Scope and Applications of 2,3-Oxidative Aryl Rearrangements for the Synthesis of Isoflavone Natural Products

DOI: 10.1021/acs.joc.1c01375

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Journal of Organic Chemistry p. 10699 - 10712 (2021)

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Kwesiga, George

Schmidt, Bernd

Sperlich, Eric

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Article abstract of DOI:10.1021/acs.joc.1c01375

The reaction of flavanones with hypervalent iodine reagents was investigated with a view to the synthesis of naturally occurring isoflavones. In contrast to several previous reports in the literature, we did not observe the formation of any benzofurans via a ring contraction pathway, but could isolate only isoflavones, resulting from an oxidative 2,3-aryl rearrangement, and flavones, resulting from an oxidation of the flavanones. Although the 2,3-oxidative rearrangement allows a synthetically useful approach toward some isoflavone natural products due to the convenient accessibility of the required starting materials, the overall synthetic utility and generality of the reaction appear to be more limited than previous literature reports suggest.

Full text of DOI:10.1021/acs.joc.1c01375

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Scope and Applications of 2,3-Oxidative Aryl Rearrangements for

the Synthesis of Isoﬂavone Natural Products

George Kwesiga, Eric Sperlich, and Bernd Schmidt*

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ABSTRACT: The reaction of ﬂavanones with hypervalent iodine reagents

was investigated with a view to the synthesis of naturally occurring

isoﬂavones. In contrast to several previous reports in the literature, we did

not observe the formation of any benzofurans via a ring contraction

pathway, but could isolate only isoﬂavones, resulting from an oxidative 2,3-

aryl rearrangement, and ﬂavones, resulting from an oxidation of the

ﬂavanones. Although the 2,3-oxidative rearrangement allows a synthetically

useful approach toward some isoﬂavone natural products due to the

convenient accessibility of the required starting materials, the overall

synthetic utility and generality of the reaction appear to be more limited

than previous literature reports suggest.

Scheme 1. Examples for Oxidative Rearrangements with 1,2-

Aryl Migration

INTRODUCTION

■

Hyper- or polyvalent iodine compounds have emerged as highly

useful reagents for organic transformations,¹⁻⁵such as oxidation

of alcohols,⁶⁻⁹oxidative dearomatization of phenols,¹⁰halo-

genations,¹⁰cyclizative C−N-bond formations,¹¹or C−C-bond

forming reactions.^11,12Of these reagents many are stable and

isolable¹⁻⁴and promote oxidative transformations with high

selectivity under fairly mild conditions, which makes them ideal

tools for the total synthesis of natural products.^13,14In some

transformations mediated by hypervalent iodine compounds an

oxidation of the organic substrate is coupled with a rearrange-

ment reaction,¹⁵⁻¹⁷which often involves a 1,2-aryl migration

step. Early examples for such transformations are the oxidative

rearrangements of aryl ethyl ketones 1 to 2-aryl propionic acids

3, mediated by (diacetoxyiodo)benzene (PIDA, 2a),¹⁸of

chalcones 4 to 1,2-diarylsubstituted propanones 6, mediated

by [hydroxyl(tosyloxy)iodo]benzene (HTIB, 5)¹⁹or of

ﬂavanones 7 to isoﬂavones 8, mediated by HTIB (5)²⁰(Scheme

1).

Related oxidative rearrangements that proceed through

similar mechanisms had previously been reported using

stoichiometric amounts of thallium-III-salts²¹⁻²⁸which nicely

illustrates the similarities in reactivity between hypervalent

iodine compounds and some heavy metal salts pointed out in

several reviews.^1,8,12,15

Our interest in such oxidative rearrangements arose from a

research project directed at the structural characterization, total

synthesis, and biological evaluation of isoﬂavones²⁹⁻³²isolated

from East African medicinal plants of the genus Erythrina.³³

Plants of this family are traditionally used for the treatment of

inﬂammations and infections³⁴⁻³⁸and secondary metabolites

with a prenylated isoﬂavone core appear to contribute notably to

their anti-infective activity (Figure 1).^33,39−43

Received: June 10, 2021

Published: July 27, 2021

https://doi.org/10.1021/acs.joc.1c01375

J. Org. Chem. 2021, 86, 10699−10712

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Scheme 2. Proposed Mechanisms for the Formation of

Oxidative Rearrangement Products from Flavanones

Figure 1. Prenylated isoﬂavones from African medicinal plants and

references describing their isolation: 5-deoxy-3′-prenylbiochanin A

(9),⁴¹erysubin F (10),⁴¹3′-prenylbiochanin A (11),⁴⁴7-methox-

yebenosin (12).⁴⁵

Isoﬂavones possess a 3-aryl ﬂavone structure 8 and are

biosynthetically derived from ﬂavanones 7 through an oxidative

rearrangement catalyzed by the cytochrome P450 enzyme

isoﬂavone synthase (IFS).⁴⁶⁻⁴⁸Intrigued by this biosynthetic

relationship and encouraged by literature precedence for the

total synthesis of isoﬂavonoids from ﬂavanones or chalcones via

Tl(III)-²³⁻²⁸or hypervalent iodine-mediated^20,49−53oxidative

1,2-aryl migration, we decided to investigate the potential of this

reaction for the total synthesis of prenylated isoﬂavones. At the

outset of this project we undertook a comprehensive survey of

the literature examples for ﬂavanone to isoﬂavone oxidative

rearrangements (reaction 7 → 8 in Scheme 1). While some

groups report the selective formation of isoﬂavones 8 upon

treatment of ﬂavanones 7 with either Tl(III)-salts²⁶⁻²⁸or

hypervalent iodine compounds,^20,54others report that benzo-

furans 13⁵⁴⁻⁶⁰or ﬂavones 14^54,61are the main or exclusive

products, or that mixtures of these three products⁶²were

obtained. The formation of all three types of oxidative

rearrangement products 8, 13, and 14 can be explained from a

common intermediate 15, which is formed by electrophilic

iodination of ﬂavanone 7 with a hypervalent iodine reagent Ph−

IX₂at the α-position of the carbonyl group.⁵⁹Isoﬂavones 8 result

from a 1,2-migration of the aryl substituent at C2 with

elimination of iodobenzene and H−X. This pathway proceeds

via an oxocarbenium ion 16. Benzofurans 13 arise from a ring

contraction by 1,2-migration of the other aryl moiety. The

intermediate acyl carbenium ion 17 is trapped by the solvent

methanol to form an ester group. Flavones 14 are formed from

intermediate 15 by β-elimination of iodobenzene and H−X

(Scheme 2).

RESULTS AND DISCUSSION

■

Screening of Hypervalent Iodine Reagents for the

Oxidative Rearrangement of 18. The screening of hyper-

valent iodine reagents was performed with the MOM-protected

ﬂavanone 18, which has previously been synthesized and used by

us to obtain the prenylated isoﬂavone 5-deoxy-3′-prenylbiocha-

nin A (9) for antibiotic testing.³³We ﬁrst tested [hydroxy-

(tosyloxy)iodo]benzene (HTIB, 5) as an oxidant because

Prakash et al. had previously reported that this reagent in

acetonitrile promotes the oxidative 2,3-aryl rearrangement of

ﬂavanones to isoﬂavones selectively.²⁰In our case we only

observed cleavage of the MOM-ether and isolated the 7-

hydroxyﬂavanone 19³³in 46% yield (Table 1, entry 1). This was

also the main product when acetonitrile was replaced by

methanol as a solvent, but in addition the chalcone 20 and the

desired deprotected isoﬂavone 22³³were isolated in notable

amounts (entry 2). When the oxidant HTIB was used in excess,

the amount of oxidative rearrangement product 22 increased to

28%, but the deprotected starting material 19 and chalcone 20

were still obtained in signiﬁcant quantities (entry 3). Heating the

reaction to 60 °C did not accelerate the desired oxidative

rearrangement reaction notably over the undesired cleavage of

the MOM-ether and the elimination leading to the chalcone

(entry 4). Replacing HTIB (5) by iodobenzene diacetate

(phenyliodonium diacetate, PIDA, 2a) resulted in the recovery

of unreacted starting material in acetonitrile (entry 5) and in

methanol (entry 6). With iodobenzene bis(triﬂuoroacetate)

(phenyliodonium bis(triﬂuoroacetate), PIFA, 2b), the same

result was observed in acetonitrile (entry 7), whereas a small

amount of MOM-protected ﬂavone 23 was isolated as the only

product, along with unreacted starting material, in methanol

(entry 8). An attempt to accelerate the reaction in acetonitrile by

adding a catalytic amount of acid failed and led to the recovery of

starting material (entry 9).

Herein we report our results on the application of the 2,3-

oxidative aryl rearrangement mediated by hypervalent iodine

compounds as a key step in the synthesis of prenylated

isoﬂavones. The main questions to be investigated are as

follows: Do these rearrangements proceed with synthetically

useful chemoselectivities toward the formation of isoﬂavones?

Can selectivity and isolated yield be inﬂuenced by the choice of

hypervalent iodine reagent, the solvent, and the reaction

conditions? Are allyl groups, which are required as precursors

for the prenyl substituents in our synthetic route, compatible

with the hypervalent iodine reagents?

We then turned our attention to conditions that have

previously been reported to preferentially induce a ring

contraction (pathway 15 → 13 in Scheme 2). These conditions

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Table 1. Evaluation of Hypervalent Iodine Reagents for 2,3-Oxidative Rearrangement

entry

oxidant (equiv)

solvent

additive (equiv)

temp (° C)

19 (%)

20 (%)

21 (%)

22 (%)

23 (%)

24 (%)

HTIB (1.0)

HTIB (1.5)

PIDA (1.0)

PIFA (1.0)

PIDA (1.0)

PIDA (1.5)

PIFA (1.5)

PIDA (1.5)

CH₃CN

−

n.d.

no conversion

n.d.

no conversion

20 n.d.

27 15

no conversion

n.d.

CH₃OH

CH₃CN

CH₃OH

CH₃CN

CH₃OH

CH₃CN

CH(OMe)₃

n.d.

p-TSA (0.4)

H₂SO₄(0.4)

CF₃CO₂H (0.4)

n.d.

n.d.: not detected.

Table 2. Synthesis of Flavanones 28 without 8-Allyl Substituent

entry

R¹

R²

R³

R⁴

yield (%)

25a

26a³³

26b⁶⁶

OCH₃

OMOM

OCH₃

CH₂CHCH₂

27aa

28aa

25b⁶³

25c⁶⁴

25d⁶⁵

25e⁶⁸

OMOM

OCH₃

OMOM

OCH₃

27ba

28ba

28ca

27ca

27db⁶⁷

27ec⁶⁹

28db⁶⁷

28ec⁶⁹

OMOM

26c

References describing synthesis and analytical data. Commercially available. Previously synthesized using diﬀerent conditions. Reference

reports no experimental details and analytical data. Conditions A. Conditions B.

involve the use of trimethylorthoformate (TMOF) as a solvent,

addition of sulfuric acid as a catalyst, and either PIDA or

these conditions to our test substrate 18, only the isoﬂavone 21

and its ﬂavone isomer 23 were isolated in comparable yields

(entry 10). With PIFA an improved selectivity toward the

oxidative 2,3-aryl migration pathway was observed and a mixture

of MOM-protected isoﬂavone 21 and deprotected isoﬂavone 22

was obtained in an overall yield of 42% (entry 11). We tried to

suppress the cleavage of the MOM group by using a somewhat

weaker acid, but no conversion was observed under these

conditions (entry 12). The most notable conclusions from this

optimization study are the reaction conditions expected to be

ideally suited for the selective synthesis of isoﬂavones (entry 1)

turned out to be unsuitable for our model substrate 18; only

those conditions that presumably yield the undesired ring

contraction product selectively provided isoﬂavones in an

acceptable yield and selectivity (entries 10, 11). The ring

contraction pathway does apparently not play a signiﬁcant role

HTIB^57,59or Tl(NO₃)₃or Pb(OAc)₄as oxidants.

Presumably, the ﬂavanone undergoes a sequence of acetalization

at C4 and elimination of methanol with formation of an enol

ether, which then reacts with the hypervalent iodine reagent to

form an acetal of the 3-iodo intermediate 15,⁵⁹which

predominantly reacts via ring contraction. In a more recent

publication identical conditions (PIDA as an oxidant, TMOF as

a solvent, and H₂SO₄as a catalyst) were applied to three

ﬂavanones with slightly diﬀerent substitution patterns. Interest-

ingly, a diﬀerent yet selective outcome was reported for all three

cases: while one ﬂavanone was reported to react selectively to

the expected benzofuran by ring contraction, the other two

underwent oxidation to the ﬂavone or oxidative 2,3-aryl

migration to the isoﬂavone, respectively.⁵⁴When we applied

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Table 3. Synthesis of 8-Allyl Flavanones 31

entry

R¹

R²

R³

R⁴

yield (%)

c 70

29a⁷⁰

29b⁷¹

26e

30ae

30bc

30bd

30ba

−

31ae

31bc

31bd

31ba

−

OCH₃

26c

OCH₃

OMOM

OCH₃

26d³³

CH₂CHCH₂

26a³³

CH₂CHCH₂

References describing synthesis and analytical data. Commercially available. Synthesized according to this literature procedure.

