Synthesis of isobavachalcone and some organometallic derivatives

FULL PAPER

DOI: 10.1002/ejoc.201201063

Synthesis of Isobavachalcone and Some Organometallic Derivatives

John P. Grealis,^[a]Helge Müller-Bunz,^[a]Yannick Ortin,^[a]Michael Casey,*^[a]and

Michael J. McGlinchey*^[a]

Keywords: Natural products / Synthesis design / Medicinal chemistry / Sandwich complexes / Chalcones

Isobavachalcone [2Ј,4,4Ј-trihydroxy-3Ј-(3ЈЈ-methyl-2ЈЈ-but-

enyl)chalcone, 1] is a prenylated chalcone that has broad

biological activity, in particular against neuroblastomas, the

most common cancer in infancy. It is currently commercially

available at a cost of $190/mg by extraction from Psoralea

corylifolia and a number of other African and Asian plants.

Several synthetic routes have been explored, and the most

efficient procedure involves the palladium-catalysed Stille

coupling of 3-iodo-2,4-bis(methoxymethoxy)acetophenone

(25) with prenyltributyltin, Claisen–Schmidt condensation

with 4-(methoxymethoxy)benzaldehyde to form the triply

MOM-protected prenylchalcone 27 and finally deprotection

with 2 M HCl in methanol to form isobavachalcone in an

overall yield of 15% over five steps. The X-ray crystal struc-

tures of 2,4-dihydroxy-3-iodoacetophenone (21) and of sev-

eral prenylated chalcones are reported, including the eluci-

dation of their hydrogen-bonding networks in the solid state.

The synthetic route has been extended to include organome-

tallic derivatives in which the 4-(methoxymethoxy)benzalde-

hyde used in the Claisen–Schmidt condensation has been re-

placed by formylferrocene, formylruthenocene or (η⁵-formyl-

cyclopentadienyl)(η⁴-tetraphenylcyclobutadiene)cobalt

to

form the corresponding analogues of isobavachalcone con-

taining organometallic sandwich moieties.

Introduction

Chalcones are one of the major classes of natural prod-

ucts and are widely distributed in fruits, vegetables, spices,

tea and soya-based foodstuffs. They display a broad spec-

trum of biological activities, including antibacterial,^[1,2]an-

tifungal,^[3]antimalarial,^[4,5]antiviral^[6,7]and antiinflamma-

tory^[8]behaviour. There are also reports of chalcones that

display cytotoxic activity.^[9]

2Ј,4,4Ј-Trihydroxy-3Ј-(3ЈЈ-methyl-2ЈЈ-butenyl)chalcone (1),

more commonly known as isobavachalcone, is a prenylated

chalcone and can be isolated from many plants, including

Psoralea corylifolia,^[10]Dorstenia zenkeri,^[11]Angelica keis-

kei,^[12]Kadsura ananosma,^[13]Erythrina burttii^[14]and Brous-

sonetia papyrifera.^[15]It has been shown to have inhibitory

effects on skin tumours^[16]and the Epstein–Barr virus,^[17]

and has significant antimicrobial activity against the hospi-

tal pathogens Staphylococcus aureus and S. epidermidi-

sat.^[18]However, perhaps the greatest potential of isobava-

chalcone lies in its demonstrated apoptosis-inducing cytoto-

xicity against neuroblastomas,^[12]the most common extra-

cranial solid cancer in childhood and the most common

cancer in infancy.

As noted, isobavachalcone can be isolated from a wide

range of African and Asian plants. Sterner and co-workers

described how 2 kg of dried plant was extracted with

MeOH/CH₂Cl₂to give 150 g of the crude organic extract.

After multiple extractions using methanol, water, dichloro-

methane and hexane, 22 g of organic material remained.

This was subjected to chromatography on silica gel using a

gradient of ethyl acetate and acetone to give four fractions.

These were subjected to further purification by MPLC.

Eventually, 150 mg of 1 were isolated after additional puri-

fication by Sephadex LH-20 GPC.^[19]Similarly, Boyom and

co-workers isolated 15 mg from 450 g of powdered twigs,^[20]

and Akihisa et al. isolated 30 mg from 300 g of dried plant

material.^[16]Isobavachalcone is commercially available at a

current cost of $190/mg. Evidently, the development of a

convenient synthetic route could be useful.

[a] School of Chemistry and Chemical Biology, University College

Dublin,

Belfield, Dublin 4, Ireland

We are aware of only two instances in which isobavachal-

cone has appeared in a chemical reaction. In 2007, Roy and

co-workers tested a range of chalcones to investigate their

capacity to inhibit matrix metalloproteinase (MMP-2) se-

cretion from brain tumour cells; they showed that 1 pos-

sesses some inhibitory activity. To determine whether the

Fax: +353-1-716-1178

E-mail: mike.casey@ucd.ie

michael.mcglinchey@ucd.ie

Homepages: www.ucd.ie/chem/staff/drmikecasey/

www.ucd.ie/chem/staff/profmichaelmcglinchey/

Supporting information for this article is available on the

WWW under http://dx.doi.org/10.1002/ejoc.201201063.

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Synthesis of Isobavachalcone and Its Organometallic Derivatives

prenyl and α,β-unsaturated double bonds were important

for biological activity, they hydrogenated the two double

bonds and found that the product was less active than the

parent compound.^[21]

Previously, Vitali et al. had attempted to add a prenyl

group to a range of 2Ј,4Ј-dihydroxychalcones by using the

prenyltransferase enzyme isolated from Morus nigra.^[22]

However, they were unable to attach the prenyl as the 4Ј-

hydroxy substituent seemed to deactivate the enzyme. In the

absence of this 4Ј-OH group, yields of 80% were isolated.

We describe herein several approaches towards finding a

straightforward synthetic route to isobavachalcone and

then report on the incorporation of a range of organome-

tallic substituents.

Results and Discussion

Synthetic Aspects

Bavachalcone (2) is an isomer of 1, differing only in the

site of attachment of the prenyl group: 3Ј-prenyl in 1, 5Ј-

prenyl in 2. The published routes to bavachalcone

(Scheme 1) involve the prenylation of 2,4-dihydroxyaceto-

Scheme 1. Reported routes to bavachalcone (2).

We chose to repeat the first step of the reaction sequence

phenone (resacetophenone, 3) using either 2-methyl-3- to see whether it was possible to isolate the prenylated resa-

[23,24]

buten-2-ol and BF₃·OEt₂

or prenyl bromide and cetophenones in higher yields. In our hands, when a solu-

KOH^[25]to form 2,4-dihydroxy-5-prenylacetophenone (4). tion of resacetophenone (3) and boron trifluoride etherate

Both methods are low-yielding and give a complex mixture in dioxane was treated with 2-methyl-3-buten-2-ol and

of compounds that is not easily purified by column heated at 50 °C for 2 h, chromatographic separation yielded

chromatography. Jain et al. then directly condensed 4 with four products (Scheme 2): the previously reported 5-prenyl

an appropriate aldehyde to give 2 in a total yield for the isomer 4 (19%), the 3,5-diprenyl derivative 7 (8%), the

two steps of 1.6%.^[23]However, when Suh and co- cyclised product 1-(7-hydroxy-2,2-dimethyl-3,4-dihydro-2H-

workers^[24]protected the 4-hydroxy group as a meth- 1-benzopyran-6-yl)ethanone (8; 12%) and the desired mate-

oxymethoxy (5) prior to the Claisen–Schmidt condensation, rial 2,4-dihydroxy-3-prenylacetophenone (9; 8%). A large

removal of the protecting group in 6 using dilute acid deliv- amount of unreacted ketone (Ͼ50%) was also recovered

ered 2 in an overall yield of 6% for the four steps.

from the aqueous workup.

Scheme 2. Acid- and base-mediated prenylation of resacetophenone (3).

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The second approach, treatment of resacetophenone (3) aromatic ring. In a model reaction to study the latter pro-

with potassium hydroxide and prenyl bromide has been cess, 4-methoxycinnamoyl chloride (11) in dry CH₂Cl₂was

variously reported^[25]to furnish 2,4-dihydroxy-3-prenylace- treated with 1,3,5-trimethoxybenzene and AlCl₃. The reac-

tophenone (9), commonly as a yellow oil. In our hands, this tion proceeded almost quantitatively to yield 2Ј,4,4Ј,6Ј-tet-

reaction yielded small quantities of 4, 7 and 9 as well as ramethoxychalcone (12; Scheme 3), the X-ray crystal struc-

the prenyloxy intermediate 10. The prenyl chain in 10 is ture of which is depicted in Figure 3. It can be seen that the

definitively located on the 4-hydroxy group; the singlet at δ cinnamoyl backbone makes a dihedral angle of 73° with the

= 12.65 ppm is characteristic of 2-hydroxyacetophenones in trimethoxybenzene ring so as to avoid steric interactions

which the 2-hydroxy substituent is intramolecularly hydro- between the carbonyl group and the methoxy substituents

gen-bonded to the adjacent ketone. A substantial amount at the 2Ј- and 6Ј-positions.

of unreacted ketone (51%) was also recovered.

For unambiguous characterisation, 2,4-dihydroxy-3-pren-

ylacetophenone (9) was recrystallised from hot benzene to

give a sample suitable for an X-ray crystallographic study.

Figure 1 shows that the hydroxy group at C2 forms a strong

intramolecular hydrogen bond (1.835 Å) with the carbonyl,

thus holding the aromatic ring and the methyl ketone al-

most coplanar (dihedral angle of 1°). The carbonyl also

forms an intermolecular hydrogen bond (1.897 Å) with the

Scheme 3. Friedel–Crafts acylation of 1,3,5-trimethoxybenzene

with 11.

hydroxy group at C4 of its neighbouring molecule, as in

bavachalcone and related hydroxychalcones.^[26–28]As de-

picted in Figure 2, the molecules are aligned in a head-to-

tail fashion and form a two-dimensional hydrogen-bonded

network.

Figure 3. Molecular structure of 2Ј,4,4Ј,6Ј-tetramethoxychalcone

(12).

Prior to lithiation, the two hydroxy functionalities in res-

orcinol were protected with either methoxymethoxy or

methoxy groups, as in 13 and 14, respectively (Scheme 4).

Lithiation of 13 or 14 and treatment with prenyl bromide

furnished the requisite products 15 or 16 in modest yields

(41 and 39%, respectively).

Figure 1. Molecular structure of 2,4-dihydroxy-3-prenylaceto-

phenone (9).

Figure 2. Hydrogen-bonding network in 2,4-dihydroxy-3-prenyl-

acetophenone (9).

Scheme 4. Prenylation of 1,3-dialkoxybenzenes.

As neither of these two routes could be optimised to give

Subsequent Friedel–Crafts acylation of the MOM-pro-

large quantities of pure 9, it was decided to try an alterna- tected species 15 with 4-methoxycinnamoyl chloride and

tive approach in which the prenyl group could be regioselec- AlCl₃led only to decomposition and unidentifiable prod-

tively attached to resorcinol by an ortho-lithiation pro- ucts. In contrast, the same reaction with 1,3-dimethoxy-2-

cedure,^[29]and then the chalcone skeleton would be as- prenylbenzene (16) yielded (E)-4-(2,6-dimethoxyphen-

sembled by a Friedel–Crafts acylation of the oxygen-rich ylmethyl)-5-chloro-1-(4-methoxyphenyl)-5-methyl-1-hexen-

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Synthesis of Isobavachalcone and Its Organometallic Derivatives

Scheme 5. Products from the cinnamylation of 1,3-dimethoxy-2-prenylbenzene (16).

1

3-one (17; Scheme 5), as revealed by its H and ¹³C NMR butyl to the enone unit led to 1-(2,4-dimethoxyphenyl)-3-

spectra. The benzylic CH₂appears as two separate doublets (4-methoxyphenyl)heptan-1-one (20; Scheme 6), and no

of doublets at δ = 3.11 ppm (J = 13 and 3 Hz) and δ = further reaction with prenyl bromide.

3.23 ppm (J = 13 and 10 Hz). Evidently, these protons are

diastereotopic with a mutual coupling of 13 Hz, but exhibit

different coupling constants to the adjacent methine pro-

ton, which appears as a doublet of doublets at δ = 3.45 ppm

(J = 10 and 3 Hz). The protons on the double bond give rise

to 16 Hz doublets at δ = 7.25 and 6.59 ppm. The product 17

appears to have been formed by acylation of the side-chain,

which suggests that the prenyl is more activated than the

aromatic ring towards this type of reaction.

When TiCl₄was used as the Lewis acid instead of

AlCl₃,^[30]two products were isolated and characterised: 17

was again formed (27%) and the second compound was

identified as 2Ј,4,4Ј-trimethoxy-3Ј-(3ЈЈ-chloro-3ЈЈ-methylbut-

yl)chalcone (18). As in the AlCl₃-promoted Friedel–Crafts

Scheme 6. Cinnamylation of 1,3-dimethoxybenzene using TiCl₄.

At this point it was decided to adopt a different approach

reaction, the prenyl is apparently a more attractive target by using a palladium coupling protocol. This was predi-

than the aromatic ring. We suggest that initially HCl adds cated on the availability of 2,4-dihydroxy-3-iodoaceto-

across the prenyl double bond with the chlorine adding at phenone (21), previously prepared in 40% yield by treat-

the site of the favoured cation. At this point, the aromatic ment of resacetophenone (3) with iodine chloride in di-

ring is subject to Friedel–Crafts acylation to form the chalc- chloromethane for 24 h.^[31]Interestingly, we were able to

1

one 18, the H NMR spectrum of which clearly shows the accomplish regioselective iodination of resacetophenone in

presence of the trans alkene protons with 16 Hz doublets at 74% yield by using NaI and KIO₃as the iodine source;^[32]

δ = 7.40 and 7.70 ppm. The addition of HCl across the the 3,5-diiodo derivative 22 was also formed in low yield

double bond of the prenyl generates two methylene groups, (Scheme 7). The molecular structure of 21 is shown in Fig-

which appear as multiplets at δ = 1.98 and 2.86 ppm. In the ure 4.

¹³C NMR spectrum the carbon bearing the chlorine is seen

Figure 5 illustrates how molecules of 21 align themselves

at δ = 71.0 ppm.

in a head-to-tail fashion to form a hydrogen-bonded net-

In light of these observations, the sequence was reversed work. Within the chain there are intramolecular hydrogen

such that the Friedel–Crafts acylation preceded lithiation bonds with lengths of 1.750 Å between the 2-hydroxy and

and incorporation of the prenyl substituent. By using TiCl₄the carbonyl groups; this is slightly shorter than in 9, poss-

as the Lewis acid, 2Ј,4,4Ј-trimethoxychalcone (19) was iso- ibly because the large 3-iodo group forces the hydroxy moi-

lated in 76% yield. However, when treated sequentially with ety closer to the carbonyl. The aromatic ring and the carb-

butyllithium and prenyl bromide, Michael addition of the onyl group are very nearly coplanar with a dihedral angle

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M. Casey, M. J. McGlinchey et al.

