Tandem Claisen Rearrangement/6-endo Cyclization Approach to Allylated and Prenylated Chromones

Article abstract of DOI:10.1002/ejoc.201501151

Allyl, dimethylallyl and prenyl ethers derived from o-acylphenols reacted upon microwave irradiation to form C-allylated or -prenylated chromone derivatives, depending on the substitution pattern of the arene and the allyl substituent. The reaction proceeds through a tandem Claisen rearrangement and 6-endo-trig or 6-endo-dig cyclization sequence. For prenyl ethers, the tandem sequence can be extended by a Cope rearrangement to furnish 6-prenylchromones. The method is potentially useful for the synthesis of natural products and drugs.

Full text of DOI:10.1002/ejoc.201501151

FULL PAPER
DOI: 10.1002/ejoc.201501151
Tandem Claisen Rearrangement/6-endo Cyclization Approach to Allylated and
Prenylated Chromones
Bernd Schmidt,*[a] Martin Riemer,[a] and Uwe Schilde[a]
Keywords: Allylic compounds / Arenes / Oxygen heterocycles / Microwave chemistry / Rearrangement / Michael addition
Allyl, dimethylallyl and prenyl ethers derived from o-acyl- ment and 6-endo-trig or 6-endo-dig cyclization sequence.
phenols reacted upon microwave irradiation to form C-all-
ylated or -prenylated chromone derivatives, depending on
the substitution pattern of the arene and the allyl substituent.
The reaction proceeds through a tandem Claisen rearrange-
For prenyl ethers, the tandem sequence can be extended by
a Cope rearrangement to furnish 6-prenylchromones. The
method is potentially useful for the synthesis of natural prod-
ucts and drugs.
orders of magnitude higher than that observed for the par-
ent compound naringenin[15–17] or its regioisomer 6-prenyl-
naringenin (Figure 1).[18] It has been reasoned that the in-
creased bioactivity might originate from an increased lipo-
philicity and facilitated permeation through cell mem-
branes.[19]
Introduction
Numerous secondary metabolites with a phenol or poly-
phenol structure are biochemically modified by prenyl-
transferase-mediated prenylation reactions.[1–4] It was re-
cently demonstrated for tyrosine-containing cyclopeptides
that C-prenylated phenols can arise through a sequence of
enzymatic reverse O-prenylation and a subsequent Claisen
rearrangement, which is facile under physiological condi-
tions in this particular case.[5] This reaction sequence is
complementary to an alternative biosynthetic mechanism
that involves the formation of carbenium ions from prenyl
diphosphate and a Friedel–Crafts-type alkylation of the
aromatic core.[6] Among aromatic secondary metabolites,
flavonoids[7,8] often occur as prenyl conjugates.[9] Interest-
ingly, prenylation has been found on several occasions to
modulate the bioactivity of natural products.[10] For exam-
ple, the prenylated flavonoids licoflavone C and isobavachin
(Figure 1) show notable cytotoxicities against C6 glioma
cells, whereas their non-prenylated analogues were found to
be inactive.[11] A series of geranylated chrysin analogues
have been synthesized and tested for their ability to inhibit
the proliferation of human tumour cell lines in comparison
with chrysin itself. In this study it was found that in most
assays the 6- and 8-geranylated chrysin derivatives were sig-
nificantly more active than chrysin.[12] An example that has
been particularly well studied is 8-prenylnaringenin (8-PN),
a highly potent phytoestrogen isolated from hops.[13] 8-PN
has been proposed as an alternative to hormone replace-
ment therapy for menopausal women.[14] Several compara-
tive studies have revealed that its estrogenic activity is by
The synthesis of prenylated flavonoids can be ac-
complished by prenylation of an appropriately O-protected
flavonoid. For example, Metz and co-workers obtained 8-
prenylnaringenin from naringenin by Mitsunobu O-prenyl-
ation at C-5 and a sequential Claisen/Cope rearrangement.
Depending on the conditions, 8-PN was obtained either as
the sole product or as a 1.2:1 mixture of 8-PN and the ini-
tial Claisen rearrangement product, 6-(1,1-dimethylallyl)na-
ringenin.[20] Very recently, Zhang and co-workers described
the synthesis of the 8-prenylated flavonoid icariin from the
5-prenyl ether of kaempferol by a europium-catalysed
Claisen/Cope rearrangement.[21] Nemoto and co-workers
synthesized various 8-prenylated flavanones and flavanols
from non-prenylated precursors through regioselective Pd-
catalysed 1,1-dimethylallylation at 7-OH followed by ther-
mal Claisen rearrangement.[22] Very recently, Wang and co-
workers synthesized sophoflavescenol and two prenyl-cy-
clized natural products in high selectivity and yields by O-
prenylation at 5-OH and microwave-promoted Claisen/
Cope rearrangement.[23] An alternative route to prenylated
flavonoids starts from appropriately prenylated aromatic
precursors that are then cyclized, for example, by Allan–
Robinson flavone synthesis or one of its variants.[24,25] This
strategy has, for example, been applied to the synthesis of
cannflavin B and its 8-prenyl isomer, isocannflavine B, by
Appendino and co-workers.[26] Recently, approaches to C-
prenylated or -allylated flavonoids and isoflavonoids have
emerged that rely on a tandem (or domino) prenylation (or
allylation) and cyclization sequence.[27–29] Examples are the
syntheses of 3-allyl-substituted chromones[30,31] and iso-
chromones[32] in which a metal-catalysed or electrophilic
[a] Institut für Chemie, Universität Potsdam,
Karl-Liebknecht-Straße 24–25, Haus 25, 14476 Potsdam-Golm,
Germany
E-mail: bernd.schmidt@uni-potsdam.de
http://www.chem.uni-potsdam.de/groups/schmidt/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201501151.