Table 4. Application of Oxidative Rearrangement Conditions to Flavanones 28 and 31

yield

(%)

yield

(%)

entry 28/31

R¹

R²

R³

R⁴

R⁵

solvent−additive

oxidant (°C)

28aa

28ba

28ca

28db

28ec

31ae

31bc

31bd

31ba

OCH₃

OMOM

OCH₃

CH₂CHCH₂

CH(OCH₃)₃H₂SO₄

CH₃OH

PIDA

PIFA

HTIB

PIFA

HTIB

PIDA

PIFA

HTIB

PIFA

HTIB

32a

32b

32c

32d

32e

32f

32g

32h

32i

33a

33b

33c

33d

33e

33f

33g

33h

33i

−

CH₂CHCH₂

−

OMOM

OCH₃

OMOM

CH₂CHCH₂

−

OCH₃

CH₂CHCH₂

−

CH(OCH₃)₃H₂SO₄

CH₃OH

CH₂CHCH₂

CH(OCH₃)₃H₂SO₄

CH₃OH

−

OCH₃

OMOM

OCH₃

CH₂CHCH₂

CH(OCH₃)₃H₂SO₄

CH₃OH

1.0 equiv. Complex mixture of products; partial oxidation at C8; compound 34 isolated in 8% yield as sole identiﬁable product. Cleavage of

MOM-ether under reaction conditions; R³= OH. Cleavage of MOM-ether under reaction conditions; R¹= OH.

with this substrate as we could never isolate any benzofurans in

the course of the optimization study.

either under conventional heating conditions or, in a notably

shorter reaction time, by microwave irradiation (Table 2).

For the synthesis of 8-allyl ﬂavanones 31, we pursued a

sequence previously developed in our group.⁷⁰To this end the o-

allyloxy acetophenones 29a and 29b were condensed with

benzaldehydes 26. The resulting chalcones 30 were ﬁrst heated

in toluene at 250 °C under microwave irradiation to induce a

Claisen rearrangement that installs the 8-allyl substituent. After

changing the solvent to methanol and addition of NaOAc as a

base, the crude reaction mixture was heated at 100 °C under

microwave irradiation to induce the oxa-Michael addition and

furnish the 8-allyl ﬂavanones 31 (Table 3).

Synthesis of Other Flavanones as Substrates for

Oxidative Rearrangement Reactions. To explore the

scope of the oxidative rearrangement reaction further, we

synthesized additional ﬂavanones. We started with three

ﬂavanones bearing the same 3′-allyl-4′-methoxyphenyl sub-

stituent as compound 18 and with two ﬂavanones without a 3′-

allyl substituent. The synthesis started from acetophenones 25

and benzaldehydes 26 that were either commercially available or

had previously been described in the literature. Through

Claisen−Schmidt condensation of 25 and 26, the chalcones

27 were obtained, which underwent cyclization to the required

ﬂavanones 28 in methanol in the presence of NaOAc as a base,

Application of the Oxidative Rearrangement Con-

ditions to Flavanones 28 and 31. We applied the two most

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Scheme 3. Cross Metathesis of Isoﬂavones 32 and Flavones 33 with 2-Methyl-2-butene

successful oxidative rearrangement conditions from Table 1, the

reaction with HTIB in methanol at 60 °C and the reaction with

PIFA in trimethylorthoformate in the presence of sulfuric acid at

ambient temperature, to ﬂavanones 28 and 31 (Table 4). The

results can be summarized as follows:

considerable extent which results in a lower yield, whereas

methyl ethers are well tolerated. For example, the

dimethyl ether 31be (entry 13) reacts to 32i and 33i in

a combined yield of 83% and a 3:1 ratio of isomers,

whereas 31bd with a MOM-ether at C4′-position reacts

to isoﬂavone 32h and ﬂavone 33h in a 1:1 ratio and a

combined yield of ca. 40% (entry 14).

a. Allyl groups, substituents that are essential precursors for

prenyl side chains along our route, are well tolerated. We

did not observe any products arising from either allylic

oxidation, oxidation of the C−C-double bond, or acid-

catalyzed isomerization.

d. An electron donating substituent is required at the

migrating aryl group. With an unsubstituted phenyl ring

no rearrangement product 32 was observed, as was shown

for 31ae (entry 9), which reacts to ﬂavone 33f in a very

low yield.

b. We could isolate only for one example, isoﬂavone 32a

(entry 3), a single reaction product. In all other cases the

ﬂavone isomer 33 was formed as a byproduct, sometimes

together with either unreacted or deprotected starting

material. Notably, we never observed benzofuran

derivatives of the general formula 13 (Scheme 2). In

light of several literature reports claiming this mode of

rearrangement to be the major pathway in the reaction of

ﬂavanones with hypervalent iodine compounds the

complete absence of ring contraction products in our

study is quite surprising. One explanation might be that in

almost all cases investigated by us an electron donating

substituent R¹is located at C7, which is the para-position

of the carbonyl carbon C4. It could be speculated that the

ring contraction pathway does not proceed through an

acyl carbenium ion 17, as commonly assumed and shown

in Scheme 1, but that this pathway is initiated by a

nucleophilic attack of methanol at C4, which would

obviously be impeded by electron donating groups at C7.

e. On the other hand, alkoxy or hydroxy groups at C5 have

apparently a strong detrimental eﬀect. Isoﬂavone 32c

(entry 5) was isolated in only 32% yield, compared to 65%

for 32a (entry 3) and 61% for 32i (entry 13) without a

C5-methoxy group. With the analogous bis-MOM-ether

32b (entry 4) a complex mixture of products was

obtained. We did not observe any signals in the NMR-

spectra pointing at the formation of isoﬂavone 32b or

ﬂavone 33b. Instead we isolated an 8-oxygenated and C5-

OH deprotected ﬂavanone 34 as the only identiﬁable

product in 8% yield. The structural assignment is based on

HMBC couplings between C5(OH) and C6 and H6 and

C8, which appears as a quaternary carbon in the HSQC

spectrum. The high resolution mass spectrum is in

agreement with the molecular formula C₂₁H₂₂O₇and thus

conﬁrms the presence of an additional OH-group.

The isoﬂavones 32d (isoformononetin) and 32e (formono-

netin) and their ﬂavone isomers 33d (isopratol) and 33e

(pratol) are naturally occurring secondary plant metabolites.

Isoformononetin (32d) has inter alia been isolated from

soybean leaves⁷²and was synthesized by methylation of daidzein

and tested for its antiestrogenic activity.⁷³Formononetin (32e)

is an ubiquitous phytoestrogen found in many edible plants⁷⁴

c. Unprotected OH-groups appear to be a major impedi-

ment for the reaction. With ﬂavanone 19 (free OH group

at C7) the yield of isoﬂavone 22 remained below 10%

(entry 14), compared to 28% starting from the MOM-

protected analogue (Table 1, entry 3). Regardless of the

reaction conditions MOM-ethers undergo cleavage to a

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and has, inter alia, been synthesized through an oxidative Pd-

catalyzed cyclization.⁷⁵Isopratol (33d) was isolated for example

from the roots of the shrub Gynerium sagittatum, an anti-

inﬂammatory remedy used in Mexico and South America,⁷⁶and

synthesized through cyclocondensation of 1,3-diketones.⁷⁷

Pratol (33e) has for example been synthesized via Co-catalyzed

dehydrogenation of a ﬂavanone precursor⁷⁸and was, inter alia,

isolated from seeds of the plant Caragana microphylla Lam.

together with its isoﬂavone isomer formononetin (32e).⁷⁹

In the case of 8,3′-diallyl-7,4′-dimethoxyﬂavone (33i) crystals

suitable for single crystal X-ray analysis were obtained and the

structure of this derivative could be unambiguously determined.

Synthesis of Prenylated Isoﬂavones and Flavones via

Cross Metathesis. The oleﬁn cross metathesis (CM) reaction

of allylarenes and 2-methyl-2-butene has emerged as a

convenient route to prenylated aromatic compounds. Isobutene,

which has also been used for this cross metathesis reaction, has

the disadvantage of being a gas at ambient temperature but gives

the prenylated products in comparable yields and selectivity.⁸⁰

Originally introduced by Grubbs and co-workers,⁸¹CM

reactions with 2-methyl-2-butene have been used for the

synthesis of prenylated ﬂavanones,⁷⁰ﬂavones,³³isoﬂavones,^33,82

coumarins,^71,83−85and other natural products.⁸⁶⁻⁸⁹The cross

metathesis reactions of allyl isoﬂavones 32g−i and their ﬂavone

isomers 33g−i with 2-methyl-2-butene in the presence of 5 mol

% second generation Grubbs’ catalyst A⁹⁰at ambient temper-

ature furnished the respective prenyl isoﬂavones 12, 35h,i, and

prenyl ﬂavones 36g−i in high yields and selectivity. The MOM-

ethers 35h and 36h could be deprotected in methanol in the

presence of aqueous HCl without concomitant acid catalyzed

addition of methanol to the prenyl substituent (Scheme 3). In

no case were CM products with a crotyl substituent observed,

which has for instance been reported by Sytniczuk et al. in a

catalyst screening for the cross metathesis functionalization of

methyl oleate with 2-methyl-2-butene.⁹¹These authors stated

that using the more active second generation catalysts for this

type of cross metathesis reactions is mandatory, as the less active

ﬁrst generation catalysts favor the self-metathesis dimerization

of the CM partner.

ﬂavanone favor an oxidation of the arene. This, together with the

incompatibility of unprotected phenols and the low tolerance

toward acid-sensitive protecting groups, are clearly limitations of

the method. Although the selectivity issue arising from the

competing formation of ﬂavones could not be completely

resolved and the substrate scope is limited, the oxidative

rearrangement/cross metathesis approach to prenyl isoﬂavones

is synthetically useful for some substitution patterns relevant for

polyphenol natural products.

EXPERIMENTAL SECTION

■

General Methods. All experiments were conducted in dry reaction

vessels under an atmosphere of dry nitrogen. Solvents were puriﬁed by

standard procedures. Unless otherwise stated, reaction mixtures were

heated with silicon oil baths. Microwave reactions were carried out in an

Anton-Paar-monowave 300 or Anton-Paar-monowave 400 reactor

(monowave, maximum power 850 W, temperature control by IR-

sensor, vial volume 20 mL). All microwave reactions were conducted in

sealed vessels; reaction mixture temperatures are reported within the

respective procedures. ¹H NMR spectra were obtained at 300, 400, or

500 MHz in CDCl₃with CHCl₃(δ = 7.26 ppm) as an internal standard.

Coupling constants are given in Hz. ¹³C{¹H} NMR spectra were

recorded at 75 MHz, 100 or 125 MHz in CDCl₃with CDCl₃(δ = 77.1

ppm) as an internal standard. Whenever the solubility of the sample was

insuﬃcient in CDCl₃, it was replaced by either acetone-d₆(acetone-d₅

as internal standard for ¹H NMR spectroscopy, δ = 2.05 ppm, acetone-

d₆as internal standard for ¹³C{¹H} NMR spectroscopy, δ = 29.9 ppm)

or DMSO-d₆(DMSO-d₅as internal standard for H NMR spectros-

copy, δ = 2.50 ppm, DMSO-d₆as internal standard for ¹³C{¹H} NMR

spectroscopy, δ = 39.5 ppm). In all cases where signal assignments are

given for H and ¹³C{¹H} NMR data, these are based on 2D-NMR-

spectra such as H,H−COSY, HSQC, HMBC, and NOESY. IR spectra

were recorded as ATR-FTIR spectra. Wavenumbers (ṽ) are given in

cm⁻¹. The peak intensities are deﬁned as strong (s), medium (m), or

weak (w). Low- and high resolution mass spectra were obtained by EI-

TOF or ESI-TOF.

Optimization of Reaction Conditions for Flavanone 18

(Table 1). General Procedure 1 for the Reaction with HTIB,

PIDA or PIFA in Methanol or Acetonitrile (Table 1, Entries 1−9;

Table 4, Entries 6, 8, 11, 13, 14). To a solution of 18 (355 mg, 1.00

mmol) in the solvent indicated in Table 1 or Table 4 (acetonitrile or

methanol, 10 mL) was added dropwise a solution of HTIB (395 mg,

1.00 mmol) or PIDA (322 mg, 1.00 mmol) or PIFA (430 mg, 1.00

mmol) in the same solvent (2 mL). The mixture was stirred at 20 °C or

at 60 °C (as indicated in Table 1 or Table 4) for 24 h. The solvent was

evaporated, water (20 mL) was added, and the mixture was stirred at 20

°C for 2 h. The mixture was extracted with ethyl acetate (three times, 15

mL each), the organic extracts were dried with MgSO₄, ﬁltered, and

evaporated. The products were separated by column chromatography

on silica, using a hexanes−ethyl acetate mixture (4:1 (v/v)) as eluent.

In a typical experiment (Table 1, entry 2: solvent methanol; oxidant

HTIB) the deprotected ﬂavanone 19³³(121 mg, 0.39 mmol, 39%), the

deprotected chalcone 20 (31 mg, 0.10 mmol, 10%), and the

deprotected isoﬂavone 22³³(47 mg, 0.15 mmol, 15%) were obtained.

