A Straightforward Approach to the Synthesis of Disubstituted Cyclopentenones

A Journal of

Accepted Article

Title: A straightforward approach to the synthesis of disubstituted

cyclopentenones

Authors: Mariane V Roldão, Luis Gustavo Souza-Filho, Wanda P.

Almeida, and Fernando Antonio Santos Coelho

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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201901850

Link to VoR: http://dx.doi.org/10.1002/ejoc.201901850

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A straightforward approach to the synthesis of disubstituted

cyclopentenones

Mariane V. Roldão,^[a]Luis Gustavo Souza-Filho,^[a]Wanda P. Almeida^[a],[b]and Fernando Coelho*^[a]

In memoriam Prof. José Augusto Rosário Rodrigues for his outstanding contribution to the field of organic chemistry in Brazil

Abstract: In this paper we describe an approach for the synthesis of

a set of new diversely di-substituted cyclopentenones using Morita-

Baylis-Hillman (MBH) adducts as building blocks. The synthesis was

performed with few steps, but the overall yield reached 34%. A key

step of this approach is a rhodium mediated 1,4-addition reaction on

adequately functionalised MBH adducts, which leads to the creation

of cinnamate ester derivatives with high E selectivity. These

intermediates were used as substrates for an intramolecular Friedel-

Crafts cyclisation reaction to achieve the required 2,3-substituted

cyclopentenones. As far as we know, this is the first report to describe

the synthesis of substituted cyclopentenones that directly employ

MBH adducts as building blocks.

Figure 1. Some examples of biologically active compounds with

cyclopentenone moiety in their structures.

Introduction

It is common for small cycles (i.e. four to seven members) to be

present on natural or synthetic biologically active compounds.¹In

the case of small five-membered rings, the cyclopentenone

moiety is present in a large amount of biologically active

compounds such as prostaglandins and structurally complex

terpenes. (Figure 1).²

Cyclopentenone prostaglandins (cPGs – 1-3) mediate several

fundamental biological processes. For instance, they induce the

cellular stress response, inhibit cell-cycle progression, suppress

viral replication and are closely related to cell differentiation and

development.^3,4Other five-membered containing compounds,

such as, (+)-Achalensolide (4), is a potent aromatase inhibitor,⁵

and Jiadifenin (5) is a neurotropic agent that serves as a model

for the design of new drugs to treat some neurodegenerative

diseases.⁶Phorbol and its esters (6) exhibit cytotoxic properties,⁷

while the guaianolide-type sesquiterpenoid dimer Ainsliadimer B

(7) shows anti-tumoral and anti-inflammatory activity.⁸

The inflammation process is routinely treated by using steroidal

(SAI) or non-steroidal (NSAI) drugs. Unfortunately, the continuous

use of these anti-inflammatory agents (mainly the NSAI) leads to

serious gastrointestinal effects.¹⁰To overcome this issue, a new

class of anti-inflammatory that selectively inhibit cyclooxygenase

2 (COX-2) and do not produce deleterious effects on gastric

mucosa (Figure 2) was discovered and launched a few years

ago.¹¹Unfortunately, these compounds had severe effects on the

vascular system and, aside from celecoxib were withdrawn from

the market (Figure 2).¹¹

In addition to their relevant roles in different biological processes,

the prostaglandins also mediate the inflammatory process.³,⁹

Figure 2. COX-2 selective anti-inflammatory agents.

[a]

[b]

Dr. L. G. Souza-Filho, Ms M. V. Roldão and Prof. Fernando Coelho

Institute of Chemistry - University of Campinas – PO Box6154 –

13093-970 – Campinas, São Paulo - Brazil

E-mail: facoelho@unicamp.br (F Coelho);

marianeroldao@hotmail.com (M. Roldão); quinquisilver@gmail.com

(L.G Souza-Filho)

However, a recent study has demonstrated that the possibility of

suffering

a vascular accident or stroke due to regular

administration of celecoxib is the same as that of commonly used

commercial anti-inflammatory agents, such as ibuprofen or

naproxen.¹²So, the discovery of new selective anti-inflammatory

agents continues to be a goal for the pharmaceutical industry.

Prof. W. P. Almeida

Faculty of Pharmaceutical Sciences - University of Campinas

Rua Cândido Portinari, 200 – 13093-971 – Campinas, São Paulo –

Brazil

The presence of the cyclopentenone motif in prostaglandin

structures (PGB2 – Figure 1),¹³associated with the anti-

inflammatory activity of this structural unity,¹⁴led us to study the

E-mail: wanda.almeida@fcf.unicamp.br

Supporting information for this article is given via a link at the end of

the document.