7602
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 7602–7611

Approach to Allylated and Prenylated Chromones
port herein an extension of the tandem sequence to 6-endo-
trig and 6-endo-dig cyclizations combined with 8- and 6-
prenylations (Scheme 1).
Scheme 1. This work: tandem Claisen rearrangement and 6-endo-
dig or 6-endo-trig cyclization sequence.
Results and Discussion
Microwave-Promoted Claisen Rearrangement
Claisen rearrangements of allyl phenyl ethers require
high temperatures, which makes the use of high-boiling-
point solvents and sometimes inconvenient heating sources
such as sand baths necessary.[40–42] Controlling reaction
temperatures higher than 200 °C over long periods of time
is sometimes difficult to achieve, resulting in reproducibility
problems.[34,43] Microwave irradiation[44–47] was early on
discovered to be a suitable method of energy supply that
avoids these obstacles in Claisen rearrangements,[48] and
interest in the further development of microwave-promoted
Claisen rearrangements continues, for example, with a view
towards scale-up by using special microwave apparatus.[49]
In our preliminary communication we identified microwave
irradiation in the solvent N,N-diethylaniline as suitable con-
ditions for the envisaged tandem Claisen rearrangement/6-
endo-trig cyclization sequence.[34] With a view to generaliz-
ing these conditions for other substituted allyl groups, we
synthesized a set of allyl ethers 1a–e and subjected them to
microwave irradiation in N,N-diethylaniline (Table 1). Mi-
crowave irradiation of a solution of 1a in N,N-diethylaniline
at 150 °C did not promote the Claisen rearrangement to o-
allylphenol (2a). Increasing the temperature to 200 °C pro-
moted the reaction, however, the conversion remained in-
complete even after 1 hour. Irradiation at 250 °C for 1 hour
resulted in full conversion to 2a, which was isolated in
Figure 1. Structures of representative bioactive flavonoids.
alkynone cyclization and a concomitant allyl migration are quantitative yield (entries 1–3). Under the same conditions,
combined. Motivated by the discovery of two new 8-substi- the crotyl ether 1b underwent a clean Claisen rearrange-
tuted chroman-4-ones, tabchromones A and B, from the to- ment to the expected 1-methylallyl-substituted phenol 2b,
bacco plant nicotiana tabacum,[33] we have very recently de- which was isolated in 94% yield (entry 4). When the cinn-
veloped a synthesis[34] based on a microwave-promoted allyl amyl ether 1c was subjected to microwave irradiation, the
aryl ether Claisen rearrangement and subsequent 6-endo- Claisen rearrangement product o-2c and the styrene p-2c
trig cyclization.
were isolated as an inseparable 1.0:0.7 mixture in nearly
6-endo-Cyclization reactions[35–39] have previously been quantitative yield (entry 5). The latter product results from
used for the synthesis of chromanones and chromones, but a Cope rearrangement of the initially formed Claisen re-
not in tandem with a Claisen rearrangement. This combina- arrangement product o-2c.[43] In an attempt to improve the
tion of synthetic steps offers the advantage that an allyl selectivity towards o-2c, we reduced the reaction time to
ether can be used as a protecting group during the prepara- 5 min (entry 6), but to no avail: the isolated yield and prod-
tion of the precursors, but that the protecting group be- uct ratio were virtually identical. In the light of a report
comes an essential part of the target structure upon its re- by Wang and co-workers, the observation of the Claisen
moval. Following our preliminary communication,[34] we re- rearrangement product o-2c was somewhat surprising.[50]
Eur. J. Org. Chem. 2015, 7602–7611
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7603

B. Schmidt, M. Riemer, U. Schilde
FULL PAPER
Wang and co-workers found for a closely related cinnamyl and III.[52] Although the reaction temperature of our stan-
ether that the initial Claisen product could not be detected dard conditions is significantly higher and the solvent N,N-
under conventional heating conditions, but that the tandem diethylaniline is basic and nucleophilic, we found that 1d
Claisen/Cope product analogous to p-2c was exclusively still selectively rearranged to 2d. In particular, no decarb-
formed, regardless of the solvent and the reaction time. onylation products were detected although they had pre-
Next, the Claisen rearrangement of the 1,1-dimethylallyl viously been observed when other O-allylated benzalde-
ether 1d was investigated under the standard conditions. hydes were heated to temperatures of 200 °C[53] or when
This starting material was synthesized by Pd-catalysed allyl- heteroaromatic aldehydes were exposed to microwave irra-
ation of p-hydroxybenzaldehyde with 1,1-dimethylallyl diation.[54]
carbonate, in analogy to the procedure used by Nemoto
Finally, we subjected the prenyl ether 1e to microwave
and co-workers for the 7-OH dimethylallylation of chro- irradiation in N,N-diethylaniline. The para-substituted
mones.[22] Thermal Claisen rearrangement of an aldol con- phenol p-2e was exclusively formed and could be isolated
densation product of 1d had previously been exploited for in 65% yield. This product results from a Claisen/Cope re-
the synthesis of prenylated carbazoles,[51] and a microwave- arrangement sequence; in contrast to the rearrangement of
promoted Claisen rearrangement of 1d in toluene at 190 °C cinnamyl ether 1c, the intermediate Claisen product was not
was used more recently for the synthesis of abyssinones II observed under our conditions. [3,3] Sigmatropic rearrange-
ments of 1e have been studied previously; Lewis acid cataly-
sis at –20 °C led to mixtures of o- and p-prenylphenol (p-
Table 1. Microwave-promoted Claisen rearrangement of allyl aryl
2e),[55] whereas conventional heating in N,N-diethylaniline
ethers.[a]
for 90 h resulted in a mixture of p-2e and an “anomalous”
product formed through a [1,5] sigmatropic shift following
the first [3,3] sigmatropic rearrangement.[43] None of these
byproducts were detected under microwave irradiation in
N,N-diethylaniline.