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tween the 4-hydroxy H and the 2-hydroxy O of a molecule

in the chain. The cross-linked molecules are offset by 49°

with the plane defined by the long head-to-tail chain.

With 2,4-dihydroxy-3-iodoacetophenone (21) in hand,

we could consider using one of the palladium coupling pro-

cedures. In a model Heck reaction using 2-iodophenol, 3-

methyl-1-butene, palladium acetate and triethylamine in

DMF, 2-prenylphenol (23) was obtained in only 10% yield;

the major product (76%) was 2-[(E)-3-methyl-1-butenyl]-

phenol (24), an undesired β-elimination product

(Scheme 8).

Scheme 7. Iodination of resacetophenone (3).

Scheme 8. Prenylation of 2-iodophenol by a Heck reaction.

However, Stille reaction of the doubly protected 2,4-bis-

(methoxymethoxy)-3-iodoacetophenone (25) with prenyltri-

butylstannane in DMF using [Pd(PPh₃)₄] as catalyst at

100 °C for 24–30 h delivered two products after chromato-

graphic separation. The first arose from the loss of iodine

(51%), but the second product was the required prenylated

product 26, obtained in 45% isolated yield (Scheme 9).

Following numerous previous examples,^[25,31]the final

step in assembling the chalcone skeleton was the Claisen–

Schmidt condensation of 26 with the MOM-protected 4-

Figure 4. Molecular structure of 2,4-dihydroxy-3-iodoaceto- hydroxybenzaldehyde. By using ethanolic KOH as the base

phenone (21).

and quenching with dilute acid, 3Ј-prenyl-2Ј,4,4Ј-tris(meth-

oxymethoxy)chalcone (27) was isolated in modest yield

1

of less than 1°. There are also intermolecular hydrogen (36%), the H NMR spectrum showing 16 Hz doublets at

bonds of 1.847 Å between the 4-hydroxy of one molecule δ = 7.63 and 7.24 ppm for the trans double bond. A second

and the carbonyl of another. These chains are cross-linked product containing only two MOM groups was also iso-

by two molecules that form hydrogen bonds of 2.071 Å be- lated and identified as the chalcone 28, presumably formed

Figure 5. X-ray crystal structure showing the hydrogen-bonding network in 21; iodine atoms are shown as large spheres.

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Synthesis of Isobavachalcone and Its Organometallic Derivatives

Scheme 9. Palladium-mediated reaction of 2,4-bis(methoxymethoxy)-3-iodoacetophenone (25) with prenyltributylstannane and Claisen–

Schmidt coupling to form doubly and triply protected isobavachalcone.

by partial deprotection of 27 during the neutralization pro-

cess. It is evident that the MOM group at the 2Ј-position

1

had been cleaved because the H NMR spectrum reveals a

sharp singlet at δ = 13.50 ppm typical of hydrogen-bonded

2-hydroxyacetophenones. In attempts to optimise the yield

of the Claisen–Schmidt condensation, a number of bases

were used. Potassium tert-butoxide and lithium diisoprop-

ylamide led to either decomposition or very poor yields,

and the best results were obtained by using a large excess

of potassium carbonate in very dry methanol to furnish 27

in 51% yield (Scheme 9).

Figure 6. Molecular structure of 2Ј-hydroxy-4,4Ј-bis(methoxy-

methoxy)-3Ј-prenylchalcone (28).

Molecule 28 has been previously reported as a yellow dently arises from the addition of HCl to the liberated iso-

oil,^[25b,25c]but can be recrystallised from 1:1 dichlorometh- bavachalcone. A second product was characterised as 2-(4-

ane/hexane to furnish X-ray quality crystals. The X-ray hydroxyphenyl)-8,8-dimethyl-2,3,9,10-tetrahydro-8H-

structure (Figure 6) reveals the expected intramolecular hy- pyrano[2,3-f]chromen-4-one (30); in this case, acid catalysis

drogen bonding (1.588 Å) between the 2-hydroxy substitu- brought about a double cyclisation in which the 2Ј-hydroxy

ent and the ketone. As with 9 and 21, the dihedral angle group reacted with the enone fragment linking the two aro-

between the aromatic ring and the ketone is very small, less matic rings, and the 4Ј-hydroxy group added to the double

than 2°.

bond of the prenyl to form a pyran ring (Scheme 10).

Finally, deprotection was optimally achieved by treat-

Initial attempts at the deprotection of 27 and isolation

of isobavachalcone (1) with 2 m HCl led to 3Ј-(3ЈЈ-chloro- ment with 12.5 equiv. of 2 m HCl in methanol at reflux for

3ЈЈ-methylbutyl)-2Ј,4,4Ј-trihydroxychalcone (29), which evi- 3 h. Two products were identified after purification by

Scheme 10. Reaction of the triple-MOM-protected isobavachalcone 27 with HCl.

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Scheme 11. Organometallic derivatives of isobavachalcone.

chromatography on silica gel. The first was the partially de- raphy column revealed that the MOM group at the 2Ј-posi-

protected product 31 and the second was isobavachalcone tion had been removed because the resonance at δ =

(1) in 89% isolated yield. The ¹H NMR spectrum of 1 exhi- 14.26 ppm is characteristic of a hydrogen-bonded phenol

bits 16 Hz doublets at δ = 7.80 and 7.43 ppm for the trans adjacent to a carbonyl group. Moreover, the doublet

alkene protons, the prenyl CH appears as a 7 Hz triplet at (10.5 Hz) of doublets (5 Hz) at δ = 5.37 ppm (1 H) and the

δ = 5.29 ppm and the prenyl CH₂as a 7 Hz doublet at δ = multiplet (2 H) at δ = 3.00 ppm indicate that HCl had

3.46 ppm. The 2-hydroxy group appears as a characteristic added across the double bond thus giving rise to dia-

sharp singlet at δ = 13.85 ppm and the carbonyl gives rise stereotopic methylene protons. The direction of addition is

to a sharp IR peak at 1630 cm^–1; 2Ј,4-dihydroxychalcone controlled by protonation to form the heavily favoured cat-

has a CO absorption at 1630 cm^–1.^[33]

ion α to the ferrocenyl substituent,^[50]thus forming 3-

chloro-1-(2-hydroxy-4-methoxymethoxy-3-prenylphenyl)-3-

ferrocenylpropan-1-one (33) in 2% yield.

Organometallic Derivatives

The incorporation of ferrocenyl or other organometallic

moieties such as [(RCϵC)Co₂(CO)₆],^[34,35][(C₄Ph₄)(C₅H₄)-

Co]^[36]or [(C₅H₄)M(CO)₃] (M = Mn, Tc, Re)^[37,38]into bio-

active molecules has significantly improved their activity

and range of applicability.^[39]Such organometallic deriva-

tives include the ferrocifens,^[40,41]ferrocenyl analogues of

Tamoxifen, which are active against hormone-dependent

and -independent breast cancers,^[42]ferrocenyl-hydantoins,

which are active against prostate cancer,^[43]anti-malarials

such as ferrochloroquin^[44–46]and, in particular, ferrocenyl-

chalcones^[47]and their glycoside derivatives, the cytotoxicit-

ies of which have been demonstrated.^[48]More recently,

ferrocenyl-flavones have been shown to exhibit cytotoxicity

against B16 melanoma cells.^[49]To this end, we chose to

prepare a series of organometallic derivatives of isobavach-

alcone containing iron, ruthenium or cobalt (Scheme 11),

and some preliminary results are reported herein.

The reaction of the bis-MOM-protected 3-prenylresace-

tophenone 26 with formylferrocene and a large excess of

potassium carbonate in methanol at reflux furnished (E)-1-

[2,4-bis(methoxymethoxy)-3-prenylphenyl]-3-ferrocenyl-2-

1

propen-1-one (32) in 39% yield. Its H NMR spectrum ex-

hibits a pair of 15.5 Hz doublets at δ = 7.52 and 6.58 ppm

attributable to the trans alkene fragment as well as ferro-

cenyl peaks at δ = 4.54 (2 H), 4.44 (2 H) and 4.17 ppm (5

Scheme 12. Organometallic derivatives of isobavachalcone.

The second product to elute was the monoprotected

H). As shown in Scheme 12, deprotection of 32 with HCl

1

in methanol yielded four isolable products: the H NMR compound 34 (25%) and the third was identified as 1-(2,4-

spectrum of the first material to elute from the chromatog- dihydroxy-3-prenylphenyl)-3-ferrocenylpropen-1-one (35;

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Synthesis of Isobavachalcone and Its Organometallic Derivatives

standard 2D NMR experiments (¹H–¹H COSY, ¹H–¹³C HSQC and

HMBC, NOESY). Electrospray mass spectrometry was performed

with a Micromass Quattro micro-instrument. IR spectra were re-

corded with a Perkin–Elmer Paragon 1000 FT-IR spectrometer and

were calibrated with polystyrene. Merck silica gel 60 (230–

400 mesh) was used for flash chromatography. Melting points were

determined with an Electrothermal ENG instrument. Elemental

analyses were carried out by the Microanalytical Laboratory at

University College Dublin.

30%), the desired ferrocenyl derivative of isobavachalcone.

In solution it is red, but once all the solvent has been re-

moved, it appears as a dark-purple solid. Interestingly, its

¹H NMR spectrum is concentration-dependent and it can

only be fully assigned at low concentrations (5 mg/mL)

when the trans alkene peaks appear as 15 Hz doublets at δ

= 7.83 and 7.17 ppm, the 2Ј-hydroxy group appears as a

sharp singlet at δ = 13.99 ppm and the 4Ј-hydroxy group

appears as a broad singlet at δ = 6.05 ppm. At higher con-

centrations (20 mg/mL), the peaks for the aromatic protons

5Ј-H and 6Ј-H and for the 4Ј-OH group start to broaden

significantly, possibly attributable to the involvement of the

4Ј-OH group in multiple intermolecular hydrogen-bonding

Reaction of 2,4-Dihydroxyacetophenone with 2-Methyl-3-buten-2-ol

and BF₃·OEt₂: BF₃·OEt₂(0.30 mL, 2.44 mmol) was slowly added

to a solution of 2,4-dihydroxyacetophenone (3; 1.15 g, 7.56 mmol)

in dry dioxane (10 mL) under nitrogen. 2-Methyl-3-buten-2-ol

(0.61 mL, 5.84 mmol) was added and the solution was heated at

situations. Likewise, the 2Ј-OH group appears as a sharp 50 °C for 90 min. After cooling to room temperature, diethyl ether

(100 mL) was added. This was washed with a 1% w/v solution of

K₂CO₃(3ϫ 50 mL). The aqueous layer was acidified and extracted

with diethyl ether to recover unreacted 3 (621 mg, 4.08 mmol,

54%). The organic layer was washed with brine, dried with MgSO₄

and condensed in vacuo. The crude product was purified by

chromatography on silica gel by using cyclohexane (75%) and di-

ethyl ether (25%) as eluent to give 2,4-dihydroxy-3,5-diprenyl-

acetophenone (7; 131 mg, 0.454 mmol, 8%), 1-(7-hydroxy-2,2-di-

methyl-3,4-dihydro-2H-1-benzopyran-6-yl)ethanone (8; 150 mg,

0.68 mmol, 12%), 2,4-dihydroxy-5-prenylacetophenone (4; 250 mg,

singlet at δ = 13.99 ppm, but at higher concentrations ad-

ditional single peaks are observed in this region. These ef-

fects were reversed upon dilution, which shows that they

are not caused by decomposition.

The ¹H NMR spectrum of the final product to elute does

not exhibit a resonance in the 13–14 ppm region, but in-

stead shows a doublet (11 Hz) of doublets (5 Hz) at 5.3 ppm

(1 H) and a multiplet (2 H) at δ = 2.99 ppm, reminiscent of

the pattern seen in the HCl adduct 33. Apparently, proton-

ation to generate the ferrocenyl-stabilised cation leads to 1.14 mmol, 19%) and the desired product 2,4-dihydroxy-3-prenyla-

cetophenone (9; 100 mg, 0.454 mmol, 8%), each as a white solid.

Data for 7: ¹H NMR (300 MHz, CDCl₃): δ = 12.92 (s, 1 H, 2-OH),

7.34 (s, 1 H, 6-H), 6.23 (s, 1 H, 4-OH), 5.26 (m, 2 H, 2 prenyl CH),

3.42 (d, J = 7 Hz, 2 H, prenyl CH₂), 3.28 (d, J = 7.0 Hz, 2 H,

prenyl CH₂), 2.53 (s, 3 H, CH₃), 1.82 (s, 3 H, prenyl CH₃), 1.78 (s,

3 H, prenyl CH₃), 1.76 (s, 3 H, prenyl CH₃), 1.74 (s, 3 H, prenyl

CH₃) ppm. Data for 8: ¹H NMR (300 MHz, CD₃OD): δ = 7.62 (s,

1 H, 5-H), 6.17 (s, 1 H, 8-H), 2.77 (t, J = 6.5 Hz, 2 H, 4-H), 2.53

(s, 3 H, CH₃), 1.83 (t, J = 6.5 Hz, 2 H, 3-H), 1.36 (m, 6 H, 2

attack by the 2Ј-OH substituent and results in ring closure

to form 2-ferrocenyl-7-hydroxy-8-prenylchroman-4-one (36;

23%).

Analogously, formylruthenocene and (η⁵-formylcyclo-

pentadienyl)(η⁴-tetraphenylcyclobutadiene)cobalt(I)

also

reacted with the bis-MOM-protected 3-prenylresaceto-

phenone 26 under basic conditions to yield the ruthenium

and cobalt complexes 37 and 40, respectively. Once again,

deprotection furnished the mono-MOM-protected species

1

CH₃) ppm. Data for 4: H NMR (300 MHz, CDCl₃): δ = 12.53 (s,

38 and 41, respectively, and the ruthenium (39) and cobalt 1 H, 2-OH), 7.41 (s, 1 H, 6-H), 6.36 (s, 1 H, 3-H), 6.32 (s, 1 H, 4-

OH), 5.29 (pseudo-sept.t, J = 7.5, J = 1.5 Hz, 1 H, prenyl CH),

3.29, (d, J = 7.5 Hz, 2 H, prenyl CH₂), 2.55 (s, 3 H, CH₃), 1.78 (s,

3 H, prenyl Z-CH₃), 1.77 (s, 3 H, prenyl E-CH₃) ppm. Data for 9:

¹H NMR (300 MHz, CDCl₃): δ = 13.07 (s, 1 H, 2-OH), 7.53 (d, J

= 9 Hz, 1 H, 6-H), 6.37 (d, J = 9 Hz, 1 H, 5-H), 6.20 (s, 1 H, 4-

OH), 5.26 (pseudo-sept.t, J = 7.5, J = 1.5 Hz, 1 H, prenyl CH),

3.43 (d, J = 7.5 Hz, 2 H, prenyl CH₂), 2.56 (s, 3 H, CH₃), 1.76 (s,

3 H, prenyl Z-CH₃), 1.82 (s, 3 H, prenyl E-CH₃) ppm.

(42) organometallic sandwich derivatives of isobavachal-

cone.