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development of new potentially anti-inflammatory compounds Results and Discussion

with a di-substituted cyclopentenone core. Preliminary docking

studies on COX 2 indicated that the 3,5-difluorophenyl residue

interacts most efficiently at enzyme’s active site, and piperonal

derivatives are less active. Based on these preliminary data we

proposed the synthesis of new substituted cyclopentenones

(Figure 3).

The synthetic strategy for preparing the planned di-substituted

cyclopentenones 8-16 can be rationalised by the retrosynthetic

sequence depicted below (Scheme 1).

Scheme 1. Retrosynthetic analysis for preparation of cyclopentenones 8-16

The formation of the cyclopentenone’s ring can be ensured by an

intramolecular Friedel-Crafts acylation reaction that uses an

adequately substituted ,-unsaturated acid, like 17, as a

substrate. In carboxylic acid 17, the double bond configuration

was already controlled, and the substituents in the double bond

are adequately placed in this key intermediate. This unsaturated

acid can be synthesised by a two-carbon homologation reaction

on an α-methylene-aryl-cinnamate derivative, such as 18. The

latter can be prepared from MBH adducts via a sequence

involving a Heck reaction,¹⁹followed by chemoselective reduction

of a keto carbonyl group and elimination of the formed hydroxyl

group.

Alternatively, a more direct approach in which 1,4-conjugate

addition is mediated by a metal can be used to obtain 18. The

success of this synthetic sequence would allow us to develop a

novel approach to synthesise 2,3-substituted cyclopentenones

starting from cheap, green and easily available substrates.

We began by synthesising MBH adducts 19 and 20 according to

a protocol we developed and described some years ago.²⁰

Figure 3. Proposed new di-substituted cyclopentenones as anti-inflamatory

agents.

The biological and commercial interest of the cyclopentenone

moiety stimulated the development of different intra- and or

intermolecular approaches to construct this ring.¹⁵Approaches

based on cycloaddition reactions, aldol type-annulation, the

Nazarov reaction, cross-coupling reactions, ring-closing

metathesis (RCM), and the Rautenstrauch reaction have already

been described.¹⁵Although rare, approaches that use an

intramolecular

cyclopentenones have also been proposed.¹⁶

However, few synthetic strategies

Friedel-Crafts

reaction

to

synthesise

for

synthesizing

cyclopentenones with the structural arrangement we desire

(Figure 3) have been described. Conrad and Fuchs¹⁷were the

first to describe a synthetic approach to prepare 2-phenyl-2-

cyclopentenones, in a sequence of five-steps, including a

Michael-type reaction of an organolithium reagent with -oxido-

,-unsaturated sulfone, followed by the treatment of the resulting

ion with an aryl halide, oxidation and sulfone elimination. Although

it is elegant, the sequence is limited to alkyl, phenyl or benzyl

substituents. In 1998, Kim et al.¹⁸described an alternative

strategy to synthesise 2-phenyl-2-cyclopentenones based on a

palladium-catalysed

tandem

epoxide

isomerization-

intramolecular aldol condensation. Their four-step sequence

provided good overall yield of di-substituted cyclopentenones (up

to 26%), but unfortunately this result is limited to only one example.

The need to obtain our target compounds and the limited

availability of synthetic alternatives to prepare cyclopentenones

with the appropriated substitution pattern led us to propose a

novel approach of synthesis. This paper describes the results we

achieved by developing an alternative approach to the synthesis

of di-substituted cycopentenones (8-16) through post-

functionalisation of the Morita-Baylis-Hillman (MBH) adducts used

as starting materials (Figure 3).

Scheme 2. Preparation of the MBH adducts.

Adduct 19 was prepared with 95% yield after 18h, while adduct

20 achieved 98% yield after 144h (Scheme 2).

Recently, we reported a Heck reaction of MBH adducts catalysed

by an oxime-derived palladacycle (a Nájera catalyst).¹⁹This

simple and straightforward methodology produced -

methylenearyl--ketoesters with good yield and a short reaction

time. In order to quickly synthesise 21 (Scheme 3), a solution of

adduct 19 in DMF, in presence of Et₃N and iodobenzene, was

treated with a Nájera catalyst (0.2 mol%) for 3 h, at 110 °C, to

produce the -ketoester 21 with a 94% yield. Chemoselective

reduction of the keto carbonyl with NaBH₄in methanol resulted in

-hydroxyl-ester 22, as a mixture of inseparable diastereoisomers,

with 81% yield.²¹A toluene solution of 22 was then treated with

The approach enabled synthesis of a set of cyclopentenones with

few steps. The key steps are rhodium-mediated 1,4-addition of

boronates to the double bond of an MBH adduct and an

intramolecular Friedel-Crafts reaction to form cyclic compounds.

