Feruloylbenzotriazole and weinreb amide as bioinspired building blocks: A reactivity study towards O-, N-, S-, and C-nucleophiles

FULL PAPER

DOI: 10.1002/ejoc.201301895

Feruloylbenzotriazole and Weinreb Amide as Bioinspired Building Blocks:

A Reactivity Study towards O-, N-, S-, and C-Nucleophiles

Bart I. Roman,^[a][‡]Jean-Christophe Monbaliu,^[b][‡]Laurens M. De Coen,^[a][‡]

Sigrid Verhasselt,^[a]Bart Schuddinck,^[a]Evelien Van Hoeylandt,^[a]and

Christian V. Stevens*^[a]

Keywords: Natural products / Biomimetic synthesis / Nucleophilic addition / Nitrogen heterocycles / Lithiation

A versatile route for the conversion of ferulic acid into biolo-

gically relevant molecules is presented. The compatibility of

a number of protection and activation strategies with the 1,2-

addition of a variety of O-, N-, S-, and C-nucleophiles to

ferulic acid is evaluated. In particular, this report contains the

first systematic study of the addition of (hetero)aryllithium

reagents to 3-phenylpropenoyl Weinreb amides. The rele-

vance of this “bioinspired” method is illustrated by the syn-

thesis of a number of natural products or analogues, such as

zingerone, curcuminoids, and (heteroaryl) chalcones.

Introduction

cooking by a retro-aldol reaction of gingerol. The biosyn-

thesis of feruloyl-SCoA (8) starts from phenylalanine (7),

which itself originates from the shikimate pathway

(Scheme 1, i).

The feruloyl moiety is present in a vast array of natural

products, and may be considered to be a “privileged frag-

ment” (Figure 1). In nature, feruloyl-SCoA (8) is the pre-

cursor to curcumins (2),^[1]chalcones (3),^[2]pungent agents

such as gingerols (4) and shogaols (5), and ferulic acid itself

All of the compounds shown in Figure 1 have been found

(1).^[3]This biosynthetic pathway is particularly significant to have interesting biological activities, not in the least in

in the Zingiberaceae (ginger family). Zingerone (6), a com- the oncological domain. However, in our opinion, and that

pound related to the pungency of ginger, is produced during of others, their benefit–risk profiles need to be defined, and

Figure 1. The feruloyl moiety is a “privileged fragment”, present in a variety of biologically relevant natural products.

major issues such as their toxicities, and their poor selectivi-

[a] Research group SynBioC, Department of Sustainable Organic ties and bioavailabilities, remain to be tackled.^[4]

Chemistry and Technology, Ghent University,

Therefore, we argue that there is a need for synthetic ana-

Coupure Links 653, 9000 Gent, Belgium

logues of curcumins, gingerols, chalcones, etc. The study of

such analogues might aid in elucidating structure–property

and structure–activity relationships.^[5,6]Hence, we have re-

cently started exploring the potential of ferulic and related

cinnamic acids as building blocks for the preparation of

such substances. Significant work had been carried out ear-

lier on cinnamic acid: in that context, cinnamoyl-benzotri-

E-mail: Chris.Stevens@UGent.be

http://ww w .synbioc.ugent.be/

[b] Center for Integrated Technology and Organic Synthesis –

CiTOS, Department of Chemistry, Building B6a – room 3/16a,

University of Liège,

Sart Tilman, 4000 Liège, Belgium

[‡] In equal contribution.

Supporting information for this article is available on the

WWW under http://dx.doi.org/10.1002/ejoc.201301895.

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Feruloylbenzotriazole and Weinreb Amide Building Blocks

Scheme 1. Parallels between our “bioinspired” synthetic strategy, the biosynthesis of feruloylated compounds, and earlier synthetic work;

TBDMS = tert-butyldimethylsilyl, MEM = (2-methoxyethoxy)methyl.

azole (9) proved to be a versatile intermediate to which a feruloylbenzotriazole (13) was chosen as the central inter-

variety of nucleophiles were successfully added (Scheme 1, mediate in the first part of our study.

ii).^[7–11]

In this paper, we describe a versatile, “bioinspired” route

to biologically relevant molecules, starting from ferulic acid.

We have evaluated the compatibility of a number of protec-

Synthesis of N-Feruloyl-Substituted Benzotriazoles

tion and activation strategies with the 1,2-addition of a

In an initial attempt to synthesize N-feruloylbenzotria-

variety of carbon and heteroatomic nucleophiles to acti-

zole (13), previously reported conditions optimized for the

vated ferulic acid derivatives 11 (Scheme 1, iii). In particu-

activation of arene carboxylic acids were evaluated

lar, this report includes the first systematic study of the ad-

(Scheme 2).^[15]However, the reaction of ferulic acid with N-

dition of (hetero)aryllithium reagents to activated feruloyl

(1-methylsulfonyl)benzotriazole, which is readily obtained

(or other cinnamoyl-type) Weinreb amides.

by direct treatment of benzotriazole with methanesulfonyl

chloride and pyridine, yielded the desired compound (i.e.,

13) in unacceptable purity and yield. An alternative ap-

proach, however, using thionyl chloride and excess 1H-

Results and Discussion

The activation of ferulic acid by conversion into the cor- benzotriazole,^[16]rapidly gave N-feruloylbenzotriazole (13).

responding acid chloride was considered to be unattractive, This intermediate was obtained in excellent yield and purity

because of the difficult preparation and the limited stability after trituration of the crude reaction mixture with diethyl

of the acid chloride. Indeed, literature references to feruloyl ether. Importantly, this activated carboxylic acid is stable

chloride^[12,13]and protocols for its preparation are scarce.^[14]when exposed to air or water at 20 °C, and it can be stored

Taking advantage of its superior stability and versatility, N- for over a year at –20 °C.

Scheme 2. Synthesis of N-feruloylbenzotriazole (13).

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Scheme 3. Preparation of MEM- and TBDMS-protected N-feruloylbenzotriazoles 14 and 15; DIPEA = diisopropylethylamine.

To broaden the utility of 13 as a synthetic intermediate, aration of an investigational prodrug for delivery to the co-

its phenolic hydroxy group was protected as a MEM ether lon of 5-aminosalicylic acid.^[19]

(in 14; Scheme 3). Here, the use of excess (2-methoxy-

In similar fashion, N-feruloylglycine (17) was obtained

ethoxy)methyl chloride is to be avoided, so that the forma- in good yield without the use of protecting groups. In this

tion of 1-[(2-methoxyethoxy)methyl]-1H-benzotriazole as a case, however, the use of a larger excess of glycine was re-

by-product is prevented. Also, the corresponding TBDMS quired so as to avoid reaction of the desired product (i.e.,

ether (i.e., 15) was obtained from 13 in very good yield by 17) with a second molecule of the acylbenzotriazole.

a standard protocol.

This feruloylamide synthesis can also be used for the syn-

thesis of heterocyclic aromatic amines. Reaction of 13 with

pyrrole gave N-feruloylpyrrole (18) in good yield under very

mild conditions. For this transformation, a number of bases

Reactivity of N-Feruloylbenzotriazoles

N-Feruloylbenzotriazole (13) is a versatile intermediate were evaluated in various amounts (Et₃N, KOtBu, NaH,

that can undergo mild condensation reactions with a variety Na₂CO₃, CsCO₃, and no base); the best results were ob-

of heteroatomic nucleophiles (Scheme 4). Reaction with tained using 3 equiv. of KOtBu.

methyl glycinate,^[17]for example, gave the corresponding

Furthermore, N-feruloylbenzotriazole (13) is also suscep-

feruloyl-substituted amino acid methyl ester 16 in good tible to condensation with O-nucleophiles, such as

yield after chromatographic purification. Such ferulic acid– the highly functionalized α-hydroxyphosphonate 19

amino acid conjugates have been found to have enzyme- (Scheme 4). For this transformation, no reaction was ob-

inhibitory activities,^[18]and they have been used in the prep- served under ambient conditions in acetonitrile; overnight

Scheme 4. Reactivity of N-feruloylbenzotriazole (13) towards N- and O-nucleophiles.

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Feruloylbenzotriazole and Weinreb Amide Building Blocks

heating to reflux temperature, however, resulted in a nearly triazole, acylation conditions did not give a clean conver-

clean conversion into ferulate 20.

sion into 2-pyrrolyl-chalcone 26 (Scheme 7). Instead, a mix-

The ambident electrophilic nature of N-feruloylbenzotri- ture containing the starting material, products of double

azole is illustrated in its reaction with benzyl mercaptan, addition, and other unwanted material was obtained. The

which gave a 1:1 mixture of 21 and 22, along with remain- desired chalcone (i.e., 26) was, however, obtained by an-

ing starting material, after prolonged heating in a mixture other route (see Scheme 17).

of acetonitrile and 2-methyltetrahydrofuran (Scheme 5).

When THF was used as a solvent, reaction at room tem-

perature gave negligible conversion (Ͻ10%). An investiga-

tion of the 1,2- or 1,4-directing effect of additives on the

reactions with S-nucleophiles^[20]is ongoing, and the results

will be presented in due course.

Scheme 7. N-Feruloylbenzotriazole (13) is not amenable to Friedel–

Crafts-type acylations with pyrroles.

Reaction of MEM-protected N-feruloylbenzotriazole 14

with an alkyllithium reagent, followed by quench with water

at –78 °C, gave a tertiary alcohol (29a or 29b, Scheme 8).

No trace of the corresponding ketone (i.e., 28) was detected

in the crude reaction mixtures. Apparently, complex 27 is

non-existent or unstable, even when the reaction mixture

was kept at –78 °C. Treatment of 14 with 2-lithiofuran also

resulted in a complex reaction mixture, containing traces of

the double addition product but not of ketone 28.

Synthesis of N-Feruloyl Weinreb Amides

Scheme 5. N-Feruloylbenzotriazole (13) behaves as an ambident

From the above, it follows that the preparation of ferulic-

electrophile towards benzyl mercaptan; mTHF = 2-methyltetra-

acid-derived ketones requires the use of an N-feruloyl Wein-

hydrofuran.

reb amide intermediate. Hence, the direct preparation of

An interesting transformation of MEM-protected N- Weinreb amide 30 from ferulic acid 1 was attempted under

feruloylbenzotriazole 14 is found in its reaction with enol- Steglich conditions. Complete consumption of the starting

ates.^[21]As shown in Scheme 6, this approach may serve as material was observed, but numerous by-products were

a convenient entry to biologically relevant scaffolds such as present. Column chromatography gave Weinreb amide 30

unsymmetrical curcuminoids 24 and 25. Evaluation of the in poor yield and moderate purity (Scheme 9). Activation

compatibility of 14 with soft enolization approaches^[22,23]is of the carboxylic acid using thionyl chloride (1 equiv., dry

ongoing.

THF, room temperature, 2 h), or using the conditions of

Various pyrroles and indoles have been shown to un- Sanders,^[27]also yielded complex reaction mixtures; hence,

dergo mild Friedel–Crafts acylation with N-acylbenzotria- no further purification efforts were made. The by-products

zoles,^[24]with a correct choice of Lewis acid^[25]and solvent formed in these reactions were identified as dimers and tri-

giving excellent regiocontrol.^[26]However, in the case of N- mers of ferulic acid, formed due to the presence of the free

feruloylbenzotriazole (13), an α,β-unsaturated acylbenzo- phenolic OH group.

Scheme 6. Conversion of MEM-protected N-feruloylbenzotriazole 14 into curcuminoids 24 and 25; KHMDS = potassium hexamethyldi-

silazide.

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Scheme 8. Reaction of MEM-protected N-feruloylbenzotriazole 14 with alkyllithium reagents gave the corresponding tertiary alcohols

29a–29c.

Scheme 9. Optimized conditions for the preparation of Weinreb amides 30 and 31 from different ferulic acid derivatives; DCC = N,NЈ-

dicyclohexylcarbodiimide, DMAP = 4-(dimethylamino)pyridine.

When N-feruloylbenzotriazole (13) was used as a sub- (1.1 equiv.) at room temperature. On addition of an extra

strate with N,O-DMHA·HCl (N,O-dimethylhydroxylamine equivalent of trimethylaluminium and N,O-DMHA·HCl,

hydrochloride) and triethylamine under ambient conditions, and leaving the reaction overnight at reflux temperature, all

poor conversion was observed.^[28]With both conventional of the starting material was consumed. Nevertheless, Wein-

and microwave heating, the reaction proved difficult to con- reb amide 30 was isolated in a fairly low yield (42%).

trol: the optimal temperature for the conversion of 13 into

The disappointing reaction outcomes observed for 1 and

30 is around 100 °C, but side-reactions take place above 13 prompted us to evaluate Weinreb amide synthesis using

70 °C, and vigorous decomposition of N,O-DMHA occurs MEM-protected feruloylbenzotriazole 14. An attempt using

above 115 °C. Moreover, scale-up proved tedious. Neverthe- sodium hydride (2.4 equiv.) and N,O-DMHA·HCl

less, under the strictly controlled microwave conditions (1.2 equiv.) gave a mixture of 31 and the bis adduct. Opti-

shown in Scheme 9, a good yield of the desired N-feruloyl mal yields of Weinreb amide 31 were obtained in the pres-

Weinreb amide (i.e., 30) was obtained (71%).

ence of trimethylaluminium at room temperature

In an alternative approach, 50% consumption of N-ferul- (Scheme 9). Under these mild conditions, only minor

oylbenzotriazole (13) was obtained in a prolonged reaction amounts of by-products were formed, and a very limited

with

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dimethylaluminium

N-methoxy-N-methylamide degree of deprotection was observed. Following extraction

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Feruloylbenzotriazole and Weinreb Amide Building Blocks

and crystallization from absolute ethanol, Weinreb amide

Similarly, reaction between MEM-protected N-feruloyl-

31 was obtained in excellent purity. When the experiment substituted Weinreb amide 31 and phenyllithium

was repeated with added triethylamine, in order to suppress (1.1 equiv.) gave the corresponding chalcone (i.e., 34;

MEM-deprotection, more by-products were formed.