Analytical data for (E)-3-(3-allyl-4-methoxyphenyl)-1-(2,4-

dihydroxyphenyl)prop-2-en-1-one (20): yellow solid, mp 163−164

^οC; ¹H NMR (400 MHz, acetone-d₆) δ 13.62 (s, 1H), 9.47 (s, 1H), 8.08

(d, J = 8.9 Hz, 1H), 7.84 (d, J = 15.4 Hz, 1H), 7.78 (d, J = 15.4 Hz, 1H),

7.69 (dd, J = 9.0, 2.4 Hz, 1H), 7.68 (d, J = 2.4 Hz, 1H), 7.04 (d, J = 9.0

Hz, 1H), 6.47 (dd, J = 8.9, 2.4 Hz, 1H), 6.38 (d, J = 2.4 Hz, 1H), 6.01

(ddt, J = 17.0, 10.2, 6.6 Hz, 1H), 5.07 (dm, J = 17.0 Hz, 1H), 5.02 (dm, J

= 10.2 Hz, 1H), 3.90 (s, 3H), 3.39 (d, J = 6.6 Hz, 2H); ¹³C{¹H} NMR

(100 MHz, acetone-d₆) δ 192.8, 167.6, 165.6, 160.6, 145.1, 137.5,

133.3, 130.9, 130.3, 130.0, 128.3, 118.8, 115.9, 114.5, 111.7, 108.7,

103.8, 56.0, 34.9; IR (ATR) ν 3283 (w), 1628 (m), 1557 (m), 1494 (s),

1259 (m), 1193 (s); HRMS (EI) calcd for C₁₉H₁₈O₄[M⁺] 310.1205,

found 310.1200.

Isoﬂavone 12 is 7-methoxyebenosin, a natural product that

was ﬁrst isolated from the seeds of Millettia griffoniana, an

indigenous tree in Western Africa.⁴⁵The same compound was

later isolated from the roots of Millettia pulchra⁹²and from roots

and rhizomes of Sophora tonkinensis⁹³in Southern China. 7-

Methoxyebenosin (12) has not been synthesized previously.

The compound shows moderate trypanocidal and antiplasmo-

dial activity⁴⁵as well as inhibitory activity toward nitric oxide

production on a low micromolar level.⁹³Isoﬂavones 35i and 37

are the di- and monomethyl ether analogues of the

antiplasmodial and antibiotic isoﬂavone erysubin F (10).^33,41

CONCLUSIONS

■

In summary, we have investigated the potential of the oxidative

rearrangement of ﬂavanones mediated by hypervalent iodine

compounds for the synthesis of prenylated isoﬂavones. In

contrast to earlier literature reports we could not detect products

formed through a ring contraction pathway for the examples

investigated in this study, but in almost all cases the desired

isoﬂavones were obtained together with ﬂavones. These

products result from an oxidation of the ﬂavanone without

concomitant migration of the 2-aryl substituent. While the

presence of allyl substituents at either of the two aromatic cores

is well tolerated, hydroxy groups at the 5-position of the

General Procedure 2 for the Reaction with PIDA or PIFA in

Trimethylorthoformate (TMOF) in the Presence of Sulfuric Acid

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(Table 1, Entries 10−11; Table 4, Entries 1−5, 7, 9, 10, 12). To a

solution of 18 (710 mg, 2.00 mmol) in TMOF (20 mL) was added

conc. H₂SO₄(40 μL, 0.75 mmol) and the solution was stirred for 5 min

at 20 °C. A solution of PIDA (966 mg, 3.00 mmol) or PIFA (1290 mg,

3.00 mmol) in TMOF (5 mL) was added dropwise and the mixture was

stirred for 24 h at 20 °C. The solvent was evaporated, water (40 mL)

was added, and the mixture was stirred for 2 h at 20 °C. The mixture was

extracted with ethyl acetate (three times, 30 mL each), the organic

extracts were dried with MgSO₄, ﬁltered, and evaporated. The products

were separated by column chromatography on silica, using hexanes−

ethyl acetate mixtures of increasing polarity (5:1 (v/v) to 3:1 (v/v)) as

eluent. In a typical experiment (Table 1, entry 10: oxidant PIDA)

MOM-protected isoﬂavone 21³³(141 mg, 0.40 mmol, 20%) and

MOM-protected ﬂavone 23 (113 mg, 0.32 mmol, 16%) were obtained.

With PIFA as oxidant (Table 1, entry 11) MOM-protected isoﬂavone

21³³(190 mg, 0.54 mmol, 27%) and deprotected isoﬂavone 22³³(91

mg, 0.30 mmol, 15%) were isolated. Analytical data for 2-(3-allyl-4-

methoxyphenyl)-7-(methoxymethoxy)-4H-chromen-4-one (23): col-

orless solid, mp 150−151^οC; ¹H NMR (400 MHz, acetone-d₆) δ 8.00

(d, J = 8.8 Hz, 1H), 7.90 (dd, J = 8.7, 2.4 Hz, 1H), 7.82 (d, J = 2.4 Hz,

1H), 7.25 (d, J = 2.4 Hz, 1H), 7.11 (d, J = 8.7 Hz, 1H), 7.08 (dd, J = 8.8,

2.4 Hz, 1H), 6.65 (s, 1H), 6.04 (ddt, J = 17.0, 10.2, 6.7 Hz, 1H), 5.37 (s,

2H), 5.10 (dm, J = 17.0 Hz, 1H), 5.04 (dm, J = 10.2 Hz, 1H), 3.92 (s,

3H), 3.50 (s, 3H), 3.44 (d, J = 6.7 Hz, 2H); ¹³C{¹H} NMR (100 MHz,

acetone-d₆) δ 177.1, 163.8, 162.4, 161.0, 158.3, 137.3, 130.1, 128.4,

127.3, 127.0, 124.6, 119.3, 116.1, 115.9, 111.6, 106.3, 104.1, 95.2, 56.5,

56.1, 34.9; IR (ATR) ν 2924 (w), 1622 (s), 1599 (m), 1445 (s), 1251

(s), 1149 (s); HRMS (ESI) calcd for C₂₁H₂₁O₅[M + H]⁺353.1389,

found 353.1379.

General Procedure 3 for the Synthesis of Chalcones 27. A

solution of KOH in MeOH (60 wt %, 20 mL) was added dropwise to a

well stirred solution of the appropriate acetophenone 25 (5.0 mmol)

and the respective benzaldehyde 26 (5.0 mmol) in methanol (10 mL)

at 20 ^οC. The reaction mixture was stirred at 20 ^οC for 48 h. It was then

poured into ice cold water (50 mL) and neutralized with HCl (aq., 4

M). The aqueous solution was extracted with ethyl acetate (three times,

30 mL each). The combined organic extracts were washed with brine

and dried with anhydrous MgSO₄. The solvent was evaporated and the

residue puriﬁed by column chromatography on silica, using hexane−

ethyl acetate mixture (5:1 (v/v)) as eluent to aﬀord the appropriate

chalcone 27.

(2E)-1-(2-Hydroxyphenyl)-3-[4-methoxy-3-(prop-2-en-1-yl)-

phenyl]-prop-2-en-1-one (27aa). Following the general procedure 3,

25a (680 mg, 5.0 mmol) and 26a (880 mg, 5.0 mmol) were reacted to

27aa (1.300 g, 4.4 mmol, 88%); puriﬁcation by chromatography

(hexanes−ethyl acetate mixtures 5:1 (v/v)): yellow crystalline solid,

mp 94−95 ^οC; ¹H NMR (300 MHz, CDCl₃) δ 12.98 (s, 1H), 7.94 (dd,

J = 8.0, 1.7 Hz, 1H), 7.89 (d, J = 15.3 Hz, 1H), 7.53 (d, J = 15.3 Hz, 1H),

7.52 (dd, J = 8.4, 2.4 Hz, 1H), 7.49 (d, J = 1.7 Hz, 1H), 7.47 (dd, J = 8.4,

1.5 Hz, 1H), 7.02 (dd, J = 8.4, 1.2 Hz, 1H), 6.94 (ddd, J = 8.4, 8.0, 1.2

Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 6.02 (ddt, J = 17.5, 9.6, 6.6 Hz, 1H),

5.11 (dm, J = 17.5 Hz, 1H), 5.06 (dm, J = 9.6 Hz, 1H), 3.87 (s, 3H), 3.42

(d, J = 6.6 Hz, 2H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 193.8, 163.7,

160.0, 145.8, 136.3, 136.2, 130.0, 129.7, 129.6, 129.5, 127.2, 120.3,

118.9, 118.7, 117.5, 116.2, 110.7, 55.7, 34.3; IR (ATR) ν 3070 (w),

2918 (w), 1633(s), 1550 (m), 1445 (s), 1256 (m), 1118 (m); HRMS

(EI) calcd for C₁₉H₁₈O₃[M⁺] 294.1256, found 294.1246.

(2E)-1-[2-Hydroxy-4,6-bis(methoxymethoxy)phenyl]-3-[4-me-

thoxy-3-(prop-2-en-1-yl)phenyl]prop-2-en-1-one (27ba). Following

the general procedure 3, 25b (1.280 mg, 5.0 mmol) and 26a (880 mg,

5.0 mmol) were reacted to 27ba (1.930 g, 4.7 mmol, 94%); puriﬁcation

by chromatography (hexanes−ethyl acetate mixtures 5:1 (v/v)): yellow

solid, mp 96−97 ^οC; ¹H NMR (300 MHz, CDCl₃) δ 13.95 (s, 1H), 7.84

(d, J = 15.5 Hz, 1H), 7.77 (d, J = 15.5 Hz, 1H), 7.45 (d, J = 2.2 Hz, 1H),

7.44 (dd, J = 9.0, 2.2 Hz, 1H), 6.88 (d, J = 9.0 Hz, 1H), 6.31 (d, J = 2.3

Hz, 1H), 6.25 (d, J = 2.3 Hz, 1H), 6.00 (ddt, J = 17.5, 9.7, 6.7 Hz, 1H),

5.28 (s, 2H), 5.19 (s, 2H), 5.09 (dm, J = 17.5 Hz, 1H), 5.08 (dm, J = 9.7

Hz, 1H), 3.88 (s, 3H), 3.54 (s, 3H), 3.48 (s, 3H), 3.40 (d, J = 6.7 Hz,

2H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 193.0, 167.4, 163.4, 159.9,

159.4, 143.1, 136.5, 129.4, 129.4, 129.0, 128.0, 125.0, 116.1, 110.6,

107.7, 97.6, 95.3, 94.8, 94.2, 57.0, 56.6, 55.7, 34.2; IR (ATR) ν 2910

(w), 2830 (w), 1617 (s), 1579 (m), 1419 (m), 1206 (m), 1148 (s);

HRMS (EI) calcd for C₂₃H₂₆O₇[M⁺] 414.1679, found 414.1672.

(2E)-1-(2-Hydroxy-4,6-dimethoxyphenyl)-3-[4-methoxy-3-(prop-

2-en-1-yl)phenyl]-prop-2-en-1-one (27ca). Following the general

procedure 3, 25c (980 mg, 5.0 mmol) and 26a (880 mg, 5.0 mmol)

were reacted to 27ca (1.420 g, 4.0 mmol, 80%); puriﬁcation by

chromatography (hexanes−ethyl acetate mixtures 5:1 (v/v)): yellow

crystalline solid, m.p 145−146 C; H NMR (300 MHz, CDCl₃) δ

14.45 (s, 1H), 7.82 (d, J = 15.5 Hz, 1H), 7.75 (d, J = 15.5 Hz, 1H), 7.46

(d, J = 2.3 Hz, 1H), 7.45 (dd, J = 8.2, 2.3 Hz, 1H), 6.87 (d, J = 8.2 Hz,

1H), 6.10 (d, J = 2.5 Hz, 1H), 6.02 (ddt, J = 17.3, 10.7, 6.6 Hz, 1H), 5.95

(d, J = 2.5 Hz, 1H), 5.11 (dm, J = 17.3 Hz, 1H), 5.09 (dm, J = 10.7 Hz,

1H), 3.91 (s, 3H), 3.87 (s, 3H), 3.83 (s, 3H), 3.40 (d, J = 6.7 Hz, 2H);

¹³C{¹H} NMR (75 MHz, CDCl₃) δ 192.7, 168.5, 166.1, 162.6, 159.3,

142.8, 136.5, 129.7, 129.3, 128.7, 128.1, 125.1, 116.1, 110.5, 106.5, 93.9,

91.3, 55.9, 55.7, 55.7, 34.1; IR (ATR) ν 2919 (w), 2844 (w), 1620 (s),

1552 (s), 1442 (m), 1205 (s), 1111 (m); HRMS (EI) calcd for

C₂₁H₂₂O₅[M⁺] 354.1467, found 354.1465.

(2E)-1-(2-Hydroxy-4-methoxyphenyl)-3-[4-(methoxymethoxy)-

phenyl]prop-2-en-1-one (27db). Following the general procedure 3,

25d (2.060 g, 10.0 mmol) and 26b (1.680 g, 10.0 mmol) were reacted

to 27db (2.200 g, 7.0 mmol, 70%); puriﬁcation by chromatography

(hexanes−ethyl acetate mixtures 5:1 (v/v)): yellow solid, mp 74−75

°C; ¹H NMR (400 MHz, CDCl₃) δ 13.52 (s, 1H), 7.86 (d, J = 15.4 Hz,

1H), 7.82 (d, J = 8.5 Hz, 1H), 7.60 (d, J = 8.6 Hz, 2H), 7.47 (d, J = 15.4

Hz, 1H), 7.08 (d, J = 8.6 Hz, 2H), 6.48 (dd, J = 8.5, 2.5 Hz, 1H), 6.47 (d,

J = 2.5 Hz, 1H), 5.22 (s, 2H), 3.86 (s, 3H), 3.49 (s, 3H); ¹³C{¹H} NMR

(100 MHz, CDCl₃) δ 192.0, 166.8, 166.2, 159.5, 144.2, 131.3, 130.4,

128.7, 118.5, 116.7, 114.3, 107.8, 101.2, 94.3, 56.3, 55.7; IR (ATR) ν

2899 (w), 1602 (s), 1507 (s), 1150 (s), 1076 (m); HRMS (EI) calcd for

C₁₈H₁₈O₅[M⁺] 314.1154, found 314.1151.