Tandem Claisen ortho-Prenylation/6-endo-trig Cyclization –
Synthesis of Pestaloficiol J
Pestaloficiol J (4) is an 8-prenylated chroman-4-one re-
cently isolated from the endophytic fungus Pestalotiopsis
fici.[56,57] Both the crude extracts of fermentation cultures
and isolated pestaloficiol J display moderate inhibitory ac-
tivity against HIV-1 cells.[58] This natural product has, to
the best of our knowledge, not been synthesized previously.
Following the general tandem approach outlined in
Scheme 1 and taking into account the results presented in
Table 1, its synthesis would require dimethylallyl ether 3,
appropriately protected at 6-OH (Scheme 2).
Scheme 2. Tandem precursor required for pestaloficiol J.
Our synthesis started from 5-hydroxysalicylaldehyde (5),
which was first monoprotected as the MOM ether 6a.[34]
Dimethylallylation of the remaining OH group was ac-
complished by using allyl alkyl carbonate 7[59] and
[a] Reagents and conditions: 1 (0.2 m) in N,N-diethylaniline, micro-
wave at temperature T for 1 h. [b] Yield of the isolated product;
[Pd(PPh3)4] as pre-catalyst. Treatment of the resulting alde-
n.d.: not determined. [c] No conversion (NMR). [d] Incomplete
hyde 8a with the 2-methylpropenyl Grignard reagent fur-
nished allylic alcohol 9a, which was oxidized to 3a accord-
conversion (NMR). [e] Ratio of o-2c/p-2c = 1.0:0.7. [f] Reaction
time: 5 min.
7604
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 7602–7611

Approach to Allylated and Prenylated Chromones
ing to the method of Ley et al.[60] Having in hand the pre-
cursor required for the tandem sequence, 3a was subjected
to microwave irradiation at 250 °C in N,N-diethylaniline.
The MOM ether of pestaloficiol J (10a) was obtained in
excellent yield, but deprotection turned out to be an insu-
perable problem. Under a variety of conditions and in the
presence of various Lewis or Brønsted acids (e.g., MgCl2,
ZnCl2, HCl, camphorsulfonic acid, pTsA or trifluoroacetic
acid), either no conversion was observed or decomposition
into multiple products occurred. The only identifiable prod-
uct from these experiments was the tertiary alcohol 11,
which was in some cases isolated in minuscule amounts.
Notably, even those conditions that had previously been de-
scribed for the deprotection of phenolic MOM ethers in
the presence of prenyl side-chains failed completely when
applied to the deprotection of 10a. This prompted us to
replace the MOM protecting group by a TBS ether. The
analogous precursor 3b was obtained in four steps from the
same dihydroxybenzaldehyde 5 in comparable yields and by
using the same synthetic methods. The microwave-pro-
moted tandem Claisen rearrangement/cyclization reaction
gave TBS ether 10b quantitatively, which was deprotected
to pestaloficiol J (4) under non-acidic conditions with tetra-
n-butylammonium fluoride (TBAF). In summary, this is the
first synthesis of pestaloficiol J, which was obtained in a
total yield of 38% over six steps (Scheme 3).
Figure 2. Single-crystal X-ray structure of 4.
All the analytical data obtained by us for the synthetic
pestaloficiol J match very well those reported for the natu-
ral product.[58] Although the natural product has been de-
scribed as a colourless oil, we obtained pestaloficiol J (4) as
a crystalline material. The structure of 4 was confirmed by
single-crystal X-ray structure analysis (Figure 2); intermo-
lecular hydrogen bonds contribute to the stabilization of the
crystal packing (see the Supporting Information for details
and graphic representation).[61]
Synthesis of Precursors for Tandem Claisen
Rearrangement/6-endo-dig Cyclization Sequences
The tandem Claisen rearrangement/6-endo-dig cycliza-
tion precursors can be obtained by a three-step synthesis
starting from various salicylaldehydes 12 (Table 2). The al-
dehydes 12 were first treated with allyl, crotyl or prenyl
bromide to furnish substituted O-allylated aldehydes 14.
These were treated with Li acetylides, obtained from alk-
ynes 15 by metallation with butyllithium, to give the prop-
argylic alcohols 18. In some cases the Li acetylide was re-
placed by the analogous Grignard reagent. Lithium hexa-
methyldisilazane (LiHMDS) had to be used instead of BuLi
for the metallation of 15f, 15j and 15k to avoid nucleophilic
attack (15f, 15j) or halogen/metal exchange (15k). Alkynes
15h–o were synthesized from the corresponding aldehydes
16 and the Bestmann–Ohira reagent 17.[62,63] The proparg-
ylic alcohols 18 were then oxidized to the ketones 19 by
using either MnO2 (method A) or the method of Ley et al.
(method B).[60]
Scheme 3. Synthesis of pestaloficiol J (4).
Eur. J. Org. Chem. 2015, 7602–7611
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7605

B. Schmidt, M. Riemer, U. Schilde
FULL PAPER
Table 2. Synthesis of Claisen rearrangement/6-endo-dig cyclization precursors.
7606
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 7602–7611

Approach to Allylated and Prenylated Chromones
Table 2. (Continued).