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KHSO₄, under reflux, for 8 h, in order to achieve a mixture of

cinnamates E-18a/Z-18a, with a ratio of 1:1, and 40% yield

(Scheme 3).

formation of boroximes, which hampers the coupling reaction.²⁹In

addition, these acids are also sensitive to protodeboronation,

requiring the use of excessive reagents. These issues could be

responsible for the moderate yield we obtained during the

coupling step. So, we substituted the boronic acid with the

corresponding potassium trifluoroborate salt (24a) (Table 1, entry

9).²⁵

Table 1. Optimizing the experimental protocol for the synthesis of -substituted

cinnamates

Scheme 3. An attempt to synthesize cinnamyl derivative 18 from MBH adduct.

Reagents and conditions: a) DMF, Et₃N, PhI, Nájera’s catalyst (0.2 mol%), 3h,

110 °C, 94%; b) NaBH₄, MeOH, 0 °C, 1.5h, 81%, mixture of isomers (7:1, by

Nuclear Magnetic Resonance - NMR); c) KHSO₄, toluene, reflux, 8h, 40%,

mixture of isomers (1:1).

Despite the simplicity of this approach, the elimination step

resulted in only moderate yield and produced an inseparable

mixture of isomers, which completely compromised its efficiency

as a synthetic alternative. Unfortunately, attempts to circumvent

these issues (e.g. changing acid catalysis, temperatures and

solvents) were unfruitful.

Previously, Genet and colleagues^22,23demonstrated that some

rhodium complexes could be used to perform 1,4-conjugate

addition reaction with MBH adducts. The main advantages of this

strategy are its high E-stereoselectivity and the economy of steps,

i.e. the required -substituted cinnamate can be prepared from an

MBH adduct in only one step.

Entry

[Rh(cod)Cl]₂

(mol%)

Boron

Solvents

derivative,

Time (h)

Yield

(%)

1

2

3

4

5

6

7

8

9

0.5

1.0

1.5

2.0

2.5

2.0

23, MeOH

3^a

-

3^a

-

3^b

-

3^b

12

-

23, Toluene

3^b

23, MeOH/Toluene

24a, MeOH/Toluene

3^b

71

69

99

Based on these results, we decided to perform the 1,4-conjugate

addition between MBH adduct 19 and commercial 4-

3^b

fluorophenylboronic acid (23) in the presence of chloro(1,5-

24

4^b

cyclooctadiene)rhodium (I) dimer [Rh(cod)Cl]₂

using the

experimental protocol originally described by Genet (Table 1,

entry 1).^22e,fHowever, we were unable to isolate any product, and

observed only extensive degradation of 19. So, we decided to

increase the catalyst loading to 1.0 and 1.5 mol%, respectively

(Table 1, entries 2 and 3, respectively). In the second case, we

performed the reaction in methanol under reflux (entry 3). Again

in both reactions no product was detected. After searching for a

condition to run this reaction, we increased the catalyst loading to

2.0 mol% and performed the reaction in methanol under reflux.

After 3h, we isolated the required cinnamate derivative 18a, but

with only 12% yield (Table 1, entry 4).

1.5^b,c

[a] These reactions were carried out using temperatures ranging from 50 to 55

⁰C. [b] These reactions were carried out under reflux. [c] In this reaction, the

boronic acid derivative 23 was replaced by the trifluoroboronate derivative 24a.

In the presence of the trifluoroboronate salt 24a, cinnamate E-18a

was obtained with 99% yield, after 1.5 h. No additional purification

step was necessary. The NMR data for this compound are

compatible with the proposed structure. The bidimensional

NOESY

spectrum

unambiguously

confirmed

the

E

Despite the low yield, this result indicated that this transformation

could be performed. In several rhodium mediated conjugated

additions, toluene was the solvent of choice. Thus, we carried out

a new assay using toluene as a solvent. However, the reaction

did not work at all (Table 1, entry 5), probably due to the low

solubility of boronic acid in toluene. To overcome this issue, we

ran an assay in a refluxing mixture of methanol and toluene (1:1).

Fortunately, the reaction worked and the cinnamate E-18a was

obtained with 71% yield (Table 1, entry 6). In an effort to improve

this result, we increased the catalyst loading to 2.5 mol%, but we

observed no change (Table 1, entry 7). Finally, we maintained the

catalyst loading and increased the reaction time, but again no

significant improvement was observed (Table 1, entry 8).