(2E)-1-[2-Hydroxy-4-(methoxymethoxy)phenyl]-3-(4-

methoxyphenyl)prop-2-en-1-one (27ec). Following the general

procedure 3, 25e (1.960 g, 10.0 mmol) and 26c (1.370 g, 10.0

mmol) were reacted to 27ec (2.140 g, 6.8 mmol, 68%); puriﬁcation by

chromatography (hexanes−ethyl acetate mixtures 5:1 (v/v)): yellow

solid, mp 80−81 ^οC; ¹H NMR (400 MHz, CDCl₃) δ 13.39 (s, 1H), 7.86

(d, J = 15.4 Hz, 1H), 7.84 (d, J = 9.0 Hz, 1H), 7.61 (d, J = 8.8 Hz, 2H),

7.45 (d, J = 15.4 Hz, 1H), 6.94 (d, J = 8.8 Hz, 2H), 6.64 (d, J = 2.6 Hz,

1H), 6.58 (dd, J = 9.0, 2.6 Hz, 1H), 5.22 (s, 2H), 3.86 (s, 3H), 3.49 (s,

3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 192.2, 166.3, 163.6, 162.0,

144.6, 131.3, 130.5, 127.6, 117.9, 115.1, 114.6, 108.2, 104.1, 94.1, 56.5,

55.6; IR (ATR) ν 2831 (w), 1626 (m), 1564 (s), 1279 (s), 1159 (s);

HRMS (ESI) calcd for C₁₈H₁₉O₅[M + H]⁺315.1232, found 315.1236.

(2E)-3-(4-Methoxyphenyl)-1-{4-methoxy-2-[(prop-2-en-1-yl)oxy]-

phenyl}prop-2-en-1-one (30bc). Following the general procedure 3,

29b (2.060 g, 10.0 mmol) and 26c (1.360 g, 10.0 mmol) were reacted

to 30bc (1.940 g, 6.0 mmol, 60%); puriﬁcation by chromatography

(hexanes−ethyl acetate mixtures 5:1 (v/v)): pale yellow solid, mp 84−

85 ^οC; ¹H NMR (400 MHz, CDCl₃) δ 7.76 (d, J = 8.7 Hz, 1H), 7.66 (d,

J = 15.7 Hz, 1H), 7.53 (d, J = 8.8 Hz, 2H), 7.48 (d, J = 15.7 Hz, 1H),

6.90 (d, J = 8.8 Hz, 2H), 6.56 (dd, J = 8.7, 2.4 Hz, 1H), 6.48 (d, J = 2.4

Hz, 1H), 6.05 (ddt, J = 17.3, 10.5, 5.2 Hz, 1H), 5.45 (dm, J = 17.3 Hz,

1H), 5.27 (dm, J = 10.5 Hz, 1H), 4.61 (dt, J = 5.2, 1.7 Hz, 2H), 3.84 (s,

3H), 3.83 (s, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 190.5, 164.0,

161.3, 159.3, 141.8, 133.0, 132.6, 130.0, 128.3, 125.3, 122.9, 118.0,

114.4, 105.7, 99.9, 69.5, 55.6, 55.5; IR (ATR) ν 2841 (w), 1644 (m),

1597 (s), 1509 (m), 1247 (s), 1170 (s); HRMS (ESI) calcd for

C₂₀H₂₁O₄[M + H]⁺325.1440, found 325.1434.

(2E)-3-[4-(Methoxymethoxy)-3-(prop-2-en-1-yl)phenyl]-1-{4-me-

thoxy-2-[(prop-2-en-1-yl)oxy]phenyl}prop-2-en-1-one (30bd). Fol-

lowing the general procedure 3, 29b (2.060 g, 10.0 mmol) and 26d

(2.060 g, 10.0 mmol) were reacted to 30bd (2.560 g, 6.5 mmol, 65%);

puriﬁcation by chromatography (hexanes−ethyl acetate mixtures 5:1

(v/v)): pale yellow crystals, mp 27−28 C; H NMR (400 MHz,

CDCl₃) δ 7.77 (d, J = 8.6 Hz, 1H), 7.64 (d, J = 15.8 Hz, 1H), 7.50 (d, J =

15.8 Hz, 1H), 7.42 (d, J = 2.3 Hz, 1H), 7.40 (dd, J = 8.3, 2.3 Hz, 1H),

7.07 (d, J = 8.3 Hz, 1H), 6.57 (dd, J = 8.6, 2.3 Hz, 1H), 6.48 (d, J = 2.3

Hz, 1H), 6.11−5.94 (m, 2H), 5.46 (dm, J = 17.3 Hz, 1H), 5.26 (dm, J =

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10.5 Hz, 1H), 5.23 (s, 2H), 5.08 (dm, J = 16.2 Hz, 1H), 5.07 (dm, J =

11.1 Hz, 1H), 4.61 (dt, J = 5.2, 1.7 Hz, 2H), 3.85 (s, 3H), 3.48 (s, 3H),

3.41 (d, J = 6.5 Hz, 2H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 190.5,

164.0, 159.4, 156.6, 141.9, 136.5, 133.0, 132.6, 130.0, 129.7, 129.1,

128.4, 125.6, 122.8, 118.1, 116.0, 113.9, 105.7, 99.8, 94.2, 69.5, 56.3,

55.6, 34.4; IR (ATR) ν 2935 (w), 2825 (w), 1595 (s), 1493 (m), 1242

(s), 1119 (m); HRMS (EI) calcd for C₂₄H₂₆O₅[M⁺] 394.1780, found

394.1783.

(2E)-1-{4-Methoxy-2-[(prop-2-en-1-yl)oxy]phenyl}-3-[4-methoxy-

3-(prop-2-en-1-yl)-phenyl]prop-2-en-1-one (30ba). Following the

general procedure 3, 29b (2.060 g, 10.0 mmol) and 26a (1.760 g, 10.0

mmol) were reacted to 30ba (2.960 g, 8.1 mmol, 81%); puriﬁcation by

chromatography (hexanes−ethyl acetate mixtures 5:1 (v/v)): pale

yellow solid, mp 106−107 ^οC; ¹H NMR (400 MHz, CDCl₃) δ 7.77 (d, J

= 8.7 Hz, 1H), 7.65 (d, J = 15.6 Hz, 1H), 7.49 (d, J = 15.6 Hz, 1H),

7.44−7.41 (m, 2H), 6.85 (d, J = 8.9 Hz, 1H), 6.57 (dd, J = 8.7, 2.3 Hz,

1H), 6.48 (d, J = 2.3 Hz, 1H), 6.12−5.94 (m, 2H), 5.46 (dm, J = 17.3

Hz, 1H), 5.27 (dm, J = 10.6 Hz, 1H), 5.07 (dm, J = 16.9 Hz, 1H), 5.06

(dm, J = 11.8 Hz, 1H), 4.61 (dt, J = 5.1, 1.7 Hz, 2H), 3.86 (s, 3H), 3.85

(s, 3H), 3.38 (d, J = 6.7 Hz, 2H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ

190.6, 164.0, 159.3, 159.1, 142.2, 136.5, 133.0, 132.6, 129.5, 129.2,

128.9, 128.0, 125.1, 122.9, 118.1, 115.9, 110.5, 105.6, 99.9, 69.5, 55.6,

55.6, 34.3; IR (ATR) ν 2840 (w), 1642 (m), 1598 (s), 1500 (m), 1250

(s), 1202 (m), 814 (s); HRMS (EI) calcd for C₂₃H₂₄O₄[M⁺] 364.1675,

found 364.1677.

= 2.3 Hz, 1H), 6.38 (d, J = 2.3 Hz, 1H), 5.99 (ddt, J = 16.8, 10.5, 6.7 Hz,

1H), 5.33 (dd, J = 13.4, 2.8 Hz, 1H), 5.27 (s, 2H), 5.16 (s, 2H), 5.07

(dm, J = 16.8 Hz, 1H), 5.06 (dm, J = 10.5 Hz, 1H), 3.84 (s, 3H), 3.53 (s,

3H), 3.47 (s, 3H), 3.40 (d, J = 6.7 Hz, 2H), 3.04 (dd, J = 16.5, 13.4 Hz,

1H), 2.74 (dd, J = 16.5, 2.8 Hz, 1H); ¹³C{¹H} NMR (75 MHz, CDCl₃)

δ 189.6, 164.8, 163.3, 159.7, 157.7, 136.6, 130.6, 129.2, 128.1, 125.5,

115.9, 110.5, 107.5, 98.2, 97.6, 95.2, 94.2, 79.2, 56.7, 56.6, 55.7, 45.8,

34.4; IR (ATR) ν 2908 (w), 2838 (w), 1670 (m), 1606 (s), 1571 (m),

1251 (s), 1143 (s); HRMS (EI) calcd for C₂₃H₂₆O₇[M⁺] 414.1679,

found 414.1676.

5,7-Dimethoxy-2-[4-methoxy-3-(prop-2-en-1-yl)phenyl]-2,3-di-

hydro-4H-1-benzopyran-4-one (28ca). Following the general proce-

dure 4, method A, 27ca (710 mg, 2.0 mmol) was converted to 28ca

(355 mg, 1.0 mmol, 50%); puriﬁcation by chromatography (hexanes−

ethyl acetate mixtures 5:1 (v/v)): pale yellow solid, mp 135−136 ^οC;

¹H NMR (300 MHz, acetone-d₆) δ 7.37 (dd, J = 8.4, 2.4 Hz, 1H), 7.32

(d, J = 2.4 Hz, 1H), 7.00 (d, J = 8.4 Hz, 1H), 6.17 (d, J = 2.4 Hz, 1H),

6.14 (d, J = 2.4 Hz, 1H), 6.00 (ddt, J = 16.9, 10.3, 6.7 Hz, 1H), 5.39 (dd,

J = 12.9, 3.0 Hz, 1H), 5.06 (dm, J = 16.9 Hz, 1H), 5.00 (dm, J = 10.3 Hz,

1H), 3.86 (s, 3H), 3.85 (s, 3H), 3.82 (s, 3H), 3.39 (d, J = 6.7 Hz, 2H),

2.98 (dd, J = 16.4, 12.9 Hz, 1H), 2.59 (dd, J = 16.4, 3.0 Hz, 1H);

¹³C{¹H} NMR (75 MHz, acetone-d₆) δ 187.2, 165.7, 164.9, 162.3,

157.5, 136.8, 131.3, 128.5, 128.0, 125.8, 114.9, 110.4, 105.8, 93.5, 92.7,

78.9, 55.3, 55.1, 55.0, 45.4, 34.1; IR (ATR) ν 2907 (w), 2838 (w), 1667

(s), 1612 (s), 1574 (m), 1455 (m), 1257 (s), 1213 (s), 1113 (s);

HRMS (EI) calcd for C₂₁H₂₂O₅[M⁺] 354.1467, found 354.1469.

7-Methoxy-2-[4-(methoxymethoxy)phenyl]-2,3-dihydro-4H-1-

benzopyran-4-one (28db). Following the general procedure 4,

method B, 27db (630 mg, 2.0 mmol) was converted to 28db (340

mg, 1.1 mmol, 54%); puriﬁcation by chromatography (hexanes−ethyl

acetate mixtures 5:1 (v/v)): yellow solid, mp 106−107 ^οC; ¹H NMR

(400 MHz, CDCl₃) δ 7.86 (d, J = 8.8 Hz, 1H), 7.40 (d, J = 8.7 Hz, 2H),

7.10 (d, J = 8.7 Hz, 2H), 6.61 (dd, J = 8.8, 2.5 Hz, 1H), 6.48 (d, J = 2.5

Hz, 1H), 5.42 (dd, J = 13.3, 3.0 Hz, 1H), 5.20 (s, 2H), 3.83 (s, 3H), 3.48

(s, 3H), 3.04 (dd, J = 16.9, 13.3 Hz, 1H), 2.80 (dd, J = 16.9, 3.0 Hz, 1H);

¹³C{¹H} NMR (100 MHz, CDCl₃) δ 190.9, 166.3, 163.7, 157.7, 132.2,

128.9, 127.8, 116.6, 114.9, 110.3, 101.0, 94.5, 79.8, 56.2, 55.8, 44.3; IR

(ATR) ν 2950 (w), 1671 (s), 1613 (s), 1593 (s), 1511 (m), 1235 (m),

1150 (s); HRMS (EI) calcd for C₁₈H₁₈O₅[M⁺] 314.1154, found

314.1150.

7-(Methoxymethoxy)-2-(4-methoxyphenyl)-2,3-dihydro-4H-1-

benzopyran-4-one (28ec). Following the general procedure 4, method

B, 27ec (630 mg, 2.0 mmol) was converted to 28ec (352 mg, 1.1 mmol,

56%); puriﬁcation by chromatography (hexanes−ethyl acetate

mixtures 5:1 (v/v)): pale yellow solid, mp 72−73 ^οC; ¹H NMR (400

MHz, CDCl₃) δ 7.87 (d, J = 8.8 Hz, 1H), 7.40 (d, J = 8.8 Hz, 2H), 6.95

(d, J = 8.8 Hz, 2H), 6.70 (dd, J = 8.8, 2.4 Hz, 1H), 6.67 (d, J = 2.4 Hz,

1H), 5.41 (dd, J = 13.3, 2.9 Hz, 1H), 5.19 (s, 2H), 3.83 (s, 3H), 3.47 (s,

3H), 3.05 (dd, J = 16.9, 13.3 Hz, 1H), 2.80 (dd, J = 16.9, 2.9 Hz, 1H);

¹³C{¹H} NMR (100 MHz, CDCl₃) δ 191.1, 163.7, 163.5, 160.1, 130.9,

128.9, 127.8, 115.7, 114.3, 112.2, 103.7, 94.2, 79.8, 56.5, 55.5, 44.3; IR

(ATR) ν 2904 (w), 1675 (m), 1603 (s), 1513 (m), 1243 (s), 1149 (s);

HRMS (ESI) calcd for C₁₈H₁₉O₅[M + H]⁺315.1232, found 315.1237.