Conclusions

We have reported herein a synthetic route to isobavachal-

cone (1) and several of its organometallic derivatives that

proceeds by the palladium-catalysed Stille coupling of 3-

iodo-2,4-(methoxymethoxy)acetophenone (25) with tribut-

ylprenyltin, Claisen–Schmidt condensation with 4-(meth-

oxymethoxy)benzaldehyde to form the triple-MOM-pro-

tected prenyl-chalcone 27 and finally deprotection with 2 m

HCl in methanol to form isobavachalcone (1) in an overall

yield of 15% over five steps. This provides an alternative

to the tedious and low-yielding extraction procedures from

Psoralea corylifolia and other plant materials. The bio-

logical activities of a range of organometallic derivatives of

isobavachalcone remain to be explored.

Reaction of 2,4-Dihydroxyacetophenone with Prenyl Bromide and

KOH: KOH (5.60 g, 99.81 mmol) was added to a stirred solution of

2,4-dihydroxyacetophenone (7.60 g, 49.95 mmol) in water (75 mL)

under nitrogen at room temperature. Prenyl bromide (4.20 mL,

37.64 mmol) was added and the solution was stirred overnight. It

was acidified with 4 n HCl (100 mL) and the product was extracted

with diethyl ether. The extract was dried with MgSO₄and concen-

trated in vacuo to yield an orange solid that was purified by

chromatography on silica gel using dichloromethane as eluent. This

yielded 2,4-dihydroxy-3,5-diprenylacetophenone (7; 540 mg,

1.87 mmol, 5%) as a white solid, 1-[4-(3-methylbut-2-enyloxy)-2-

hydroxyphenyl]ethanone (10; 20 mg, 0.91 mmol, 2%) as an orange

oil, the desired 2,4-dihydroxy-3-prenylacetophenone (9; 960 mg,

4.36 mmol, 12%) as a white powder and 2,4-dihydroxy-5-prenyl-

acetophenone (4; 972 mg, 4.41 mmol, 12%) as a white solid. A

large amount of unreacted 3 (3.88 g, 25.20 mmol, 51%) was also

recovered. A sample of 9 was recrystallised from hot benzene to

yield crystals suitable for an X-ray crystallographic study. Data for

Experimental Section

General: ¹H and ¹³C NMR spectra were recorded with Varian 300,

400, 500 or 600 MHz spectrometers. Assignments were based on

Eur. J. Org. Chem. 2013, 332–347

www.eurjoc.org

339

M. Casey, M. J. McGlinchey et al.

FULL PAPER

10: ¹H NMR (300 MHz, CDCl₃): δ = 12.65 (s, 1 H, 2-OH), 7.51 It was warmed slowly to room temperature and prenyl bromide

(d, J = 8.5 Hz, 1 H, 6-H), 6.33 (dd, J = 2.5, J = 8.5 Hz, 1 H, 5-H), (1.80 mL, 16.13 mmol) was added. The solution was heated at re-

6.32 (d, J = 2.5 Hz, 1 H, 3-H), 5.37 (t, J = 6.5 Hz, 1 H, prenyl

flux for 3 h, cooled to room temperature, added to NaHCO₃

CH), 4.40 (d, J = 6.5 Hz, 2 H, prenyl CH₂), 2.44 (s, 3 H, CH₃), (50 mL) and the product extracted with ethyl acetate. The organic

1.70 (s, 3 H, prenyl Z-CH₃), 1.65 (s, 3 H, prenyl E-CH₃) ppm.

layer was washed with water, dried with MgSO₄to give an orange

oil that was purified by chromatography on silica gel using pentane

as eluent. 1,3-Dimethoxy-2-prenylbenzene (16) was recovered as a

colourless oil (870 mg, 4.22 mmol, 39%). Unreacted starting mate-

rial was recovered by using 2% diethyl ether in pentane as eluent.

(110 mg, 0.796 mmol, 7%). Data for 16: ¹H NMR (300 MHz,

CDCl₃): δ = 7.17 (t, J = 8.5 Hz, 1 H, 5-H), 6.59 (d, J = 8.5 Hz, 2

H, 4-H, 6-H), 5.27 (t, J = 7 Hz, 1 H, prenyl CH), 3.86 (s, 6 H, 2

OMe), 3.43 (d, J = 7 Hz, 2 H, prenyl CH₂), 1.84 (s, 3 H, prenyl Z-

CH₃), 1.73 (s, 3 H, prenyl E-CH₃) ppm.

2Ј,4,4Ј,6Ј-Tetramethoxychalcone (12): AlCl₃(140 mg, 1.05 mmol)

was added to a stirred solution of 4-methoxycinnamoyl chloride

(200 mg, 1.02 mmol) in dry dichloromethane (10 mL) under nitro-

gen and the reaction mixture was stirred for 20 min. 1,3,5-Tri-

methoxybenzene (180 mg, 1.07 mmol) was then added and the

solution became turned red. The mixture was stirred at room tem-

perature for 20 h, quenched with water, extracted with dichloro-

methane, washed with water, dried with MgSO₄and condensed in

vacuo to give 2Ј,4,4Ј,6Ј-tetramethoxychalcone (12) as an orange oil.

Recrystallisation from acetone gave crystals (330 mg, 1.00 mmol,

95%) suitable for X-ray crystallography. Data for 12: ¹H NMR

(400 MHz, CDCl₃): δ = 7.46 (d, J = 8 Hz, 2 H, 2-H, 6-H), 7.31 (d,

J = 16 Hz, 1 H, 7-H), 6.88 (d, J = 8 Hz, 2 H, 3-H, 5-H), 6.84 (d,

J = 16 Hz, 1 H, 8-H), 6.16 (s, 2 H, 3Ј-H, 5Ј-H), 3.85 (s, 3 H, OMe),

3.81 (s, 3 H, OMe), 3.75 (s, 6 H, 2 OMe) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 193.4 (C=O), 161.2 (C-4Ј), 160.4 (C-4),

157.7 (C-2Ј, C-6Ј), 143.2 (C-7), 129.1 (C-2, C-6), 126.6 (C-1), 126.0

(C-8), 113.3 (C-3, C-5), 110.9 (C-1Ј), 89.7 (C-3Ј, C-5Ј), 54.9 (2Ј-

OMe, 6Ј-OMe), 54.4 (OMe), 54.3 (OMe) ppm.

Friedel–Crafts Acylation of 1,3-Dimethoxy-2-prenylbenzene (16)

Using 4-Methoxycinnamoyl Chloride and AlCl₃: AlCl₃(130 mg,

0.975 mmol) was added to 4-methoxycinnamoyl chloride (190 mg,

0.966 mmol) in dry dichloromethane (10 mL) under nitrogen and

the solution was stirred for 20 min at room temperature. 1,3-Di-

methoxy-2-prenylbenzene (200 mg, 0.968 mmol) as a solution in

dry dichloromethane (5 mL) was then added and the reaction mix-

ture turned red. It was stirred overnight at room temperature,

quenched with water, extracted with dichloromethane and the or-

ganic layer was washed with water (3ϫ 50 mL), dried with MgSO₄

and condensed in vacuo to give a red-brown oil. It was purified by

chromatography on a column of silica using a gradient of diethyl

ether (25–75%) in pentane. The main product was found to be (E)-

4-(2,6-dimethoxyphenylmethyl)-5-chloro-1-(4-methoxyphenyl)-

5-methyl-1-hexen-3-one (17; 100 mg, 0.263 mmol, 27%). Data for

17: ¹H NMR (500 MHz, CDCl₃): δ = 7.36 (d, J = 8.5 Hz, 2 H, 2ЈЈ-

H, 6ЈЈ-H), 7.25 (d, J = 16 Hz, 1 H, 1-H), 7.10 (t, J = 8.5 Hz, 1 H,

4Ј-H), 6.87 (d, J = 8.5 Hz, 2 H, 3ЈЈ-H, 5ЈЈ-H), 6.59 (d, J = 16 Hz,

1 H, 2-H), 6.47 (d, J = 8.5 Hz, 2 H, 3Ј-H, 5Ј-H), 3.83 (s, 3 H, 4ЈЈ-

OMe), 3.75 (s, 6 H, 2Ј-OMe, 6Ј-OMe), 3.45 (dd, J = 10, J = 3 Hz,

1 H, 4-H), 3.23 (dd, J = 13, J = 10 Hz, 1 H, benzyl H_a), 3.11 (dd,

J = 13, J = 3 Hz, 1 H, benzyl H_b), 1.81 (s, 3 H, 6-H), 1.79 (s, 3 H,

C-5-Me) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 201.0 (C-3),

161.5 (C-4ЈЈ), 158.5 (C-2Ј, C-6Ј), 141.1 (C-1), 130.1 (C-2ЈЈ, C-6ЈЈ),

127.9 (C-1ЈЈ), 127.8 (C-4Ј), 125.8 (C-2), 116.2 (C-1Ј), 114.5 (C-3ЈЈ,

C-5ЈЈ), 103.8 (C-3Ј, C-5Ј), 72.5 (C-5), 61.0 (C-4), 55.8 (2Ј-OMe, 6Ј-

OMe), 55.6 (4ЈЈ-OMe), 31.5 (C-6), 30.8 (5-Me), 23.7 (C_benzyl) ppm.

1,3-Bis(methoxymethoxy)benzene (13): Fresh NaH (1.10 g,

45.84 mmol) was added to a stirred solution of resorcinol (2.00 g,

18.16 mmol) in dry DMF (125 mL) under nitrogen. Chloromethyl

methyl ether (3.50 mL, 46.08 mmol) at 0 °C was added and the

solution was stirred at room temperature overnight. The reaction

was quenched with water and extracted with pentane. The organic

layers were then washed with water to remove DMF and then dried

with MgSO₄to give 1,3-bis(methoxymethoxy)benzene (13) as a yel-

low oil (2.25 g, 11.35 mmol, 63%). Data for 13: ¹H NMR

(300 MHz, CDCl₃): δ = 7.19 (t, J = 8 Hz, 1 H, 5-H), 6.74 (d, 1 H,

J = 2 Hz, 2-H), 6.70 (dd, J = 8, J = 2 Hz, 2 H, 4-H, 6-H), 5.16 (s,

4 H, 2 CH₂), 3.48 (s, 6 H, 2 CH₃) ppm.

1,3-Bis(methoxymethoxy)-2-prenylbenzene (15): In a typical reac-

tion, nBuLi (7.50 mL of a 1.6 m solution, 12.0 mmol) was added to

a stirred solution of 1,3-bis(methoxymethoxy)benzene (13; 2.00 g,

10.09 mmol) in dry cyclohexane (10 mL) under nitrogen at –78 °C.

After warming slowly to room temperature, prenyl bromide

(1.70 mL, 15.24 mmol) was added as a solution in cyclohexane

(10 mL) and heated at reflux for 5 d. The reaction was quenched

with water and the product extracted with diethyl ether. The or-

ganic layer was dried with MgSO₄and concentrated in vacuo. The

crude oil was purified by chromatography on silica gel using 10%

diethyl ether in pentane as eluent to yield 1,3-bis(methoxymeth-

oxy)-2-prenylbenzene (15) as a colourless oil (1.10 g, 4.13 mmol,

41%). Unreacted starting material was also recovered (440 mg,

IR (CH Cl ): ν = 2938, 2839, 1682, 1591, 1511, 1474, 1172, 1107,

˜

2

1083 cm^–1. MS: calcd. for C₂₃H₂₈ClO₄403.9; found 403.9 [M +

H]⁺and 425.9 [M + Na]⁺.

Friedel–Crafts Acylation of 1,3-Dimethoxy-2-prenylbenzene (16)

Using 4-Methoxycinnamoyl Chloride and TiCl₄: Analogously, 4-

methoxycinnamoyl chloride (230 mg, 1.17 mmol), TiCl₄(2.90 mL

of a 1 m solution, 2.9 mmol) and 1,3-dimethoxy-2-prenylbenzene

(16; 200 mg, 0.968 mol) were allowed to react for 20 min at room

temperature in dry dichloromethane (10 mL) under N₂. The crude

mixture was purified by chromatography on silica gel using a gradi-

ent of diethyl ether in pentane to yield (E)-5-chloro-4-(2,6-dimeth-

oxyphenylmethyl)-1-(4Ј-methoxyphenyl)-5-methyl-1-hexen-3-one

(17; 105 mg, 0.260 mmol, 27%) and a yellow oil that was identified

as 2Ј,4,4Ј-trimethoxy-3Ј-(3ЈЈ-chloro-3ЈЈ-methylbutyl)chalcone (18;

15 mg, 0.037 mmol, 4%). Data for 18: ¹H NMR (400 MHz,

CDCl₃): δ = 7.70 (d, J = 16 Hz, 1 H, 7-H), 7.59 (d, J = 8.5 Hz, 1

H, 6Ј-H), 7.58 (d, J = 8.5 Hz, 2 H, 2-H, 6-H), 7.40 (d, J = 16 Hz,

1 H, 8-H), 6.92 (d, J = 8.5 Hz, 2 H, 3-H, 5-H), 6.72 (d, J = 8.5 Hz,

1 H, 5Ј-H), 3.89 (s, 3 H, 2Ј-OMe), 3.85 (s, 3 H, 4Ј-OMe), 3.74 (s, 3

1

2.22 mmol, 22%). Data for 15: H NMR (500 MHz, CDCl₃): δ =

7.08 (t, J = 8.5 Hz, 1 H, 5-H), 6.77 (d, J = 8.5 Hz, 2 H, 4-H, 6-H),

5.23 (t, J = 7 Hz, 1 H, prenyl CH), 5.20 (s, 4 H, 2 MOM CH₂),

3.49 (s, 6 H, 2 MOM CH₃), 3.42 (d, J = 7 Hz, 2 H, prenyl CH₂),

1.81 (s, 3 H, prenyl Z-CH₃), 1.68 (s, 3 H, prenyl E-CH₃) ppm. ¹³C

NMR (125 MHz, CDCl₃): δ = 155.9 (C-1, C-3), 131.20 (Me₂C),

127.0 (C-5), 123.1 (prenyl CH), 120.4 (C-2), 108.2 (C-4, C-6), 94.7

(2 MOM CH₂), 56.2 (2 MOM CH₃), 26.0 (prenyl E-CH₃), 23.0

(prenyl CH₂), 18.00 (prenyl Z-CH₃) ppm. HRMS: calcd. for

C₁₀H₁₃O₄[M – prenyl]⁺197.0819; found 197.0736.