[a] Purchased reagents. [b] Grignard reagent used instead of Li acetylide. [c] LiHMDS used instead of BuLi. [d] E/Z-ratio approx. 6:1,
1
as determined by H NMR spectroscopy.
For the synthesis of biaryl 19x, aldehyde 12f was re- the reaction of the bis-acetylides 15p,q with 2 equiv. of alde-
quired, which was synthesized by Suzuki–Miyaura coupling hyde 14a followed by the oxidation of the resulting proparg-
of 12c and boronic acid 20 (Scheme 4) under conditions ylic alcohols 18y,z to the corresponding ketones 19y,z
recently developed by us.[64] With a view to synthesizing (Scheme 5). 1,4-Diethynylbenzene (15p) was obtained from
dimeric chromones, precursors 19y,z were synthesized by terephthaldehyde and 2 equiv. of the Bestmann–Ohira rea-
gent 17.
Microwave-Promoted Sigmatropic Rearrangements/6-endo-
dig Cyclization Sequences
Precursors 19a–z were subjected to microwave irradiation
Scheme 4. Synthesis of 5-arylsalicylic aldehyde 12f.
using the optimized conditions (Table 3). The majority of
Scheme 5. Synthesis of precursors for an envisaged double-tandem Claisen rearrangement/6-endo-dig cyclization sequence.
Eur. J. Org. Chem. 2015, 7602–7611
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7607

B. Schmidt, M. Riemer, U. Schilde
FULL PAPER
alkynones 19 were successfully converted into chromones group. An interesting observation was made for the micro-
21 in moderate-to-good yields. A notable exception was the wave-promoted Claisen rearrangement/cyclization of 19f: in
p-nitrophenyl-substituted precursor 19j, which reacted to this case the saturated product 21f was the only isolable
give a complex mixture of highly polar compounds without product. We assume that the presence of two electron-with-
a defined and isolable major product. Difficulties were also drawing groups favours the transfer hydrogenation of the
observed for all precursors with more than one allyl or alk- intermediate chromone. The solvent N,N-diethylaniline
ynone moiety, that is, 19v, 19y and 19z. Microwave irradia- might be the hydrogen source.
tion of these precursors resulted in the formation of com-
The substitution patterns of chromones 21 reflect those
plex product mixtures. Defined products, albeit in low observed upon microwave irradiation of the simple allyl and
yields, were obtained from 19a, 19e and 19f. The 2-unsub- prenyl ethers 1 (Table 1). Thus, prenyl ethers 19o, 19s, 19t,
stituted chromone 21a, which was obtained from a 6-endo- 19u and 19w underwent a dual [3,3] sigmatropic “Claisen-
dig cyclization of a terminal alkyne, was isolated in a yield then-Cope” rearrangement cascade to the expected 6-pren-
comparable to that observed for the analogous 6-endo-trig ylated chromones, whereas rearrangement of the crotyl
cyclization.[34] In the case of chromone 21e, the cyclization ether 19n stops at the Claisen stage to give an 8-(1Ј-methyl-
is probably hampered by the steric demand of the SiMe3 allyl)-substituted chromone 21n. A remarkable side-reac-
Table 3. Microwave-promoted Claisen/Cope rearrangement/6-endo-dig cyclization sequence of precursors 19.[a]
[a] Only examples leading to defined products are shown. [b] 19f yielded chroman-4-one 21f rather than the expected chromone, see
discussion. [c] In N,N-dimethylaniline; yield in N,N-diethylaniline 67%. [d] Quantitative cleavage of the MOM ether at C-5 occurred
during microwave irradiation. [e] Partial cleavage of the MOM ether at C-5 occurred during microwave irradiation. [f] 21w and 21wЈ were
obtained from 19w as a separable mixture.
7608
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 7602–7611

Approach to Allylated and Prenylated Chromones
tion was observed for some samples bearing MOM ethers: 6-endo-dig fashion to the major product 21w. The minor
upon microwave irradiation, selective partial or quantitative pathway, leading to 21wЈ, might involve transfer of an all-
cleavage of the MOM ether at C-5 was observed for 21r, ylic hydrogen to the carbonyl oxygen, cleavage of the C–C-
21s/21sЈ and 21u/21uЈ. The structures of these examples bond and formation of isoprene to give C, which eventually
were elucidated by using 2D NMR methods. In particular, undergoes 6-endo-dig cyclization.
HMBC experiments were found to be useful for locating
the prenyl or allyl substituent, and in the case of partially
Conclusions
deprotected products, the remaining MOM group and the
unprotected phenol.[65] Currently we cannot decide whether
the partial MOM deprotection occurs during microwave ir-
radiation (probably induced by trace amounts of water in
the solvent) or upon work-up.
We have reported herein a microwave-promoted tandem
sequence that combines one or two [3,3] sigmatropic re-
arrangements with a 6-endo cyclization. The starting mate-
rials are allyl or prenyl aryl ethers with an adjacent enone
or alkynone moiety. During the synthesis of the precursors,
the allyl or prenyl ether serves as a phenol protecting group,
which becomes an essential part of the target structure
upon cleavage, that is, an 8-allyl or 6-prenyl substituent,
respectively. Allylated or prenylated chromones or chro-
man-4-ones are widespread in nature and can also be used
as building blocks for the synthesis of other natural or non-
natural chromone derivatives. The usefulness of the method
is illustrated by the first synthesis of the fungal metabolite
pestaloficiol J. In addition, several chromones synthesized
in the course of this study have substitution and oxy-
genation patterns that are present in bioactive plant metab-
olites, for example, 21r (eranthin[69]), 21s (peucenin[70]), 21u
(6-prenylapigenin[71]) and 21w (licoflavone A[72]). Investi-
gations into the application of microwave-promoted tandem
sigmatropic rearrangement/cyclization cascades for target
molecule synthesis are currently underway in our labora-
tory.