General Procedure 5 for the Synthesis of 8-Allyl Flavanones

31. A solution of the respective o-allyloxy chalcone 30 (2.00 mmol) in

toluene (10 mL) was placed in a vessel suited for microwave irradiation.

The vessel was sealed and irradiated in a microwave reactor at 250 °C

for 1.5 h. The solvent was evaporated, and the residue was redissolved in

methanol (20 mL) in a vessel suited for microwave irradiation. NaOAc

(1.68 g, 20.00 mmol) was added to the solution, the vessel was sealed

again, and the mixture was further irradiated in a microwave reactor at

100 ^οC for 2 h. The solvent was then evaporated, and water (50 mL)

was added to the residue. The mixture was extracted with ethyl acetate

(three times, 30 mL each). The combined organic extract was washed

with brine and dried with anhydrous MgSO₄. The solvent was

evaporated under reduced pressure and the residue was puriﬁed by

column chromatography on silica using hexanes−MTBE mixture (4:1

(v/v)) to aﬀord the respective 8-allyl ﬂavanone 31.

General Procedure 4 for the Synthesis of Flavanones 28.

Method A (conventional heating): To a solution of the appropriate

chalcone 27 (2.0 mmol) in methanol (20 mL) was added NaOAc

(1.640 g, 20.0 mmol) and the mixture was heated at 65 °C for 48 h. It

was then cooled to ambient temperature and the solvent was

evaporated. Water (50 mL) was added to the residue and the mixture

was extracted with ethyl acetate (three times, 30 mL each). The

combined organic layers were washed with brine and dried with

anhydrous MgSO₄. The solvent was evaporated under reduced pressure

and the residue puriﬁed by column chromatography on silica using

hexanes−ethyl acetate mixture (5:1 (v/v)) as eluent to aﬀord the

respective ﬂavanone 28. Method B (microwave heating): A solution of

the appropriate chalcone 28 (2.0 mmol) in methanol (20 mL) was

placed in a vessel suitable for microwave irradiation. NaOAc (1.680 g,

20.0 mmol) was added, the vessel was sealed, and the mixture irradiated

in a dedicated microwave reactor at 100 C for 2 h. The mixture was

transferred to a ﬂask and the solvent was evaporated. The residue was

mixed with water (50 mL) and the mixture was extracted with ethyl

acetate (three times, 30 mL each). The organic extract was washed with

brine and dried with anhydrous MgSO₄. The solvent was evaporated,

and the residue was puriﬁed by column chromatography on silica using

hexane−EtOAc mixture (5:1 (v/v)) as eluent to aﬀord the respective

ﬂavanone 28.

2-[4-Methoxy-3-(prop-2-en-1-yl)phenyl]-2,3-dihydro-4H-1-ben-

zopyran-4-one (28aa). Following the general procedure 4, method A,

27aa (590 mg, 2.0 mmol) was converted to 28aa (295 mg, 1.0 mmol,

50%); puriﬁcation by chromatography (hexanes−ethyl acetate

mixtures 5:1 (v/v)): pale yellow solid, mp 64−65 ^οC; ¹H NMR (300

MHz, CDCl₃) δ 7.92 (dd, J = 8.1, 1.8 Hz, 1H), 7.49 (td, J = 7.2, 1.8 Hz,

1H), 7.31 (dd, J = 8.4, 2.4 Hz, 1H), 7.26 (d, J = 2.4 Hz, 1H), 7.07−7.02

(m, 2H), 6.89 (d, J = 8.4 Hz, 1H), 5.99 (ddt, J = 16.8, 10.5, 6.7 Hz, 1H),

5.40 (dd, J = 13.5, 3.0 Hz, 1H), 5.08 (dm, J = 16.8 Hz, 1H), 5.06 (dm, J

= 10.5 Hz, 1H), 3.85 (s, 3H), 3.41 (d, J = 6.7 Hz, 2H), 3.11 (dd, J = 17.1,

13.5 Hz, 1H), 2.84 (dd, J = 17.1, 3.0 Hz, 1H); ¹³C{¹H} NMR (75 MHz,

CDCl₃) δ 192.5, 161.8 157.8, 136.6, 136.3, 130.6, 129.3, 128.1, 127.2,

125.6, 121.6, 121.1, 118.3, 116.0, 110.5, 79.7, 55.7, 44.6, 34.4; IR

(ATR) ν 2920 (w), 1690 (s), 1606 (m), 1462 (s), 1254 (s), 1153 (m);

HRMS (EI) calcd for C₁₉H₁₈O₃[M⁺] 294.1256, found 294.1248.

5,7-Bis(methoxymethoxy)-2-[4-methoxy-3-(prop-2-en-1-yl)-

phenyl]-2,3-dihydro-4H-1-benzopyran-4-one (28ba). Following the

general procedure 4, method A, 27ba (830 mg, 2.0 mmol) was

converted to 28ba (424 mg, 1.0 mmol, 50%); puriﬁcation by

chromatography (hexanes−ethyl acetate mixtures 5:1 (v/v)): yellow

solid, mp 84−85 ^οC; ¹H NMR (300 MHz, CDCl₃) δ 7.28 (dd, J = 8.4,

2.3 Hz, 1H), 7.22 (d, J = 2.3 Hz, 1H), 6.88 (d, J = 8.4 Hz, 1H), 6.43 (d, J

7-Methoxy-2-(4-methoxyphenyl)-8-(prop-2-en-1-yl)-2,3-dihydro-

4H-1-benzopyran-4-one (31bc). Following the general procedure 5,

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30bc (650 mg, 2.00 mmol) was converted to 31bc (305 mg, 0.94 mmol,

47%); puriﬁcation by chromatography (hexanes-MTBE mixtures 4:1

1H), 5.11 (dm, J = 17.6 Hz, 1H), 5.10 (dm, J = 11.1 Hz, 1H), 3.91 (s,

3H), 3.44 (d, J = 6.7 Hz, 2H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ

178.5, 164.1, 160.4, 156,3, 136.1, 133.7, 129.7, 128.0, 126.4, 125.8,

125.2, 123.9, 123.8, 118.1, 116.4, 110.6, 106.2, 55.8, 34.3; IR (ATR) ν

2915 (s), 2849 (m), 1729 (m), 1636 (m), 1602 (s), 1374 (s), 1248 (s);

HRMS (EI) calcd for C₁₉H₁₆O₃[M⁺] 292.1099, found 292.1092.

Attempted Oxidative Rearrangement of 28ba. 5,8-Dihydroxy-7-

(methoxymethoxy)-2-[4-methoxy-3-(prop-2-en-1-yl)phenyl]-2,3-di-

hydro-4H-1-benzopyran-4-one (34). Following the general procedure

2, 28ba (415 mg, 1.00 mmol) was converted to a complex mixture of

products from which only compound 34 (30 mg, 0.08 mmol, 8%) could

be isolated and characterized; separation and puriﬁcation by

chromatography (hexanes−ethyl acetate mixtures of increasing polar-

(v/v)): pale yellow solid, mp 109−110 ^οC; H NMR (400 MHz,

CDCl₃) δ 7.86 (d, J = 8.8 Hz, 1H), 7.39 (d, J = 8.7 Hz, 2H), 6.95 (d, J =

8.7 Hz, 2H), 6.65 (d, J = 8.8 Hz, 1H), 5.91 (ddt, J = 17.0, 10.2, 6.4 Hz,

1H), 5.41 (dd, J = 12.8, 3.0 Hz, 1H), 4.98 (dm, J = 17.0 Hz, 1H), 4.95

(dm, J = 10.2 Hz, 1H), 3.90 (s, 3H), 3.84 (s, 3H), 3.41 (d, J = 6.4 Hz,

2H), 3.00 (dd, J = 17.0, 12.8 Hz, 1H), 2.85 (dd, J = 17.0, 3.0 Hz, 1H);

¹³C{¹H} NMR (100 MHz, CDCl₃) δ 191.8, 163.5, 160.5, 159.8, 136.0,

131.5, 127.5, 126.9, 116.1, 115.5, 114.8, 114.2, 105.0, 79.2, 56.1, 55.5,

44.4, 27.3; IR (ATR) ν 2970 (w), 1666 (s), 1600 (s), 1255 (s), 1120

(s); HRMS (ESI) calcd for C₂₀H₂₁O₄[M + H] 325.1440, found

325.1432.

ity, 5:1 to 3:1 (v/v)): yellow solid, mp 129−130 C; H NMR (500

MHz, acetone-d₆) δ 11.63 (s, 1H), 7.41 (dd, J = 8.4, 2.3 Hz,1H), 7.36

(d, J = 2.3 Hz, 1H), 7.01 (d, J = 8.4 Hz, 1H), 6.28 (s, 1H), 6.00 (ddt, J =

17.0, 10.2, 6.7 Hz, 1H), 5.48 (dd, J = 12.6, 3.0 Hz, 1H), 5.29 (s, 2H),

5.07 (dm, J = 17.0 Hz, 1H), 5.00 (dm, J = 10.2 Hz, 1H), 3.87 (s, 3H),

3.46 (s, 3H), 3.39 (d, J = 6.7 Hz, 2H), 3.21(dd, J = 17.0, 12.6 Hz, 1H),

2.78 (dd, J = 17.0, 3.0 Hz, 1H); ¹³C{¹H} NMR (125 MHz, acetone-d₆)

δ 198.1, 158.5, 156.8, 154.7, 149.4, 137.7, 131.8, 129.4, 129.2, 128.9,

127.1, 115.9, 111.3, 104.3, 96.5, 95.6, 80.3, 56.7, 56.0, 44.1, 35.1; IR

(ATR) ν 3287 (w), 2834 (w), 1645 (m), 1620 (s), 1496 (s), 1224 (s),

1049 (s); HRMS (EI) calcd for C₂₁H₂₂O₇[M⁺] 386.1360, found

386.1354.

5,7-Dimethoxy-3-[4-methoxy-3-(prop-2-en-1-yl)phenyl]-4H-1-

benzopyran-4-one (32c). Following the general procedure 2, 28ca

(355 mg, 1.00 mmol) was converted to 32c (112 mg, 0.32 mmol, 32%);

puriﬁcation by chromatography (hexanes−ethyl acetate mixtures of

increasing polarity, 5:1 to 3:1 (v/v)): colorless solid, mp 128−129 ^οC;

¹H NMR (300 MHz, acetone-d₆) δ 7.94 (s, 1H), 7.37 (dd, J = 8.2, 2.4

7-Methoxy-2-[4-(methoxymethoxy)-3-(prop-2-en-1-yl)phenyl]-8-

(prop-2-en-1-yl)-2,3-dihydro-4H-1-benzopyran-4-one (31bd). Fol-

lowing the general procedure 5, 30bd (790 mg, 2.00 mmol) was

converted to 31bd (355 mg, 0.90 mmol, 45%); puriﬁcation by

chromatography (hexanes-MTBE mixtures 4:1 (v/v)): yellow solid, mp

74−75 ^οC; ¹H NMR (400 MHz, CDCl₃) δ 7.85 (d, J = 8.8 Hz, 1H),

7.29−7.26 (m, 2H), 7.12 (d, J = 9.0 Hz, 1H), 6.64 (d, J = 8.8 Hz, 1H),

6.05−5.86 (m, 2H), 5.39 (dd, J = 12.8, 2.9 Hz, 1H), 5.23 (s, 2H), 5.09

(dm, J = 17.3 Hz, 1H), 5.07 (dm, J = 11.2 Hz, 1H), 5.00 (dm, J = 17.0

Hz, 1H), 4.96 (dm, J = 10.0 Hz, 1H), 3.89 (s, 3H), 3.49 (s, 3H), 3.44 (d,

J = 6.7 Hz, 2H), 3.41 (d, J = 6.2 Hz, 2H), 2.99 (dd, J = 16.8, 12.8 Hz,

1H), 2.84 (dd, J = 16.8, 2.9 Hz, 1H); ¹³C{¹H} NMR (100 MHz,

CDCl₃) δ 191.7, 163.4, 160.5, 155.0, 136.6, 136.0, 132.5, 129.7, 126.8,

127.9, 125.1, 116.1, 116.0, 115.4, 114.9, 114.0, 105.0, 94.5, 79.2, 56.2,

56.1, 44.5, 34.5, 27.3; IR (ATR) ν 3075 (w), 2901 (w), 1664 (m), 1602

(s), 1440 (m), 1341 (m), 1274 (m), 1068 (s), 1015 (s); HRMS (EI)

calcd for C₂₄H₂₆O₅[M⁺] 394.1780, found 394.1779.