Because we obtained only moderate yield, we decided to maintain

the solvent condition and change the boronic derivative. The

instability of boronic acids is well known; these acids are

susceptible to hydrolysis in the reaction medium, leading to the

stereochemistry of the double bond and only E-18a was

detected.^22cBased on that result (Table 1, entry 9) MBH adduct

19 was treated with adequately functionalized potassium

trifluoroboronates (24b-h) to produce the corresponding

cinnamates (E-18b-g) with almost quantitative yield, after a few

hours, in all cases (Scheme 4).

To synthesise of cinnamate E-18h we needed a trifluoroboronate

salt with a 4-aminosulfonylphenyl moiety. Unfortunately, this salt

is not commercially available. We tried to prepare it according to

a protocol described in the literature,²⁵but all attempts failed.

Therefore, we performed the reaction using the 4-aminosulphonyl

boronic acid (25) to provide cinnamate 18h with 55% yield, after

0

8 h at 50 C (Scheme 4). To synthesise of cinnamate 18h we

needed to carefully identify the best conditions. We found that the

yield was improved when an additive like triphenylphoshine was

used in the reaction.^22,23,26

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Scheme 4. Diastereoselective synthesis of functionalized cinnamates 18b-h.

Unfortunately, the reaction between the Morita-Baylis-Hillman

adduct 20 and trifluoroboronate salt 24a (see Table 1) furnished

18i in low yield (13%), after 18h. We changed catalyst load,

temperature and solvents, but we were unable to solve this issue.

So, MBH 20 was treated with boronic acid 23 to produce E-

cinnamate E-18i, with 72% yield after 3 hours. (Scheme 5).

substituents of our target cyclopentenones into the structure of

these new -substituted cinnamates and controlled the

stereochemistry of the double bond with high stereoselectivity.

With the obtained cinnamates 18a-i, we followed

a

straightforward synthetic sequence to achieve our goals. First, we

homologated two adequately functionalised carbon atoms to

enable a cyclisation reaction via Friedel-Crafts acylation at the

end of the synthesis process. This task was easily accomplished

by employing a sequence based on malonate chemistry followed

by decarboxylation (see the proposed retrosynthetic analysis,

Scheme 1). Initially, -substituted cinnamate derivatives 18a-i

were transformed into the corresponding allylic bromides through

a two-step synthetic sequence and these bromides were used as

alkylating agents in a reaction with alkyl malonate. Thus, a

solution of cinnamates 18a-i in dichloromethane was treated

Scheme 5. Diastereoselective synthesis of functionalized cinnamate 18i

independently, at -78 ⁰C, with

a

1M solution of

It was possible to achieve all required cinnamates derivatives

(18a-i) directly from MBH adducts with moderate to excellent yield,

and a high degree of control over the configuration of the double

bond. ¹H NMR and NOESY analysis of 18a-i proved,

unambiguously, that the E double bond stereochemistry was

present in all cases (see supplementary material and Table 1). No

trace of Z diastereoisomers could be detected, even in the spectra

of the crude product. We adequately incorporated the required

diisobutylaluminium hydride (DIBAL) in toluene to produce the

corresponding allylic alcohols 26a-i, with yields of 67-98%

(Scheme 6). Dichloromethane solutions of these allylic alcohols

were reacted with tetrabromomethane (CBr₄) in the presence of

triphenylphosphine to provide the corresponding bromides 27a-i

with excellent yields (ranging from 81-97%) (Scheme 6).

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Scheme 6. Two-step sequence for the preparation of -substituted allyl bromides. Reagents and conditions: a) DIBAL-H (1M solution in toluene, 3 equiv.), CH₂Cl₂,

-78 °C, 1 h; b) CBr₄(1.5 equiv.) PPh₃(1.3 equiv.), CH₂Cl₂0 °C  r.t., 2h.

It is well established that malonates or derivatives as can be used

to homologate two carbon atoms in a given substrate. Due to the

high acidity of the proton between the two carbonyls, Meldrum’s

acid, a malonate derivative, facilitates C2 homologation, after a

decarboxylation reaction in mild conditions.^27,28In our research, a

solution of allyl bromide 27b in dry DMF was treated with 1

equivalent of potassium carbonate in the presence of Meldrum’s

acid (1 equiv.) at room temperature. In an alternative experiment

a crown ether (dibenzo-(18)-crown-6 – DB-(18)C-6) and a phase

transfer catalysis (tetrabutyl ammonium bromide) were added to

the reaction medium.²⁸Unfortunately, in both cases we isolated

only the product resulting of double alkylation and all attempts to

solve this issue failed. In light of these results, we treated a

solution of ethyl malonate in dry tetrahydrofuran, at 0 ºC, with NaH

and added solution of the allyl bromides 27a-h dry

a

tetrahydrofuran, separatedly, to obtain the mono-alkylated

compounds 28a-h (69% - 83%), after chromatographic filtration in

a silica gel column. Compounds 28a-f were then treated with an

excess of 20% HCl solution, under reflux conditions, for 120 h, to

achieve the corresponding 4-substituted arylpent-4-enoic acids

(17a-f) with 50% - 74% (Scheme 7). Surprisingly, when

compounds 28g-h were treated with an excess of HCl we

observed extensive decomposition that led to a complex mixture

of products. So, we used a somewhat different sequence to

prepare acids 17g-h.

