consumes 2 and gives 3 in 31% isolated yield.
To establish that this reaction is not catalyzed by triflic acid pro-
duced by adventitious hydrolysis of the triflate, 2,6-di-tert-butyl-
pyridine was added. A slight improvement in yield occurs, and
the lack of product formation when triflic acid itself is used shows
that protons do not catalyze this process.
Kinetic studies were performed on the zinc triflate-catalyzed
rearrangement of 2 to determine the rate acceleration compared
to the uncatalyzed process. Reactions were performed in triplicate
at 80 °C and monitored by NMR for >3 half-lives. Percent conver-
sion data were fitted to a standard first-order kinetic equation.
Rate constants are 0.035 sꢀ1 and 0.001 sꢀ1, respectively, making
the catalytic rate acceleration at 80 °C a reasonable 35-fold.
The low yields of purified product and the seeming inconsis-
tency of conversions and yields with some catalysts in Table 1
were puzzling. One hypothesis was formed that an elimination
reaction was occurring in competition with the rearrangement
(Scheme 2). This would give isoprene and kojic acid, neither of
which would be isolated after chromatography. To provide evi-
dence for the elimination pathway, benzoate 4 was prepared and
examined under the milder reaction conditions. The rearrange-
ment product is obtained in only 20% yield, and 5 accounts for
more than half of the converted 4. While this process affects the
production of 3, other reactants can have different tendencies to-
ward elimination and therefore give higher yields at full conver-
sion (vide infra). The proportion of elimination also depends on
conditions (vide supra).
The combination of metal salts with ditopic or tritopic
C2-symmetric donor ligands (box, pybox, etc.) has been among
the most successful catalysts for the asymmetric aliphatic Claisen
Further experimental variations in the superior Zn(OTf)2-cata-
lyzed reaction were examined. A mild solvent effect is observed,
as reaction in dichloroethane causes a drop in the product yield
(23%), but a mixed solvent of 1:1 toluene: dichloroethane pro-
vides a slight yield enhancement (38%). Dropping the temperature
to 80 °C increases the isolated yield of 3 to 48%, but reaction is
incomplete; extending the reaction time to 2 h provides 3 in
54% yield.
Scheme 2. Support for a possible elimination pathway in reducing the yield of
Claisen rearrangement products.
Table 1
Catalysis of the conversion of 2–3 under various conditions at 100 °C for 1 h
Table 2
Catalyzed Claisen rearrangement of O-allyl kojates
Catalyst
Conversion (%)
Yield of 3 (%)
None
7
4
BF3ꢁOEt2
PdCl2(ACN)2
Ph3PAuCl
Ph3PAuOTf
AgOTf
<1
<1
1
8
9
<1
<1
<1
5
Conditions
Reactant
Product
Yield
49
a
120 °C/200 min
5
Yb(OTf)3
Cu(OTf)2
Eu(fod)3
Ph2GuanBArF
Zn(OTf)2
100
100
a
10
100
100
1
15
12
8
14
31
39
<1
b
80 °C/120 min
80 °C/120 min
46
84
b
Zn(OTf)2
HOTf
c
a
Eu salts prevented NMR analysis of the crude reaction.
10 mol % tBu2Pyr added as an acid scavenger.
b
d
e
120 °C/200 min
120 °C/200 min
33
59
f
120 °C/60 min
41
Chart 2. Organocatalyst investigated for the kojic acid Claisen rearrangement.

3754
M. C. Pirrung, J. N. Nalbandian / Tetrahedron Letters 54 (2013) 3752–3754
rearrangement, and they show ligand-accelerated catalysis. We
examined the combination of 10 mol% each of pybox ligand and
zinc triflate for the 2–3 conversion (80 °C, 2 h). There is a negligible
increase in product formation. Aiming for evidence that
ligand-accelerated catalysis of this rearrangement is possible (to
encourage investigation of this catalyst with reactants that gener-
ate stereochemistry), the amount of pybox ligand was doubled to
maximize the proportion of metal–ligand complex at equilibrium.