The formation of 21w, which is unsubstituted at C-5, pro-
ceeded without notable cleavage of the MOM ethers at C-
7 or C-4Ј, but was accompanied to a minor extent by depre-
nylation to yield 21wЈ. Reports describing the traceless re-
moval of a prenyl group[66] in the absence of acids or bases
are scarce. We are aware of an example described by Lauer
and Moe, who investigated the pyrolysis of the prenyl ether
of p-hydroxybenzoate.[67] They found that heating this com-
pound at temperatures above 200 °C for longer periods of
time resulted in the formation of p-hydroxybenzoate and
isoprene. More recently, Jun and co-workers discussed ther-
mal deprenylation as a major obstacle in the synthesis of
prenylated chalcones from prenyl ethers.[68] We assume that
21wЈ also results from the cleavage of isoprene, either at the
stage of the Claisen rearrangement or at the stage of the
Cope rearrangement (Scheme 6). According to this mech-
anistic scenario, the prenyl group in 19w would first un-
dergo Claisen rearrangement to A, which would then
rapidly isomerize to B by a Cope rearrangement. Tauto-
merization would then give phenol D, which cyclizes in a
Experimental Section
General: All experiments were conducted in dry reaction vessels
under dry nitrogen. Solvents were purified by standard procedures.
1H NMR spectra were obtained at 300 or 500 MHz in CDCl3 with
CHCl3 (δ = 7.26 ppm) as internal standard. Chemical shifts are
given in ppm and coupling constants are given in Hz. 13C NMR
spectra were recorded at 75 or 125 MHz in CDCl3, which also
acted as internal standard (δ = 77.0 ppm). If the sample was insuf-
ficiently soluble in CDCl3, [D6]DMSO {[D5]DMSO as internal
standard for 1H NMR spectroscopy (δ = 2.50 ppm), [D6]DMSO as
internal standard for 13C NMR spectroscopy (δ = 39.5 ppm)} or
[D4]methanol [CD2HOD as internal standard for 1H NMR spec-
troscopy (δ = 3.31 ppm), CD3OD as internal standard for 13C
NMR spectroscopy (δ = 49.2 ppm)] was used. IR spectra were re-
corded as ATR-FTIR spectra. The peak intensities are defined as
strong (s), medium (m), or weak (w). Low- and high-resolution
mass spectra were obtained by means of the EI-TOF or ESI-TOF
technique.
General Procedure for the Microwave-Promoted Tandem Sigma-
tropic Rearrangement/6-endo-Cyclization Sequence: The appropri-
ate precursor 3 or 19 (1.0 mmol) was dissolved in N,N-diethylanil-
ine (5–10 mL) in a vessel suited for microwave irradiation. The ves-
sel was sealed and irradiated in a dedicated microwave reactor at
250 °C for 1 h. After cooling to ambient temperature, the mixture
was diluted with ethyl acetate (50 mL) and extracted with aqueous
HCl (1 m, 3ϫ10 mL for each extraction) to remove the aniline. The
organic extracts were dried with MgSO4, filtered and the solvents
Scheme 6. Possible scenarios leading to 21wЈ.
Eur. J. Org. Chem. 2015, 7602–7611
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7609

B. Schmidt, M. Riemer, U. Schilde
FULL PAPER
evaporated. The residue was purified by column chromatography
on silica with hexane/MTBE mixtures of increasing polarity as elu-
ent to furnish the chroman-4-ones 10 or chromones 21.
133.2, 133.1, 124.8, 123.0, 121.3, 108.4, 79.3, 49.2, 28.9, 26.7, 25.9,
17.9 ppm. IR (ATR): ν = 3362 (br w), 2925 (s), 1670 (m), 1465 (s),
˜
1166 (m) cm–1. HRMS (EI): calcd. for C16H20O3 [M]+ 260.1412;
found 260.1406. The spectroscopic data match those reported by
Liu et al.[58] for the natural product pestaloficiol J.
6-[(tert-Butyldimethylsilyl)oxy]-2,2-dimethyl-8-(3-methylbut-2-en-
1-yl)chroman-4-one (10b): Following the general procedure, 3b
(89 mg, 0.24 mmol) was converted into 10b (89 mg, 0.24 mmol,
1
quant.). Colourless oil. H NMR (300 MHz, C6D6): δ = 7.73 (d, J
Acknowledgments
= 3.1 Hz, 1 H), 7.11 (d, J = 3.1 Hz, 1 H), 5.42–5.31 (m, 1 H), 3.37
(d, J = 7.4 Hz, 2 H), 2.30 (s, 2 H), 1.65 (s, 3 H), 1.60 (s, 3 H), 1.05
(s, 6 H), 0.98 (s, 9 H), 0.15 (s, 6 H) ppm. 13C NMR (75 MHz,
C6D6): δ = 191.5, 152.8, 149.5, 132.9, 132.7, 128.7, 122.6, 121.2,
The authors thank Evonik-Oxeno for generous donations of sol-
vents. Support from the equal opportunities fund of the faculty of
113.4, 78.6, 48.7, 28.8, 26.4, 25.9, 25.8, 18.4, 17.9, –4.4 ppm. IR science is gratefully acknowledged.
(ATR): ν = 1691 (m), 1610 (w), 1463 (s), 1253 (m), 1167 (m) cm–1.
˜
HRMS (EI): calcd. for C22H34O3Si [M]+ 374.2277; found 374.2273.