Scheme 11). To a minor extent, formation of the 1,4-ad-

dition product (i.e., 35) was observed. MEM-deprotection

yielded 1,3-diarylpropenone 36. This compound does not

readily crystallize from ethanol, but it was obtained in high

purity by column chromatography.

Reactivity of MEM-Protected N-Feruloyl Weinreb Amide

31

MEM-protected N-feruloyl Weinreb amide 31 offers a

Addition of excess n-butyllithium (2 equiv.) to 31 gave an

versatile approach to a variety of natural and “bioinspired” unfavourable outcome: the formation of several unidenti-

ketones with pharmacological relevance.^[29,30]Treatment fied by-products was observed; one of them was formed in

with methyllithium, for example, gave methyl ketone 32 in an equal amount to the desired ketone. Interestingly, reac-

good yield and purity after simple extraction (Scheme 10). tion with 1.1 equiv. of n-butyllithium gave full conversion

Subsequent MEM-deprotection and hydrogenation of the into a mixture of the expected 1,2-addition product 37 and

alkene gave the natural product zingerone (6) in good yield. 1,4-adduct 38 in a 2:1 ratio (Scheme 11). Compound 37 was

Scheme 10. Illustration of the use of MEM-protected N-feruloyl-substituted Weinreb amide 31 for the synthesis of ketones: preparation

of zingerone (6).

Scheme 11. Ketone synthesis from Weinreb amide 31.

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isolated in 35% yield by column chromatography. In a sec-

It should be noted that while we^[32]and others^[33]have

ond, identical run, the mixture of 37 and 38 was depro- shown that 1-(2-furyl)-3-phenylprop-2-en-1-ones are also

tected under standard conditions, and chromatographic accessible by a Claisen–Schmidt condensation using 2-acet-

separation gave heptenone 39 in excellent purity. Weinreb ylfuran, the same is not true of the 3-furyl analogues using

amide 40 was obtained as an impure substance, but its 3-acetylfuran 47 (Scheme 13).^[34,35]Indeed, literature re-

structure was confirmed spectroscopically. It may be worth ports of aldol reactions with 3-acetylfuran, and of 1-(3-fu-

noting that nucleophilic attack of nBuLi in a less polar reac- ryl)-3-arylprop-2-en-1-ones in general, are scarce. To the

tion medium (THF/Et₂O/hexane, 5:5:3) resulted in a small best of our knowledge, only a single protocol for the prepa-

improvement in the 1,2/1,4-addition ratio. The addition of ration of such a compound has been published to date: a

ZnCl₂had the opposite effect, and led to a lower 1,2/1,4- Pd-catalysed carbonylative coupling of 3-(tri-n-butylstann-

addition ratio.

yl)furan and 2-phenyliodoethene gave the product in 40%

Yields similar to those of 36 and 39 were obtained by yield.^[36]Thus, the pathway presented here using activated

Kumar and co-workers for the addition of nBuLi and phen- cinnamoyl equivalents is a more convenient route to 3-fur-

yllithium to benzoyl and cinnamoyl Weinreb amides.^[31]

yl-chalcones.

MEM-protected N-feruloyl-substituted Weinreb amide

Lithiated thiaheterocycles also react successfully with

31 reacted with 2-lithiofuran in a clean and almost quanti- MEM-protected N-feruloyl-substituted Weinreb amide 31.

tative reaction (Scheme 12). Subsequent deprotection of the Attack of 2-lithiothiophene gave a fair yield of the pure 2-

phenolic hydroxy group gave furyl-chalcone 42 in excellent thienyl ketone (i.e., 50) after crystallization from absolute

yield. In a similar fashion, a good yield of the pure re- ethanol (Scheme 14). Direct submission of the crude 50 to

gioisomeric ketone 44 was obtained by lithium–halogen ex- MEM-cleavage, and purification by column chromatog-

change of 3-bromofuran, deprotection, and purification by raphy gave 1-(2-thienyl)-3-(4-hydroxy-3-methoxyphenyl)-

column chromatography.

prop-2-en-1-one (51) in excellent yield (89% from 31).

Scheme 12. Conversion of Weinreb amide 31 into furyl-chalcones.

Scheme 13. Aldol reaction of 3-acetylfuran 47 is not a straightforward route to 3-furyl-chalcones; PCC = pyridinium chlorochromate.

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Feruloylbenzotriazole and Weinreb Amide Building Blocks

Scheme 14. Conversion of Weinreb amide 31 into thienyl-chalcones 50–53.

For the synthesis of 3-thienyl regioisomer 53, Weinreb

In a subsequent attempt, hexane/diethyl ether was chosen

amide 31 was treated with 3-lithiothiophene, prepared from as a solvent mixture in order to promote regioselective lithi-

3-bromothiophene (1.2 equiv.) and nBuLi (1.34 equiv.). Al- ation at the 3-position,^[39]and a small excess of 3-bromo-

though the desired intermediate (i.e., 52) was obtained, the thiophene was used (Scheme 14). Under these optimized

reaction was more sluggish than that with 2-lithiothio- conditions, 52 was obtained in high yield and purity, and

phene, and several by-products were formed in the reaction was immediately deprotected to give 53 (combined yield of

mixture. Based on LC/MS data, one of these compounds 60% over two steps). Good crystallization yields for 53 were

was identified as the product of butyl addition, formed due only obtained starting from sufficiently pure 52, as obtained

to the presence of excess nBuLi. Another by-product was using the optimized protocol. For characterization of inter-

50, presumably formed by halogen dance rearrangement of mediate 52, a small product sample underwent extra purifi-

3-lithiothiophene.^[37,38]

cation by column chromatography over aluminium oxide.

Scheme 15. Conversion of Weinreb amide 31 into pyridyl-chalcones 54–58.

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These propenones are biologically relevant, as 3-thienyl-

Attempts at the isolation of 4-pyridyl-chalcone 58 failed

chalcones have been found to have antimicrobial and anti- (Scheme 15). As 4-bromopyridine is prone to self-condensa-

cancer properties at micromolar concentrations in in vitro tion, it is commercially available as its (stable) hydro-

models.^[40,41]

chloride salt. In a first unsuccessful attempt to synthesize

Pyridyl ketones are also accessible from Weinreb amide 58, the optimized procedure for the preparation of 54 was

31 (Scheme 15). Reaction with 2-lithiopyridine, for example, used, with the addition of an extra equivalent of nBuLi to

gave a fairly clean conversion into ketone 54. A minor neutralize the HCl salt. In a second attempt, 4-bromopyr-

amount of the butyl ketone was obtained, due to the small idine was isolated before the reaction by neutralization of

excess of nBuLi used. Unfortunately, purification of the the hydrochloride salt with sodium carbonate (5% aq.) and

crude product proved difficult, and the pure MEM-pro- extraction with diethyl ether.^[43]The free 4-bromopyridine

tected ketone was therefore not isolated. Moreover, this was immediately lithiated, and Weinreb amide 31 was

product proved to be unstable at room temperature. There- added. This approach yielded a mixture containing the

fore, no further attempts at the isolation of 54 were made, product of butyl addition as the major constituent, together

and the crude product was immediately subjected to MEM- with traces of the desired product (i.e., 58). In a final at-

deprotection. Under the conditions used earlier [HCl (5% tempt, 4-bromopyridine was converted into the correspond-

aq.)/THF, reflux], a complex reaction mixture was formed. ing Grignard reagent by reaction with isopropylmagnesium

However, treatment with TFA (trifluoroacetic acid) in chloride. Subsequent reaction with 31 again gave traces of

dichloromethane at room temperature yielded 2-pyridyl- 58, amongst a multitude of by-products.

chalcone 55 in high purity after flash chromatography over

In conclusion, the preparation and deprotection of pyr-

silica and subsequent crystallization from absolute ethanol. idyl-chalcones from Weinreb amide 31 proved more difficult

Reaction of 31 with 3-lithiopyridine proceeded signifi- than was found for the corresponding furyl and thienyl ana-

cantly more slowly: using the procedure described above for logues. The results of our evaluation of alternative lithiation

the synthesis of 2-pyridyl ketone 54, full conversion of the and deprotection conditions will be reported in due course.

starting material was only obtained after prolonged reac-

MEM-protected N-feruloyl-substituted Weinreb amide

tion times, warming to room temperature, and addition of 31 also provides

a

route to 3-pyrrolyl-chalcones

extra lithiopyridine reagent. When a solvent mixture of hex- (Scheme 16). Upon lithium–halogen exchange of commer-

ane and diethyl ether (8:5) was used, however, a swift con- cially available 3-bromo-1-TIPS-pyrrole (TIPS = triisoprop-

version into feruloylpyridine 56 was observed (Scheme 15). ylsilyl),^[44]and subsequent reaction with 31, complete con-

Isolation of 56 proved difficult, and required chromatog- sumption of the Weinreb amide was observed. A mixture

raphy followed by crystallization. Therefore, the crude of 59, 60, and minor impurities was obtained, for which the

product was submitted directly to a mild deprotection step ratio 59/60 varied over different runs. Complete conversion

using TFA, which gave the desired 3-pyridyl-chalcone (i.e., into 60 was easily obtained by treatment with TBAF (tetra-

57) in high purity after crystallization from absolute eth- butylammonium fluoride) under mild conditions. Given the

anol. Closely related cinnamoyl pyridines were recently re- stability problems often encountered with pyrroles, subse-

ported to be PAR1 antagonists with in vitro anti-aggrega- quent removal of the MEM protecting group was per-

tion properties and potent in vivo antithrombotic activity formed using the milder TFA protocol. Purification by col-

in rats.^[42]

umn chromatography gave 3-(4-hydroxy-3-methoxyphenyl)-

Scheme 16. Conversion of Weinreb amide 31 into 3-pyrrolyl-chalcones 59–63; TBAI = tetrabutylammonium iodide.

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Feruloylbenzotriazole and Weinreb Amide Building Blocks

Scheme 17. Conversion of Weinreb amide 31 into 2-pyrrolyl-chalcone 26; NBS = N-bromosuccinimide.

1-(3-pyrrolyl)prop-2-en-1-one (61) in good purity and 39% hydrolysis step under basic conditions, and purification by

overall yield (from 31).

column chromatography, pyrrole 26 was obtained in 42%

N-Functionalized 3-pyrrolyl-chalcones, such as N-methyl overall yield (from 31).

analogue 63, can be obtained by alkylation and MEM

cleavage (Scheme 16). Methylation of 60 proceeded well un-

der mild conditions. Intermediate 62 was immediately sub-

jected to MEM-cleavage conditions to give the desired N-

methyl-3-pyrrolyl-substituted chalcone (i.e., 63) in high pu-

rity after purification by column chromatography or pre-

parative TLC. MEM-protected ketone intermediate 62

could also be isolated in excellent purity by crystallization

from absolute ethanol. Interestingly, while free pyrrole 61

proved to be reasonably stable, its N-methylated analogue

63 was found to be highly photolabile.

To obtain the corresponding 2-pyrrolyl-chalcone 26, the

ortho-directing SEM [2-(trimethylsilyl)ethoxymethyl] group

was introduced onto 1H-pyrrole (Scheme 17).^[45]Lithiation

of the resulting 1-SEM-1H-pyrrole (i.e., 65) with an equi-

molar amount of nBuLi was sluggish, even when the reac-

tion was run at room temperature. Hence, subsequent reac-

tion with Weinreb amide 31 gave the corresponding butyl

ketone as a major product. This apparent inertness of 1-

SEM-1H-pyrrole 65 has also been observed by Muchowski

et al.^[46]

Conclusions

A bioinspired route for the conversion of ferulic acid into

physiologically relevant molecules is presented. A conve-

nient preparation of (MEM-protected) feruloylbenzotria-

zoles 13 and 14, and the regioselective 1,2-addition of O-,

N-, and C-nucleophiles to this versatile intermediate were

demonstrated. The S-nucleophile benzyl mercaptan was

found to add in both a 1,2- and 1,4-fashion. Next, MEM-

protected feruloyl-substituted Weinreb amide 31 was shown

to allow convenient access to a wide variety of heteroaryl-

substituted chalcones upon addition of (hetero)aryllithium

reagents. In most cases, competing 1,4-addition and ad-

dition of n-butyllithium could be suppressed by choice of

the correct reaction conditions, namely the use of a limited

excess of the (hetero)aryllithium compound, and the use of

excess heteroaryl compound with respect to n-butyllithium.