7-Methoxy-2-[4-methoxy-3-(prop-2-en-1-yl)phenyl]-8-(prop-2-

en-1-yl)-2,3-dihydro-4H-1-benzopyran-4-one (31ba). Following the

general procedure 5, 30ba (730 mg, 2.00 mmol) was converted to 31ba

(330 mg, 0.90 mmol, 45%); puriﬁcation by chromatography (hexanes-

MTBE mixtures 4:1 (v/v)): yellow solid, mp 76−77 ^οC; ¹H NMR (400

MHz, CDCl₃) δ 7.86 (d, J = 8.8 Hz, 1H), 7.30 (dd, J = 8.4, 2.4 Hz, 1H),

7.26 (d, J = 2.4 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 6.64 (d, J = 8.8 Hz,

1H), 6.05−5.86 (m, 2H), 5.39 (dd, J = 12.9, 3.0 Hz, 1H), 5.09 (dm, J =

17.1 Hz, 1H), 5.07 (dm, J = 10.0 Hz, 1H), 5.00 (dm, J = 17.1 Hz, 1H),

4.95 (dm, J = 10.0 Hz, 1H), 3.90 (s, 3H), 3.86 (s, 3H), 3.41 (d, J = 6.2

Hz, 4H), 3.00 (dd, J = 16.8, 12.9 Hz, 1H), 2.84 (dd, J = 16.8, 3.0 Hz,

1H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 191.8, 163.4, 160.5, 157.4,

136.6, 136.1, 131.3, 129.1, 127.8, 126.8, 125.1, 116.1, 116.0, 115.5,

114.9, 110.4, 105.0, 79.3, 56.1, 55.6, 44.4, 34.3, 27.3; IR (ATR) ν 3077

(w), 2838 (w), 1667 (s), 1594 (s), 1503 (m), 1265 (s), 1116 (s);

HRMS (EI) calcd for C₂₃H₂₄O₄[M⁺] 364.1675, found 364.1685.

Oxidative Rearrangement of Flavanones 19, 28, and 31. 3-[4-

Methoxy-3-(prop-2-en-1-yl)phenyl]-4H-1-benzopyran-4-one (32a)

and 2-[4-Methoxy-3-(prop-2-en-1-yl)phenyl]-4H-1-benzopyran-4-

one (33a). Following the general procedure 2 using PIDA as an

oxidant, 28aa (295 mg, 1.00 mmol) was converted to 32a (138 mg, 0.47

mmol, 47%) and 33a (58 mg, 0.20 mmol, 20%). Following the general

procedure 2 using PIFA as an oxidant, 28aa (295 mg, 1.00 mmol) was

converted selectively to 32a (190 mg, 0.65 mmol, 65%); separation and

puriﬁcation by chromatography (hexanes−ethyl acetate mixtures of

increasing polarity, 5:1 to 3:1 (v/v)). Analytical data for 32a: colorless

solid, mp 98−100 ^οC; ¹H NMR (300 MHz, CDCl₃) δ 8.32 (dd, J = 8.1,

1.8 Hz, 1H), 7.99 (s, 1H), 7.67 (td, J = 7.8, 1.8 Hz, 1H), 7.49−7.39 (m,

3H), 7.35 (d, J = 2.4 Hz, 1H), 6.93 (d, J = 8.4 Hz, 1H), 6.02 (ddt, J =

17.0, 10.3, 6.7 Hz, 1H), 5.09 (dm, J = 17.0 Hz, 1H), 5.05 (dm, J = 10.3

Hz, 1H), 3.87 (s, 3H), 3.43 (d, J = 6.7 Hz, 2H); ¹³C{¹H} NMR (75

MHz, CDCl₃) δ 176.6, 157.5, 156.3,152.6, 136.9, 133.6, 130.5, 128.9,

128.2, 126.5, 125.3,125.2, 124.7, 124.0, 118.1, 115.8,110.5, 55.7, 34.4;

IR (ATR) ν 3072 (w), 2913 (w), 1715 (m), 1632 (m), 1607 (s), 1461

(s), 1247 (s), 762 (s); HRMS (EI) calcd for C₁₉H₁₆O₃[M⁺] 292.1099,

found 292.1090. Analytical data for 33a: pale yellow solid, mp 146−147

^οC; ¹H NMR (300 MHz, CDCl₃) δ 8.22 (dd, J = 8.1, 1.8 Hz, 1H), 7.81

Hz, 1H), 7.35 (d, J = 2.4 Hz, 1H), 6.95 (d, J = 8.2 Hz, 1H), 6.51 (d, J =

2.4 Hz, 1H), 6.44 (d, J = 2.4 Hz, 1H), 6.00 (ddt, J = 17.0, 10.1, 6.7 Hz,

1H), 5.07 (dm, J = 17.0 Hz, 1H), 4.99 (dm, J = 10.1 Hz, 1H), 3.90 (s,

3H), 3.86 (s, 3H), 3.85 (s, 3H), 3.38 (d, J = 6.7 Hz, 2H); ¹³C{¹H} NMR

(75 MHz, acetone-d₆) δ 174.7, 164.9, 162.5, 160.7, 158.0, 151.2, 138.1,

131.6, 129.2, 128.7, 126.6, 125.8, 115.7, 111.0, 110.7, 96.9, 93.6, 56.6,

56.4, 55.9, 35.1; IR (ATR) ν 2968 (w), 1650 (s), 1607 (s), 1452 (m),

1243 (s), 1213 (s); HRMS (EI) calcd for C₂₁H₂₀O₅[M⁺] 352.1311,

found 352.1306.

3-(4-Hydroxyphenyl)-7-methoxy-4H-1-benzopyran-4-one (Iso-

formononetin, 32d) and 2-(4-Hydroxyphenyl)-7-methoxy-4H-1-

benzopyran-4-one (Isopratol, 33d). Following the general procedure

1, 28db (315 mg, 1.00 mmol) was converted to 32d (70 mg, 0.26 mmol,

26%) and 33d (20 mg, 0.08 mmol, 8%); separation and puriﬁcation by

chromatography (hexanes−ethyl acetate mixtures of increasing polar-

ity, 5:1 to 3:1 (v/v)). Analytical data for isoformononetin (32d): pale

yellow solid, mp 225−226 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 9.55

(s, 1H), 8.35 (s, 1H), 8.02 (d, J = 8.8 Hz, 1H), 7.40 (d, J = 8.6 Hz, 2H),

7.13 (d, J = 2.4 Hz, 1H), 7.06 (dd, J = 8.8, 2.4 Hz, 1H), 6.82 (d, J = 8.6

Hz, 2H), 3.89 (s, 3H); ¹³C{¹H} NMR (100 MHz, DMSO-d₆) δ 174.7,

163.7, 157.4, 157.3, 153.1, 130.1, 126.9, 123.7, 122.4, 117.6, 115.0,

114.7, 100.5, 56.1; IR (ATR) ν 3167 (w), 1620 (s), 1582 (m), 1438 (s),

1252 (s); HRMS (ESI) calcd for C₁₆H₁₃O₄[M + H]⁺269.0814, found

269.0806. Analytical data match those previously reported in the

literature.⁹⁴Analytical data for isopratol (33d): pale yellow solid, mp

265−266 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 10.28 (s, 1H), 7.93 (d,

J = 8.8 Hz, 2H), 7.91 (d, J = 8.8 Hz, 1H), 7.25 (d, J = 2.4 Hz, 1H), 7.03

(dd J = 8.8, 2.4 Hz, 1H), 6.93 (d, J = 8.8 Hz, 2H), 6.76 (s, 1H), 3.90 (s,

3H); ¹³C{¹H} NMR (100 MHz, DMSO-d₆) δ 176.3, 163.7, 162.7,

160.8, 157.4, 128.2, 126.1, 121.7, 117.1, 115.9, 114.4, 104.6, 100.9,

56.0; IR (ATR) ν 3025 (w), 1623 (m), 1573 (s), 1440 (s), 1224 (m),

1165 (s); HRMS (ESI) calcd for C₁₆H₁₃O₄[M + H]⁺269.0814, found

269.0804. Analytical data match those previously reported in the

literature.⁹⁵

7-Hydroxy-3-(4-methoxyphenyl)-4H-1-benzopyran-4-one (For-

mononetin, 32e) and 7-Hydroxy-2-(4-methoxyphenyl)-4H-1-ben-

zopyran-4-one (Pratol, 33e). Following the general procedure 1, 28ec

(315 mg, 1.00 mmol) was converted to 32e (113 mg, 0.42 mmol, 42%)

and 33e (25 mg, 0.09 mmol, 9%); separation and puriﬁcation by

(dd, J = 8.7, 2.4 Hz, 1H), 7.71 (d, J = 2.4 Hz, 1H), 7.67 (td, J = 7.1, 1.8

Hz, 1H), 7.56 (dd, J = 8.6, 1.2 Hz, 1H), 7.40 (td, J = 7.1, 1.2 Hz, 1H),

6.96 (d, J = 8.7 Hz, 1H), 6.80 (s, 1H), 6.00 (ddt, J = 17.6, 11.1, 6.7 Hz,

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chromatography (hexanes−ethyl acetate mixtures of increasing polar-

ity, 5:1 to 3:1 (v/v)). Analytical data for formononetin (32e): pale

yellow solid, mp 256−257 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 10.84

(s, 1H), 8.33 (s, 1H), 7.97 (d, J = 8.6 Hz, 1H), 7.50 (d, J = 8.8 Hz, 2H),

6.98 (d, J = 8.8 Hz, 2H), 6.94 (dd, J = 8.6, 2.3 Hz, 1H), 6.87 (d, J = 2.3

Hz, 1H), 3.78 (s, 3H); ¹³C{¹H} NMR (100 MHz, DMSO-d₆) δ 174.7,

162.6, 159.0, 157.5, 153.2, 130.2, 127.5, 124.3, 123.2, 116.7, 115.3,

113.7, 102.2, 55.2; IR (ATR) ν 3077 (w), 1594 (m), 1512 (s), 1451 (s),

1245 (s), 1178 (s); HRMS (ESI) calcd for C₁₆H₁₃O₄[M + H]⁺

269.0814, found 269.0814. Analytical data match those previously

reported in the literature.⁷⁵Analytical data for pratol (33e): pale yellow

solid, mp 262−263 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 8.00 (d, J =

9.0 Hz, 2H), 7.87 (d, J = 8.6 Hz, 1H), 7.09 (d, J = 9.0 Hz, 2H), 6.98 (d, J

= 2.2 Hz, 1H), 6.91 (dd J = 8.6, 2.2 Hz, 1H), 6.78 (s, 1H), 3.84 (s, 3H);

¹³C{¹H} NMR (100 MHz, DMSO-d₆) δ 176.4, 162.7, 162.1, 162.0,

157.5, 128.1, 126.6, 123.5, 116.1, 115.0, 114.6, 105.2, 102.6, 55.6; IR

(ATR) ν 3500 (w), 2842 (w), 1609 (m), 1576 (s), 1549 (s), 1509(s),

1386 (m), 1264 (s), 1175 (s); HRMS (ESI) calcd for C₁₆H₁₃O₄[M +

H]⁺269.0814, found 269.0797. Analytical data match those previously

reported in the literature.⁹⁵

Attempted Oxidative Rearrangement of 31ae. 2-Phenyl-8-(prop-

2-en-1-yl)-4H-1-benzopyran-4-one (33f). Following the general

procedure 2, 31ae (265 mg, 1.00 mmol) was converted to 33f (32

mg, 0.12 mmol, 12%) and unreacted starting material was recovered;

puriﬁcation by chromatography (hexanes−ethyl acetate mixtures of

increasing polarity, 5:1 to 3:1 (v/v)): colorless solid, mp 134−135 ^οC;

¹H NMR (300 MHz, CDCl₃) δ 8.12 (dd, J = 8.0, 1.8 Hz, 1H), 7.94−

= 8.7, 2.3 Hz, 1H), 7.37 (d, J = 2.3 Hz, 1H), 7.13 (d, J = 8.7 Hz, 1H),

7.03 (d, J = 8.9 Hz, 1H), 6.07−5.92 (m, 2H), 5.23 (s, 2H), 5.11−4.99

(m, 4H), 3.96 (s, 3H), 3.62 (d, J = 6.1 Hz, 2H), 3.49 (s, 3H), 3.45 (d, J =

6.7 Hz, 2H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 176.5, 161.2, 155.3,

155.0, 152.6, 136.9, 135.3, 130.8, 129.4, 128.1, 125.9, 125.5, 124.4,

118.7, 115.8, 115.8, 115.3, 114.0, 109.1, 94.4, 56.3, 56.2, 34.6, 27.1; IR

(ATR) ν 3076 (w), 2944 (w), 1638 (m), 1599 (s), 1430 (m), 1265 (s),

1067 (s); HRMS (EI) calcd for C₂₄H₂₄O₅[M⁺] 392.1624, found

392.1621. Analytical data for 33h: colorless solid, mp 143 °C; ¹H NMR

(400 MHz, CDCl₃) δ 8.11 (d, J = 9.0 Hz, 1H), 7.75 (dd, J = 8.7, 2.4 Hz,

1H), 7.74 (d, J = 2.4 Hz, 1H), 7.19 (d, J = 8.7 Hz, 1H), 7.02 (d, J = 9.0

Hz, 1H), 6.75 (s, 1H), 6.06−5.96 (m, 2H), 5.28 (s, 2H), 5.15−5.01 (m,

4H), 3.96 (s, 3H), 3.71 (d, J = 6.1 Hz, 2H), 3.49 (s, 3H), 3.47 (d, J = 6.8

Hz, 2H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 178.5, 163.6, 161.4,

157.7, 155.2, 136.0, 135.4, 130.1, 128.1, 126.0, 125.3, 125.1, 117.8,

116.6, 116.0, 115.5, 114.0, 109.0, 105.6, 94.2, 56.4, 56.3, 34.4, 27.5; IR

(ATR) ν 2963 (w), 1632 (s), 1594 (s), 1380 (s), 1247 (s), 1081 (m);

HRMS (EI) calcd for C₂₄H₂₄O₅[M⁺] 392.1624, found 392.1626.