1,3-Dimethoxy-2-prenylbenzene (16): BuLi (6.00 mL of a 2.5 m solu- H, 4-OMe), 2.86 (m, 2 H, 1ЈЈ-H), 1.98 (m, 2 H, 2ЈЈ-H), 1.69 (s, 6

tion, 15.00 mmol) was added to 1,3-dimethoxybenzene (1.50 g,

10.86 mmol) in dry cyclohexane (50 mL) under nitrogen at –78 °C.

H, 3ЈЈ-Me) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 191.7 (CO),

161.5 (C-2Ј), 161.4 (C-4Ј), 158.9 (C-4), 143.2 (C-β), 130.2 (C-2, C-

340

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Eur. J. Org. Chem. 2013, 332–347

Synthesis of Isobavachalcone and Its Organometallic Derivatives

6), 129.7 (C-6Ј), 127.9 (C-1), 126.3 (C-1Ј), 124.0 (C-α), 123.7 (C- C-4), 141.2 (C-6), 116.3 (C-1), 75.6 (C-3), 69.2 (C-5), 26.3

3Ј), 114.4 (C-3, C-5), 106.2 (C-5Ј), 71.0 (C-3ЈЈ), 63.2 (4-OMe), 55.8

(2-OMe), 55.4 (4Ј-OMe), 45.3 (C-1ЈЈ), 32.3 (3ЈЈ-Me), 19.6 (C-

(CH₃) ppm.

2-Prenylphenol (23): 3-Methyl-1-butene (7.30 mL, 1 m solution in

DMF, 7.3 mmol) and Pd(OAc)₂(4 mg, 0.018 mmol) were added

to 2-iodophenol (400 mg, 1.82 mmol) and triethylamine (1.00 mL,

7.18 mmol) in a sealed tube. The tube was sealed and heated for

20 h at 100 °C. The reaction changed from yellow to brown and

finally a metallic precipitate was observed. Water was added and

the product extracted with dichloromethane. It was then washed

with water (3ϫ 30 mL), NaHCO₃(30 mL) and brine (30 mL). The

extract was dried with MgSO₄and the solvent removed to give a

brown oil that was purified by chromatography on silica gel using

5% ethyl acetate in cyclohexane as eluent. The first fraction was a

mixture of two isomers: 2-prenylphenol (23; 30 mg, 0.185 mmol,

10%) and 2-[(E)-3-methylbut-1-enyl]phenol (24; 224 mg,

1.38 mmol, 76%). The second fraction contained phenol (16 mg,

2ЈЈ) ppm. IR (CH Cl ): ν = 3006, 2939, 2839, 1655 (CO), 1593,

˜

2

1511, 1463, 1172, 1088 cm^–1. HRMS: calcd. for C₂₃H₂₈O₄Cl [M +

H]⁺403.1669; found 403.1676.

2Ј,4,4Ј-Trimethoxychalcone (19): Analogously, 4-methoxycinn-

amoyl chloride (200 mg, 1.02 mmol), TiCl₄(1.02 mL of a 1 m solu-

tion,

1.02 mmol)

and

1,3-dimethoxybenzene

(0.13 mL,

0.993 mmol) in dry dichloromethane (10 mL) under nitrogen were

stirred at room temperature for 1 h and worked up as above (50%

diethyl ether, 50% cyclohexane as eluent on silica). The product

2Ј,4,4Ј-trimethoxychalcone (19) was isolated as a yellow solid

(226 mg, 0.758 mmol, 76%). ¹H NMR (400 MHz, CDCl₃): δ = 7.73

(d, J = 8.5 Hz, 1 H, 6Ј-H), 7.64 (d, J = 16 Hz, 1 H, 7-H), 7.54 (d,

J = 9 Hz, 2 H, 2-H, 6-H), 7.39 (d, J = 16 Hz, 1 H, 8-H), 6.90 (d,

J = 9 Hz, 2 H, 3-H, 5-H), 6.55 (dd, J = 8.5, J = 2 Hz, 1 H, 5Ј-H),

6.49 (d, J = 2 Hz, 1 H, 3Ј-H), 3.89 (s, 3 H, OMe), 3.85 (s, 3 H,

OMe), 3.83 (s, 3 H, OMe) ppm. ¹³C NMR (100 MHz, CDCl₃): δ

= 190.8 (CO), 164.2 (C-2Ј), 161.5 (C-4Ј), 160.5 (C-4), 142.3 (C-7),

132.9 (C-6Ј), 130.2 (C-2, C-6), 128.4 (C-1), 125.2 (C-8), 122.7 (C-

1Ј), 114.5 (C-3, C-5), 105.4 (C-5Ј), 98.9 (C-3Ј), 56.0 (OMe), 55.8

(OMe), 55.6 (OMe) ppm.

1

0.170 mmol, 9%). Data for 23: H NMR (300 MHz, CDCl₃): δ =

7.14 (m, 1 H), 6.91–6.76 (m, 3 H), 5.32 (t, J = 7 Hz, 1 H, prenyl

CH), 3.35 (d, J = 7 Hz, 2 H, CH₂), 1.81 (s, 3 H, CH₃), 1.80 (s, 3

1

H, CH₃) ppm. Data for 24: H NMR (300 MHz, CDCl₃): δ = 7.31

(d, J = 8 Hz, 1 H), 7.09 (t, J = 8 Hz, 1 H), 6.89 (t, J = 8 Hz, 1 H),

6.77 (d, J = 8 Hz, 1 H), 6.53 (d, J = 16 Hz, 1 H), 6.16 (dd, J = 16,

J = 7 Hz, 1 H), 2.49 (m, 1 H), 1.13 (d, J = 7 Hz, 6 H) ppm.

3-Iodo-2,4-bis(methoxymethoxy)acetophenone (25): NaH (720 mg

of a 60% dispersion in mineral oil, 18.00 mmol) was added in small

pieces to 2,4-dihydroxy-3-iodoacetophenone (1.60 g, 5.75 mmol) in

dry THF (10 mL) under nitrogen at –78 °C. The solution was

stirred at –78 °C for 1 h and then slowly warmed to room tempera-

ture. Chloromethyl methyl ether (1.40 mL, 18.43 mmol) was then

added as a solution in THF (10 mL) dropwise over 10 min. The

mixture was stirred at room temperature overnight, water was

added slowly and the product extracted with dichloromethane. The

organics were combined and washed with water and brine and

dried with MgSO₄to give 3-iodo-2,4-bis(methoxymethoxy)aceto-

phenone (25; 2.07 g, 5.65 mmol, 98%) as a pale-yellow oil. ¹H

NMR (500 MHz, CDCl₃): δ = 7.56 (d, J = 8.5 Hz, 1 H, 6-H), 6.89

(d, J = 8.5 Hz, 1 H, 5-H), 5.27 (s, 2 H, MOM CH₂), 5.05 (s, 2 H,

MOM CH₂), 3.54 (s, 3 H, MOM CH₃), 3.49 (s, 3 H, MOM CH₃)

2.58 (s, 3 H, CH₃) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 198.7

(CO), 160.2, 157.2 (C-2, C-4), 131.1 (C-6), 129.2 (C-1), 110.2 (C-

5), 101.3 (MOM CH₂), 95.0 (MOM CH₂), 87.1 (C-3), 58.7 (MOM

1-(2,4-Dimethoxyphenyl)-3-(4-methoxyphenyl)heptan-1-one

(20):

nBuLi (0.30 mL of a 1.6 m solution, 0.480 mmol) was added to

2Ј,4,4Ј-trimethoxychalcone (19; 140 mg, 0.469 mmol) in dry THF

(10 mL) at 0 °C under nitrogen and after slowly warming to room

temperature, prenyl bromide (0.07 mL, 0.618 mmol) was added.

The mixture was stirred at room temperature overnight, quenched

with water and the product extracted with dichloromethane (3ϫ

50 mL). The organic layers were combined, washed with water and

brine, dried with MgSO₄, the solvent removed and the crude puri-

fied by chromatography on silica gel using a gradient of diethyl

ether in pentane. 1-(2,4-Dimethoxyphenyl)-3-(4-methoxyphenyl)-

heptan-1-one (20) was isolated as a yellow oil (142 mg, 0.398 mmol,

1

85%). H NMR (300 MHz, CDCl₃): δ = 7.63 (d, J = 8.5 Hz, 1 H,

6Ј-H), 7.09 (d, J = 8.5 Hz, 2 H, 2ЈЈ-H, 6ЈЈ-H), 6.80 (d, J = 8.5 Hz,

2 H, 3ЈЈ-H, 5ЈЈ-H), 6.48 (dd, J = 8.5, J = 2 Hz, 1 H, 5Ј-H), 6.43 (d,

J = 2 Hz, 1 H, 3Ј-H), 3.85 (s, 3 H, OMe), 3.84 (s, 3 H, OMe), 3.81

(m, 1 H, 3-H), 3.77 (s, 3 H, OMe), 3.19 (m, 2 H, 2-H), 1.61 (m, 2

H, 4-H), 1.22 (m, 4 H, 5-H, 6-H), 0.81 (t, J = 7 Hz, 3 H, 7-H) ppm.

CH ), 56.7 (MOM CH ) 30.2 (CH ) ppm. IR (CH Cl ): ν = 2937,

˜

3

2

2,4-Dihydroxy-3-iodoacetophenone (21): 2,4-Dihydroxyacetophen-

one (3; 8.00 g, 52.58 mmol) was dissolved in warm acetic acid

(80 mL). After allowing the solution to cool to room temperature,

KIO₃(4.03 g, 18.83 mmol) and NaI (6.80 g, 45.36 mmol) were

added and the solution was stirred at room temperature for 4 h.

Water (150 mL) was added and the resulting solid filtered. It was

washed with water to remove traces of acetic acid and the solid

was dissolved in diethyl ether, washed with water (100 mL), sodium

thiosulfate, water and brine to give a white material that was puri-

fied by chromatography on silica gel using 20% ethyl acetate in

pentane as eluent to yield 2,4-dihydroxy-3,5-diiodoacetophenone

(22; 1.43 g, 3.54 mmol, 7%) and 2,4-dihydroxy-3-iodoaceto-

phenone (21; 10.84 g, 38.99 mmol, 74%), each as a white solid.

Data for 21: ¹H NMR (400 MHz, CDCl₃): δ = 13.76 (s, 1 H, 2-

OH), 7.66 (d, J = 9 Hz, 1 H, 6-H), 6.61 (d, J = 9 Hz, 1 H, 5-H),

6.16 (br. s, 1 H, 4-OH), 2.60 (s, 3 H, CH₃) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 202.4 (CO), 163.7, 161.8 (C-2, C-4), 132.8

2906, 2831, 1682 (CO), 1584, 1487, 1377, 1200, 1152, 1094,

1031 cm^–1. HRMS: calcd. for C₁₂H₁₅O₅NaI [M + Na]⁺388.9876;

found 388.9862.

Prenyltributylstannane: Prenyltributylstannane was prepared as de-

scribed previously.^[51]B.p. 94 °C at 0.5 Torr, or 122 °C at 1.5 Torr.

¹H NMR (500 MHz, CDCl₃): δ = 5.35 (t, J = 9 Hz, 1 H, prenyl

CH), 1.73 (s, 3 H, prenyl Z-CH₃), 1.72 (d, J = 9 Hz, 2 H, prenyl

CH₂), 1.63 (s, 3 H, prenyl E-CH₃), 1.56 (m, 6 H, 2-H), 1.37 (m, 6

H, 3-H), 0.96 (m, 9 H, 4-H), 0.91 (m, 6 H, 1-H) ppm. ¹³C NMR

(125 MHz, CDCl₃): δ = 125.3 (t, J = 24 Hz, Me₂C), 123.1 (t, J =

23 Hz, prenyl CH), 29.5 (t, J = 10 Hz, C-2), 27.7 (t, J = 25 Hz, C-

3), 25.7 (t, J = 6 Hz, prenyl E-CH₃), 17.5 (t, J = 6 Hz, prenyl Z-

CH₃), 13.9 (s, C-4), 10.9 (t, J = 130 Hz, prenyl CH₂), 9.6 (t, J =

151 Hz, C-1) ppm. ¹¹⁹Sn NMR (186 MHz, CDCl₃): δ = –27.78

(using Bu₃SnCl as standard: 140.96 ppm).

2,4-Bis(methoxymethoxy)-3-prenylacetophenone (26): [Pd(PPh₃)₄]

(C-6), 114.2 (C-1), 106.9 (C-5), 77.7 (C-3), 26.2 (CH₃) ppm. Data (14 mg, 0.012 mmol) was added to a solution of 3-iodo-2,4-bis-

1

for 22: H NMR (400 MHz, CDCl₃): δ = 13.60 (br. s, 1 H, 2-OH),

8.09 (s, 1 H, 6-H), 6.40 (br. s, 1 H, 4-OH), 2.61 (s, 3 H, CH₃) ppm. yltributylstannane (105 mg, 0.292 mmol) in reagent grade DMF

¹³C NMR (100 MHz, CDCl₃): δ = 201.6 (CO), 163.7, 159.8 (C-2,

(4 mL) under nitrogen and the reaction mixture was heated at

(methoxymethoxy)acetophenone (25; 90 mg, 0.246 mmol) and pren-

Eur. J. Org. Chem. 2013, 332–347

www.eurjoc.org

341

M. Casey, M. J. McGlinchey et al.

FULL PAPER

100 °C for 40 h. The solution was cooled to room temperature, di-

luted with ethyl acetate and filtered through Celite. DMF was re-

moved by vacuum distillation to give a yellow oil that was purified

by chromatography on silica gel using 10% ethyl acetate in pentane

as eluent to give a yellow oil identified as 2,4-bis(methoxymeth-

oxy)acetophenone (30 mg, 0.125 mmol, 51%)^[52]and the desired

(C-3, C-5), 115.3 (C-1Ј), 105.0 (C-5Ј), 94.4 (4-MOM CH₂), 94.0

(4Ј-MOM CH₂), 56.4 (4Ј-MOM CH₃), 56.3 (4-MOM CH₃), 25.9

(prenyl E-CH₃), 22.1 (prenyl CH₂), 18.0 (prenyl Z-CH₃) ppm. IR

(liquid, CDCl ): ν = 2961, 2932, 2829, 1635 (CO), 1566, 1422, 1310,

˜

3

1235, 1153, 1050 cm^–1. C₂₄H₂₈O₆·(H₂O)_0.5(421.48) calcd. C 68.38,

H 6.95; found C 68.47, H 7.17. A sample of 28 suitable for X-ray

crystallographic analysis was obtained by recrystallisation from a

1:1 mixture of dichloromethane and hexane.

product

2,4-bis(methoxymethoxy)-3-prenylacetophenone

(26;

1

34 mg, 0.110 mmol, 45%) as an orange oil. Data for 26: H NMR

(400 MHz, CDCl₃): δ = 7.46 (d, J = 8.5 Hz, 1 H, 6-H), 6.89 (d, J

= 8.5 Hz, 1 H, 5-H), 5.24 (s, 2 H, 4-MOM CH₂), 5.20 (m, 1 H,

prenyl CH), 4.96 (s, 2 H, 2-MOM CH₂), 3.51 (s, 3 H, 2-MOM

CH₃), 3.46 (s, 3 H, 4-MOM CH₃), 3.44 (d, J = 7 Hz, 2 H, prenyl

CH₂), 2.57 (s, 3 H, CH₃), 1.78 (s, 3 H, prenyl E-CH₃), 1.67 (s, 3 H,

prenyl Z-CH₃) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 199.6 (CO),

159.1 (C-4), 155.7 (C-2), 131.8 (Me₂C), 128.8 (C-6), 127.8 (C-1),

125.3 (C-3), 122.6 (prenyl CH), 109.4 (C-5), 101.5 (2-MOM CH₂),

94.1 (4-MOM CH₂), 58.0 (2-MOM CH₃), 56.2 (4-MOM CH₃),

30.0 (CH₃), 25.8 (prenyl E-CH₃), 23.5 (prenyl CH₂), 18.0 (prenyl

Z-CH₃) ppm.