The MEM group was found to be a stable protecting group,

and its removal proved straightforward in most cases. Our

method is not without its limitations: the synthesis and de-

protection of pyridyl-chalcones proved tedious, and optimi-

zation remains necessary. The relevance of our “bioin-

spired” method was illustrated by the synthesis of a number

of natural products or their analogues, such as zingerone,

curcuminoids, and (heteroaryl) chalcones.

In an attempt to achieve higher reactivity, a bromide sub-

stituent was introduced at the 2-position of 1-SEM-pyrrole

under mild conditions (Scheme 17).^[47]Filtration through a

silica plug gave 66, which proved to be more susceptible to

lithiation under standard conditions. 2-Pyrrolyl-chalcone 67

was obtained upon reaction with 31, and it was immediately

submitted to TFA-mediated deprotection of the SEM and

MEM ether moieties. Curiously, these conditions did not

give the free pyrrole (i.e., 26), but rather its N-

(hydroxymethyl) analogue 68. Compound 68 proved to be

surprisingly stable, and its formation was confirmed by LC/

Experimental Section

General Remarks: All reagents were purchased from commercial

suppliers (Sigma–Aldrich, Acros, TCI), and were used without fur-

MS and ¹H NMR spectroscopic data. After an extra ther purification. Solvents were dried with sodium (THF, diethyl

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C. V. Stevens et al.

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ether) or calcium hydride (dichloromethane), and distilled before

use. Other solvents were purchased from commercial suppliers and

used as supplied. The petroleum ether used during product purifi-

cation steps had a boiling range of 40–60 °C.

(ESI^–): m/z (%) = 294.0 (100) [M – H]^–. HRMS (ESI): calcd. for

C₁₆H₁₃N₃O₃295.0957; found 295.0956.

(2E)-1-(Benzotriazol-1-yl)-3-[3-methoxy-4-(2-methoxyethoxy-

methoxy)phenyl]propenone (14): (2E)-1-(Benzotriazol-1-yl)-3-(4-

hydroxy-3-methoxyphenyl)propenone (13; 8 g, 27.09 mmol,

1 equiv.) was put into a flame-dried flask (250 mL) under an inert

atmosphere, and dissolved in a mixture of dry dichloromethane

and dry THF (4:1; 200 mL). The mixture was cooled to 0 °C in an

ice bath, and diisopropylethylamine (9 mL, 54.18 mmol, 2 equiv.)

and MEM chloride (3.12 mL, 27.36 mmol, 1.01 equiv.) were added.

After the addition, the ice bath was removed, and the reaction mix-

ture was stirred at room temperature for 24 h. The reaction mixture

was washed with equal volumes of saturated sodium hydrogen

carbonate solution, sodium hydroxide (1 n aq.), and brine, dried

with MgSO₄, and evaporated in vacuo. The resulting solid was

recrystallized from ethyl acetate to give 14 (9.66 g, 93%) as pale

yellow crystals, m.p. 139–140 °C. ¹H NMR (400 MHz, CDCl₃): δ

= 3.38 (s, 3 H, CH₂OCH₃), 3.55–3.60 (m, 2 H, CH₂OCH₃), 3.86–

3.92 (m, 2 H, CH₂CH₂OCH₃), 3.99 (s, 3 H, ArOCH₃), 5.40 (s, 2

H, OCH₂O), 7.23–7.31 (m, 3 H, 2-H, 5-H, 6-H), 7.48–7.54 (m, 1

H, 5Ј-H), 7.63–7.69 (m, 1 H, 6Ј-H), 7.96 (d, J = 15.8 Hz, 1 H, 8-

H), 8.07 (d, J = 15.8 Hz, 1 H, 7-H), 8.13 (d, J = 8.2 Hz, 1 H, 7Ј-

H), 8.39 (d, J = 8.2 Hz, 1 H, 4Ј-H) ppm. ¹³C NMR (100.6 MHz,

CDCl ₃) : δ = 5 6 . 1 ( A r O C H ₃) , 5 9 . 0 ( C H ₂OC H₃) , 68 . 1

(CH₂CH₂OCH₃), 71.5 (CH₂OCH₃), 94.0 (OCH₂O), 110.4 (C-2),

113.9 (C-8), 114.8 (C-4Ј), 115.6 (C-5), 120.1 (C-7Ј), 124.1 (C-6),

126.1 (C-5Ј), 128.4 (C-1), 130.2 (C-6Ј), 131.5 (C-3Јa), 146.3 (C-7Јa),

148.6 (C-7), 149.7 (C-4), 149.8 (C-3), 164.0 (C=O) ppm. IR (ATR):

Microwave reactions were carried out in a CEM Benchmate appa-

ratus (maximum power: 300 W). Crude reaction mixtures were ana-

lysed by LC/MS/UV. Thin-layer chromatography was carried out

on silica gel 60F₂₅₄plates (Merck). Preparative HPLC separations

were carried out using

a

ZORBAX XDB-C18 column

(21.2ϫ150 mm, 5 μm).

High-resolution ¹H and ¹³C magnetic resonance (NMR) spectra

were recorded with Jeol Eclipse+ 300 or Bruker AVANCE III 400

FT NMR spectrometers in deuterated solvents. Chemical shifts

were calibrated using tetramethylsilane, which was used as an in-

ternal reference, unless otherwise indicated. Peak assignments were

obtained with the aid of DEPT, HSQC, HMBC, and COSY spec-

tra. Attenuated total reflection (ATR) IR spectra were recorded

with a Perkin–Elmer Spectrum BX spectrometer, equipped with a

ZnSe crystal, at room temperature (neat). Low-resolution mass

spectra were recorded with an Agilent Technologies 1100 series VL

mass spectrometer (ESI, 70 eV). HRMS analyses were carried out

with an HPLC coupled to an Agilent Technologies 6210 series

time-of-flight mass spectrometer equipped with an ESI/APCI-

multimode source. Melting points were measured with a Büchi B-

540 apparatus.

4-(4-Hydroxy-3-methoxyphenyl)butan-2-one (zingerone, 6): (3E)-4-

(4-Hydroxy-3-methoxyphenyl)but-3-en-2-one

(33;

0.120 g,

ν = 977, 1077, 1084, 1255 cm^–1. MS (ESI⁺): m/z (%) = 406.1 (100)

0.62 mmol, 1 equiv.) was dissolved in methanol (4 mL), and pow-

dered Rh on alumina (0.5 wt.-%; 24 mg, 0.2 mol-%) was added.

The reaction mixture was put under a hydrogen atmosphere (1 bar).

The mixture was stirred at room temperature for 2 h, then it was

filtered through Celite, and the filter cake was rinsed with meth-

anol. The solvent was removed under reduced pressure to give pure

4-(4-hydroxy-3-methoxyphenyl)butan-2-one (6; 120 mg, quantita-

tive). All spectroscopic data were in accordance with those reported

in the literature.^[48]

˜

[M + Na]⁺, 189.0 (40), 265.1 (38).

(2E)-1-(1H-Benzotriazol-1-yl)-3-{4-[(tert-butyldimethyl-

silyl)-oxy]-3-methoxyphenyl}prop-2-en-1-one (15): (2E)-1-(Benzotri-

azol-1-yl)-3-(4-hydroxy-3-methoxyphenyl)propenone (13; 1 g,

3.39 mmol, 1 equiv.) was put into a flame-dried flask (100 mL) un-

der a nitrogen atmosphere, and dissolved in dry THF (50 mL). The

mixture was cooled to 0 °C in an ice bath, and diisopropylethyl-

amine (1.2 mL, 6.8 mmol, 2 equiv.) and TBDMSCl (766 mg,

5.08 mmol, 1.5 equiv.) were added. After the addition, the ice bath

was removed, and the reaction mixture was stirred at room tem-

perature for 1 h. The reaction was quenched with saturated sodium

hydrogen carbonate solution (50 mL), and the crude product was

extracted with ethyl acetate (3ϫ 50 mL). The combined organic

layers were washed with brine, dried with MgSO₄, and concen-

trated in vacuo. The resulting solid was recrystallized from ethyl

acetate to give 15 (1.07 g, 77%) as pale yellow crystals, m.p. 117–

118 °C. ¹H NMR (400 MHz, CDCl₃): δ = 0.20 [s, 6 H, Si(CH₃)₂C-

(CH₃)₃], 1.01 [s, 9 H, Si(CH₃)₂C(CH₃)₃], 3.92 (s, 3 H, OCH₃), 6.91

(d, J = 8.0 Hz, 1 H, 5-H), 7.22–7.26 (m, 2 H, 2-H, 6-H), 7.49–7.54

(m, 1 H, 5Ј-H), 7.64–7.69 (m, 1 H, 6Ј-H), 7.96 (d, J = 15.7 Hz, 1

H, 8-H), 8.08 (d, J = 15.7 Hz, 1 H, 7-H), 8.14 (d, J = 8.3 Hz, 1 H,

7Ј-H), 8.41 (d, J = 8.3 Hz, 1 H, 4Ј-H) ppm. ¹³C NMR (100.6 MHz,

CDCl₃): δ = –4.5 [Si(CH₃)₂C(CH₃)₃], 18.5 [Si(CH₃)₂C(CH₃)₃], 25.7

[Si(CH₃)₂C(CH₃)₃], 55.6 (OCH₃), 111.1 (C-2), 113.4 (C-8), 114.9

(C-4Ј), 120.1 (C-7Ј), 121.2 (C-5), 124.1 (C-6), 126.1 (C-5Ј), 128.1

(C-1), 130.2 (C-6Ј), 131.6 (C-3Јa), 146.3 (C-7Јa), 148.9 (C-7), 149.1

(2E)-1-(Benzotriazol-1-yl)-3-(4-hydroxy-3-methoxyphenyl)prop-

enone (13): Dry THF (250 mL) was put into a flame-dried flask

(500 mL) under an inert atmosphere, and then ferulic acid (10 g,

51.5 mmol, 1 equiv.) and 1H-benzotriazole (20 g, 167.9 mmol,

3.2 equiv.) were added. Then thionyl chloride (3.74 mL, 51.5 mmol,

1 equiv.) was added, and the reaction mixture was stirred at room

temperature for 2.5 h. A yellow suspension was formed during this

step. Next, the solids were removed by filtration through a glass

filter, and the filter cake was rinsed with dichloromethane until the

solvent came out of the filter colourless. The filtrate was concen-

trated in vacuo, then diethyl ether (250 mL) was added, and the

suspended product was triturated intensively to dissolve any re-

maining 1H-benzotriazole. The product was collected by filtration

on a glass filter, and was washed with diethyl ether (5ϫ 20 mL).

After air-drying, compound 13 (14.14 g, 93%) was obtained as a

fine yellow powder, m.p. 202–203 °C. ¹H NMR (400 MHz, [D₆]-

DMSO): δ = 3.90 (s, 3 H, OCH₃), 6.89 (d, J = 8.2 Hz, 1 H, 5-H),

7.34 (dd, J = 8.2, J = 1.5 Hz, 1 H, 6-H), 7.50 (d, J = 1.5 Hz, 1 H,

2-H), 7.59 (t, J = 7.6 Hz, 1 H, 5Ј-H), 7.76 (t, J = 7.6 Hz, 1 H, 6Ј-

H), 7.88 (d, J = 15.7 Hz, 1 H, 8-H), 8.04 (d, J = 15.7 Hz, 1 H, 7-

H), 8.24 (d, J = 8.3 Hz, 1 H, 7Ј-H), 8.31 (d, J = 8.3 Hz, 1 H, 4Ј-

H), 9.97 (s, 1 H, OH) ppm. ¹³C NMR (100.6 MHz, [D₆]DMSO): δ

= 56.2 (OCH₃), 112.3, 112.4 (C-2, C-8), 114.8 (C-4Ј), 116.2 (C-5),

120.5 (C-7Ј), 125.3 (C-6), 125.9 (C-1), 126.8 (C-5Ј), 131.4 (C-6Ј),

131.0 (C-3Јa), 146.1 (C-7Јa), 148.6 (C-4), 149.8 (C-7), 151.3 (C-3),

(C-4), 151.4 (C-3), 164.1 (C=O) ppm. IR (ATR): ν = 754, 906, 985,

˜

1282, 1514, 1594, 1618, 1707 cm^–1. MS (ESI⁺): m/z (%) = 291.1

(100) [M – Bt]⁺.