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Scheme 7. Synthesis of 4-substituted arylpent-4-enoic acid. Reagents and conditions: a) Ethyl malonate (1.1 equiv.), NaH (1.2 equiv.), THF, 0 °C, under nitrogen

atmosphere, 1 h; b) HCl 20% (133 equiv.), H₂O, reflux, 120 h; c) NaCl, H₂O, DMSO, reflux, 18-24h; d) NaOH (2 M), EtOH, reflux, 6.5 h. (* The number between

parentheses corresponds to the yield based on the recovered substrate).

Initially, the diesters 28g-h were subjected to Krapcho

decarboxylation.²⁹Solutions of 28g-h in a mixture of DMF and

H₂O (1:1) were treated with NaCl, at 180-190 °C, to provide the

corresponding mono-ethyl esters 29g-h with moderate to good

yields (69% - 82%). Base-catalysed hydrolysis of these esters in

refluxing ethanol produced acids 17g-h with yields of 73% - 91%,

after 6.5 h (Scheme 7).

All spectral data for acids 17a-h are compatible with the proposed

structure (see SI for more details). Some of the key intermediate

acids (17a-f) were obtained from MBH adducts through five steps,

with an overall yield of 33% - 45%, while acids 17g-h were

synthesized in seven steps and overall yield varied from 13% -

30%.

Finally, the,-unsaturated acids 17a-h were employed as

substrates for intramolecular Friedel-Crafts acylation reactions.

Thus, dichloromethane solutions of carboxylic acids 17a-h were

treated with oxalyl chloride in the presence of DMF (1 drop), at

0 °C, for 15 min, and then at room temperature for 1 h. After that

time, the solutions were again cooled to 0 °C and a suspension of

freshly sublimated aluminium trichloride in dichloromethane was

added for 10 minutes with aid of a canula. The resulting mixtures

were stirred for 1-3 h and after that the reaction was quenched

with an aqueous HCl solution (1 M) to produce the required 2,3-

disubstituted cyclopentenones as a single compound (Scheme 8).

Scheme 8. Synthesis of 4-substituted arylpent-4-enoic acid.

All the ¹H and ¹³C NMR spectra are compatible with the structure

proposed for each cyclopentenone. For instance, the ¹H NMR

spectrum (250 MHZ, C₆D₆) of cyclopentenone 8 showed signals

between 6.40-6.78 ppm, with integration proportional to six

hydrogens, which can be attributed to the aromatic hydrogens. At

3.10 ppm, a singlet, proportional to two hydrogens, was attributed

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phosphomolibdate in ethanol or vanillin in sulphuric acid as revealing

agents or using an UV lamp at 254nm. The ¹H and ¹³C NMR spectra were

recorded in a Bruker spectrometer (250 MHz for ¹H and 62.5 MHz for ¹³C)

and Varian Inova 500 (500 MHz for ¹H and 125 MHz for ¹³C). The chemical

shifts () were expressed in ppm using as internal standard: deuterated

chloroform (CDCl₃)  = 7.27 ppm for ¹H and  = 77.23 ppm for ¹³C,

deuterated acetone (acetone-D₆)  = 2.05 ppm for ¹H and  = 29.92 ppm

for ¹³C, deuterated methanol (methanol-D₄)  = 3.31 and 4.78 ppm for ¹H

and  = 49.15 ppm for ¹³C and deuterated benzene (benzene-D₆),  = 7.16

ppm for ¹H and  = 128.39 ppm for ¹³C. The value os the coupling

constants (J) were expressed in Hertz (Hz).

to the benzylic methylene. In addition, two multiplet centred at

1.80 and 1.65 ppm, were attributed to the five-membered ring

methylene in positions - and - within the ketone carbonyl group,

respectively. Furthermore, the ¹³C NMR spectrum showed a

singlet centred at 209 ppm, which was attributed to the ketone

carbonyl group (for details see the SI file).