3Ј-Prenyl-2Ј,4,4Ј-tri(methoxymethoxy)chalcone (27) Using K₂CO₃in

Methanol: Magnesium sulfate was added to methanol until satu-

rated and the solution was filtered through Celite to give a clear

solution, which was degassed by bubbling nitrogen through it for

10 min. K₂CO₃(3.36 g, 24.31 mmol) was added to 2,4-bis(me-

thoxymethoxy)-3-prenylacetophenone (26; 250 mg, 0.81 mmol) and

4-methoxymethoxybenzaldehyde (270 mg, 1.62 mmol) in this “dry”

methanol (20 mL) and the solution was heated at reflux overnight.

After cooling to room temperature, the MeOH was removed in

vacuo. Ethyl acetate was added and the solution was filtered

through a pad of MgSO₄/Celite. It was then condensed in vacuo to

give an orange oil that was purified by chromatography on a col-

umn of silica gel using 10% ethyl acetate in pentane as eluent to

give recovered aldehyde (132 mg, 0.794 mmol, 49%) and 3Ј-prenyl-

2Ј,4,4Ј-tris(methoxymethoxy)chalcone (27; 189 mg, 0.414 mmol,

51%).

2Ј,4,4Ј-Tris(methoxymethoxy)-3Ј-prenylchalcone (27) using KOH:

KOH (0.55 mL of a 7 m solution in H₂O, 3.85 mmol) was added to

a solution of 2,4-bis(methoxymethoxy)-3-prenylacetophenone (26;

504 mg, 1.63 mmol) and 4-(methoxymethoxy)benzaldehyde

(276 mg, 1.66 mmol) in EtOH (20 mL) under nitrogen and the solu-

tion was stirred at room temperature overnight. The reaction was

quenched with dilute HCl until slightly acidic (litmus paper) and

the product was extracted with dichloromethane (50 mL), washed

with water and brine, dried with MgSO₄and concentrated in vacuo

to give a yellow oil that was purified by chromatography on a silica

gel column using ethyl acetate (20%) in pentane as eluent to give

the partly deprotected product 2Ј-hydroxy-4,4Ј-bis(methoxymeth-

oxy)-3Ј-prenylchalcone (28; 69 mg, 0.167 mmol, 10%), recovered

aldehyde (85 mg, 0.512 mmol, 31%) and 3Ј-prenyl-2Ј,4,4Ј-tris-

Deprotection of 27 with 2

M HCl at Reflux Temperature for 20 h:

HCl (3.60 mL of a 2 m solution, 7.2 mmol) was added to a solution

of 3Ј-prenyl-2Ј,4,4Ј-tris(methoxymethoxy)chalcone (27; 260 mg,

0.570 mmol) in MeOH (20 mL) and the solution was heated at re-

flux for 20 h. The product was extracted in ethyl acetate, washed

with water and brine and dried with MgSO₄to give a red oil that

was purified by chromatography on a column of silica gel using

ethyl acetate (20%) in pentane as eluent to give 3Ј-(3ЈЈ-chloro-3ЈЈ-

methylbutyl)-2Ј,4,4Ј-trihydroxychalcone (29; 27 mg, 0.075 mmol,

13%) and a yellow oil identified as 2-(4-hydroxyphenyl)-8,8-di-

(methoxymethoxy)chalcone (27) as

a

yellow oil (270 mg,

1

0.591 mmol, 36%). Data for 27: H NMR (400 MHz, CDCl₃): δ =

7.63 (d, J = 16 Hz, 1 H, 7-H), 7.55 (d, J = 8.5 Hz, 1 H, 6Ј-H), 7.47

(d, J = 8.5 Hz, 2 H, 2-H, 6-H), 7.24 (d, J = 16 Hz, 1 H, 8-H), 7.05

(d, J = 8.5 Hz, 2 H, 3-H, 5-H), 6.94 (d, J = 8.5 Hz, 1 H, 5Ј-H),

5.25 (s, 2 H, 4Ј-MOM CH₂), 5.22 (m, 1 H, prenyl CH), 5.20 (s, 2

H, 4-MOM CH₂), 4.92 (s, 2 H, 2Ј-MOM CH₂), 3.48 (s, 3 H, 4Ј-

MOM CH₃), 3.47 (s, 3 H, 4-MOM CH₃), 3.45 (s, 3 H, 2Ј-MOM

CH₃), 3.46 (m, 2 H, prenyl CH₂), 1.80 (s, 3 H, prenyl Z-CH₃), 1.69

(s, 3 H, prenyl E-CH₃) ppm. ¹³C NMR (100 MHz, CDCl₃): δ =

192.5 (CO), 159.2 (C-4), 158.8 (C-4Ј), 155.6 (C-2Ј), 143.4 (C-7),

131.8 (prenyl Me₂C), 130.2 (C-2, C-6), 128.9 (C-6Ј), 128.8 (C-1),

128.2 (C-1Ј), 125.1 (C-3Ј), 124.9 (C-8), 122.6 (prenyl CH), 116.6

(C-3, C-5), 109.7 (C-5Ј), 101.4 (2Ј-MOM CH₂), 94.3 (4-MOM

CH₂), 94.2 (4Ј-MOM CH₂), 58.0 (2Ј-MOM CH₃), 56.3 (4Ј-MOM

CH₃, 4-MOM CH₃), 25.8 (prenyl E-CH₃), 23.5 (prenyl CH₂), 18.0

methyl-2,3,9,10-tetrahydro-8H-pyrano[2,3-f]chromen-4-one

(30;

22 mg, 0.068 mmol, 12%). Data for 29: ¹H NMR (400 MHz,

CDCl₃): δ = 13.92 (s, 1 H, 2Ј-OH), 7.82 (d, J = 15.5 Hz, 1 H, 7-

H), 7.68 (d, J = 9 Hz, 1 H, 6Ј-H), 7.54 (d, J = 8.5 Hz, 2 H, 2-H,

6-H), 7.45 (d, J = 15.5 Hz, 1 H, 8-H), 6.87 (d, J = 8.5 Hz, 2 H, 3-

H, 5-H), 6.38 (d, J = 9 Hz, 1 H, 5Ј-H), 5.95 (br. s, 1 H, 4Ј-OH),

2.72 (t, J = 6.5 Hz, 2 H, 1ЈЈ-H), 1.83 (t, J = 6.5 Hz, 2 H, 2ЈЈ-H),

1.80 (br. s, 1 H, 4-OH), 1.37 (s, 6 H, 2 Me) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 192.2 (CO), 164.2 (C-2Ј), 160.9 (C-4Ј), 158.3

(C-4), 144.0 (C-7), 130.7 (C-2, C-6), 128.7 (C-6Ј), 127.8 (C-1), 118.2

(C-8), 116.2 (C-3, C-5), 113.0 (C-1Ј), 109.5 (C-3Ј), 109.3 (C-5Ј),

76.0 (C-3ЈЈ), 32.0 (C-2ЈЈ), 26.9 (C-4ЈЈ, 3ЈЈ-Me), 16.5 (C-1ЈЈ) ppm.

IR (CDCl ): ν = 3052, 2983, 2928, 2855, 1631 (CO), 1604, 1586,

˜

3

1512, 1365, 1261, 1169, 1047 cm^–1. HRMS: calcd. for C₂₀H₁₉O₄

[M – HCl]⁺323.1270; found 323.1283. Data for 30: ¹H NMR

(400 MHz, CDCl₃): δ = 7.73 (d, J = 9 Hz, 1 H, 5-H), 7.34 (d, J =

8.5 Hz, 2 H, 2Ј-H, 6Ј-H), 6.91 (d, J = 8.5 Hz, 2 H, 3Ј-H, 5Ј-H),

6.50 (d, J = 9 Hz, 1 H, 6-H), 6.20 (br. s, 1 H, 4Ј-OH), 5.41 (dd, J

= 13, J = 3 Hz, 1 H, 2-H), 3.02 (dd, J = 17, J = 13 Hz, 1 H,

3-H_a), 2.82 (dd, J = 17, J = 3 Hz, 1 H, 3-H_b), 2.67 (m, 2 H, 10-H),

1.79 (m, 2 H, 9-H), 1.36 (s, 3 H, 8-Me), 1.34 (s, 3 H, 8-Me) ppm.

(prenyl Z-CH ) ppm. IR (CHCl ): ν = 3052, 2985, 2829, 1658 (CO),

˜

3

1594, 1535, 1508, 1423, 1265, 1238, 1079, 1039 cm^–1. HRMS: calcd.

for C₂₆H₃₃O₇[M + H]⁺457.2226; found 457.2206. Data for 28:

M.p. 64–65 °C. ¹H NMR (400 MHz, CDCl₃): δ = 13.46 (s, 1 H, 2Ј-

OH), 7.85 (d, J = 15.5 Hz, 1 H, 7-H), 7.75 (d, J = 9 Hz, 1 H, 6Ј-

H), 7.60 (d, J = 8.5 Hz, 2 H, 2-H, 6-H), 7.48 (d, J = 15.5 Hz, 1 H,

8-H), 7.08 (d, J = 8.5 Hz, 2 H, 3-H, 5-H), 6.68 (d, J = 9 Hz, 1 H,

5Ј-H), 5.28 (s, 2 H, 4Ј-MOM CH₂), 5.25 (m, 1 H, prenyl CH), 5.22

Deprotection of 27 with 2

M HCl at Reflux Temperature for 3 h: HCl

(s, 2 H, 4-MOM CH₂), 3.49 (s, 3 H, 4Ј-MOM CH₃), 3.48 (s, 3 H, (0.80 mL of a 2 m solution, 1.6 mmol) was added to a solution of

4-MOM CH₃), 3.42 (d, J = 7 Hz, 2 H, prenyl CH₂), 1.81 (s, 3 3Ј-prenyl-2Ј,4,4Ј-tris(methoxymethoxy)chalcone (27; 53 mg,

H, prenyl Z-CH₃), 1.68 (s, 3 H, prenyl E-CH₃) ppm. ¹³C NMR 0.128 mmol) in MeOH (10 mL) and the solution was heated at re-

(100 MHz, CDCl₃): δ = 192.6 (CO), 163.4 (C-2Ј), 160.9 (C-4Ј), flux for 3 h. After cooling to room temperature, the product was

159.5 (C-4), 144.1 (C-7), 131.9 (CMe₂), 130.3 (C-2, C-6), 128.9 (C- extracted with ethyl acetate, washed with water and brine and dried

6Ј), 128.8 (C-1), 122.2 (prenyl CH), 118.8 (C-8), 118.7 (C-3Ј), 116.7 with MgSO₄to yield a yellow solid that was purified by chromatog-

342

www.eurjoc.org

Eur. J. Org. Chem. 2013, 332–347

Synthesis of Isobavachalcone and Its Organometallic Derivatives

raphy on a column of silica gel using a mixture of dichloromethane

(94%), acetone (5%) and methanol (1%) as eluent to give 2Ј,4-

tion was dried with MgSO₄and the solvent removed to give a pur-

ple solid that was purified by chromatography on a column of silica

gel using a gradient of (10–20%) ethyl acetate in pentane as eluent

to give four fractions: the first was identified as 3-chloro-1-(2-hy-

droxy-4-methoxymethoxy-3-prenylphenyl)-3-ferrocenylpropan-

1-one (33; 5 mg, 0.010 mmol, 2%) as a pink solid, the second was

(E)-1-(2-hydroxy-4-methoxymethoxy-3-prenylphenyl)-3-ferrocenyl-

2-propen-1-one (34; 54 mg, 0.117 mmol, 25%) as a red solid, the

third fraction contained the desired product (E)-1-(2,4-dihydroxy-

dihydroxy-4Ј-methoxymethoxy-3Ј-prenylchalcone

(31;

3 mg,

0.008 mmol, 6%) and the desired product isobavachalcone (1;

37 mg, 0.114 mmol, 89%). Data for 31: ¹H NMR (500 MHz,

CDCl₃): δ = 13.45 (s, 1 H, 2Ј-OH), 7.84 (d, J = 15.5 Hz, 1 H, 7-

H), 7.74 (d, J = 9 Hz, 1 H, 6Ј-H), 7.57 (d, J = 8.5 Hz, 2 H, 2-H,

6-H), 7.46 (d, J = 15.5 Hz, 1 H, 8-H), 6.88 (d, J = 8.5 Hz, 2 H, 3-

H, 5-H), 6.67 (d, J = 9 Hz, 1 H, 5Ј-H), 5.28 (s, 2 H, 4Ј-MOM CH₂),

5.26 (t, J = 5 Hz, 1 H, prenyl CH), 3.49 (s, 3 H, 4Ј-MOM CH₃),

3.41 (d, J = 5 Hz, 2 H, prenyl CH₂), 1.81 (s, 3 H, prenyl Z-CH₃),

3-prenylphenyl)-3-ferrocenyl-2-propen-1-one

(35;

59 mg,

0.142 mmol, 30%), which was red in solution but purple in the

solid state, and the final fraction was identified as 2-ferrocenyl-7-

hydroxy-8-prenylchroman-4-one (36; 46 mg, 0.110 mmol, 23%) as

a red oil. Data for 33: ¹H NMR (300 MHz, CDCl₃): (numbering as

below): δ = 14.26 (s, 1 H, 2-OH), 7.79 (d, J = 9 Hz, 1 H, 6Ј-H),

6.79 (d, J = 9 Hz, 1 H, 5Ј-H), 5.31 (dd, J = 10.5, J = 5 Hz, 1 H,

3-H), 5.28 (s, 2 H, 4Ј-MOM CH₂), 5.21 (t, J = 6.5 Hz, 1 H, prenyl

CH), 4.34 (m, 1 H, 2ЈЈ-H), 4.30 (m, 1 H, 5ЈЈ-H), 4.23 (s, 2 H, 3ЈЈ-

H, 4ЈЈ-H), 4.20 (s, 5 H, 6ЈЈ-H), 3.47 (s, 3 H, 4Ј-MOM CH₃), 3.40

(m, 2 H, prenyl CH₂), 3.00 (m, 2 H, 2-H_a, 2-H_b), 1.76 (s, 3 H,

1

1.68 (s, 3 H, prenyl E-CH₃) ppm. Data for 1: M.p. 109–110 °C. H

NMR (500 MHz, [D₆]acetone): δ = 14.01 (s, 1 H, 2Ј-OH), 9.18 (br.