(2E)-Methyl [3-(4-Hydroxy-3-methoxyphenyl)acryloylamino]acetate

(16): Acetonitrile (50 mL) was put into a flask (100 mL), and (2E)-

1-(benzotriazol-1-yl)-3-(4-hydroxy-3-methoxyphenyl)propenone

(13; 1 g, 3.39 mmol, 1 equiv.) and methyl glycinate hydrochloride

164.2 (C=O) ppm. IR (ATR): ν = 1016, 1125, 1244, 1586 cm^–1. MS

˜

2604

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Eur. J. Org. Chem. 2014, 2594–2611

Feruloylbenzotriazole and Weinreb Amide Building Blocks

(0.85 g, 6.77 mmol, 2 equiv.) were added. Then triethylamine 5), 119.3 (C-7), 123.3 (C-6), 126.9 (C-1), 146.9 (C-3), 147.8 (C-β),

(0.95 mL, 6.77 mmol, 2 equiv.) was added, and the reaction mixture

was heated at reflux for 5 h. The mixture was allowed to cool to

room temperature, and the solvent was removed in vacuo. The resi-

due was dissolved in ethyl acetate (50 mL), and this solution was

washed with HCl (0.1 n aq.; 50 mL), water (50 mL), and brine

(50 mL). The organic layer was dried with MgSO₄and evaporated

in vacuo. The residue is purified by column chromatography over

silica with ethyl acetate/petroleum ether (1:2) as eluent, and then

the product was recrystallized from acetonitrile to give 16 (567 mg,

63%) as pale yellow crystals, m.p. 111–112 °C. R_f(EtOAc) = 0.64.

¹H NMR (400 MHz, [D₆]DMSO): δ = 3.65 [s, 3 H, C(O)OCH₃],

3.81 (s, 3 H, ArOCH₃), 3.96 (d, J = 5.8 Hz, 2 H, CH₂), 6.53 (d, J

= 15.7 Hz, 1 H, 8-H), 6.80 (d, J = 8.1 Hz, 1 H, 5-H), 7.02 (dd, J

= 8.1, J = 1.2 Hz, 1 H, 6-H), 7.16 (d, J = 1.2 Hz, 1 H, 2-H), 7.36

(d, J = 15.7 Hz, 1 H, 7-H), 8.39 (t, J = 5.8 Hz, 1 H, NH), 9.48 (s,

1 H, OH) ppm. ¹³C NMR (100.6 MHz, [D₆]DMSO): δ = 41.2

(CH₂), 52.2 [C(O)OCH₃], 56.0 (ArOCH₃), 111.3 (C-2), 116.1 (C-

5), 118.6 (C-8), 122.2 (C-6), 126.7 (C-1), 140.3 (C-7), 148.3 (C-3),

148.9 (C-4), 166.3 [C(O)NH], 171.0 [C(O)OCH₃] ppm. IR (ATR):

148.6 (C-4), 163.2 (C=O) ppm. IR (ATR): ν = 822, 1117, 1269,

˜

1585 cm^–1. MS (ESI⁺): m/z (%) = 244.0 (100) [M + H]⁺. HRMS

(ESI): calcd. for C₁₄H₁₃NO₃243.0895; found 243.0894.

2-(tert-Butoxycarbonyl)amino-1-(diethoxyphosphoryl)ethyl (2E)-3-

(4-Hydroxy-3-methoxyphenyl)prop-2-enoate (20): Acetonitrile

(50 mL), diethyl (2-tert-butoxycarbonylamino-1-hydroxyethyl)-

phosphonate (19; 0.5 g, 1.68 mmol, 1.1 equiv.), and N-feruloylben-

zotriazole (13; 0.4514 g, 1.53 mmol, 1 equiv.) were put into a

round-bottomed flask (100 mL). Et₃N (0.72 mL, 5.04 mmol,

3.3 equiv.) was added, and the mixture was heated to reflux tem-

perature overnight. Next, the solvent was removed in vacuo, and

the residue was dissolved in EtOAc (50 mL). The resulting mixture

was washed with HCl (0.1 n; 50 mL) and brine (50 mL), dried with

MgSO₄, and concentrated in vacuo. The residue was purified by

column chromatography over silica gel (EtOAc/petroleum ether,

1:2) to give 20 (420 mg, 58%; purity Ͼ90%) as a pale yellow, vis-

cous oil. R_f(EtOAc) = 0.36. ¹H NMR (300 MHz, CDCl₃): δ = 1.35

(td, J = 7.2, J = 5.5 Hz, 6 H, 2 OCH₂CH₃), 1.42 [s, 9 H, OC-

(CH₃)₃], 2.00 (s, 1 H, OH), 3.47–3.65, 3.70–3.82 (m, 2 H, NHCH₂),

3.88 (s, 3 H, OCH₃), 4.12–4.26 (m, 4 H, 2 OCH₂), 5.18–5.31 (m, 1

H, NH), 5.47–5.54 (m, 1 H, OCHP), 6.28 (d, J = 15.4 Hz, 1 H, α-

H), 6.92 (d, J = 8.3 Hz, 1 H, 5-H), 6.99 (s, 1 H, 2-H), 7.01 (d, J =

8.3 Hz, 1 H, 6-H), 7.65 (d, J = 15.4 Hz, 1 H, β-H) ppm. ¹³C NMR

(CDCl₃, 75 MHz): δ = 14.6 (d, J = 5.8 Hz, OCH₂CH₃), 14.7 (d, J

= 5.8 Hz, OCH₂CH₃), 26.5 [OC(CH₃)₃], 38.5 (NHCH₂), 54.1

(OCH₃), 61.4 (d, J = 6.9 Hz, OCH₂CH₃), 61.7 (d, J = 6.9 Hz,

OCH₂CH₃), 64.8 (d, J = 166.1 Hz, OCHP), 77.9 [OC(CH₃)₃], 108.2

(C-2), 111.6 (C-α), 113.4 (C-5), 121.6 (C-6), 124.4 (C-1), 145.0 (C-

3), 145.6 (C-4), 147.3 (C-β), 154.1 [OC(O)NH], 164.2 (C=O) ppm.

ν = 1187, 1197, 1224, 1235, 1252, 1516, 1592 cm^–1. MS (ESI^–): m/z

˜

(%) = 264.3 (100) [M – H]^–. HRMS (ESI): calcd. for C₁₃H₁₅NO₅

265.0950; found 265.0955.

(2E)-[3-(4-Hydroxy-3-methoxyphenyl)acryloylamino]acetic Acid

(17): A mixture of acetonitrile and water (21:9; 30 mL) was put

into a flask (50 mL), and (2E)-1-(benzotriazol-1-yl)-3-(4-hydroxy-

3-methoxyphenyl)propenone (13; 0.5 g, 1.69 mmol, 1 equiv.) and

glycine (0.635 g, 8.47 mmol, 5 equiv.) were added. Then triethyl-

amine (1.18 mL, 8.47 mmol, 5 equiv.) was added, and the reaction

mixture was stirred for 10 h at room temperature. The acetonitrile

was removed in vacuo, and the remaining aqueous solution was

transferred to a separation funnel, acidified with HCl (0.1 n) until

the pH reached 2, and then extracted (2ϫ) with an equal volume

of ethyl acetate. The combined organic layers were dried with

MgSO₄and evaporated in vacuo. The residue was recrystallized

from acetonitrile to give 17 (318 mg, 75%) as white crystals, m.p.

217–218 °C. ¹H NMR (400 MHz, [D₆]DMSO): δ = 3.82 (s, 3 H,

OCH₃), 3.89 (d, J = 5.6 Hz, 2 H, CH₂), 6.57 (d, J = 15.7 Hz, 1 H,

8-H), 6.81 (d, J = 8.1 Hz, 1 H, 5-H), 7.03 (d, J = 8.1 Hz, 1 H, 6-

H), 7.16 (s, 1 H, 2-H), 7.37 (d, J = 15.7 Hz, 1 H, 7-H), 8.25 (t, J

= 5.6 Hz, 1 H, NH) ppm. ¹³C NMR (100.6 MHz, [D₆]DMSO): δ

= 41.3 (CH₂), 56.0 (OCH₃), 111.3 (C-2), 116.1 (C-5), 118.9 (C-8),

122.1 (C-6), 126.7 (C-1), 140.0 (C-7), 148.3, 148.8 (C-3, C-4), 166.2

IR (ATR): ν = 1019, 1144, 1244 cm^–1. MS (ESI^–): m/z (%): 472.3

˜

(100) [M – 1]^–.

(1E,4Z,6E)-5-Hydroxy-1-{3-methoxy-4-[(2-methoxyethoxy)meth-

oxy]phenyl}-7-phenylhepta-1,4,6-trien-3-one (24): 4-Phenyl-3-buten-

2-one (23; 187 mg, 1.27 mmol, 1.4 equiv.) and dry THF (10 mL)

were put into a flame-dried round-bottomed flask (25 mL) under

a nitrogen atmosphere. The resulting solution was cooled to 0 °C,

and KHMDS (1 m solution in THF; 2 mL, 2 mmol, 2.15 equiv.)

was added. The resulting homogeneous red mixture was stirred at

room temperature for 2 h. Then the solution was cooled to 0 °C,

and 14 (350 mg, 0.91 mmol, 1 equiv.) was added in one portion.

The mixture was stirred at room temperature for 3 h. Next, water

(10 mL) was added, and the crude product was extracted with ethyl

acetate (2ϫ 15 mL). The combined organic layers were washed

with saturated aqueous Na₂CO₃(3ϫ 10 mL), dried with MgSO₄,

and concentrated in vacuo to give pure 24 (284 mg, 76%) as a vis-

cous, orange oil. R_f(EtOAc/petroleum ether, 1:1) = 0.33. ¹H NMR

(400 MHz, CDCl₃): δ = 3.38 (s, 3 H, OCH₃), 3.54–3.59 (m, 2 H,

CH₂CH₂O), 3.86–3.90 (m, 2 H, CH₂CH₂O), 3.93 (s, 3 H, Ar-

OCH₃), 5.37 (s, 2 H, OCH₂O), 5.85 (s, 1 H, OH), 6.53 (d, J =

15.8 Hz, 1 H, αЈ-H), 6.63 (d, J = 15.8 Hz, 1 H, γ-H), 7.09 (d, J =

1.9 Hz, 1 H, 2Ј-H), 7.13 (dd, J = 8.5, J = 1.9 Hz, 1 H, 6Ј-H), 7.22

[C(O)NH], 171.9 [C(O)OH] ppm. IR (ATR): ν = 1020, 1153, 1170,

˜

1196, 1216, 1241, 1514 cm^–1. MS (ESI⁺): m/z (%) = 252.1 (100) [M

+ H]⁺, 274.0 (78) [M + Na]⁺.

(2E)-3-(4-Hydroxy-3-methoxyphenyl)-1-(pyrrol-1-yl)propenone (18):

Freshly distilled pyrrole (0.14 mL, 2.02 mmol, 2 equiv.) was dis-

solved in acetonitrile (10 mL). Then, potassium tert-butoxide

(342 mg, 3.05 mmol, 3 equiv.) was added to the reaction mixture,

followed by (2E)-1-(benzotriazol-1-yl)-3-(4-hydroxy-3-meth-

oxyphenyl)propenone (13; 300 mg, 1.01 mmol, 1 equiv.). The reac-

tion mixture was stirred at room temperature for 1 h, then it was

quenched with HCl (0.1 n aq.; 50 mL) and extracted with ethyl (d, J = 8.5 Hz, 1 H, 5Ј-H), 7.32–7.46 (m, 4 H, α-H, 3-H, 4-H, 5-

acetate (3ϫ 50 mL). The combined organic layers were dried with

MgSO₄and evaporated in vacuo. The brown residue was recrys-

tallized from ethanol to give 18 (177 mg, 72%) as pale yellow crys-

H), 7.56 (dd, J = 7.5, J = 1.9 Hz, 2 H, 2-H, 6-H), 7.62 (d, J =

15.8 Hz, 1 H, βЈ-H), 7.66 (d, J = 15.8 Hz, 1 H, δ-H) ppm. ¹³C

NMR (100.6 MHz, [D₆]DMSO): δ = 56.3 (OMe), 59.1 (OMe), 68.4

(CH₂CH₂O), 71.9 (CH₂CH₂O) , 9 4. 7 ( OC H₂O), 101.8

1

tals, m.p. 164–165 °C. H NMR (400 MHz, CDCl₃): δ = 3.96 (s, 3

H, OCH₃), 6.00 (s, 1 H, OH), 6.27–6.47 (m, 2 H, 3Ј-H), 6.97 (d, J [CH=CH(OH)], 111.5 (C-5Ј), 116.9 (C-2Ј), 122.5, 123.1, 124.5 (2

= 7.5 Hz, 1 H, 5-H), 6.98 (d, J = 15.3 Hz, 1 H, α-H), 7.09 (s, 1 H, CH=CHAr, C-6Ј), 128.3, 129.2 (C-2, C-4, C-3, C-5), 129.9 (C-1Ј),

2-H), 7.21 (d, J = 7.5 Hz, 1 H, 6-H), 7.41–7.55 (m, 2 H, 2Ј-H), 7.92

130.2 (C-4), 135.4 (C-1), 140.9, 140.6 (2 =CHAr), 149.0, 150.5 (C-

(d, J = 15.3 Hz, 1 H, β-H) ppm. ¹³C NMR (100.6 MHz, CDCl₃): 3Ј, C-4Ј), 184.2, 182.9 [C=O, =C(OH)] ppm. IR (ATR): ν = 699,

˜

δ = 56.1 (OCH₃), 110.2 (C-2), 113.1 (C-α), 113.2 (C-8), 115.0 (C- 970, 1080, 1100, 1130, 1252, 1420, 1449, 1508, 1579, 1625, 1714,

Eur. J. Org. Chem. 2014, 2594–2611

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2605

C. V. Stevens et al.

FULL PAPER

2924 cm^–1. MS (ESI⁺): m/z (%) = 411.1 (100) [M + H]⁺, 412.2 (26).