Conclusions

We described herein a new, simple and direct approach to the

synthesis of functionalized cyclopentenone in seven or eight

steps. This approach uses Morita-Baylis-Hillman adducts as

building blocks, and combines a rhodium-mediated Michael

addition type reaction, C2 homologation based on the chemistry

of malonate and intramolecular Friedel-Crafts acylation.

Cyclopentenones were obtained with overall yields of 10-34%. To

our knowledge, the synthesis of compounds 8-16 is the first

The IR spectra were expressed in cm^-1and recorded in a FT-IR Nicolet

Impact 410 spectrometer. The samples were applied as a film on a NaCl

cell.

The high-resolution mass spectra were recorded in an equipment

Micromass (Manchester-UK) Q-Tof configuration ESI-QqTof with

a

precision resolution of 5.000 e 50.0 ppm in a TOF analyser. The melting

points were measured in triplicate in an equipment GEHAKA model PF

1000. The nomenclature of the chemical compounds follows the IUPAC

rules according the Chemaxon.com/Marvin program

described

approach

to

preparing

2,3-disubstituted

cyclopentenones from MBH adducts.³⁰This approach may allow

the access to other derivatives by simply varying the substitution

pattern on both the structure of aldehydes used in the preparation

of the adducts and in the boronic acids or boronate salts used for

conjugate addition. Preliminary studies evaluating the anti-

inflammatory activity of these cyclopentenones demonstrated that

all compounds exhibit good anti-inflammatory activity. Most

detailed studies about the mechanism of the biological action of

these compounds are being conducted, and the results will be

disclosed in the future.

General procedure for the preparation of Morita-Baylis-Hillman

adducts (19 and 20)

To a stirred solution of 3,5-difluorobenzaldehyde (2.0 mmol, 0.284 g) or 6-

bromo-1,3-benzodioxole-5-carboxaldehyde (3.7 mmol, 0.847 g) in methyl

or ethyl acrylate (40-74 mmol, 20 equiv.), at room temperature, was added

1,4-diazabicyclo[2.2.2]octane (DABCO, 2.0 equiv.) and acetic acid (2.0

equiv.). The resulting mixture was immersed in an ultrasonic bath (1000W)

and the evolution of the reaction was followed by thin layer

chromatography (TLC). After completion, the excess of acrylate was

removed under reduced pressure (ATTENTION: this operation must be

done under a hood fitted with an efficient exhaustion system. The

recovered acrylate can be reused several times). The residue was

diluted with ethyl acetate (50 mL) and the resulting solution washed with

brine (3 x 15 mL), dried over anhydrous Na₂SO₄, filtered and the solvent

removed under reduced pressure. The crude mixture was purified by sílica

gel column chromatography, using a mixture of ethyl acetate:hexane

(20:80) as eluent to provide the required adducts

Experimental Section

General

The reactions involving moisture sensitive reagents were performed under

inert atmosphere of argon or nitrogen on previously dry recipient.

Commercial solvents were previously treated and distilled before use.

Ethyl 2-[(3,5-difluorophenyl)(hydroxy)methyl]prop-2-enoate (19). Yield:

95%, light yellow oil. IR (Film, _max): 3453, 2985, 1710, 1624, 1597, 1461,

All anhydrous solvents were dried using specific procedure just before use.

Dichloromethane was dried under calcium hydride and distilled.

Tetrahydrofuran (THF) was distilled from sodium and benzophenone. N,N-

Dimethylformamide (DMF) was dried over calcium hydride and distilled

under reduced pressure. After distillation, the solvent was maintained in a

flask containing activated 4 Å molecular sieve.³⁶

1

1312, 1119, 1055 cm^-1. H NMR (250 MHz, CDCl₃):  ppm 6.96-6.91 (m,

1H), 6.91-6.87 (m, 1H), 6.71 (tt, ⁵J = 2.3 Hz and ³J = 8.9 Hz, 1H), 6.37 (s,

1H), 5.82 (s, 1H), 5.48 (d, ³J = 5.6 Hz, OH - 1H), 4.19 (q, ³J = 7.1 Hz, 2H),

3

3.36 (d, J = 5.8 Hz, 1H - OH), 1.26 (t, J = 7.1 Hz, 3H). ¹³C NMR (62,5

MHz, CDCl₃),  ppm: 166.0, 163.0 (dd, ¹J = 248.6 Hz and ³J = 12.5 Hz, C-

F), 162.8 (dd, ¹J = 248.6 Hz and ³J = 12.5 Hz, C-F), 145,7 (t, ³J = 8.4 Hz,

C-F), 141.2, 126.7, 109.4 (d, ²J = 8.6 Hz, C-F), 109.2 (d, ²J = 8.6 Hz, C-F),

102.9 (t, ²J = 25.4 Hz, C-F), 72.4 (t, ⁴J = 2.0 Hz, C-F), 61.2, 13.9. HRMS

(EI, m/z): Calcd. for C₁₂H₁₂F₂O₃242.0755; found 242.0748.