7-Methoxy-3-[4-methoxy-3-(prop-2-en-1-yl)phenyl]-8-(prop-2-

en-1-yl)-4H-1-benzo-pyran-4-one (32i) and 7-Methoxy-2-[4-me-

thoxy-3-(prop-2-en-1-yl)phenyl]-8-(prop-2-en-1-yl)-4H-1-benzopyr-

an-4-one (33i). Following the general procedure 1, 31be (365 mg, 1.00

mmol) was converted to 32i (222 mg, 0.61 mmol, 61%) and 33i (80

mg, 0.22 mmol, 22%); separation and puriﬁcation by chromatography

(hexanes−ethyl acetate mixtures of increasing polarity, 5:1 to 3:1 (v/

v)). To obtain crystals suitable for single crystal X-ray analysis,

compound 33i (80 mg) was dissolved in methanol (2.0 mL) and the

solution was kept at 20 °C for 24 h in an open vessel. Crystals in form of

needles were isolated by decanting the supernatant solution. The

crystals were dried at 20 °C at air. Analytical data for 32i: pale yellow

solid, mp 106−107 °C; ¹H NMR (400 MHz, CDCl₃) δ 8.21 (d, J = 8.9

Hz, 1H), 7.89 (s, 1H), 7.44 (dd, J = 8.5, 2.3 Hz, 1H), 7.40 (d, J = 2.3 Hz,

1H), 7.03 (d, J = 8.9 Hz, 1H), 6.92 (d, J = 8.5 Hz, 1H), 6.03−5.94 (m,

2H), 5.11−4.99 (m, 4H), 3.96 (s, 3H), 3.86 (s, 3H), 3.62 (d, J = 6.1 Hz,

2H), 3.43 (d, J = 6.6 Hz, 2H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ

176.6, 161.1, 157.4, 155.3, 152.5, 136.9, 135.4, 130.5, 128.8, 128.2,

125.9, 124.4, 124.2, 118.7, 115.8, 115.7, 115.3, 110.5, 109.1, 56.3, 55.6,

34.4, 27.1; IR (ATR) ν 3072 (w), 2901 (w), 1648 (s), 1500 (m), 1426

(m), 1235 (s), 1059 (m); HRMS (EI) calcd for C₂₃H₂₂O₄[M⁺]

362.1518, found 362.1526. Analytical data for 33i: colorless crystalline

solid, mp 160−161 °C; ¹H NMR (400 MHz, CDCl₃) δ 8.11 (d, J = 8.8

Hz, 1H), 7.78 (dd, J = 8.6, 2.4 Hz, 1H), 7.72 (d, J = 2.4 Hz, 1H), 7.01 (d,

J = 8.8 Hz, 1H), 6.96 (d, J = 8.6 Hz, 1H), 6.75 (s, 1H), 6.06−5.95 (m,

2H), 5.15−5.00 (m, 4H), 3.96 (s, 3H), 3.90 (s, 3H), 3.71 (d, J = 6.2 Hz,

2H), 3.43 (d, J = 6.8 Hz, 2H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ

178.4, 163.8, 161.4, 160.2, 155.2, 136.0, 135.4, 129.7, 127.8, 126.1,

125.1, 124.1, 117.7, 116.6, 116.0, 115.5, 110.6, 109.0, 105.3, 56.3, 55.8,

34.1, 27.5; IR (ATR) ν 3072 (w), 2841 (w), 1594 (s), 1500 (m), 1431

(m), 1378 (m), 1257 (s), 1124 (s); HRMS (EI) calcd for C₂₃H₂₂O₄

[M⁺] 362.1518, found 362.1514.

7.91 (m, 2H), 7.57−7.51 (m, 4H), 7.36 (t, J = 7.7 Hz, 1H), 6.84 (s, 1H),

6.08 (ddt, J = 17.6, 9.6, 6.6 Hz, 1H), 5.17 (dm, J = 17.6 Hz, 1H), 5.16

(dm, J = 9.6 Hz, 1H), 3.77 (d, J = 6.6 Hz, 2H); ¹³C{¹H} NMR (75

MHz, CDCl₃) δ 178.9, 163.2, 154.4, 135.4, 134.2, 132.2, 131.7, 129.7,

129.3, 126.4, 125.1, 124.2, 124.1, 117.1, 107.6, 34.1; IR (ATR) ν 3061

(w), 2922 (w), 1632 (s), 1584 (m), 1482 (m), 1378 (s), 1212 (w),

1139 (w); HRMS (EI) calcd for C₁₈H₁₄O₂[M⁺] 262.0994, found

262.0982.

7-Methoxy-3-(4-methoxyphenyl)-8-(prop-2-en-1-yl)-4H-1-ben-

zopyran-4-one (32g) and 7-Methoxy-2-(4-methoxyphenyl)-8-

(prop-2-en-1-yl)-4H-1-benzopyran-4-one (33g). Following the gen-

eral procedure 1, 31bc (325 mg, 1.00 mmol) was converted to 32g (168

mg, 0.52 mmol, 52%) and 33g (65 mg, 0.20 mmol, 20%); separation

and puriﬁcation by chromatography (hexanes−ethyl acetate mixtures

of increasing polarity, 5:1 to 3:1 (v/v)). Analytical data for 32g: pale

yellow solid, mp 97−98 ^οC; ¹H NMR (400 MHz, CDCl₃) δ 8.20 (d, J =

8.8 Hz, 1H), 7.97 (s, 1H), 7.51 (d, J = 8.8 Hz, 2H), 7.03 (d, J = 8.8 Hz,

1H), 6.97 (d, J = 8.8 Hz, 2H), 5.97 (ddt, J = 16.9, 10.2, 6.2 Hz, 1H), 5.03

(dm, J = 16.9 Hz, 1H), 5.01 (dm, J = 10.2 Hz, 1H), 3.95 (s, 3H), 3.84 (s,

3H), 3.62 (d, J = 6.2 Hz, 2H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ

176.5, 161.2, 159.6, 155.3, 152.5, 135.3, 130.2, 125.9, 124.5, 124.3,

118.7, 115.8, 115.3, 114.1, 109.1, 56.3, 55.4, 27.1; IR (ATR) ν 2840

(w), 1636 (m), 1607 (s), 1513 (m), 1268 (s), 1251 (s); HRMS (EI)

calcd for C₂₀H₁₈O₄[M⁺] 322.1205, found 322.1194. Analytical data for

33g: colorless solid, mp 154−155 °C; ¹H NMR (400 MHz, CDCl₃) δ

8.11 (d, J = 8.8 Hz, 1H), 7.86 (d, J = 8.7 Hz, 2H), 7.02 (d, J = 8.7 Hz,

2H), 7.01 (d, J = 8.8 Hz, 1H), 6.76 (s, 1H), 6.02 (ddt, J = 16.8, 10.2, 6.1

Hz, 1H), 5.06 (dm, J = 16.8 Hz, 1H), 5.02 (dm, J = 10.2 Hz, 1H), 3.96

(s, 3H), 3.87 (s, 3H), 3.71 (d, J = 6.1 Hz, 2H); ¹³C{¹H} NMR (100

MHz, CDCl₃) δ 178.4, 163.6, 162.5, 161.4, 155.2, 135.3, 128.1, 125.1,

124.4, 117.7, 116.0, 115.5, 114.6, 109.1, 105.3, 56.3, 55.6, 27.5; IR

(ATR) ν 2843 (w), 1635 (s), 1595 (s), 1375 (m), 1249 (m), 1186 (s),

823 (s), 812 (s); HRMS (EI) calcd for C₂₀H₁₈O₄[M⁺] 322.1205, found

322.1201.

General Procedure 6 for the Cross Metathesis of Allyl

Flavones and Allyl Isoﬂavones with 2-Methyl-2-Butene. To a

solution of the cross metathesis precursor 32 or 33 (1.00 mmol) in dry

and degassed CH₂Cl₂(10 mL) were added 2-methyl-2-butene (10.54

mL (100 mmol) per allyl group) and catalyst A (42 mg, 5 mol %) at

ambient temperature. The solution was stirred at ambient temperature

for 48 h, all volatiles were evaporated and the residue was puriﬁed by

column chromatography on silica, using hexanes−ethyl acetate mixture

(3:1 (v/v)), to furnish the respective prenyl isoﬂavone 12 or 35 or

prenyl ﬂavone 36.

7-Methoxy-3-(4-methoxyphenyl)-8-(3-methylbut-2-en-1-yl)-4H-

1-benzopyran-4-one (7-Methoxyebenosin, 12). Following the

general procedure 6, 32g (210 mg, 0.65 mmol) was converted to 7-

methoxyebenosin (12) (226 mg, 0.65 mmol, quant.); puriﬁcation by

chromatography (hexanes−ethyl acetate mixture 3:1 (v/v)): yellow oil;

¹H NMR (400 MHz, CDCl₃) δ 8.17 (d, J = 8.9 Hz, 1H), 7.98 (s, 1H),

7-Methoxy-3-[4-(methoxymethoxy)-3-(prop-2-en-1-yl)phenyl]-8-

(prop-2-en-1-yl)-4H-1-benzopyran-4-one (32h) and 7-Methoxy-2-

[4-(methoxymethoxy)-3-(prop-2-en-1-yl)phenyl]-8-(prop-2-en-1-

yl)-4H-1-benzopyran-4-one (33h). Following the general procedure 2,

31bd (395 mg, 1.00 mmol) was converted to 32h (80 mg, 0.20 mmol,

20%) and 33h (67 mg, 0.17 mmol, 17%); separation and puriﬁcation by

chromatography (hexanes−ethyl acetate mixtures of increasing polar-

ity, 5:1 to 3:1 (v/v)). Analytical data for 32h: yellowish oil; ¹H NMR

(400 MHz, CDCl₃) δ 8.20 (d, J = 8.9 Hz, 1H), 7.97 (s, 1H), 7.38 (dd, J

7.51 (d, J = 8.8 Hz, 2H), 7.01 (d, J = 8.9 Hz, 1H), 6.97 (d, J = 8.8 Hz,

2H), 5.21 (tm, J = 7.2 Hz, 1H), 3.96 (s, 3H), 3.84 (s, 3H), 3.56 (d, J =

7.2 Hz, 2H), 1.82 (s, 3H), 1.69 (s, 3H); ¹³C{¹H} NMR (100 MHz,

CDCl₃) δ 176.6, 161.0, 159.6, 155.2, 152.5, 132.6, 130.2, 125.4, 124.6,

10708

https://doi.org/10.1021/acs.joc.1c01375

J. Org. Chem. 2021, 86, 10699−10712

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

124.2, 121.5, 118.7, 117.7, 114.1, 109.1, 56.3, 55.5, 25.9, 22.2, 18.0; IR

(ATR) ν 2912 (w), 2838 (w), 1640 (m), 1511 (s), 1428 (m), 1265 (s),

1176 (s); HRMS (EI) calcd for C₂₂H₂₂O₄[M⁺] 350.1518, found

350.1532. Analytical data match those previously reported for the

natural product.⁴⁵

puriﬁcation by chromatography (hexanes−ethyl acetate mixture 3:1

(v/v)): colorless crystalline solid, mp 144−145 °C; H NMR (400

MHz, CDCl₃) δ 8.09 (d, J = 8.9 Hz, 1H), 7.78 (dd, J = 8.6, 2.4 Hz,

1H),7.72 (d, J = 2.4 Hz, 1H), 7.00 (d, J = 8.6 Hz, 1H), 6.95 (d, J = 8.9

Hz, 1H), 6.70 (s, 1H), 5.32 (tm, J = 7.4 Hz, 1H), 5.28 (tm, J = 7.1 Hz,

1H), 3.96 (s, 3H), 3.92 (s, 3H), 3.66 (d, J = 7.1 Hz, 2H), 3.38 (d, J = 7.4

Hz, 2H), 1.83 (s, 3H), 1.77 (s, 3H), 1.72 (s, 3H), 1.68 (s, 3H); ¹³C{¹H}

NMR (100 MHz, CDCl₃) δ 178.7, 163.7, 161.1, 160.2, 155.1, 133.9,

132.6, 131.0, 127.4, 125.7, 124.6, 124.2, 121.8, 121.5, 118.0, 117.9,

110.4, 108.9, 105.5, 56.2, 55.7, 28.4, 25.9, 25.9, 22.6, 18.1, 17.9; IR

(ATR) ν 2963 (w), 2912 (w), 1642 (m), 1595 (s), 1428 (m), 1375 (s),

1253 (s); HRMS (EI) calcd for C₂₇H₃₀O₄[M⁺] 418.2144, found

418.2143.

7-Methoxy-2-(4-methoxyphenyl)-8-(3-methylbut-2-en-1-yl)-4H-

1-benzopyran-4-one (36g). Following the general procedure 6, 33g

(55 mg, 0.17 mmol) was converted to 36g (50 mg, 0.14 mmol, 84%);

puriﬁcation by chromatography (hexanes−ethyl acetate mixture 3:1

(v/v)): colorless solid, mp 162−163 °C; ¹H NMR (400 MHz, CDCl₃)

δ 8.08 (d, J = 8.9 Hz, 1H), 7.87 (d, J = 9.0 Hz, 2H), 7.01 (d, J = 9.0 Hz,

2H), 7.00 (d, J = 8.9 Hz, 1H), 6.72 (s, 1H), 5.25 (tm, J = 7.0 Hz, 1H),

3.95 (s, 3H), 3.88 (s, 3H), 3.66 (d, J = 7.0 Hz, 2H), 1.83 (s, 3H), 1.69 (s,

3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 178.5, 163.4, 162.4, 161.2,

155.2, 132.6, 128.1, 124.6, 124.6, 121.8, 121.8, 117.9, 114.6, 109.0,

105.5, 56.3, 55.6, 25.9, 22.6, 18.1; IR (ATR) ν 2847 (w), 1636 (s), 1595

(s), 1383 (s), 1262 (s), 1089 (s); HRMS (EI) calcd for C₂₂H₂₂O₄[M⁺]

350.1518, found 350.1515.