HRMS (ESI): calcd. for C₂₄H₂₆O₆410.1729; found 410.1746.

1051, 1107, 1205, 1276, 1402, 1425, 1509, 1542, 1563 (C=C), 1637

(C=O), 3260 (OH) cm^–1. MS (ESI⁺): m/z (%) = 244.0 (100) [M +

H]⁺, 509.2.

General Procedure for the Hydrochloric-Acid-Mediated Deprotec-

tion of MEM Ethers: In a round-bottomed flask equipped with a

reflux condenser, a MEM-protected phenol (0.5 g) was dissolved in

a mixture of THF (20 mL) and HCl (5% aq.; 10 mL). The mixture

was heated at reflux for 5 h, then it was carefully quenched with

saturated aqueous sodium hydrogen carbonate (until pH = 5), and

the mixture was extracted with ethyl acetate (3ϫ 30 mL). The com-

bined organic layers were washed with brine (50 mL), dried with

MgSO₄, and concentrated in vacuo.

(2E)-3-(4-Hydroxy-3-methoxyphenyl)-N-methoxy-N-methylacryl-

amide (30): Acetonitrile (4 mL) was put into a a microwave vial

(10 mL), and (2E)-1-(benzotriazol-1-yl)-3-(4-hydroxy-3-meth-

oxyphenyl)propenone (13; 0.2953 g, 1 mmol, 1 equiv.) and N,O-di-

methylhydroxylamine hydrochloride (0.1463 g, 1.5 mmol,

1.5 equiv.) were added. Then, triethylamine (0.21 mL, 1.5 mmol,

1.5 equiv.) was added, and the reaction mixture was heated in a

microwave reactor at 100 °C for 15 min. Next, the solvent was evap-

orated in vacuo. The residue was dissolved in ethyl acetate (25 mL),

and this solution was washed with equal volumes of HCl (0.1 n)

and brine. The organic layer was dried with MgSO₄and evaporated

in vacuo. The residue was purified by column chromatography over

silica with ethyl acetate/petroleum ether (1:2) as eluent, and the

product was recrystallized from absolute ethanol to give 30

(168 mg, 71%) as white crystals, m.p. 99–100 °C. R_f(EtOAc/petro-

(1E,4Z,6E)-5-Hydroxy-1-(4-hydroxy-3-methoxyphenyl)-7-phenyl-

hepta-1,4,6-trien-3-one (25): (1E,4Z,6E)-5-Hydroxy-1-{3-methoxy-

4-[(2-methoxyethoxy)methoxy]phenyl}-7-phenylhepta-1,4,6-trien-

3-one (24; 200 mg, 0.61 mmol) was deprotected following the gene-

ral procedure for the hydrochloric-acid-mediated deprotection of

MEM ethers to give a solid (209 mg). A sample of this crude prod-

uct 25 (40.9 mg) was purified by preparative TLC (petroleum ether/

EtOAc/HCOOH, 40:9:1) to give 25 (4.3 mg, 14%) as an orange

powder. All spectroscopic data were in accordance with those re-

ported in the literature.^[49]

1

leum ether, 1:1) = 0.52. H NMR (400 MHz, CDCl₃): δ = 3.31 (s,

3 H, NCH₃), 3.77 (s, 3 H, NOCH₃), 3.93 (s, 3 H, ArOCH₃), 6.13

(s, 1 H, OH), 6.88 (d, J = 15.7 Hz, 1 H, 8-H), 6.93 (d, J = 8.2 Hz,

1 H, 5-H), 7.04 (d, J = 1.9 Hz, 1 H, 2-H), 7.15 (dd, J = 8.2, J =

1.9 Hz, 1 H, 6-H), 7.67 (d, J = 15.7 Hz, 1 H, 7-H) ppm. ¹³C NMR

(100.6 MHz, CDCl₃): δ = 32.6 (NCH₃), 56.0 (ArOCH₃), 61.9

(NOCH₃), 110.1 (C-2), 113.1 (C-8), 114.8 (C-5), 122.4 (C-6), 127.7

(C-1), 143.7 (C-7), 146.7 (C-4), 147.6 (C-3), 167.3 (C=O) ppm. IR

(2E)-3-(4-Hydroxy-3-methoxyphenyl)-1-(1H-pyrrol-2-yl)propenone

(26): Bromopyrrole 66 (255 mg, 0.92 mmol, 1.2 equiv.) and dry

THF (10 mL) were put into a flame-dried flask (25 mL) under an

inert atmosphere. The solution was cooled to –78 °C in a dry ice/

acetone bath. Then, n-butyllithium (2.12 n solution in hexanes;

0.4 mL, 0.85 mmol, 1.1 equiv.) was added dropwise to the reaction

mixture. The reaction mixture was stirred for 30 min at –78 °C, and

then (2E)-N-methoxy-3-[3-methoxy-4-(2-methoxyethoxymethoxy)-

phenyl]-N-methylacrylamide (31; 0.25 g, 0.77 mmol, 1 equiv.) was

added. The reaction mixture was stirred at –78 °C for 1 h, and the

temperature was then allowed to gradually rise to room tempera-

ture, after which the reaction mixture was stirred at room tempera-

ture overnight. The reaction was carefully quenched with saturated

sodium hydrogen carbonate (10 mL), and the mixture was ex-

tracted with ethyl acetate (2ϫ 20 mL). The combined organic lay-

ers were washed with brine (20 mL), dried with MgSO₄, and evapo-

rated in vacuo.

(ATR): ν = 990, 1269, 1509, 1597, 1584 cm^–1. MS (ESI⁺): m/z (%)

˜

= 238.1 (100) [M + H]⁺.

(2E)-N-Methoxy-3-[3-methoxy-4-(2-methoxyethoxymethoxy)phen-

yl]-N-methylacrylamide (31): Dry dichloromethane (50 mL) and

N,O-dimethylhydroxylamine hydrochloride (2.55 g, 26.2 mmol,

2 equiv.) were put into a flame-dried flask (500 mL) under an inert

atmosphere. Next, Me₃Al (2 n solution in toluene; 13.1 mL,

26.2 mmol, 2 equiv.) was slowly added to the reaction mixture. The

mixture was stirred at room temperature for 15 min, then a solution

of (2E)-1-(benzotriazol-1-yl)-3-[3-methoxy-4-(2-methoxyethoxy-

methoxy)phenyl]propenone (14; 5.03 g, 13.1 mmol, 1 equiv.) in dry

dichloromethane (200 mL) was added to the reaction mixture. The

mixture was stirred at room temperature for 2 h, then it was

quenched carefully with saturated sodium hydrogen carbonate

(250 mL). The resulting emulsion was filtered through Celite, and

the filter cake was rinsed with dichloromethane (2ϫ 25 mL). The

layers were separated, and the organic layer was washed with equal

volumes of sodium hydroxide (1 n aq.; 2ϫ) and brine, dried with

MgSO₄, and evaporated in vacuo. The residue was recrystallized

from absolute ethanol to give 31 (2.98 g, 70%) as white crystals,

m.p. 58–59 °C. ¹H NMR (CDCl₃, 400 MHz): δ = 3.31 (s, 3 H,

NCH₃), 3.37 (s, 3 H, CH₂OCH₃), 3.53–3.59 (m, 2 H, CH₂OCH₃),

3.78 (s, 3 H, NOCH₃), 3.84–3.90 (m, 2 H, CH₂CH₂OCH₃), 3.92 (s,

3 H, ArOCH₃), 5.36 (s, 2 H, OCH₂O), 6.92 (d, J = 15.7 Hz, 1 H,

8-H), 7.08 (d, J = 1.8 Hz, 1 H, 2-H), 7.15 (dd, J = 8.4, J = 1.8 Hz,

1 H, 6-H), 7.21 (d, J = 8.4 Hz, 1 H, 5-H), 7.68 (d, J = 15.7 Hz, 1

H, 7-H) ppm. ¹³C NMR (CDCl₃, 100.6 MHz): δ = 32.5 (NCH₃),

56.0 (ArOCH₃), 59.0 (CH₂OCH₃), 61.9 (NOCH₃), 67.9

(CH₂CH₂OCH₃), 71.5 (CH₂OCH₃), 94.2 (OCH₂O), 110.9 (C-2),

114.1 (C-8), 115.9 (C-5), 121.7 (C-6), 129.6 (C-1), 143.3 (C-7), 148.1

The residue was dissolved in dry dichloromethane (9 mL), and tri-

fluoroacetic acid (3 mL) was added. The reaction mixture was

stirred at room temperature for 1 h, and then it was carefully neu-

tralized with saturated sodium hydrogen carbonate solution. The

mixture was extracted with ethyl acetate (2ϫ 20 mL). The com-

bined organic layers were washed with brine (20 mL), dried with

MgSO₄, and evaporated in vacuo.

The residue was dissolved in a mixture of acetonitrile (10 mL) and

NaOH (0.3 n aq.; 10 mL). The mixture was stirred for 5 min at

room temperature, then it was neutralized with dilute aqueous HCl

and extracted with ethyl acetate (2ϫ 20 mL). The combined or-

ganic layers were washed with brine (20 mL), dried with magne-

sium sulfate, and evaporated in vacuo. The crude product was puri-

fied by column chromatography using ethyl acetate/petroleum ether

(1:3) as an eluent (R_f= 0.1) to give 26 (79 mg, 42%) as a yellow

oil. ¹H NMR (CDCl₃, 400 MHz): δ = 3.93 (s, 3 H, OCH₃), 6.27

(br. s, 1 H, NH), 6.33–6.35 (m, 1 H, 4Ј-H), 6.95 (d, J = 8.2 Hz, 1

H, 5-H), 7.08–7.10 (m, 1 H, 5Ј-H), 7.11–7.13 (m, 2 H, 2-H, 3Ј-H),

7.20 (dd, J = 8.2, J = 1.6 Hz, 1 H, 6-H), 7.22 (d, J = 15.6 Hz, 1 H,

α-H), 7.79 (d, J = 15.6 Hz, 1 H, β-H), 10.25 (br. s, 1 H, OH) ppm.

¹³C NMR (CDCl₃, 100.6 MHz): δ = 56.0 (OCH₃), 110.2 (C-2),

(C-3), 149.6 (C-4), 167.1 (C=O) ppm. IR (ATR): ν = 972, 1098,

˜

1256, 1598 cm^–1. MS (ESI⁺): m/z (%) = 326.3 (100) [M + H]⁺.

HRMS (ESI): calcd. for C₁₆H₂₃NO₆325.1525; found 325.1534.