The other solvents were purchased from specialized furnishers and used

without additional purification. The 3,5-difluorobenzaldehyde, 4-

fluorophenyl boronic acid and 4-(methylsulphonyl)phenyl boronic acid

were

purchased

from

Aldrich

Chemical

Company.

4-

(Aminosulphonyl)phenyl boronic acid was purchased from Combi-Blocks,

Inc. All commercial reagents were used without additional purification. The

Morita-Baylis-Hillman (MBH) reaction was performed in an ultrasound bath

of 1000 W and 25 KHz. The other reactions were carried out under stirring

and when necessary heating or cooling was used.

Methyl

2-[(6-Bromo-2H-1,3-benzodioxol-5-yl)(hydroxy)methyl]prop-2-

enoate (20). Yield: 98%, amorphous solid. M.p 83-84 ºC. IV (Film, _max):

3427, 1721, 1631, 1503, 1478, 1438, 1264, 1196, 1038 cm^-1. ¹H NMR (250

MHz, CDCl₃),  ppm: 7.02 (s, 1H), 6.99 (s, 1H), 6.34 (s, 1H), 5.98 (s,

2H)5.86 (d, ³J = 4.1 Hz, OH, 1H), 5.61 (s, 1H), 3.78 (s, 3H), 3.14 (d, ³J =

4.2Hz, 1H, OH). ¹³C NMR (62.5 MHz, CDCl₃), ppm: 166.9, 147.9, 147.6,

140.6133.1, 126.8, 113.6, 112.6, 108.2, 101.8, 71.4, 52.1. HRMS (ESI,

m/z): Calcd.for C₁₂H₁₁BrNaO₅336.9688; found 336.9691

The reaction products were purified by sílica gel column chromatography

(70-230 mesh). The reactions were followed by thin layer chromatography

(TLC) using Merck^®, chromatoplates, using a 5% solution of ammonium

10.1002/ejoc.201901850

European Journal of Organic Chemistry

FULL PAPER

General procedure for the preparation of α-substituted cinnamates

18a-18h.

Ethyl

(2E)-3-(3,5-difluorophenyl)-2-[(3-methylphenyl)methyl]prop-2-

enoate (18e). Yield: 99%, light yellow oil. IR (ATR, _max): 3082, 2982, 2924,

1711, 1620, 1590, 1432, 1370, 1326, 1259, 1201, 1121, 1085, 856 cm^-1.

¹H NMR (250 MHz, CDCl₃),  ppm: 7.77 (s, 1H), 7.21 – 7.50 (m, 1H), 7.04

– 6.73 (m, 6H), 4.22 (q, ³J = 7.2 Hz, 2H), 3.87 (s, 2H), 2.32 (s , 3H), 1.25

(t, ³J = 7.0 Hz, 3H). ¹³C NMR (126 MHz, CDCl₃),  ppm: 167.9, 163.3 (dd,

¹J = 248.8 Hz and J = 12.8 Hz, C-F), 139.0, 138.9 (t, J = 9.6 Hz, C-F),

138.5, 138.1 (t, ⁴J = 2.5 Hz, C-F), 134.1, 129.0, 128.8, 127.4, 125.2, 112.2

(dd, ²J = 16.6 Hz and ⁴J = 8.8 Hz, C-F), 104.3 (t, ²J = 25.41 Hz, C-F), 61.5,

33.3, 21.8, 14.4. HRMS (EI, m/z): Calcd. for C₁₉H₁₈F₂O₂[M⁺] 316.1275;

found 316.1279

To a solution of MBH adduct (19, 1 equiv.) in a mixture of toluene/MeOH

(1: 1) were added the potassium trifluorophenylborate salt (2 equiv.) and

the rhodium catalyst ([Rh(cod )Cl] 2, (0.2 equiv.) at room temperature. The

resulting mixture was then refluxed, under magnetic stiring, and reaction

evolution was followed by TLC analysis. After completion, the solvents

were removed under reduced pressure. The residue was dissolved in ethyl

acetate (20 mL) and the organic solution was washed with saturated NaCl

solution (3 x 20 mL), dried over Na₂SO₄, filtered and then the solvent was

evaporated under vaccum. The residue was purified by flash silica gel

column chromatography using ethyl acetate/hexane (20:80), as eluent, to

provide the α-substituted cinnamates in high yields.