[1] X. Yu, S.-M. Li, in: Methods in Enzymology, vol. 516 (Ed.:
D. A. Hopwood), Academic Press, Oxford, 2012, p. 259–278.
[2] W. Brandt, L. Bräuer, N. Günnewich, J. Kufka, F. Rausch, D.
Schulze, E. Schulze, R. Weber, S. Zakharova, L. Wessjohann,
Phytochemistry 2009, 70, 1758–1775.
8-Allyl-2-propyl-4H-chromen-4-one (21c): Following the general
procedure, 19c (158 mg, 0.69 mmol) was converted into 21c
(110 mg, 0.48 mmol, 70%). Colourless oil. 1H NMR (300 MHz,
CDCl3): δ = 8.01 (dd, J = 7.9, 1.2 Hz, 1 H), 7.43 (d, J = 7.3 Hz, 1
H), 7.24 (t, J = 7.6 Hz, 1 H), 6.13 (s, 1 H), 5.95 (ddd, J = 17.1,
10.3, 6.1 Hz, 1 H), 5.07 (d, J = 10.3 Hz, 1 H), 5.05 (d, J = 17.1 Hz,
1 H), 3.56 (d, J = 6.5 Hz, 2 H), 2.57 (t, J = 7.5 Hz, 2 H), 1.74 (qt,
J = 7.5, 7.4 Hz, 2 H), 0.98 (t, J = 7.4 Hz, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 178.6, 169.1, 154.5, 135.4, 133.7, 129.2,
124.6, 123.8, 123.8, 116.7, 109.8, 36.2, 33.8, 20.2, 13.5 ppm. IR
[3] K. Yazaki, K. Sasaki, Y. Tsurumaru, Phytochemistry 2009, 70,
1739–1745.
[4] R. Chen, X. Liu, J. Zou, Y. Yin, B. Ou, J. Li, R. Wang, D. Xie,
P. Zhang, J. Dai, Adv. Synth. Catal. 2013, 355, 1817–1828.
[5] J. A. McIntosh, M. S. Donia, S. K. Nair, E. W. Schmidt, J. Am.
Chem. Soc. 2011, 133, 13698–13705.
[6] O. Saleh, Y. Haagen, K. Seeger, L. Heide, Phytochemistry 2009,
(ATR): ν = 2964 (w), 1648 (s), 1586 (m), 1380 (m), 757 (m) cm–1.
˜
70, 1728–1738.
HRMS (EI): calcd. for C15H16O2 [M]+ 228.1150; found 228.1156.
[7] S. K. Sharma, S. Kumar, K. Chand, A. Kathuria, A. Gupta,
R. Jain, Curr. Med. Chem. 2011, 18, 3825–3852.
[8] N. C. Veitch, R. J. Grayer, Nat. Prod. Rep. 2011, 28, 1626–1695.
[9] D. Barron, R. K. Ibrahim, Phytochemistry 1996, 43, 921–982.
[10] A. M. Alhassan, M. I. Abdullahi, A. Uba, A. Umar, Trop. J.
Pharm. Res. 2014, 13, 307–314.
[11] W. Wätjen, N. Weber, Y. j. Lou, Z. q. Wang, Y. Chovolou, A.
Kampkötter, R. Kahl, P. Proksch, Food Chem. Toxicol. 2007,
45, 119–124.
[12] P. Basabe, M. de Román, I. S. Marcos, D. Diez, A. Blanco, O.
Bodero, F. Mollinedo, B. G. Sierra, J. G. Urones, Eur. J. Med.
Chem. 2010, 45, 4258–4269.
[13] S. R. Milligan, J. C. Kalita, V. Pocock, V. Van De Kauter, J. F.
Stevens, M. L. Deinzer, H. Rong, D. De Keukeleire, J. Clin.
Endocrinol. Metab. 2000, 85, 4912–4915.
6-(3-Methylbut-2-en-1-yl)-2-propyl-4H-chromen-4-one (21o): Fol-
lowing the general procedure, 19o (147 mg, 0.57 mmol) was con-
verted into 21o (83 mg, 0.32 mmol, 56%). Colourless oil. 1H NMR
(300 MHz, CDCl3): δ = 7.94 (s, 1 H), 7.42 (dd, J = 8.6, 2.1 Hz, 1
H), 7.30 (dd, J = 8.6, 0.8 Hz, 1 H), 6.13 (s, 1 H), 5.29 (tm, J =
7.3 Hz, 1 H), 3.39 (d, J = 7.3 Hz, 2 H), 2.55 (t, J = 7.5 Hz, 2 H),
1.81–1.65 (m, 2 H), 1.72 (s, 3 H), 1.69 (s, 3 H), 0.98 (t, J = 7.3 Hz,
3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 178.6, 169.4, 155.1,
138.9, 134.0, 133.4, 124.4, 123.5, 122.5, 117.8, 109.8, 36.2, 33.8,
25.8, 20.3, 17.9, 13.6 ppm. IR (ATR): ν = 2965 (w), 1648 (s), 1483
˜
(m), 1447 (m), 1373 (m) cm–1. HRMS (EI): calcd. for C17H20O2
[M]+ 256.1463; found 256.1488.
[14] M. Rad, M. Hümpel, O. Schaefer, R. C. Schoemaker, W. D.
Schleuning, A. F. Cohen, J. Burggraaf, Br. J. Clin. Pharmacol.
2006, 62, 288–296.
[15] O. Zierau, S. Gester, P. Schwab, P. Metz, S. Kolba, M. Wulf,
G. Vollmer, Planta Med. 2002, 68, 449–451.
[16] F. Roelens, N. Heldring, W. Dhooge, M. Bengtsson, F. Com-
haire, J.-Å. Gustafsson, E. Treuter, D. De Keukeleire, J. Med.