110.9 (C-4Ј), 115.0 (C-5), 116.4 (C-5Ј), 119.6 (C-α), 123.1 (C-6), (3E)-4-[3-Methoxy-4-(2-methoxyethoxymethoxy)phenyl]but-3-en-2-

125.5 (C-3Ј), 127.6 (C-1), 133.2 (C-1Ј), 142.7 (C-β), 146.9 (C-4), one (32): Dry THF (5 mL) and (2E)-N-methoxy-3-[3-methoxy-4-(2-

148.1 (C-3), 179.1 (C=O) ppm. IR (ATR): ν = 721, 735, 748, 1031, methoxyethoxymethoxy)phenyl]-N-methylacrylamide (31; 0.178 g,

˜

2606

www.eurjoc.org

Eur. J. Org. Chem. 2014, 2594–2611

Feruloylbenzotriazole and Weinreb Amide Building Blocks

0.545 mmol, 1 equiv.) were put into a flame-dried flask (10 mL)

under an inert atmosphere. The reaction mixture was cooled to

–78 °C in a dry ice/acetone bath, and methyllithium (1.6 n solution

in THF; 0.375 mL, 0.6 mmol, 1.1 equiv.) was added dropwise to

the reaction mixture. The mixture was stirred at –78 °C for 2 h,

then it was carefully quenched with water (2 mL), and warmed up

to room temperature. Water (40 mL) was added, and the pH was

adjusted to pH = 7 by the addition of HCl (0.1 n). Next, the mix-

ture was extracted with dichloromethane (40 mL). The organic

layer was washed with an equal volume of brine, dried with

MgSO₄, and evaporated in vacuo to give 32 (113 mg, 74%) as a

yellow oil. ¹H NMR (300 MHz, CDCl₃): δ = 2.38 [s, 3 H, C(O)-

CH₃], 3.37 (s, 3 H, CH₂OCH₃), 3.52–3.60 (m, 2 H, CH₂OCH₃),

3.83–3.91 (m, 2 H, CH₂CH₂OCH₃), 3.92 (s, 3 H, ArOCH₃), 5.37

(s, 2 H, OCH₂O), 6.62 (d, J = 16.2 Hz, 1 H, 8-H), 7.09 (br. s, 1 H,

2-H), 7.11 (dd, J = 8.5, J = 2.2 Hz, 1 H, 6-H), 7.22 (d, J = 8.5 Hz,

1 H, 5-H), 7.47 (d, J = 16.2 Hz, 1 H, 7-H) ppm. ¹³C NMR

combined organic layers were washed with brine (10 mL), dried

with MgSO₄, and evaporated in vacuo. The residue was purified

by column chromatography over silica with ethyl acetate/petroleum

ether (1:4) as an eluent to give 37 (87 mg, 35%) as white crystals,

1

m.p. 53–54 °C. R_f(EtOAc) = 0.86. H NMR (CDCl₃, 300 MHz):

δ = 0.95 (t, J = 7.4 Hz, 3 H, 12-H), 1.31–1.46 (m, 2 H, 11-H), 1.57–

1.73 (m, 2 H, 10-H), 2.66 (t, J = 7.4 Hz, 2 H, 9-H), 3.37 (s, 3 H,

CH₂OCH₃), 3.52–3.59 (m, 2 H, CH₂CH₂OCH₃), 3.83–3.90 (m, 2

H, CH₂CH₂OCH₃), 3.92 (s, 3 H, ArOCH₃), 5.37 (s, 2 H, OCH₂O),

6.64 (d, J = 15.9 Hz, 1 H, 8-H), 7.11 (m, 2 H, 2-H, 6-H), 7.22 (d,

J = 7.7 Hz, 1 H, 5-H), 7.49 (d, J = 15.9 Hz, 1 H, 7-H) ppm. ¹³C

NMR (CDCl₃, 75 MHz): δ = 13.9 (C-12), 22.5 (C-11), 26.6 (C-10),

4 0 . 5 ( C - 9 ) , 5 5 . 9 ( A r O C H ₃) , 5 9 . 0 ( C H ₂O C H ₃) , 6 8 . 0

(CH₂CH₂OCH₃), 71.5 (CH₂OCH₃), 94.2 (OCH₂O), 110.3 (C-2),

115.9 (C-5), 122.5 (C-6), 124.9 (C-8), 128.9 (C-1), 142.2 (C-7),

148.7, 149.8 (C-3, C-4), 200.7 (C=O) ppm. IR (ATR): ν = 975,

˜

1082, 1099, 1256, 1510, 1652 cm^–1. MS (ESI⁺): m/z (%) = 323.3

(75 MHz, CDCl₃): δ = 27.4 [C(O)CH₃], 55.9 (ArOCH₃), 59.0 (100) [M + H]⁺. HRMS (ESI): calcd. for C₁₈H₂₆O₅322.1780; found

(CH₂OCH₃), 68.0 (CH₂CH₂OCH₃), 71.5 (CH₂OCH₃), 94.1

(OCH₂O), 110.2 (C-2), 115.8 (C-5), 122.7 (C-6), 125.7 (C-8), 128.7

(C-1), 143.4 (C-7), 148.8 (C-4), 149.8 (C-3), 198.4 (C=O) ppm. IR

322.1788.

(1E)-1-(4-Hydroxy-3-methoxyphenyl)hept-1-en-3-one (39): Com-

pound 37 was synthesized as described above, but it was not puri-

fied by column chromatography. Instead, crude 37 was deprotected

following the general procedure for the hydrochloric-acid-mediated

deprotection of MEM ethers. The crude product obtained after

(ATR): ν = 974, 1100, 1242, 1509 cm^–1. MS (ESI⁺): m/z (%) = 281.3

˜

(100) [M + H]⁺. HRMS (ESI): calcd. for C₁₅H₂₀O₅280.1311; found

280.1318.

(3E)-4-(4-Hydroxy-3-methoxyphenyl)but-3-en-2-one (33): (3E)-4-[3- deprotection was purified by column chromatography using ethyl

Methoxy-4-(2-methoxyethoxymethoxy)phenyl]but-3-en-2-one (32;

113 mg, 0.4 mmol) was deprotected following the general procedure

for the hydrochloric-acid-mediated deprotection of MEM ethers.

The crude product was recrystallized from absolute ethanol to give

33 (75 mg, 72% from 31) as yellow crystals. All spectroscopic data

were in accordance with those reported in the literature.^[50]

acetate/petroleum ether (1:5) as an eluent (R_f= 0.23) to give 39

(129 mg, 52% from 31) as a yellow oil. All spectroscopic data were

in accordance with those reported in the literature.^[50]

(2E)-1-(Furan-2-yl)-3-[3-methoxy-4-(2-methoxyethoxymethoxy)phen-

yl]prop-2-en-1-one (41): n-Butyllithium (2.33 n solution in hexanes;

2.77 mL 6.45 mmol, 2.1 equiv.) and dry THF (40 mL) were put into

(2E)-3-(4-hydroxy-3-methoxyphenyl)-1-phenylprop-2-en-1-one (36): a flame-dried flask (100 mL) under an inert atmosphere. The mix-

(2E)-N-Methoxy-3-[3-methoxy-4-(2-methoxyethoxymethoxy)

phenyl]-N-methylacrylamide (31; 0.25 g, 0.77 mmol, 1 equiv.) was

dissolved in dry THF (10 mL) in a flame-dried flask (25 mL) under

a nitrogen atmosphere. The mixture was cooled to –78 °C in a dry

ice/acetone bath, and phenyllithium (2.0 n solution in dibutyl ether;

ture was cooled to –78 °C in a dry ice/acetone bath, and then furan

(0.45 mL, 6.15 mmol, 2 equiv.) was added dropwise. The reaction

mixture was stirred at –78 °C for 5 min, then it was warmed up to

0 °C with an ice bath, and stirred at 0 °C for 1.5 h. The mixture

was cooled to –78 °C again, and (2E)-N-methoxy-3-[3-methoxy-4-

0.43 mL, 0.85 mmol, 1.1 equiv.) was added dropwise. The mixture (2-methoxyethoxymethoxy)phenyl]-N-methylacrylamide (31; 1 g,

was stirred at –78 °C for 1 h, then the reaction temperature was

allowed to rise gradually to room temperature, and the reaction

mixture was stirred overnight. Next, the mixture was carefully

quenched with water and extracted with ethyl acetate (3ϫ). The

organic layers were combined, washed with brine, dried with

MgSO₄, and evaporated in vacuo. The crude product 35 was depro-

tected following the general procedure for the hydrochloric-acid-

mediated deprotection of MEM ethers. The crude product ob-

tained after deprotection was purified by column chromatography

over silica with ethyl acetate/petroleum ether (1:5) as an eluent to

give 36 (116 mg, 59% from 31) as a yellow oil. R_f(EtOAc/petro-

leum ether, 1:5) = 0.13. All spectroscopic data were in accordance

with those reported in the literature.^[51]

3.08 mmol, 1 equiv.) was added. The reaction mixture was stirred

at –78 °C for 30 min and then at 0 °C for 15 min. Next, the reaction

mixture was carefully quenched with saturated sodium hydrogen

carbonate solution (10 mL), and extracted with diethyl ether

(10 mL). The aqueous layer was extracted (2ϫ) with an equal vol-

ume of diethyl ether, and the combined organic extracts were

washed with an equal volume of brine, dried with MgSO₄, and

evaporated in vacuo to give compound 41 (1 g, 98%) as a yellow-

orange oil. ¹H NMR (CDCl₃, 300 MHz): δ = 3.38 (s, 3 H,

CH₂OCH₃), 3.54–3.59 (m, 2 H, CH₂CH₂OCH₃), 3.85–3.91 (m, 2

H, CH₂OCH₃), 3.95 (s, 3 H, ArOCH₃), 5.38 (s, 2 H, OCH₂O), 6.60

(dd, J = 3.9, J = 1.4 Hz, 1 H, 4Ј-H), 7.17 (s, 1 H, 2-H), 7.22–7.25

(m, 2 H, 5-H, 6-H), 7.33 (d, J = 3.9 Hz, 1 H, 5Ј-H), 7.34 (d, J =

15.7 Hz, 1 H, α-H), 7.66 (d, J = 1.4 Hz, 1 H, 3Ј-H), 7.84 (d, J =

15.7 Hz, 1 H, β-H) ppm. ¹³C NMR (CDCl₃, 75 MHz): δ = 56.0

(OCH₃), 59.0 (ArOCH ₃) , 6 8. 0 ( CH₂CH₂OCH₃), 71.5

(CH₂CH₂OCH₃), 94.1 (OCH₂O), 111.0 (C-4Ј), 112.5 (C-2), 115.7

(C-5), 117.3 (C-6), 119.6 (C-5Ј), 122.8 (C-α), 129.1 (C-1), 144.0 (C-

β), 146.4 (C-3Ј), 148.9, 149.8 (C-3, C-4), 154.0 (C-1Ј), 178.0 (C=O)

(1E)-1-[3-Methoxy-4-(2-methoxyethoxymethoxy)phenyl]hept-1-en-3-

one (37): (2E)-N-Methoxy-3-[3-methoxy-4-(2-methoxyethoxy-

methoxy)phenyl]-N-methylacrylamide (31; 0.25 g, 0.77 mmol,

1 equiv.) was dissolved in dry THF (10 mL) in a flame-dried flask

(25 mL) under a nitrogen atmosphere. The mixture was cooled to

–78 °C in a dry ice/acetone bath, and n-butyllithium (2.5 n solution

in hexanes; 0.34 mL 0.85 mmol, 1.1 equiv.) was added dropwise.

The mixture was stirred at –78 °C for 1 h, then the reaction was

carefully quenched with saturated sodium hydrogen carbonate

(10 mL), and the mixture was warmed up to room temperature.

The mixture was extracted with ethyl acetate (3 ϫ 10 mL). The

ppm. IR (ATR): ν = 1286, 1464, 1508, 1580, 1590 (C=C), 1654

˜

(C=O) cm^–1. MS (ESI⁺): m/z (%) = 332.8 (100) [M + H]⁺, 354.7

(50) [M + Na]⁺.

(2E)-1-(Furan-2-yl)-3-(4-hydroxy-3-methoxyphenyl)prop-2-en-1-one

(42): (2E)-1-(Furan-2-yl)-3-[3-methoxy-4-(2-methoxyethoxy-

Eur. J. Org. Chem. 2014, 2594–2611

www.eurjoc.org

2607

C. V. Stevens et al.

FULL PAPER

methoxy)phenyl]prop-2-en-1-one (41; 1 g, 3.01 mmol, 1 equiv.) was

MEM-deprotected according to the general procedure for the

hydrochloric-acid-mediated deprotection of MEM ethers. The re-

sulting oil was recrystallized from absolute ethanol to give com-

pound 42 (720 mg, 98%) as green crystals, m.p. 128.5–129.5 °C. ¹H

ture was allowed to rise gradually to room temperature, and the

reaction mixture was stirred overnight. The reaction was carefully

quenched with saturated sodium hydrogen carbonate (10 mL) and

extracted with ethyl acetate (3ϫ 10 mL). The combined organic

layers were washed with brine (20 mL), dried with MgSO₄, and

NMR (CDCl₃, 300 MHz): δ = 3.98 (s, 3 H, OCH₃), 5.93 (s, 1 H, concentrated in vacuo to give a yellow oil. Recrystallization from

OH), 6.60 (dd, J = 1.4, J = 3.6 Hz, 1 H, 4Ј-H), 6.96 (d, J = 8.3 Hz, absolute ethanol gave compound 50 (142 mg, 53%) as yellow crys-

1

1 H, 5-H), 7.14 (d, J = 2.2 Hz, 1 H, 2-H), 7.24 (dd, J = 2.2, J =

8.3 Hz, 1 H, 6-H), 7.32 (d, J = 16.0 Hz, 1 H, α-H), 7.33 (dd, J =

3.6 Hz, 1 H, 5Ј-H), 7.65 (dd, J = 1.4 Hz, 1 H, 3Ј-H), 7.83 (d, J =

16.0 Hz, 1 H, β-H) ppm. ¹³C NMR (CDCl₃, 75 MHz): δ = 56.0

(OCH₃), 110.2 (C-4Ј), 112.5 (C-2), 115.0 (C-5), 117.3 (C-6), 118.6

tals, m.p. 69.5–70.5 °C. H NMR (CDCl₃, 300 MHz): δ = 3.38 (s,

3 H, OCH₃), 3.54–3.59 (m, 2 H, CH₂CH₂OCH₃), 3.85–3.90 (m, 2

H, CH₂OCH₃), 3.95 (s, 3 H, ArOCH₃), 5.38 (s, 2 H, OCH₂O), 7.15

(br. s, 1 H, 2-H), 7.19 (dd, J = 5.0, J = 3.9 Hz, 1 H, 4Ј-H), 7.23–

7.26 (m, 2 H, 5-H, 6-H), 7.31 (d, J = 15.4 Hz, 1 H, α-H), 7.68 (dd,

(C-5Ј), 123.6 (C-α), 127.3 (C-1), 144.5 (C-β), 146.4 (C-3Ј), 146.9 J = 5.0, J = 1.1 Hz, 1 H, 3Ј-H), 7.81 (d, J = 15.4 Hz, 1 H, β-H),

(C-4), 148.6 (C-3), 153.8 (C-1Ј), 178.2 (C=O) ppm. IR (ATR): ν = 7.87 (dd, J = 3.9, J = 1.1 Hz, 1 H, 5Ј-H) ppm. ¹³C NMR (CDCl₃,

˜

1123, 1280, 1422, 1460, 1527, 1552, 1569 (C=C), 1651 (C=O), 2358,

75 MHz): δ = 56.0 (OCH₃), 59.0 (ArOCH₃), 68.0 (CH₂CH₂OCH₃),

71.5 (CH₂CH₂OCH₃), 94.1 (OCH₂O), 111.1 (C-2), 115.9 (C-5),

120.0 (C-6), 122.5 (C-α), 128.2 (C-4Ј), 129.0 (C-1), 131.6 (C-3Ј),

133.7 (C-5Ј), 144.0 (C-β), 145.7, 148.9, 149.7 (C-1Ј, C-3, C-4), 182.0

3288 (OH) cm^–1. MS (ESI⁺): m/z (%) = 245.1 (100) [M + H]⁺.