s, 1 H, OH), 7.99 (d, J = 9 Hz, 1 H, 6Ј-H), 7.86 (d, J = 15 Hz, 1

H, 7-H), 7.77 (d, J = 15 Hz, 1 H, 8-H), 7.75 (d, J = 8.5 Hz, 2 H,

2-H, 6-H), 6.95 (d, J = 8.5 Hz, 2 H, 3-H, 5-H), 6.55 (d, J = 9 Hz,

1 H, 5Ј-H), 5.30 (sept.t, J = 7, J = 1 Hz, 1 H, prenyl CH), 3.40 (d,

J = 7 Hz, 2 H, prenyl CH₂), 1.80 (d, J = 1 Hz, 3 H, prenyl Z-CH₃),

1.66 (d, J = 1 Hz, 3 H, prenyl E-CH₃) ppm. ¹³C NMR (125 MHz,

[D₆]acetone): δ = 193.0 (CO), 165.1 (C-2Ј), 162.7 (C-4Ј), 160.9 (C-

4), 144.9 (C-7), 131.7 (C-2, C-6), 131.5 (Me₂C), 130.2 (C-6Ј), 127.6

(C-1), 123.3 (prenyl CH), 118.5 (C-8), 116.8 (C-3, C-5), 116.1 (C-

3Ј), 114.4 (C-1Ј), 108.0 (C-5Ј), 25.9 (prenyl E-CH₃), 22.3 (prenyl

prenyl Z-CH ), 1.68 (s, 3 H, prenyl E-CH ) ppm. IR (CDCl ): ν =

˜

3

2960, 2927, 2854, 1631 (CO), 1583, 1487, 1365, 1261, 1154,

1042 cm^–1. HRMS: calcd. for C₂₄H₂₅FeO₃[M – Cl – MOM]⁺

417.1153; found 417.1220. Data for 34: ¹H NMR (500 MHz,

CDCl₃): δ = 13.61 (s, 1 H, 2Ј-OH), 7.84 (d, J = 15 Hz, 1 H, 3-H),

7.70 (d, J = 8 Hz, 1 H, 6Ј-H), 7.18 (d, J = 15 Hz, 1 H, 2-H), 6.67

(d, J = 8 Hz, 1 H, 5Ј-H), 5.28 (s, 2 H, 4Ј-MOM CH₂), 5.27 (t, J =

7 Hz, 1 H, prenyl CH), 4.61 (br. s, 2 H, 2ЈЈ-H, 5ЈЈ-H), 4.50 (br. s,

2 H, 3ЈЈ-H, 4ЈЈ-H), 4.18 (s, 5 H, 6ЈЈ-H), 3.49 (s, 3 H, 4Ј-MOM

CH₃), 3.43 (d, J = 7 Hz, 2 H, prenyl CH₂), 1.82 (s, 3 H, prenyl Z-

CH₃), 1.68 (s, 3 H, prenyl E-CH₃) ppm. ¹³C NMR (125 MHz,

CDCl₃): δ = 191.8 (C-1), 163.4 (C-2Ј), 160.5 (C-4Ј), 146.5 (C-3),

131.8 (Me₂C), 128.6 (C-6Ј), 122.3 (prenyl CH), 118.6 (C-3Ј), 117.4

(C-2), 115.1 (C-1Ј), 104.8 (C-5Ј), 93.6 (4Ј-MOM CH₂), 79.3 (C-1ЈЈ),

71.6 (C-3ЈЈ, C-4ЈЈ), 70.0 (C-6ЈЈ), 69.2 (C-2ЈЈ, C-5ЈЈ), 56.3 (4Ј-MOM

CH₃), 25.9 (prenyl E-CH₃), 22.1 (prenyl CH₂), 18.0 (prenyl Z-

CH ), 17.9 (prenyl Z-CH ) ppm. IR (KBr): ν = 3413, 2965, 2921,

˜

2

3

1630 (CO), 1604, 1543, 1512, 1485, 1440, 1371, 1290, 1240, 1165,

1109 cm^–1. HRMS: calcd. for C₂₀H₂₁O₄[M + H]⁺325.1440; found

325.1430.

(E)-1-[2,4-Bis(methoxymethoxy)-3-prenylphenyl]-3-ferrocenyl-2-

propen-1-one (32): By analogy to the synthesis of 27, K₂CO₃

(4.03 g, 29.16 mmol) was added to a stirred solution of 2,4-bis-

(methoxymethoxy)-3-prenylacetophenone

(26;

300 mg,

0.973 mmol) and formylferrocene (250 mg, 1.17 mmol) in MeOH

(20 mL) under nitrogen and the solution was heated at reflux for

20 h. After cooling to room temperature, the MeOH was removed

in vacuo, ethyl acetate was added and the solution filtered through

a pad of MgSO₄/Celite. It was condensed in vacuo to give an

orange oil that was purified by chromatography on a column of

silica gel using 10% ethyl acetate in pentane as eluent to give reco-

vered aldehyde (122 mg, 0.570 mmol, 49%) and (E)-1-[2,4-bis-

CH ) ppm. IR (KBr): ν = 3435, 2954, 2919, 2853, 1627 (CO), 1559,

˜

3

1492, 1383, 1290, 1239, 1113, 1047 cm^–1. HRMS: calcd. for

C₂₆H₂₉O₄Fe [M + H]⁺461.1415; found 461.1432. Data for 35: M.p.

(methoxymethoxy)-3-prenylphenyl]-3-ferrocenyl-2-propen-1-one 58–59 °C. ¹H NMR (500 MHz, CDCl₃): δ = 13.99 (s, 1 H, 2Ј-OH),

(32; 189 mg, 0.375 mmol, 39%) as a red oil. Data for 32: ¹H NMR

(500 MHz, CDCl₃): δ = 7.52 (d, J = 15.5 Hz, 1 H, 3-H), 7.41 (d, J

= 8.5 Hz, 1 H, 6Ј-H), 6.93 (d, J = 8.5 Hz, 1 H, 5Ј-H), 6.88 (d, J =

15.5 Hz, 1 H, 2-H), 5.24 (s, 2 H, 4Ј-MOM CH₂), 5.23 (m, 1 H,

prenyl CH), 4.94 (s, 2 H, 2Ј-MOM CH₂), 4.54 (s, 2 H, 2ЈЈ-H, 5ЈЈ-

H), 4.44 (s, 2 H, 3ЈЈ-H, 4ЈЈ-H), 4.17 (s, 5 H, 6ЈЈ-H), 3.48 (s, 6 H,

2Ј-MOM CH₃, 4Ј-MOM CH₃), 3.47 (m, 2 H, prenyl CH₂), 1.80 (s,

3 H, prenyl Z-CH₃), 1.70 (s, 3 H, prenyl E-CH₃) ppm. ¹³C NMR

(125 MHz, CDCl₃): δ = 192.3 (C-1), 158.5 (C-4Ј), 155.3 (C-2Ј),

146.1 (C-3), 131.8 (Me₂C), 128.7 (C-6Ј), 128.3 (C-1Ј), 125.1 (C-3Ј),

124.2 (C-2), 122.8 (prenyl CH), 109.7 (C-5Ј), 101.2 (2Ј-MOM CH₂),

94.3 (4Ј-MOM CH₂), 79.4 (C-1ЈЈ), 71.3 (C-3ЈЈ, C-4ЈЈ), 69.8 (C-6ЈЈ),

69.1 (C-2ЈЈ, C-5ЈЈ), 58.0 (2-MOM CH₃), 56.3 (4Ј-MOM CH₃), 25.9

(prenyl E-CH₃), 23.6 (prenyl CH₂), 18.1 (prenyl Z-CH₃) ppm. IR

7.83 (d, J = 15 Hz, 1 H, 3-H), 7.67 (d, J = 7 Hz, 1 H, 6Ј-H), 7.17

(d, J = 15 Hz, 1 H, 2-H), 6.42 (d, J = 7 Hz, 1 H, 5Ј-H), 6.05 (br.

s, 1 H, 4Ј-OH), 5.30 (t, J = 7 Hz, 1 H, prenyl CH), 4.61 (br. s, 2

H, 2ЈЈ-H, 5ЈЈ-H), 4.51 (br. s, 2 H, 3ЈЈ-H, 4ЈЈ-H), 4.19 (s, 5 H, 6ЈЈ-

H), 3.48 (d, J = 7 Hz, 2 H, prenyl CH₂), 1.84 (s, 3 H, prenyl Z-

CH₃), 1.77 (s, 3 H, prenyl E-CH₃) ppm. ¹³C NMR (125 MHz,

CDCl₃): δ = 191.3 (C-1), 163.9 (C-2Ј), 161.4 (C-4Ј), 146.8 (C-3),

135.7 (Me₂C), 129.2 (C-6Ј), 121.3 (prenyl CH), 116.7 (C-2), 114.3

(C-3Ј), 113.6 (C-1Ј), 107.7 (C-5Ј), 79.0 (C-1ЈЈ), 71.8 (C-3ЈЈ, C-4ЈЈ),

70.0 (C-6ЈЈ), 69.2 (C-2ЈЈ, C-5ЈЈ), 26.1 (prenyl E-CH₃), 21.8 (prenyl

CH ), 18.1 (prenyl Z-CH ) ppm. IR (KBr): ν = 3429, 2959, 2923,

˜

2

3

2852, 1615 (CO), 1542, 1488, 1383, 1290, 1243, 1109, 1043 cm^–1.

HRMS: calcd. for C₂₄H₂₅O₃Fe [M

+

H]⁺417.1153; found

1

417.1156. Data for 36: H NMR (500 MHz, CDCl₃): δ = 7.74 (d,

J = 6 Hz, 1 H, 5-H), 6.73 (br. s, 1 H, 7-OH), 6.55 (d, J = 7 Hz, 1

H, 6-H), 5.30 (dd, J = 11, J = 6 Hz, 1 H, 2-H), 5.27 (t, J = 7 Hz,

1 H, prenyl CH), 4.34 (m, 1 H, 2Ј-H), 4.29 (m, 1 H, 5Ј-H), 4.23

(m, 2 H, 3Ј-H, 4Ј-H), 4.20 (s, 5 H, 6Ј-H), 3.43 (m, 2 H, prenyl

CH₂), 2.99 (m, 2 H, 3-H_a, 3-H_b), 1.79 (s, 3 H, prenyl Z-CH₃), 1.73

(s, 3 H, prenyl E-CH₃) ppm. ¹³C NMR (125 MHz, CDCl₃): δ =

191.0 (C-4), 160.6 (C-7), 160.0 (C-8a), 133.6 (Me₂C), 125.5 (C-5),

120.5 (prenyl CH), 114.1 (C-4a), 113.9 (C-8), 109.5 (C-6), 85.3 (C-

1Ј), 75.7 (C-2), 68.0 (C-6Ј), 67.6 (C-3Ј), 67.5 (C-4Ј), 66.8 (C-2Ј),

(CDCl ): ν = 2967, 2929, 2852, 2827, 1656 (CO), 1592, 1479, 1454,

˜

3

1315, 1261, 1155, 1097, 1041 cm^–1. HRMS: calcd. for C₂₈H₃₃O₅Fe

[M + H]⁺505.1677; found 505.1684.

Deprotection of 32 with HCl in Methanol: HCl (0.50 mL of a 0.12 m

solution, 0.060 mmol) was added to a stirred solution of (E)-1-[2,4-

bis(methoxymethoxy)-3-prenylphenyl]-3-ferrocenyl-2-propen-1-one

(32; 240 mg, 0.476 mmol) in methanol (15 mL) and the solution

heated at reflux for 24 h. After cooling to room temperature and

removing the methanol in vacuo, ethyl acetate was added, the solu-

Eur. J. Org. Chem. 2013, 332–347

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343

M. Casey, M. J. McGlinchey et al.

FULL PAPER

65.3 (C-5Ј), 42.0 (C-3), 24.9 (prenyl E-CH₃), 21.5 (prenyl CH₂),

propen-1-one (38; 20 mg, 0.040 mmol, 45%) as a yellow-green solid

and (E)-1-(2,4-dihydroxy-3-prenylphenyl)-3-ruthenocenyl-2-

17.1 (prenyl Z-CH ) ppm. IR (CH Cl ): ν = 3063, 2986, 2684, 1682

˜

3

2

(CO), 1604, 1550, 1346, 1157 1105, 1071 cm^–1. HRMS: calcd. for propen-1-one (39; 13 mg, 0.028 mmol, 32%) as a pale-green solid.

C₂₄H₂₅O₃Fe [M + H]⁺417.1153; found 417.1166.