Chem. 2006, 49, 7357–7365.
[17] G. Kretzschmar, O. Zierau, J. Wober, S. Tischer, P. Metz, G.
Vollmer, J. Steroid Biochem. Mol. Biol. 2010, 118, 1–6.
[18] C. Urmann, E. Oberbauer, S. Couillard-Després, L. Aigner, H.
Riepl, Planta Med. 2015, 81, 305–311.
8-Allyl-6-(2-methoxyphenyl)-2-phenyl-4H-chromen-4-one (21x): Fol-
lowing the general procedure, 19x (141 mg, 0.38 mmol) was con-
verted into 21x (92 mg, 0.25 mmol, 65%). Colourless oil. 1H NMR
(300 MHz, CDCl3): δ = 8.31 (d, J = 2.2 Hz, 1 H), 7.99–7.91 (m, 2
H), 7.81 (d, J = 2.2 Hz, 1 H), 7.57–7.53 (m, 3 H), 7.41 (dd, J =
7.2, 1.7 Hz, 1 H), 7.36 (dd, J = 8.1, 1.7 Hz, 1 H), 7.07 (td, J = 7.5,
1.0 Hz, 1 H), 7.03 (d, J = 8.2 Hz, 1 H), 6.89 (s, 1 H), 6.16 (ddt, J
= 16.6, 10.1, 6.5 Hz, 1 H), 5.26 (dm, J = 16.8 Hz, 1 H), 5.22 (dm,
J = 10.1 Hz, 1 H), 3.85 (s, 3 H), 3.83 (d, J = 6.7 Hz, 2 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 178.8, 162.9, 156.5, 153.4, 135.8,
135.6, 135.4, 132.1, 131.6, 130.9, 129.2, 129.1, 129.0, 128.9, 126.2,
124.3, 124.8, 121.0, 117.0, 111.3, 107.4, 55.6, 34.1 ppm. IR (ATR):
[19] S. P. Wong, P. Shen, L. Lee, J. Li, E. L. Yong, J. Pharm. Bio-
med. Anal. 2009, 50, 216–223.
ν = 1640 (s), 1463 (m), 1364 (s), 1244 (m), 1025 (m) cm–1. HRMS
˜
[20] S. Gester, P. Metz, O. Zierau, G. Vollmer, Tetrahedron 2001, 57,
(EI): calcd. for C25H20O3 [M]+ 368.1412; found 368.1409.
1015–1018.
6-Hydroxy-2,2-dimethyl-8-(3-methylbut-2-en-1-yl)chroman-4-one [21] Q. Mei, C. Wang, Z. Zhao, W. Yuan, G. Zhang, Beilstein J.
Org. Chem. 2015, 11, 1220–1225.
[22] T. Kawamura, M. Hayashi, R. Mukai, J. Terao, H. Nemoto,
Synthesis 2012, 44, 1308–1314.
[23] V.-S. Nguyen, L.-P. Dong, S.-C. Wang, Q. Wang, Eur. J. Org.
Chem. 2015, 2297–2302.
[24] J. Allan, R. Robinson, J. Chem. Soc. Trans. 1924, 125, 2192–
2195.
[25] J. Santamaria, C. Valdés, in: Modern Heterocyclic Chemistry,
vol. 3 (Eds.: J. Alvarez-Builla, J. J. Vaquero, J. Barluenga),
Wiley-VCH, Weinheim, Germany, 2011, p. 1631–1682.
(Pestaloficiol J, 4): TBAF·3H2O (62 mg, 0.20 mmol) was added to
a solution of 10b (67 mg, 0.18 mmol) in THF (2 mL) at 0 °C. The
solution was stirred for 0.5 h, all the volatiles were evaporated and
the residue was purified by column chromatography to give 4
(43 mg, 0.17 mmol, 93%). Colourless solid, m.p. 116–118 °C. 1H
NMR (300 MHz, [D6]acetone): δ = 8.08 (s, 1 H), 7.06 (d, J =
3.0 Hz, 1 H), 6.93 (d, J = 2.9 Hz, 1 H), 5.27 (t, J = 7.4 Hz, 1 H),
3.27 (d, J = 7.4 Hz, 2 H), 2.68 (s, 2 H), 1.72 (s, 6 H), 1.42 (s, 6
H) ppm. 13C NMR (75 MHz, [D6]acetone): δ = 192.6, 152.1, 151.5,
7610
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 7602–7611

Approach to Allylated and Prenylated Chromones
[26] A. Minassi, A. Giana, A. Ech-Chahad, G. Appendino, Org. [52] R. L. Farmer, M. M. Biddle, A. E. Nibbs, X. Huang, R. C.
Lett. 2008, 10, 2267–2270.
Bergan, K. A. Scheidt, ACS Med. Chem. Lett. 2010, 1, 400–
[27] L. F. Tietze, Chem. Rev. 1996, 96, 115–136.
[28] A. C. Jones, J. A. May, R. Sarpong, B. M. Stoltz, Angew. Chem.
Int. Ed. 2014, 53, 2556–2591.
405.
[53] F. Dallacker, R. Sluysmans, Monatsh. Chem. 1969, 100, 560–
566.
[29] Y.-L. Shi, M. Shi, Org. Biomol. Chem. 2007, 5, 1499–1504.
[30] J. Renault, Z. Qian, P. Uriac, N. Gouault, Tetrahedron Lett.
2011, 52, 2476–2479.
[54] S. M. Sakya, B. Abrams, S. L. Snow, B. Rast, Tetrahedron Lett.
2008, 49, 2280–2282.