(2E)-1-(Furan-3-yl)-3-(4-hydroxy-3-methoxyphenyl)propenone (44):

3-Bromofuran (0.20 mL, 2.23 mmol, 1.2 equiv.) was dissolved in

dry diethyl ether (20 mL) in a flame-dried flask (50 mL) under an

inert atmosphere. The mixture was cooled to –78 °C in a dry ice/

acetone bath, then n-butyllithium (1.9 n solution in hexanes;

1.3 mL, 2.47 mmol, 1.34 equiv.) was added dropwise. The mixture

was stirred at –78 °C for 30 min, then (2E)-N-methoxy-3-[3-meth-

oxy-4-(2-methoxyethoxymethoxy)phenyl]-N-methylacrylamide (31;

0.6 g, 1.84 mmol, 1 equiv.) was added. The reaction mixture was

stirred at –78 °C for 1 h, and then stirred at room temperature over-

night. Next, the reaction mixture was poured in a mixture of HCl

(2 n; 25 mL), ethanol (50 mL), and ice (25 g). Water (170 mL) was

then added, and the mixture was extracted with dichloromethane

(150 mL). The aqueous layer was extracted again with dichloro-

methane (100 mL), and the combined organic extracts were washed

with an equal volume of brine, dried with MgSO₄, and evaporated

in vacuo.

(C=O) ppm. IR (ATR): ν = 1260, 1415, 1513, 1584, 1599 (C=C),

˜

1643 (C=O) cm^–1. MS (ESI⁺): m/z (%) = 348.7 (100) [M + H]⁺,

370.7 (64) [M + Na]⁺. HRMS (ESI): calcd. for C₁₈H₂₀O₅S

348.1031; found 348.1039.

(2E)-3-(4-Hydroxy-3-methoxyphenyl)-1-(thiophen-2-yl)prop-2-en-1-

one (51): 2-Thienyl-chalcone 50 was synthesized as described above,

but it was not purified by recrystallization. Instead, the crude prod-

uct 50 was deprotected following the general procedure for the hy-

drochloric-acid-mediated deprotection of MEM ethers. The crude

solid product was purified by column chromatography over silica

with ethyl acetate/petroleum ether (1:3) as an eluent to give 51

(178 mg, 89%) as yellow crystals, m.p. 122.5–123.5 °C. R_f(EtOAc/

petroleum ether, 1:3) = 0.21. ¹H NMR (CDCl₃, 300 MHz): δ = 3.97

(s, 3 H, OCH₃), 5.95 (s, 1 H, OH), 6.97 (d, J = 8.3 Hz, 1 H, 5-H),

7.12 (d, J = 2.0 Hz, 1 H, 2-H), 7.18 (dd, J = 4.7, J = 3.9 Hz, 1 H,

4Ј-H), 7.24 (dd, J = 8.3, J = 2.0 Hz, 1 H, 6-H), 7.28 (d, J = 15.4 Hz,

1 H, α-H), 7.67 (dd, J = 4.7, J = 1.1 Hz, 1 H, 3Ј-H), 7.80 (d, J =

15.4 Hz, 1 H, β-H), 7.87 (dd, J = 3.9, J = 1.1 Hz, 1 H, 5Ј-H) ppm.

¹³C NMR (CDCl₃, 75 MHz): δ = 56.0 (OCH₃), 110.3 (C-2), 115.0

(C-5), 119.2 (C-6), 123.3 (C-α), 127.2 (C-1), 128.2 (C-4Ј), 131.6 (C-

3Ј), 133.6 (C-5Ј), 144.5 (C-β), 145.7, 146.9 (C-1Ј, C-4), 148.4 (C-3),

The crude product 43 was immediately MEM-deprotected accord-

ing to the general procedure for the hydrochloric-acid-mediated de-

protection of MEM ethers. The product was purified by column

chromatography over silica with ethyl acetate/petroleum ether (1:2)

as eluent and finally recrystallized from absolute ethanol to give

compound 44 (364 mg, 81%) as yellow crystals, m.p. 115–116 °C.

R_f(EtOAc) = 0.64. ¹H NMR (CDCl₃, 400 MHz): δ = 3.94 (s, 3 H,

OCH₃), 6.18 (s, 1 H, OH), 6.90 (dd, J = 1.7, J = 0.8 Hz, 1 H, 10-

H), 6.95 (d, J = 8.2 Hz, 1 H, 5-H), 7.03 (d, J = 15.6 Hz, 1 H, 8-

H), 7.09 (d, J = 1.8 Hz, 1 H, 2-H), 7.19 (dd, J = 8.2, J = 1.8 Hz,

1 H, 6-H), 7.48 (t, J = 1.7 Hz, 1 H, 11-H), 7.74 (d, J = 15.6 Hz, 1

H, 7-H), 8.13–8.18 (m, 1 H, 12-H) ppm. ¹³C NMR (CDCl₃,

100.6 MHz): δ = 56.0 (OCH₃), 109.2 (C-10), 110.2 (C-2), 115.0 (C-

5), 120.6 (C-8), 123.2 (C-6), 127.1, 128.6 (C-1, C-9), 144.0 (C-7),

144.3 (C-11), 146.9 (C-4), 147.1 (C-12), 148.4 (C-3), 184.3 (C=O)

182.1 (C=O) ppm. IR (ATR): ν = 1122, 1210, 1408, 1420, 1509,

˜

1525, 1556, 1594 (C=C), 1641 (C=O), 3318 (OH) cm^–1. MS (ESI⁺):

m/z (%) = 261.0 (100) [M + H]⁺, 283.0 (36) [M + Na]⁺.

(2E)-3-[3-Methoxy-4-(2-methoxyethoxymethoxy)phenyl]-1-(thio-

phen-3-yl)prop-2-en-1-one (52): 3-Bromothiophene (0.18 mL,

1.9 mmol, 1.15 equiv.) was dissolved in a mixture of hexane (8 mL)

and diethyl ether (5 mL) under an inert atmosphere, and the solu-

tion was cooled to –78 °C in a dry ice/acetone bath. Then, n-butyl-

lithium (2.38 n solution in hexanes; 0.77 mL, 1.8 mmol, 1.1 equiv.)

was added dropwise, and the reaction mixture was stirred at –78 °C

for 1 h. Next, (2E)-N-methoxy-3-[3-methoxy-4-(2-methoxyethoxy-

methoxy)phenyl]-N-methylacrylamide (31; 0.543 g, 1.67 mmol,

1 equiv.) was dissolved in dry THF (10 mL), and this solution was

cooled to –78 °C and then added to the reaction mixture. The reac-

tion mixture was stirred at –78 °C for 1.5 h, and then at room tem-

perature for 8 h. The reaction mixture was quenched with saturated

sodium hydrogen carbonate (20 mL), and extracted with dichloro-

methane (2ϫ 30 mL). The combined organic layers were washed

with brine, dried with MgSO₄, and evaporated in vacuo. The resi-

due was purified by column chromatography over neutral Al₂O₃

with ethyl acetate/petroleum ether (1:3) as eluent to give compound

52 (500 mg, 86%) as a yellow oil. R_f(EtOAc/petroleum ether, 1:3)

= 0.12. ¹H NMR (CDCl₃, 300 MHz): δ = 3.38 (s, 3 H, OCH₃),

3.55–3.58 (m, 2 H, CH₂CH₂OCH₃), 3.87–3.90 (m, 2 H,

ppm. IR (ATR): ν = 1154, 1268, 1283, 1510, 1579 cm^–1. MS (ESI⁺):

˜

m/z (%) = 245.1 (100) [M + H]⁺. HRMS (ESI): calcd. for C₁₄H₁₂O₄

244.0736; found 244.0743.

(2E)-3-[3-Methoxy-4-(2-methoxyethoxymethoxy)phenyl]-1-(thio-

phen-2-yl)prop-2-en-1-one (50): Thiophene (0.09 mL, 1.16 mmol,

1.5 equiv.) and dry THF (10 mL) were put into a flame-dried flask

(25 mL) under an inert atmosphere. The mixture was cooled to

0 °C in an ice bath, then n-butyllithium (2.12 n solution in hexanes;

0.44 mL, 0.93 mmol, 1.2 equiv.) was added dropwise. The reaction

mixture was stirred for 30 min at 0 °C, then it was cooled to –78 °C

in a dry ice/acetone bath. Then, (2E) N methoxy-3-[3-methoxy-4-

(2-methoxyethoxymethoxy)phenyl]-N-methylacrylamide (31;

0.25 g, 0.77 mmol, 1 equiv.) was added in one portion, and the re-

action mixture was stirred at –78 °C for 1 h. The reaction tempera-

2608

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Eur. J. Org. Chem. 2014, 2594–2611

Feruloylbenzotriazole and Weinreb Amide Building Blocks

CH₂OCH₃), 3.95 (s, 3 H, ArOCH₃), 5.38 (s, 2 H, OCH₂O), 7.15

(br. s, 1 H, 2-H), 7.22–7.24 (m, 2 H, 5-H, 6-H), 7.28 (d, J = 15.7 Hz,

1 H, α-H), 7.37 (dd, J = 5.0, J = 2.8 Hz, 1 H, 4Ј-H), 7.67 (dd, J =

5.0, J = 1.1 Hz, 1 H, 5Ј-H), 7.77 (d, J = 15.7 Hz, 1 H, β-H), 8.17

(dd, J = 2.8, J = 1.1 Hz, 1 H, 2Ј-H) ppm. ¹³C NMR (CDCl₃,

The resulting oil was purified by column chromatography over sil-

ica with ethyl acetate/petroleum ether (5:6) as eluent, and the prod-

uct was recrystallized from ethanol to give compound 55 (41 mg,

21%) as green crystals, m.p. 101.5–102.5 °C. R_f(EtOAc/petroleum

1

ether, 5:6) = 0.22. H NMR (CDCl₃, 300 MHz): δ = 3.97 (s, 3 H,

75 MHz): δ = 56.0 (OCH₃), 59.0 (ArOCH₃), 68.0 (CH₂CH₂OCH₃), OCH₃), 6.07 (br. s, 1 H, OH), 6.95 (d, J = 8.3 Hz, 1 H, 5-H), 7.22–

71.5 (CH₂CH₂OCH₃), 94.1 (OCH₂O), 111.0 (C-2), 115.9 (C-5), 7.33 (m, 2 H, 2-H, 6-H), 7.45–7.54 (m, 1 H, 4Ј-H), 7.84–7.97 (m,

121.2 (C-6), 122.5 (C-α), 126.4 (C-2Ј), 127.5 (C-3Ј), 129.2 (C-1), 2 H, 5Ј-H, α-H), 8.14 (d, J = 16.0 Hz, 1 H, β-H), 8.20 (d, J =

131.8 (C-5Ј), 143.2 (C-1Ј), 144.1, 148.8, 149.8 (C-β, C-3, C-4), 184.0

7.7 Hz, 1 H, 6Ј-H), 8.75 (d, J = 4.4 Hz, 1 H, 3Ј-H) ppm. ¹³C NMR

(CDCl₃, 75 MHz): δ = 56.1 (OCH₃), 109.9 (C-2), 114.8 (C-5), 118.2

(C-α), 123.0 (C-6Ј), 124.5 (C-6), 126.8 (C-4Ј), 127.8 (C-1), 137.1 (C-

5Ј), 145.3 (C-β), 146.8 (C-4), 148.5 (C-3), 148.8 (C-3Ј), 154.5 (C-

(C=O) ppm. IR (ATR): ν = 1253, 1417, 1513, 1589, 1653 (C=O)

˜

cm^–1. MS (ESI⁺): m/z (%) = 349.3 (100) [M + H]⁺. HRMS (ESI):

calcd. for C₁₈H₂₀O₅S 348.1031; found 348.1041.