Data for 38: ¹H NMR (500 MHz, CDCl₃): δ = 13.53 (s, 1 H, 2-

OH), 7.68 (d, J = 15 Hz, 1 H, 3-H), 7.65 (d, J = 9 Hz, 1 H, 6Ј-H),

7.12 (d, J = 15 Hz, 1 H, 2-H), 6.65 (d, J = 9 Hz, 1 H, 5Ј-H), 5.27

(s, 2 H, 4Ј-MOM CH₂), 5.13 (t, J = 7 Hz, 1 H, prenyl CH), 4.97

(m, 2 H, 2ЈЈ-H, 5ЈЈ-H), 4.76 (m, 2 H, 3ЈЈ-H, 4ЈЈ-H), 4.56 (s, 5 H,

6ЈЈ-H), 3.48 (s, 3 H, 4Ј-MOM CH₃), 3.41 (d, J = 7 Hz, 2 H, prenyl

CH₂), 1.80 (s, 3 H, prenyl Z-CH₃), 1.68 (s, 3 H, prenyl E-

CH₃) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 192.2 (C-1), 163.4

(C-2Ј), 160.6 (C-4Ј), 144.7 (C-3), 131.8 (Me₂C), 128.7 (C-6Ј), 122.3

(prenyl CH), 118.7 (C-3Ј), 117.0 (C-2), 115.1 (C-1Ј), 104.8 (C-5Ј),

94.0 (4Ј-MOM CH₂), 83.7 (C-1ЈЈ), 72.8 (C-3ЈЈ, C-4ЈЈ), 72.0 (C-6ЈЈ),

70.9 (C-2ЈЈ, C-5ЈЈ), 56.4 (4Ј-MOM CH₃), 25.9 (prenyl E-CH₃), 22.1

(E)-1-[2,4-Bis(methoxymethoxy)-3-prenylphenyl]-3-ruthenocenyl-

2-propen-1-one (37): As for 32, K₂CO₃(1.00 g, 7.24 mmol) was

added to a stirred solution of 2,4-bis(methoxymethoxy)-3-prenyl-

acetophenone (26; 76 mg, 0.246 mmol) and formylruthenocene^[53]

(58 mg, 0.224 mmol) in EtOH (20 mL) and the solution was heated

at reflux for 20 h. After cooling to room temperature and removing

the EtOH in vacuo, ethyl acetate was added and the solution was

filtered through a pad of MgSO₄/Celite and condensed in vacuo to

give a yellow oil that was purified by chromatography on a column

of silica gel using 10% ethyl acetate in pentane as eluent to give

(E)-1-[2,4-bis(methoxymethoxy)-3-prenylphenyl]-3-ruthenocenyl-

2-propen-1-one (37; 48 mg, 0.087 mmol, 39%) as a yellow oil. Data

(prenyl CH ), 18.0 (prenyl Z-CH ) ppm. IR (MeCN): ν =

˜

2

3

1633 cm^–1(CO). HRMS: calcd. for ⁹⁹RuC₂₆H₂₉O₄[M + H]⁺

505.0953; found 505.0953. Data for 39: ¹H NMR (500 MHz,

CDCl₃): δ = 13.94 (s, 1 H, 2Ј-OH), 7.69 (d, J = 15 Hz, 1 H, 3-H),

7.63 (d, J = 8.5 Hz, 1 H, 6Ј-H), 7.12 (d, J = 15 Hz, 1 H, 2-H), 6.39

(d, J = 8.5 Hz, 1 H, 5Ј-H), 6.06 (br. s, 1 H, 4Ј-OH), 5.26 (m, 1 H,

prenyl CH), 4.96 (br. s, 2 H, 2ЈЈ-H, 5ЈЈ-H), 4.77 (br. s, 2 H, 3ЈЈ-H,

4ЈЈ-H), 4.60 (s, 5 H, 6ЈЈ-H), 3.47 (d, J = 7 Hz, 2 H, prenyl CH₂),

1.84 (s, 3 H, prenyl Z-CH₃), 1.77 (s, 3 H, prenyl E-CH₃) ppm. ¹³C

NMR (125 MHz, CDCl₃): δ = 128.8 (C-6Ј), 124.0 (C-2), 83.4 (C-

1ЈЈ), 72.7 (C-3ЈЈ, C-4ЈЈ), 71.8 (C-6ЈЈ), 70.7 (C-2ЈЈ, C-5ЈЈ), 18.4 (pren-

yl Z-CH₃) ppm [very dilute sample, peaks have been assigned by

1

for 37: H NMR (500 MHz, CDCl₃): δ = 7.39 (d, J = 8.5 Hz, 1 H,

6Ј-H), 7.38 (d, J = 15.5 Hz, 1 H, 3-H), 6.91 (d, J = 8.5 Hz, 1 H,

5Ј-H), 6.82 (d, J = 15.5 Hz, 1 H, 2-H), 5.24 (s, 2 H, 4Ј-MOM CH₂),

5.22 (t, J = 5 Hz, 1 H, prenyl CH), 4.91 (t, J = 2 Hz, 2 H, 2ЈЈ-H,

5ЈЈ-H) 4.89 (s, 2 H, 2Ј-MOM CH₂), 4.72 (t, J = 2 Hz, 2 H, 3ЈЈ-H,

4ЈЈ-H), 4.55 (s, 5 H, 6ЈЈ-H), 3.47 (s, 3 H, 4Ј-MOM CH₃), 3.46 (s, 3

H, 2Ј-MOM CH₃), 3.45 (d, J = 5 Hz, 2 H, prenyl CH₂), 1.79 (s, 3

H, prenyl Z-CH₃), 1.69 (s, 3 H, prenyl E-CH₃) ppm. ¹³C NMR

(125 MHz, CDCl₃): δ = 192.5 (C-1), 158.5 (C-4Ј), 155.4 (C-2Ј),

144.2 (C-3), 131.8 (Me₂C), 128.7 (C-6Ј), 128.2 (C-1Ј), 125.0 (C-3Ј),

123.7 (C-2), 122.8 (prenyl CH), 109.6 (C-5Ј), 101.2 (2Ј-MOM CH₂),

94.3 (4Ј-MOM CH₂), 83.7 (C-1ЈЈ), 72.6 (C-3ЈЈ, C-4ЈЈ), 71.8 (C-6ЈЈ),

70.8 (C-2ЈЈ, C-5ЈЈ), 58.0 (2-MOM CH₃), 56.3 (4Ј-MOM CH₃), 25.9

(prenyl E-CH₃), 23.6 (prenyl CH₂), 18.1 (prenyl Z-CH₃) ppm. IR

HSQC, and not all peaks are visible]. IR (MeCN): ν = 1632 cm^–1

˜

(CO). HRMS: calcd. for ⁹⁹RuC₂₄H₂₅O₃[M + H]⁺461.0691; found

461.0840.

(E)-1-[2,4-Bis(methoxymethoxy)-3-prenylphenyl]-3-[(η⁵-cyclo-

pentadienyl)cobalt(η⁴-tetraphenylcyclobutadiene)]-2-propen-1-one

(40): As for 37, 2,4-bis(methoxymethoxy)-3-prenylacetophenone

(26; 91 mg, 0.295 mmol), (η⁵-cyclopentadienylcarbaldehyde)co-

balt(η⁴-tetraphenylcyclobutadiene)^[54](160 mg, 0.315 mmol) in

EtOH (20 mL) and K₂CO₃(1.22 g, 8.83 mmol) were heated at re-

flux for 48 h. Following the same workup procedure, chromatog-

raphy on a column of silica gel using 5% ethyl acetate in pentane

as eluent gave recovered aldehyde (47 mg, 0.092 mmol, 29%) and

(E)-1-[2Ј,4Ј-bis(methoxymethoxy)-3-prenylphenyl]-3-[(η⁵-cyclopen-

tadienyl)cobalt(η⁴-tetraphenylcyclobutadiene)]-2-propen-1-one (40;

(CDCl ): ν = 3689, 2958, 2927, 2855, 1653 (CO), 1593, 1462, 1314,

˜

3

1260, 1153, 1095, 1041 cm^–1. HRMS: calcd. for ⁹⁹RuC₂₈H₃₃O₅[M

+ H]⁺551.1371; found 551.1396.

(E)-1-(2,4-Dihydroxy-3-prenylphenyl)-3-ruthenocenyl-2-propen-1-

one (39): HCl (0.11 mL of a 0.12 m solution, 0.013 mmol) was

added to a stirred solution of (E)-1-[2,4-bis(methoxymethoxy)-3-

prenylphenyl]-3-ruthenocenyl-2-propen-1-one (37; 48 mg,

0.087 mmol) in methanol (15 mL) and the solution was heated at

reflux for 24 h. After cooling to room temperature and removing

the methanol in vacuo, ethyl acetate was added, the solution was

dried with MgSO₄and the solvent was removed to give a yellow 48 mg, 0.060 mmol, 20%) as a red solid. Data for 40: ¹H NMR

solid that was purified by chromatography on a column of silica

gel using 10% ethyl acetate in pentane as eluent to give (E)-1-(2-

hydroxy-4-methoxymethoxy-3-prenylphenyl)-3-ruthenocenyl-2-

(500 MHz, CDCl₃): δ = 7.41 (d, J = 7.5 Hz, 8 H, 8 Ph H_ortho), 7.22

(m, 4 H, 4 Ph H_para), 7.20 (m, 8 H, 8 Ph H_meta), 7.06 (d, J = 16 Hz,

1 H, 3-H), 6.98 (d, J = 8.5 Hz, 1 H, 6Ј-H), 6.87 (d, J = 8.5 Hz, 1

344

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Eur. J. Org. Chem. 2013, 332–347

Synthesis of Isobavachalcone and Its Organometallic Derivatives

H, 5Ј-H), 6.52 (d, J = 16 Hz, 1 H, 2-H), 5.29 (s, 2 H, 4Ј-MOM

¹H NMR (500 MHz, CDCl₃): δ = 13.49 (s, 1 H, 2Ј-OH), 7.40 (d, J

CH₂), 5.26 (t, J = 6.5 Hz, 1 H, prenyl CH), 4.90 (m, 2 H, 2ЈЈ-H, = 5.5 Hz, 8 H, 8 Ph H_ortho), 7.31 (d, J = 8.5 Hz, 1 H, 6Ј-H), 7.23

5ЈЈ-H), 4.81 (s, 2 H, 2Ј-MOM CH₂), 4.81 (m, 2 H, 3ЈЈ-H, 4ЈЈ-H), (d, J = 15 Hz, 1 H, 3-H), 7.18 (m, 4 H, 4 Ph H_para), 7.16 (m, 8 H,

3.53 (s, 3 H, 4Ј-MOM CH₃), 3.48 (d, J = 6.5 Hz, 2 H, prenyl CH₂),

8 Ph H_meta), 6.67 (d, J = 15 Hz, 1 H, 2-H), 6.60 (d, J = 8.5 Hz, 1

3.43 (s, 3 H, 2Ј-MOM CH₃), 1.82 (s, 3 H, prenyl Z-CH₃), 1.71 (s, H, 5Ј-H), 5.28 (s, 2 H, 4Ј-MOM CH₂), 5.28 (m, 1 H, prenyl CH),

3 H, prenyl E-CH₃) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 191.6

(C-1), 158.2 (C-4Ј), 155.3 (C-2Ј), 140.6 (C-3), 135.3 (4 Ph C_ipso),

131.6 (Me₂C), 128.9 (8 Ph C_ortho), 128.7 (C-6Ј), 128.2 (8 Ph C_meta),

4.94 (m, 2 H, 3ЈЈ-H, 4ЈЈ-H), 4.83 (m, 2 H, 2ЈЈ-H, 5ЈЈ-H), 3.50 (s, 3

H, 4Ј-MOM CH₃), 3.42 (d, J = 7 Hz, 2 H, prenyl CH₂), 1.82 (s, 3

H, prenyl Z-CH₃), 1.69 (s, 3 H, prenyl E-CH₃) ppm. ¹³C NMR

127.8 (C-1Ј), 126.7 (4 Ph C_para), 125.6 (C-2), 125.0 (C-3Ј), 122.9 (125 MHz, CDCl₃): δ = 191.6 (C-1), 163.2 (C-2Ј), 160.4 (C-4Ј),

(prenyl CH), 109.2 (C-5Ј), 101.2 (2Ј-MOM CH₂), 94.2 (4Ј-MOM

CH₂), 92.2 (C-1ЈЈ), 87.1 (C-3ЈЈ, C-4ЈЈ), 82.7 (C-2ЈЈ, C-5ЈЈ), 76.5 (4

140.9 (C-3), 135.3 (4 Ph C_ipso), 131.8 (Me₂C), 128.8 (8 Ph C_ortho),

128.5 (8 Ph C_meta), 128.2 (C-6Ј), 126.7 (4 Ph C_para), 122.4 (prenyl

C-6ЈЈ), 57.8 (2Ј-MOM CH₃), 56.2 (4Ј-MOM CH₃), 25.9 (prenyl E- CH), 118.8 (C-2), 118.4 (C-3Ј), 115.1 (C-1Ј), 104.5 (C-5Ј), 94.1 (4Ј-

CH ), 23.6 (prenyl CH ), 18.1 (prenyl Z-CH ) ppm. IR (CH Cl ): ν

MOM CH₂), 92.0 (C-1ЈЈ), 87.1 (C-2ЈЈ, C-5ЈЈ), 83.1 (C-3ЈЈ, C-4ЈЈ),

76.7 (4 C-6ЈЈ), 56.4 (4Ј-MOM CH₃), 25.9 (prenyl E-CH₃), 22.1 (pre-

˜

3

2

3

2

= 3684, 3602, 2927, 1644 (CO), 1597, 1498, 1350, 1162, 1041 cm^–1.

HRMS: calcd. for C₅₁H₄₈O₅Co [M + H]⁺799.2834; found

799.2856.

nyl CH ), 18.0 (prenyl Z-CH ) ppm. IR (MeCN): ν = 3623, 3541,

˜

2

3

1632 cm^–1(CO). HRMS: calcd. for C₄₉H₄₄O₄Co [M + H]⁺

755.2601; found 755.2572. Data for 42: IR (MeCN): ν = 3617,

˜

(E)-1-(2,4-Dihydroxy-3-prenylphenyl)-3-[(η⁴-tetraphenylcyclobuta-

diene)-cobalt-(η⁵-cyclopentadienyl)]-2-propen-1-one (42): By analogy

to the preparation of 39, (E)-1-[2,4-bis(methoxymethoxy)-3-prenyl-

3549, 1632 cm^–1(CO). HRMS: calcd. for C₄₇H₄₀O₃Co [M + H]⁺

711.2304; found 711.2048.

phenyl]-3-[(η⁵-cyclopentadienyl)cobalt(η⁴-tetraphenylcyclobuta- X-ray Crystal Structure Determinations of 9, 12, 21 and 28: Crystal-

diene)]-2-propen-1-one (40; 35 mg, 0.044 mmol) in methanol

(10 mL) and HCl (0.05 mL of a 0.12 m solution, 0.006 mmol) were

heated at reflux for 22 h. Following the same workup procedure,

chromatography on a column of silica gel using 10% ethyl acetate

in pentane as eluent gave (E)-1-(2-hydroxy-4-methoxymethoxy-3-

prenylphenyl)-3-[(η⁵-cyclopentadienyl)cobalt(η⁴-tetraphenyl-

cyclobutadiene)]-2-propen-1-one (41; 14 mg, 0.019 mmol, 42%) as

a red solid and (E)-1-(2,4-dihydroxy-3-prenylphenyl)-3-[(η⁵-cyclo-

pentadienyl)cobalt(η⁴-tetraphenylcyclobutadiene)]-2-propen-1-

one (42; 8 mg, 0.011 mmol, 26%) also as a red solid. Data for 41:

lographic data were collected with a Bruker SMART APEX CCD

area detector diffractometer using Mo-K_αradiation and are listed

in Table 1. A full sphere of reciprocal space was scanned by φ–θ

scans. Pseudo-empirical absorption correction based on redundant

reflections was performed by using the SADABS program.^[55]The

structures were solved by direct methods using SHELXS-97^[56]and

refined by full-matrix least-squares on F²for all data using

SHELXL-97.^[56]In 28, the hydrogen atom attached to oxygen was

located in the difference Fourier map and allowed to refine freely.

All other hydrogen atoms were added at calculated positions and

Table 1. Crystallographic data for 9, 12, 21 and 28.