[55] P. Wipf, S. Rodríguez, Adv. Synth. Catal. 2002, 344, 434–440.
[56] L. Liu, Mycologia 2011, 2, 37–45.
[57] S. Liu, L. Guo, Y. Che, L. Liu, Fitoterapia 2013, 85, 114–118.
[58] L. Liu, S. Liu, S. Niu, L. Guo, X. Chen, Y. Che, J. Nat. Prod.
2009, 72, 1482–1486.
[59] M. Riemer, Synlett 2014, 25, 1041–1042.
[60] S. V. Ley, J. Norman, W. P. Griffith, S. P. Marsden, Synthesis
1994, 639–666.
[61] Crystal data for 4: C16H20O3, Mr = 260.32, crystal dimensions
0.70ϫ0.60ϫ0.25 mm, monoclinic, space group P21/n (No. 14),
a = 15.3879(10), b = 5.9334(3), c = 70.3096(11) Å, β =
114.196(5)°, V = 1441.57(16) Å3, Z = 4, ρcalcd. = 1.199 g/cm3,
μ(Mo-Kα) = 0.082 mm–1 (λ = 0.0173 Å), 2θmax = 25.00°, 4780
reflections measured, 4780 unique (Rint = 0.0150), R1 = 0.0295,
wR = 0.072 [IϾ2σ(I)]. CCDC-1415432 contains the supple-
mentary crystallographic data for this compound. These data
can be obtained free of charge from the Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request.cif.
Further crystallographic details can be found in the Supporting
Information.
[31] X. Wang, G. Cheng, X. Cui, Chem. Commun. 2014, 50, 652–
654.
[32] K. R. Prasad, C. Nagaraju, Org. Lett. 2013, 15, 2778–2781.
[33] D. R. Mou, W. Zhao, T. Zhang, L. Wan, G. Y. Yang, Y. K.
Chen, Q. F. Hu, M. M. Miao, Heterocycles 2012, 85, 2485–
2490.
[34] B. Schmidt, M. Riemer, U. Schilde, Synlett 2014, 25, 2943–
2946.
[35] D. Iguchi, R. Erra-Balsells, S. M. Bonesi, Tetrahedron Lett.
2014, 55, 4653–4656.
[36] M. Yoshida, Y. Fujino, K. Saito, T. Doi, Tetrahedron 2011, 67,
9993–9997.
[37] A. K. Ghosh, X. Cheng, B. Zhou, Org. Lett. 2012, 14, 5046–
5049.
[38] B. R. Nawghare, S. S. Sakate, P. D. Lokhande, J. Heterocycl.
Chem. 2014, 51, 291–302.
[39] C. Taylor, Y. Bolshan, Tetrahedron Lett. 2015, 56, 4392–4396.
[40] L. Claisen, Ber. Dtsch. Chem. Ges. 1912, 45, 3157–3166.
[41] D. S. Tarbell, Org. React. 1944, 2, 1.
[42] A. M. Martín Castro, Chem. Rev. 2004, 104, 2939–3002.
[43] F. Scheinmann, R. Barner, H. Schmid, Helv. Chim. Acta 1968,
51, 1603–1608.
[62] S. Ohira, Synth. Commun. 1989, 19, 561–564.
[63] S. Müller, B. Liepold, G. J. Roth, H. J. Bestmann, Synlett 1996,
521–522.
[64] B. Schmidt, M. Riemer, J. Org. Chem. 2014, 79, 4104–4118.
[65] See the Supporting Information for details.
[66] F. Guibé, Tetrahedron 1997, 53, 13509–13556.
[67] W. M. Lauer, O. Moe, J. Am. Chem. Soc. 1943, 65, 289–293.
[68] J.-H. Jeon, M. R. Kim, J.-G. Jun, Synthesis 2011, 370–376.
[69] M. Bruder, P. L. Haseler, M. Muscarella, W. Lewis, C. J.
Moody, J. Org. Chem. 2010, 75, 353–358.
[70] E. S. Waight, T. K. Razdan, B. Qadri, S. Harkar, Phytochemis-
try 1987, 26, 2063–2069.
[71] B. T. Ngadjui, E. Dongo, B. M. Abegaz, S. Fotso, H. Tamboue,
Phytochemistry 2002, 61, 99–104.
[44] C. O. Kappe, Angew. Chem. Int. Ed. 2004, 43, 6250–6284; An-
gew. Chem. 2004, 116, 6408.
[45] C. O. Kappe, Chimia 2006, 60, 308–312.
[46] C. O. Kappe, Chem. Soc. Rev. 2008, 37, 1127–1139.
[47] A. de la Hoz, A. Loupy (Eds.), Microwaves in Organic Synthe-
sis, Wiley-VCH, Weinheim, Germany, 2012.
[48] R. J. Giguere, T. L. Bray, S. M. Duncan, G. Majetich, Tetrahe-
dron Lett. 1986, 27, 4945–4948.
[49] M. D. Bowman, J. R. Schmink, C. M. McGowan, C. M.
Kormos, N. E. Leadbeater, Org. Process Res. Dev. 2008, 12,
1078–1088.
[50] K.-S. Huang, E.-C. Wang, H.-M. Chen, J. Chin. Chem. Soc.
2004, 51, 585–605.
[51] T. Martin, C. J. Moody, J. Chem. Soc. Perkin Trans. 1 1988,
241–246.
[72] S.-I. Ayabe, M. Kobayashi, M. Hikichi, K. Matsumoto, T. Fu-
ruya, Phytochemistry 1980, 19, 2179–2183.
Received: September 4, 2015
Published Online: October 29, 2015
Eur. J. Org. Chem. 2015, 7602–7611
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7611