1Ј), 189.3 (C=O) ppm. IR (ATR): ν = 1227, 1306, 1573, 1584, 1616,

˜

(2E)-3-(4-Hydroxy-3-methoxyphenyl)-1-(thiophen-3-yl)prop-2-en-1-

one (53): 3-Thienyl-chalcone 52 was synthesized as described above,

but it was not purified by column chromatography. Instead, the

crude product 52 was MEM-deprotected. To remove the MEM

protecting group, the residue was dissolved in dichloromethane

(9 mL) and trifluoroacetic acid (3 mL), and this solution was

stirred at room temperature overnight. The solvent was removed in

vacuo. The residue was dissolved in ethyl acetate (20 mL), and this

solution was washed with water (20 mL). The aqueous layer was

extracted with ethyl acetate (2ϫ 20 mL), and the combined organic

layers were washed with brine (50 mL), dried with MgSO₄, and

evaporated in vacuo. The crude product was purified by column

chromatography over silica with ethyl acetate/petroleum ether (1:4)

as eluent to give a yellow solid. Recrystallization from methanol

gave 53 (261 mg, 60 % from 31) as yellow crystals, m.p. 137.5–

1683, 3344, 3445 cm^–1. MS (ESI⁺): m/z (%) = 256.3 (100)

[M + H]⁺. HRMS (ESI): calcd. for C₁₅H₁₃NO₃255.0895; found

255.0902. IR data and m.p. were in accordance with literature val-

ues.^[51]

(2E)-3-(4-Hydroxy-3-methoxyphenyl)-1-(pyridin-3-yl)prop-2-en-1-

one (57): 3-Bromopyridine (0.27 g, 2.8 mmol, 1.73 equiv.), dry di-

ethyl ether (5 mL), and hexane (8 mL) were put into a flame-dried

flask (50 mL) under an inert atmosphere. The mixture was cooled

to –78 °C in a dry ice/acetone bath, and n-butyllithium (2.38 n solu-

tion in hexanes; 1.12 mL, 2.67 mmol, 1.64 equiv.) was added drop-

wise. The reaction mixture was stirred at –78 °C for 1 h. Next, a

solution of (2E)-N-methoxy-3-[3-methoxy-4-(2-methoxyethoxy-

methoxy)phenyl]-N-methylacrylamide (31; 0.53 g, 1.62 mmol,

1 equiv.) in dry THF (10 mL), cooled to –78 °C, was added. The

mixture was stirred at –78 °C for 1 h, then it was warmed to room

temperature, and stirred at room temperature overnight. Next, the

1

138.5 °C. H NMR (CDCl₃, 400 MHz): δ = 3.97 (s, 3 H, OCH₃),

5.92 (s, 1 H, OH), 6.96 (d, J = 8.2 Hz, 1 H, 5-H), 7.12 (d, J =

1.8 Hz, 1 H, 2-H), 7.23 (dd, J = 8.2, J = 1.8 Hz, 1 H, 6-H), 7.26 mixture was carefully quenched with a saturated sodium hydrogen

(d, J = 15.5 Hz, 1 H, α-H), 7.37 (dd, J = 5.1, J = 2.9 Hz, 1 H, 4Ј-

H), 7.67 (dd, J = 5.1, J = 1.2 Hz, 1 H, 5Ј-H), 7.76 (d, J = 15.5 Hz,

1 H, β-H), 8.16 (dd, J = 2.9, J = 1.2 Hz, 1 H, 2Ј-H) ppm. ¹³C

NMR (CDCl₃, 100.6 MHz): δ = 56.0 (OCH₃), 110.1 (C-2), 114.9

(C-5), 120.4 (C-6), 123.2 (C-α), 126.4 (C-5Ј), 127.5 (C-1), 127.6 (C-

4Ј), 131.7 (C-2Ј), 143.3 (C-1Ј), 144.5 (C-β), 146.8 (C-4), 148.3 (C-

carbonate solution (15 mL), and extracted with dichloromethane

(2ϫ 40 mL). The combined organic extracts were washed with an

equal volume of brine, dried with MgSO₄, and evaporated in vacuo.

To remove the MEM protecting group, the residue was dissolved

in dichloromethane (9 mL) and trifluoroacetic acid (3 mL), and the

mixture was stirred at room temperature for 24 h. The reaction

mixture was neutralized by carefully adding a saturated sodium

hydrogen carbonate solution, and extracted with dichloromethane

(2ϫ 30 mL). The combined organic extracts were washed with an

equal volume of brine, dried with MgSO₄, and evaporated in vacuo.

The crude product was purified by silica column chromatography

with ethyl acetate/petroleum ether (1:1) as an eluent to give pure

57 (115 mg, 28%) as a yellow solid, m.p. 185–186 °C. R_f(EtOAc/

petroleum ether, 1:1) = 0.25. ¹H NMR (CDCl₃, 400 MHz): δ = 3.98

(s, 3 H, OCH₃), 6.32 (br. s, 1 H, OH), 6.98 (d, J = 8.2 Hz, 1 H, 5-

H), 7.15 (d, J = 1.8 Hz, 1 H, 2-H), 7.24 (dd, J = 8.2, J = 1.8 Hz,

1 H, 6-H), 7.34 (d, J = 15.6 Hz, 1 H, α-H), 7.48 (dd, J = 7.8, J =

4.9 Hz, 1 H, 5Ј-H), 7.79 (d, J = 15.6 Hz, 1 H, β-H), 8.30 (d, J =

7.8 Hz, 1 H, 6Ј-H), 8.72–8.91 (m, 1 H, 4Ј-H), 9.15–9.34 (m, 1 H,

2Ј-H) ppm. ¹³C NMR (CDCl₃, 100.6 MHz): δ = 56.0 (OCH₃),

110.1 (C-2), 115.1 (C-5), 119.0 (C-α), 123.8 (C-5Ј), 124.0 (C-6),

127.0 (C-1), 133.9 (C-1Ј), 136.0 (C-6Ј), 146.5 (C-β), 147.0 (C-4),

149.0 (C-3), 149.6 (C-2Ј), 152.8 (C-4Ј), 189.1 (C=O) ppm. IR

3), 184.1 (C=O) ppm. IR (ATR): ν = 1033, 1121, 1246, 1511, 1562,

˜

1591 (C=C), 1648 (C=O), 3262 (OH) cm^–1. MS (ESI⁺): m/z (%) =

261.0 (100) [M + H]⁺. HRMS (ESI): calcd. for C₁₄H₁₂O₃S

260.0507; found 260.0514.

(2E)-3-(4-Hydroxy-3-methoxyphenyl)-1-(pyridin-2-yl)prop-2-en-1-

one (55): 2-Bromopyridine (0.146 g, 0.92 mmol, 1.2 equiv.) was dis-

solved in dry THF (13 mL) in a flame-dried flask (25 mL) under

an inert atmosphere. The mixture was cooled to –78 °C in a dry

ice/acetone bath, and n-butyllithium (1.8 n solution in hexanes;

0.57 mL, 1.03 mmol, 1.34 equiv.) was added dropwise. The reaction

mixture was stirred at –78 °C for 30 min, and then (2E)-N-meth-

oxy-3-[3-methoxy-4-(2-methoxyethoxymethoxy)phenyl]-N-meth-

ylacrylamide (31; 0.250 g, 0.77 mmol, 1 equiv.) was added. The

mixture was stirred at –78 °C for 1.5 h, and then at 0 °C for 10 min.

The reaction was carefully quenched with saturated sodium hydro-

gen carbonate solution (10 mL). Next, the mixture was extracted

with dichloromethane (2ϫ 30 mL). The combined organic extracts

were washed with an equal volume of brine, dried with MgSO₄,

and evaporated in vacuo.

(ATR): ν = 982, 1018, 1591 (C=C), 1656 (C=O). MS (ESI⁺): m/z

˜

(%) = 256.0 (100) [M + H]⁺. HRMS (ESI): calcd. for C₁₅H₁₃NO₃

255.0895; found 255.0903. IR data^[52]and m.p.^[53]were in accord-

ance with literature references.

To remove the MEM protecting group, the residue was dissolved

in dichloromethane (9 mL) and trifluoroacetic acid (3 mL), and the

mixture was stirred at room temperature for 1 h. The reaction mix-

ture was neutralized by adding saturated sodium hydrogen carb-

onate solution, and then it was extracted with dichloromethane

(2ϫ 30 mL). The combined organic extracts were washed with an

equal volume of brine, dried with MgSO₄, and evaporated in vacuo.

(2E)-3-(4-Hydroxy-3-methoxyphenyl)-1-(1H-pyrrol-3-yl)prop-2-en-

1-one (61): 3-Bromo-1-(triisopropylsilyl)pyrrole (0.169 g,

0.65 mmol, 1.2 equiv.) was dissolved in dry THF (13 mL) in a

flame-dried flask (25 mL) under an inert atmosphere. The mixture

was cooled to –78 °C in a dry ice/acetone bath, and n-butyllithium

Eur. J. Org. Chem. 2014, 2594–2611

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2609

C. V. Stevens et al.

FULL PAPER

(2.17 n solution in hexanes; 0.24 mL, 0.65 mmol, 1.1 equiv.) was

added dropwise. The reaction mixture was stirred at –78 °C for

and TBAI (0.51 g, 1.38 mmol, 3 equiv.) were added, and the reac-

tion mixture was stirred at room temperature for 30 min. Then,

30 min, and then (2E)-N-methoxy-3-[3-methoxy-4-(2-methoxy- methyl iodide (0.086 mL, 1.38 mmol, 3 equiv.) was added, and the

ethoxymethoxy)phenyl]-N-methylacrylamide (31; 0.150 g,

0.46 mmol, 1 equiv.) was added. The mixture was stirred at –78 °C

for 1 h, and at room temperature overnight. The reaction was care-

fully quenched with saturated sodium hydrogen carbonate solution

(10 mL). Next, the mixture was extracted with dichloromethane

(2ϫ 20 mL). The combined organic extracts were washed with an

equal volume of brine, dried with MgSO₄, and evaporated in vacuo.

reaction mixture was stirred at room temperature overnight. Ethyl

acetate(20 mL) was added, and the mixture was washed with brine

(3ϫ 20 mL). The organic layer was dried with MgSO₄and evapo-

rated in vacuo.

To remove the MEM protecting group, the crude product was dis-

solved in dichloromethane (30 mL) and trifluoroacetic acid

(10 mL), and the mixture was stirred at room temperature for 1 h.

The reaction mixture was neutralized by adding saturated sodium

hydrogen carbonate solution, and then it was extracted with dichlo-

romethane (2ϫ 30 mL). The combined organic extracts were

washed with an equal volume of brine, dried with MgSO₄, and

evaporated in vacuo. The resulting oil was purified by column

chromatography over silica with ethyl acetate/petroleum ether (1:1)

as an eluent to give compound 63 (42 mg, 35%) as orange crystals.

A sample of extra high purity was obtained by preparative HPLC

(water/CH₃CN; 0–20 min, 65:35; 20–35 min, 0:100; 35–45 min,

65:35), m.p. 64.5–65.5 °C. R_f(EtOAc/petroleum ether, 1:1) = 0.09.

¹H NMR (CDCl₃, 300 MHz): δ = 3.72 (s, 3 H, NCH₃), 3.95 (s, 3

H, OCH₃), 5.99 (br. s, 1 H, OH), 6.62 (br. t, J = 2.7 Hz, 1 H, 4Ј-

H), 6.72 (dd, J = 2.7, J = 1.8 Hz, 1 H, 5Ј-H), 6.94 (d, J = 8.3 Hz,

1 H, 5-H), 7.09 (d, J = 1.9 Hz, 1 H, 2-H), 7.12 (d, J = 15.6 Hz, 1

H, α-H), 7.19 (dd, J = 8.3, J = 1.9 Hz, 1 H, 6-H), 7.38 (t, J =

1.8 Hz, 1 H, 2Ј-H), 7.70 (d, J = 15.6 Hz, 1 H, β-H) ppm. ¹³C NMR

(CDCl₃, 75 MHz): δ = 36.7 (NCH₃), 56.0 (OCH₃), 109.7 (C-5Ј),

110.1 (C-2), 114.8 (C-5), 121.4 (C-α), 122.6 (C-6), 123.4 (C-4Ј),

126.8 (C-1 or C-1Ј), 126.9 (C-2Ј), 127.9 (C-1 or C-1Ј), 142.0 (C-β),

To remove the TIPS protecting group, the crude product was dis-

solved in THF (10 mL), TBAF (1 n solution in THF; 0.46 mL,

0.46 mmol, 1 equiv.) was added, and the reaction mixture was

stirred at room temperature for 5 min. Next, the volatiles were re-

moved in vacuo.