7-Methoxy-3-[4-(methoxymethoxy)-3-(3-methylbut-2-en-1-yl)-

phenyl]-8-(3-methylbut-2-en-1-yl)-4H-1-benzopyran-4-one (35h).

Following the general procedure 6, 32h (150 mg, 0.38 mmol) was

converted to 35h (130 mg, 0.29 mmol, 76%); puriﬁcation by

chromatography (hexanes−ethyl acetate mixture 3:1 (v/v)): yellow

oil; ¹H NMR (400 MHz, CDCl₃) δ 8.17 (d, J = 8.9 Hz, 1H), 7.97 (s,

1H), 7.36 (dd, J = 8.8, 2.4 Hz, 1H), 7.35 (d, J = 2.4 Hz, 1H), 7.12 (d, J =

8.9 Hz, 1H), 7.01 (d, J = 8.8 Hz, 1H), 5.33 (tm, J = 7.3 Hz, 1H), 5.24 (s,

2H), 5.21 (tm, J = 7.1 Hz, 1H), 3.96 (s, 3H), 3.56 (d, J = 7.1 Hz, 2H),

3.49 (s, 3H), 3.39 (d, J = 7.3 Hz, 2H), 1.82 (s, 3H), 1.73 (s, 3H), 1.72 (s,

3H), 1.69 (s, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 176.6, 161.0,

155.2, 155.0, 152.6, 152.6, 132.6, 132.5, 131.0, 130.4, 127.8, 125.5,

125.4, 122.7, 121.5, 118.8, 117.7, 113.9, 109.1, 94.4, 56.2, 56.1, 29.0,

25.9, 25.9, 22.2, 18.0, 18.0; IR (ATR) ν 2963 (w), 2911 (w), 1642 (s),

1598 (m), 1429 (s), 1265 (s), 1068 (s); HRMS (EI) calcd for

C₂₈H₃₂O₅[M⁺] 448.2250, found 448.2242.

3-[4-Hydroxy-3-(3-methylbut-2-en-1-yl)phenyl]-7-methoxy-8-(3-

methylbut-2-en-1-yl)-4H-1-benzopyran-4-one (7-Methoxyerysubin

F, 37). To a solution of 35h (105 mg, 0.23 mmol) in methanol (10 mL)

was added aqueous HCl (4 M, 175 μL, 0.70 mmol) and the mixture was

heated to reﬂux at 60 °C for 2 h. The mixture was then cooled to

ambient temperature, diluted with water (30 mL) and extracted with

ethyl acetate (three times, 20 mL each). The combined organic extracts

were dried with MgSO₄. The solvent was evaporated under reduced

pressure and the residue puriﬁed by column chromatography on silica,

using hexanes−ethyl acetate mixture (3:1 (v/v)) as eluent to aﬀord 37

(70 mg, 0.17 mmol, 75%): yellow solid, mp 104−105 °C; H NMR

(400 MHz, CDCl₃) δ 8.18 (d, J = 8.9 Hz, 1H), 7.97 (s, 1H), 7.27 (d, J =

2.3 Hz, 1H), 7.23 (dd, J = 8.2, 2.3 Hz, 1H), 7.02 (d, J = 8.9 Hz, 1H), 6.80

(d, J = 8.2 Hz, 1H), 6.18 (s(br), 1H), 5.35 (tm, J = 7.2 Hz, 1H), 5.21

(tm, J = 7.1 Hz, 1H), 3.96 (s, 1H), 3.56 (d, J = 7.1 Hz, 2H), 3.37 (d, J =

7.2 Hz, 2H), 1.82 (s, 3H), 1.76 (s, 3H), 1.76 (s, 3H), 1.69 (s, 3H);

¹³C{¹H} NMR (100 MHz, CDCl₃) δ 177.0, 161.1, 155.3, 154.7, 152.7,

134.3, 132.6, 130.6, 128.2, 127.5, 125.4, 124.7, 124.0, 122.2, 121.5,

118.7, 117.7, 116.0, 109.2, 56.3, 29.7, 25.9, 25.9, 22.2, 18.0, 18.0; IR

(ATR) ν 3264 (w), 2913 (w), 1619 (s), 1591 (m), 1428 (s), 1266 (s),

1070 (m); HRMS (EI) calcd for C₂₆H₂₈O₄[M⁺] 404.1988, found

404.1983.

7-Methoxy-2-[4-(methoxymethoxy)-3-(3-methylbut-2-en-1-yl)-

phenyl]-8-(3-methylbut-2-en-1-yl)-4H-1-benzopyran-4-one (36h).

Following the general procedure 6, 33h (205 mg, 0.52 mmol) was

converted to 36h (201 mg, 0.45 mmol, 86%); puriﬁcation by

chromatography (hexanes−ethyl acetate mixture 3:1 (v/v)): colorless

solid, mp 91−92 °C; ¹H NMR (400 MHz, CDCl₃) δ 8.08 (d, J = 8.8 Hz,

1H), 7.74 (dd, J = 9.0, 2.4 Hz, 1H), 7.73 (d, J = 2.4 Hz, 1H), 7.17 (d, J =

9.0 Hz, 1H), 6.99 (d, J = 8.8 Hz, 1H), 6.70 (s, 1H), 5.33 (tm, J = 7.3 Hz,

1H), 5.29 (s, 2H), 5.27 (tm, J = 7.0 Hz, 1H), 3.96 (s, 3H), 3.66 (d, J =

7.0 Hz, 2H), 3.50 (s, 3H), 3.40 (d, J = 7.3 Hz, 2H), 1.82 (s, 3H), 1.77 (s,

3H), 1.74 (s, 3H), 1.68 (s, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ

178.7, 163.5, 161.2, 157.7, 155.1, 133.7, 132.6, 131.6, 127.7, 125.6,

125.4, 124.6, 121.7, 121.6, 118.0, 117.9, 113.8, 108.9, 105.7, 94.2, 56.3,

56.2, 28.7, 25.9, 25.9, 22.5, 18.1, 17.9; IR (ATR) ν 2911 (w), 1636 (s),

1599 (m), 1376 (m), 1240 (m), 1072 (s); HRMS (EI) calcd for

C₂₈H₃₂O₅[M⁺] 448.2250, found 448.2249.

7-Methoxy-3-[4-methoxy-3-(3-methylbut-2-en-1-yl)phenyl]-8-(3-

methylbut-2-en-1-yl)-4H-1-benzopyran-4-one (7,4′-Dimethoxyery-

subin F, 35i). Following the general procedure 6, 32i (260 mg, 0.72

mmol) was converted to 35i (286 mg, 0.68 mmol, 94%); puriﬁcation by

chromatography (hexanes−ethyl acetate mixture 3:1 (v/v)): yellow

solid, mp 50−51 °C; ¹H NMR (400 MHz, CDCl₃) δ 8.17 (d, J = 8.9 Hz,

1H), 7.97 (s, 1H), 7.41 (dd, J = 8.4, 2.4 Hz, 1H), 7.31 (d, J = 2.4 Hz,

1H), 7.01 (d, J = 8.9 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H), 5.34 (tm, J = 7.3

Hz, 1H), 5.22 (tm, J = 7.2 Hz, 1H), 3.96 (s, 1H), 3.86 (s, 1H), 3.56 (d, J

= 7.2 Hz, 2H), 3.36 (d, J = 7.3 Hz, 2H), 1.83 (s, 3H), 1.73 (s, 3H), 1.72

(s, 3H), 1.70 (s, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 176.7,

160.9, 157.4, 155.2, 152.5, 132.6, 132.6, 130.3, 130.1, 127.9, 125.4,

124.6, 124.2, 122.6, 121.6, 118.8, 117.7, 110.4, 109.1, 56.2, 55.6, 28.7,

26.0, 25.9, 22.2, 18.0, 18.0; IR (ATR) ν 2964 (w), 2911 (w), 1640 (s),

1598 (s), 1500 (m), 1484 (s), 1264 (s), 1070 (s); HRMS (EI) calcd for

C₂₇H₃₀O₄[M⁺] 418.2144, found 418.2137.

2-[4-Hydroxy-3-(3-methylbut-2-en-1-yl)phenyl]-7-methoxy-8-(3-

methylbut-2-en-1-yl)-4H-1-benzopyran-4-one (4′-Hydroxy-7-me-

thoxy-8,3′-diprenylﬂavone, 38). Following the procedure given

above for the synthesis of 37, compound 36h (150 mg, 0.33 mmol)

was converted to 38 (100 mg, 0.25 mmol, 75%); puriﬁcation by

chromatography (hexanes−ethyl acetate mixture 3:1 (v/v)): colorless

solid, mp 189−190 °C; H NMR (400 MHz, DMSO-d₆) δ 10.29 (s,

1H), 7.87 (d, J = 8.7 Hz, 1H), 7.73 (d, J = 2.5 Hz, 1H),7.72 (dd, J = 8.4,

2.5 Hz, 1H), 7.15 (d, J = 8.7 Hz, 1H), 6.93 (d, J = 8.4 Hz, 1H), 6.70 (s,

1H), 5.30 (tm, J = 7.6 Hz, 1H), 5.20 (tm, J = 7.2 Hz, 1H), 3.91 (s, 3H),

3.55 (d, J = 7.2 Hz, 2H), 3.27 (d, J = 7.6 Hz, 2H), 1.74 (s, 3H), 1.69 (s,

3H), 1.68 (s, 3H), 1.61 (s, 3H); ¹³C{¹H} NMR (100 MHz, DMSO-d₆)

δ 176.8, 162.9, 160.6, 158.6, 154.1, 132.3, 131.9, 128.4, 127.4, 125.7,

123.9, 122.1, 121.9, 121.5, 117.3, 117.0, 115.4, 109.4, 104.1, 56.4, 28.0,

25.5, 25.5, 22.0, 17.8, 17.6; IR (ATR) ν 3191 (w), 2912 (w), 1625 (m),

1597 (s), 1383 (s), 1267 (s), 1092 (s); HRMS (ESI) calcd for

C₂₆H₂₉O₄[M + H]⁺405.2066, found 405.2076.

ASSOCIATED CONTENT

■

sı

* Supporting Information

The Supporting Information is available free of charge at

https://pubs.acs.org/doi/10.1021/acs.joc.1c01375.

Copies of ¹H and ¹³C{¹H} NMR spectra for all

compounds; 2D-NMR-spectra for representative com-

pounds; crystallographic details and reﬁnement data;

tables of atomic coordinates, bond lengths, and angles

(PDF)

Accession Codes

CCDC 2083190 contains the supplementary crystallographic

data for this paper. These data can be obtained free of charge via

www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_

request@ccdc.cam.ac.uk, or by contacting The Cambridge

7-Methoxy-2-[4-methoxy-3-(3-methylbut-2-en-1-yl)phenyl]-8-(3-

methylbut-2-en-1-yl)-4H-1-benzopyran-4-one (7,4′-Dimethoxy-

8,3′-diprenylﬂavone, 36i). Following the general procedure 6, 33i

(95 mg, 0.26 mmol) was converted to 36i (98 mg, 0.23 mmol, 88%);

10709

https://doi.org/10.1021/acs.joc.1c01375

J. Org. Chem. 2021, 86, 10699−10712

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

(15) Singh, F. V.; Wirth, T. Oxidative Rearrangements with

Hypervalent Iodine Reagents. Synthesis 2013, 45, 2499−2511.

(16) Maertens, G.; Canesi, S. Rearrangements induced by Hyper-

valent Iodine. Top. Curr. Chem. 2015, 373, 223−241.

Crystallographic Data Centre, 12 Union Road, Cambridge CB2

1EZ, UK; fax: +44 1223 336033.

AUTHOR INFORMATION

■

(17) Zhang, B.; Li, X.; Guo, B.; Du, Y. Hypervalent iodine reagent-

mediated reactions involving rearrangement processes. Chem. Commun.

2020, 56, 14119−14136.

Corresponding Author

Bernd Schmidt − Universitaet Potsdam, Institut fuer Chemie,

D-14476 Potsdam-Golm, Germany; orcid.org/0000-

0002-0224-6069; Email: bernd.schmidt@uni-potsdam.de

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Authors

George Kwesiga − Universitaet Potsdam, Institut fuer Chemie,

D-14476 Potsdam-Golm, Germany

Eric Sperlich − Universitaet Potsdam, Institut fuer Chemie, D-

14476 Potsdam-Golm, Germany

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1,2-Aryl Shift in the Hypervalent Iodine Oxidation of Flavanones: A

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Sutherland, I. O. The oxidative rearrangement of olefins by thallium-

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Complete contact information is available at:

https://pubs.acs.org/10.1021/acs.joc.1c01375

Notes

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The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

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(23) Farkas, L.; Gottsegen, A.; Nógrádi, M.; Antus, S. Synthesis of

We thank Evonik Oxeno for generous donations of solvents and

Umicore (Hanau, Germany) for generous donations of catalysts.

A Ph.D. scholarship for G.K. (2018-2021) from the German

Academic Exchange Service (DAAD, grant number 57381412)

is gratefully acknowledged.

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