However, catalysis decreases and only 18% of 3 is obtained. The
addition of excess ligand evidently competes substrate away from
the Lewis acid. Interestingly, it was reported (in a footnote)12 that a
Zn(OTf)2ꢁpybox complex catalyzes the asymmetric Claisen
rearrangement of a substituted allyl kojate in a 74:26 er, which is
at odds with the observations here.
Scheme 3. Catalyzed kojic acid Claisen rearrangement to prepare an (indolyl)kojic
acid.
The breadth of the zinc triflate-catalyzed Claisen rearrangement
was examined with the reactants given in Table 2. Most (6a–d)
were prepared from kojic acid by allylic bromide alkylations anal-
ogous to Scheme 1. The remainder (6e and 6f) was prepared by
semi-hydrogenation of the corresponding alkynes, themselves syn-
thesized via alkylation with the mesylate made from 3-butyn-2-ol
(20%), or Sonogashira coupling of iodobenzene with propargyl kojic
acid (34%), respectively. Variations in reaction time and tempera-
ture were used to optimize yields of the rearrangement products
7. O-Propargyl kojic acid (not shown) was also examined, but it
gives no reaction under these conditions. Control experiments
show that these reactants undergo no rearrangements at the
reported temperatures in the absence of Zn(OTf)2. The more
stringent conditions required for a, d, and e show that greater
a0-substitution on the allyl fragment facilitates rearrangement.
The superior yield observed with 6c, which cannot eliminate, sup-
ports the idea that elimination is an important yield-limiting side
reaction. Yet, other reactants also cannot eliminate, but their yields
of rearrangement products are only moderate. The only reactant
that creates stereochemistry, 6e, gives a single geometric isomer.
Interestingly, we found that, among all reactants in Table 2, 6b
uniquely undergoes thermal Claisen rearrangement somewhat
easily, upon evaporation of solvent with heating or storage neat
at ambient temperature. Care had to be taken in handling it to en-
sure that the reported conversion was due only to the catalyzed
reaction. Heating it at 45 °C for 3 d gives 8% of the rearrangement
product. In contrast, 6c is completely stable under these condi-
tions. Since 6b has the same alkene substitution as the reactant
earlier reported to be subject to asymmetric catalysis,12 it may
have been a fortunate selection for that work.
Recognition that elimination was an important side reaction
suggested that we could have missed valuable catalysts in our ini-
tial screen by using 2 as the reactant. We therefore reinvestigated
some catalysts using 6c, owing to its lack of elimination pathways
and high yield. Since Yb(III) and Cu(II) triflates both provide full
conversion of 2, they were examined with 6c. The isolated yields
of 7c are only 64% and 60%, respectively, confirming zinc triflate
as the superior catalyst.
One purpose in examining catalysis of kojic acid Claisen rear-
rangements was to apply the method to the heterobiaryl synthesis
we have developed based on this reaction.3 Reactant 9 was assem-
bled for this purpose (Scheme 3). Known indole 8 was N-protected
and the ester was reduced to the alcohol (55%, 2 steps). It was
converted to the chloride, which was used to alkylate kojic acid,
giving 9 (54%, 2 steps). Its treatment under catalyzed rearrange-
ment conditions gives 85% conversion, with an isolated yield of
10 of 32%. The uncatalyzed version of this reaction, performed
neat, requires 7 h at 150 °C (96%).
In summary, zinc triflate has been identified as a good catalyst
for the Claisen rearrangement of O-allyl kojic acid ethers. Surpris-
ingly, most catalysts that accelerate the rearrangement of the clo-
sely related (allyloxy)acrylates are not effective for these reactants.
Zinc triflate provides a significant rate acceleration over purely
thermal reactions with far milder conditions, but ligand-acceler-
ated catalysis is not observed.
Acknowledgments
Fellowship support from NIH (GM086130, J.N.N.) is appreciated.
Mass spectra were obtained on an instrument purchased with NSF
grant CHE0541848. We thank Andrew Carlson for preparing start-
ing materials.
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