9

12

21

28

Formula

M

Crystal system

Space group

a [Å]

b [Å]

c [Å]

C₁₃H₁₆O₃

220.26

C₁₉H₂₀O₅

328.35

C₈H₇O₃I

278.04

C₂₄H₂₈O₆

412.46

orthorhombic

Fdd2 (#43)

10.6118(11)

41.797(5)

10.2748(11)

90

orthorhombic

Pna2₁(#33)

21.575(8)

5.761(2)

13.418(5)

90

monoclinic

P2₁/c (#14)

7.3991(7)

32.491(3)

7.1582(7)

90

monoclinic

P2₁/c (#14)

17.873(2)

11.8934(17)

9.9350(14)

90

α [°]

β [°]

90

4557.3(8)

16

1.284

100(2)

0.090

1888

90

95.549(2)

90

1712.8(3)

8

2.156

100(2)

90.278(3)

90

2111.8(5)

4

1.297

100(2)

γ [°]

V [Å³]

1667.8(11)

4

1.308

293(2)

0.094

Z

ρ_calcd.[gcm^–3]

T [K]

μ [mm^–1]

F(000)

3.701

1056

0.093

880

696

θ range [°]

Index ranges

1.95–30.49

–15 Յ h Յ 15

–59 Յ k Յ 59

–14 Յ l Յ 14

23784

1.89–27.00

–27 Յ h Յ 27

–7 Յ k Յ 7

–17 Յ lՅ 17

25584

1.25–30.50

–10 Յ h Յ 10

–46 Յ k Յ 46

–10 Յ l Յ 10

40098

2.06–24.75

–19 Յ h Յ 21

–13 Յ k Յ 13

–6 Յ l Յ 11

10493

Reflections measured

Independent reflections

R_int

1834

0.0286

1903

0.0396

5229

0.0298

3567

0.0286

Data/restraints/parameters

Final R values [I Ͼ 2σ(I)]

1834/17/185

1905/56/294

5229/0/224

3567/0/279

21

R1

wR2

0.0414

0.1087

0.0350

0.0916

0.0301

0.0619

0.04

0.1025

R values (all data):

R1

0.0420

0.1095

1.073

0.0433

0.0991

1.048

0.0309

0.0622

1.359

0.0551

0.1104

1.035

wR2

GOF on F²

Eur. J. Org. Chem. 2013, 332–347

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345

M. Casey, M. J. McGlinchey et al.

FULL PAPER

[20] B. Ngameni, J. Watchueng, F. F. Boyom, F. Keumedjio, B. T.

Ngadjui, J. Gut, B. M. Abegaz, P. J. Rosenthal, ARKIVOC

2007, 116–123.

[21] B. Ngameni, M. Touaibia, A. Belkaid, P. Ambassa, J. Wat-

chueng, R. Patnam, B. T. Ngadjui, B. Annabi, R. Roy, ARKI-

VOC 2007, 91–103.

[22] A. Vitali, B. Giardina, G. D. Monache, F. Rocca, A. Silvestrini,

A. Tafi, B. Botta, FEBS Lett. 2004, 557, 33–38.

[23] A. C. Jain, P. Lal, T. R. Seshadri, Tetrahedron 1970, 26, 2631–

2635.

[24] S. Lee, J.-K. Kim, J. G. Lee, J.-S. Lee, M. Leem, Y.-H. Chung,

Y.-O. Song, H. Suh, Bull. Korean Chem. Soc. 2001, 22, 1295–

1296.

[25] a) W. Tan, W.-D. Z. Li, C. Huang, Y. Li, Y. Xing, Synth. Com-

mun. 1999, 29, 3369–3377; b) R. A. Diller, H. M. Riepl, O.

Rose, C. Frias, G. Henze, A. Prokop, Chem. Biodiversity 2005,

2, 1331–1337; c) X. Dong, Y. Fan, L. Yu, Y. Hu, Arch. Pharm.

Chem. Life Sci. 2007, 340, 372–376; d) X. Dong, J. Chen, C.

Jiang, T. Liu, Y. Hu, Arch. Pharm. Chem. Life Sci. 2009, 342,

428–432; e) X. Dong, T. Liu, J. Yan, P. Wu, J. Chen, Y. Hu,

Bioorg. Med. Chem. 2009, 17, 716–726.

refined by using a riding model. Their isotropic thermal displace-

ment parameters were fixed to 1.2 times (1.5 times for methyl

groups) that of the parent atom. Anisotropic thermal displacement

parameters were used for all non-hydrogen atoms.

CCDC-835397 (for 12), -835298 (for 9), -835299 (for 28) and

-835300 (21) contain the supplementary crystallographic data for

this paper. These data can be obtained free of charge from The

Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/

data_request/cif.

Supporting Information (see footnote on the first page of this arti-

cle): ¹H, ¹³C and selected COSY, DEPT, HSQC and HMBC NMR

spectra.

Acknowledgments

We thank Science Foundation Ireland, the Irish Research Council

for Science, Engineering and Technology (IRCSET), University

College Dublin and the Centre for Synthesis and Chemical Biology

funded by the Higher Education Authority’s Programme for Re-

search in Third-Level Institutions (PRTLI) for generous financial

support, and the reviewers for helpful comments.

[26] C. O. Miles, L. Main, B. K. Nicholson, Aust. J. Chem. 1989,

42, 1103–1113.

[27] K. Ravikumar, B. Sridar, P. Aparna, J. M. Rao, Acta Crys-

tallogr., Sect. E 2005, 61, o1020–01022.

[28] H. G. Brittain, J. Pharm. Sci. 2007, 96, 705–728.

[29] K. Iikubo, Y. Ishikawa, N. Ando, K. Umezawa, S. Nishiyama,

Tetrahedron Lett. 2002, 43, 291–293.

[1] R. I. Tsukiyama, H. Katsura, N. Tokuriki, M. Kobayashi,

Antimicrob. Agents Chemother. 2002, 46, 1226–1230.

[2] A. Friis-Moller, M. Chen, K. Fuursted, S. B. Christensen, A.

Kharazmi, Planta Med. 2002, 68, 416–419.

[3] L. Svetaz, A. Tapia, S. N. Lopez, R. L. E. Furlan, E. Petenatti,

R. Pioli, G. Schmeda-Hirschmann, S. A. Zacchino, J. Agric.

Food Chem. 2004, 52, 3297–3300.

[4] M. Liu, P. Wilairat, M. L. Go, J. Med. Chem. 2001, 44, 4443–

4452.

[5] M.-L. Go, M. Liu, P. Wilairat, P. J. Rosenthal, K. J. Saliba, K.

Kirk, Antimicrob. Agents Chemother. 2004, 48, 3241–3245.

[6] Q. Wang, Z.-H. Ding, J.-K. Liu, Y.-T. Zheng, Antiviral Res.

2004, 64, 189–194.

[7] V. E. Buckwold, R. J. H. Wilson, A. Nalca, B. B. Beer, T. G.

Voss, J. A. Turpin, R. W. Buckheit III, J. Wei, M. Wenzel-Ma-

thers, E. M. Walton, R. J. Smith, M. Pallansch, P. Ward, J.

Wells, L. Chuvala, S. Sloane, R. Paulman, J. Russell, T. Hart-

man, R. Ptak, Antiviral Res. 2004, 61, 57–62.

[8] J. Rojas, J. N. Dominguez, J. E. Charris, G. M. Lobo, M. Paya,

M. L. Ferrandiz, Eur. J. Med. Chem. 2002, 37, 699–705.

[9] N. J. Lawrence, A. T. McGown, Curr. Pharm. Des. 2005, 11,

1679–1693.

[10] H. Matsuda, S. Sugimoto, T. Morikawa, K. Matsuhira, E. Mi-

zuguchi, S. Nakamura, M. Yoshikawa, Chem. Pharm. Bull.

2007, 55, 106–110.

[11] B. M. Abegaz, B. T. Ngadjui, E. Dongo, B. Ngameni, M. N.

Nindi, M. Bezabih, Phytochemistry 2002, 59, 877–883.

[12] R. Nishimura, K. Tabata, M. Arakawa, Y. Ito, Y. Kimutra, T.

Akihisa, H. Nagai, A. Sakuma, H. Kohono, T. Suzuki, Biol.

Pharm. Bull. 2007, 10, 1878–1883.

[30] H.-J. Knölker, W. Fröhner, K. R. Reddy, Synthesis 2002, 4,

557–564.

[31] C. F. Chee, Y. K. Lee, M. J. C. Buckle, N. A. Rahman, Tetrahe-

dron Lett. 2011, 52, 1797–1799.

[32] Segalle, Monatsh. Chem. 1894, 17, 314.

[33] J. H. Adams, J. Org. Chem. 1967, 32, 3992–3998.

[34] M. Savignac, G. Jaouen, C. A. Rodger, R. E. Perrier, B. G.

Sayer, M. J. McGlinchey, J. Org. Chem. 1986, 51, 2328–2332.

[35]

K. Schmidt, M. Jung, R. Keilitz, B. Schnurr, R. Gust, Inorg.

Chim. Acta 2000, 306, 6–16.

[36]

K. Nikitin, Y. Ortin, H. Müller-Bunz, M.-A. Plamont, G. Ja-

ouen, A. Vessières, M. J. McGlinchey, J. Organomet. Chem.

2010, 695, 595–608.

[37]

[38]

[39]

[40]

[41]

S. Top, E. B. Kaloun, S. Toppi, A. Herrbach, M. J. McGlin-

chey, G. Jaouen, Organometallics 2001, 20, 4554–4561.

G. Jaouen, S. Top, A. Vessières, R. Alberto, J. Organomet.

Chem. 2000, 600, 23–26.

G. Jaouen, S. Top, A. Vessières, G. Leclercq, M. J. McGlinchey,

Curr. Med. Chem. 2004, 11, 2505–2517.

S. Top, B. Dauer, J. Vaissermann, G. Jaouen, J. Organomet.

Chem. 1997, 541, 355–361.

S. Top, A. Vessières, C. Cabestaing, I. Laios, G. Leclercq, C.

Provot, G. Jaouen, J. Organomet. Chem. 2001, 637–639, 500–

506.

[42]

[43]

[44]

[45]

O. Zekri, S. Top, P. Pigeon, M.-A. Plamont, E. A. Hillard, M.

Huché, A. Vessières, S. Boutamine, M. J. McGlinchey, H.

Müller-Bunz, G. Jaouen, Dalton Trans. 2009, 4318–4326.

O. Payen, S. Top, A. Vessières, E. Brulé, M.-A. Plamont, M. J.

McGlinchey, H. Müller-Bunz, G. Jaouen, J. Med. Chem. 2008,

51, 1791–1799.

L. Delhaes, H. Abessiki, C. Biot, L. Berry, P. Delcourt, L. Mac-

iejewski, L. Brocard, D. Camus, D. Dive, Parasitol. Res. 2001,

87, 239–244.

O. Domarle, G. Blampain, H. Agnaniet, T. Nzadiyabi, J. Leb-

ibi, L. Delhaes, H. Abessiki, C. Biot, L. Berry, P. Delcourt, L.

Maciejewski, J. Brocard, L. Maciejewski, C. Biot, A. J.

Georges, P. Millet, Antimicrob. Agents Chemother. 1998, 42,

540–544.

[13] Y.-G. Chen, X.-P. Song, L.-N. Hai, Y.-P. Lv, A. Fang, F. Halaw-

eish, X.-R. Liao, Pharmazie 2006, 61, 891–892.

[14] A. Yenesew, J. O. Midiwo, S. M. Guchu, M. Heydenreich,

M. G. Peter, Phytochemistry 2002, 59, 337–341.

[15] D. Lee, K. P. L. Bhat, H. H. S. Fong, N. R. Farnsworth, J. M.

Pezzuto, A. D. Kinghorn, J. Nat. Prod. 2001, 64, 1286–1293.

[16] T. Akihisa, H. Tokuda, D. Hasegawa, M. Ukiya, Y. Kimura,

F. Enjo, T. Suzuki, H. Nishino, J. Nat. Prod. 2006, 69, 38–42.

[17] T. Akihisa, H. Tokuda, M. Ukiya, M. Iizuka, S. Schneider, K.

Ogasawara, T. Mukainaka, K. Iwatsuki, T. Suzuki, H. Nishino,

Cancer Lett. 2003, 201, 133–137.

[46]

[47]

C. Biot, G. Glorian, L. Maciejewski, J. Brocard, J. Med. Chem.

1997, 40, 3715–3718.

X. Wu, P. Wilairat, M.-L. Go, Bioorg. Med. Chem. Lett. 2002,

12, 2299–2302.

[18] S. Yin, C.-Q. Fan, Y. Wang, L. Dong, J.-M. Yue, Bioorg. Med.

Chem. 2004, 12, 4387–4392.

[19] A. Tsopmo, M. Tene, P. Kamnaing, J. F. Ayafor, O. Sterner, J.

Nat. Prod. 1999, 62, 1432–1434.

346

www.eurjoc.org

Eur. J. Org. Chem. 2013, 332–347

Synthesis of Isobavachalcone and Its Organometallic Derivatives

[48] V. Zsoldos-Mády, A. Csámpai, R. Szabó, E. Mészáros-Alapi, [52]

B. I. Kamara, D. T. L. Manong, E. V. Brandt, Phytochemistry

2005, 66, 1126–1132.

L. Jinzhen, M. V. Baker, D. H. Brown, Inorg. Chim. Acta 2006,

359, 1299–1302.

Y. Ortin, K. Ahrenstorf, P. O’Donohue, D. Foede, H. Müller-

Bunz, P. McArdle, A. R. Manning, M. J. McGlinchey, J. Or-

ganomet. Chem. 2004, 689, 4683–4690.

J. Pásztor, F. Hudecz, P. Sohár, ChemMedChem 2006, 1, 1119–

1125.

[53]

[54]

[49] a) J.-P. Monserrat, G. G. Chabot, L. Hamon, L. Quentin, D.

Scherman, G. Jaouen, E. A. Hillard, Chem. Commun. 2010, 46,

5145–5147; b) K. N. Tiwari, J.-P. Momserrat, F. de Montigny,

G. Jaouen, M.-N. Rager, E. A. Hillard, Organometallics 2011,

30, 5424–5432.

[55] SADABS, Bruker AXS Inc., Madison, Wisconsin, 2001.

[56] G. M. Sheldrick, Acta Crystallogr., Sect. A 2008, 64, 112–122.

Received: August 19, 2012

[50] L. E. Harrington, N. Reginato, I. Vargas-Baca, M. J. McGlin-

chey, Organometallics 2003, 22, 663–669.

[51] A. E. Mattson, K. A. Scheidt, J. Am. Chem. Soc. 2007, 129,

4508–4509.

Published Online: November 9, 2012

Eur. J. Org. Chem. 2013, 332–347

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Synthesis of isobavachalcone and some organometallic derivatives

DOI: 10.1002/ejoc.201201063

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