3

Ethyl (2E)-3-(3,5-difluorophenyl)-2-[(4-chlorophenyl)methyl]prop-2-enoate

(18f). Yield: 99%, dark yellow oil. IR (ATR, _max): 3090, 2982, 2907, 1696,

1618, 1588, 1490, 1434, 1272, 1121, 1087, 860 cm^-1. ¹H NMR (250 MHz,

CDCl₃),  ppm: 7.78 (s, 1H), 7.26 (d, ³J = 8.2 Hz, 2H), 7.08 (d, ³J = 8.2 Hz,

2H), 6.87 – 6.74 (m, 3H), 4.21 (q, ³J = 7.0 Hz, 2H), 3.86 (s, 2H), 1.25 (t, ³J

= 7.2 Hz, 3H). ¹³C NMR (151 MHz, CDCl₃),  ppm: 167.6, 163.3 (dd, ¹J =

249.0 Hz and ³J = 12.0. Hz, C-F), 138.7 (t, ³J = 10.6 Hz, C-F), 138.5, 133.5,

132.5, 129.6, 129.1, 112.2 (dd, ²J = 19.6 Hz and ⁴J = 4.5 Hz, C-F), 104.5

(t, ²J = 25.6 Hz, C-F), 61.7, 32.8, 14.5. HRMS (EI, m/z): Calcd. for

C₁₈H₁₅ClF₂NaO₂359.0621; found 359.0615

Ethyl (2E)-3-(3,5-difluorophenyl)-2-[(4-fluorophenyl)methyl]prop-2-enoate

(18a). Yield: 99%, yellowish oil. IR (Film, _max): 3086, 2983, 2928, 1713,

1

1619, 1590, 1508, 1258, 1120, 1090 cm^-1. H NMR (500 MHz, CDCl₃), 

ppm: 7.77 (s, 1H), 7.11 – 7.09 (m, 2H), 6.99 – 6.95 (m, 2H), 6.88 – 6.77

(m, 3H), 4.21 (q, ³J = 7.5 Hz, 2H), 3.86 (s, 2H), 1.25 (t, ³J = 7.0 Hz, 3H).

¹³C NMR (126 MHz, CDCl₃),  ppm: 163.3 (dd, ¹J = 249.1 Hz and ³J = 12.9

Hz, C-F), 161.9 (d, ¹J = 244.6 Hz, C-F), 138.7 (t, ³J = 9.5 Hz, C-F), 138.3

3

(t, ⁴J = 1.,8 Hz, C-F), 129.7 (d, J = 7.9 Hz, C-F), 115.8 (d, ²J = 21.4 Hz,

C-F), 112.2 (dd, ²J = 19.7 Hz and ⁴J = 6.2 Hz, C-F), 104.4 (t, ²J = 25.4 Hz,

C-F), 61.6, 32.7, 14.5. HRMS (EI, m/z): Calcd. for C₁₈H₁₆F₃O₂[M+H]

321.1097; found 321.1186

Ethyl

(2E)-3-(3,5-difluorophenyl)-2-[(4-

methanesulfonylphenyl)methyl]prop-2-enoate (18g). Yield: 99%, yellowish

oil. IR (Film, _max): 3422, 1708, 1619, 1591, 1307, 1262, 1120, 1150, 1091

cm^-1. ¹H NMR (250 MHz, CDCl₃):  ppm 7.92-7.79 (m, 3H), 7.33 (d, J = 8.2

Hz, 2H), 6.87-6.73 (m, 3H), 4.20 (q, ³J = 7.1 Hz, 2H), 3.96 (s, 2H), 3.03 (s,

3H), 1.23 (t, J = 7.0 Hz, 3H). ¹³C NMR (63 MHz, CDCl₃):  ppm 166.8,

163.1 (dd, ¹J = 249.5 Hz and ³J = 12.8 Hz, C-F), 162.9 (dd, ¹J = 250.0 Hz

and ³J = 13.3 Hz, C-F), 145.4, 139.0 (t, ⁴J = 2.5 Hz, C-F), 138.6, 138.0 (t,

³J = 9.5 Hz, C-F), 132.1, 128.8, 127.7, 111.8 (d, J = 8.8 Hz, C-F), 111.5

(d, ²J = 8.8 Hz, C-F), 104.3 (t, J = 25.2 Hz, C-F), 61.4, 44.5, 33.1, 14.0.

HRMS (EI, m/z): Calcd. for C₁₉H₁₈F₂O₄S 380.0894; found 380.0895.

Ethyl (2E)-2-benzyl-3-(3,5-difluorophenyl)prop-2-enoate (18b). Yield: 99%,

yellowish oil. IR (ATR, _max): 3080, 2980, 1709, 1620, 1590, 1434, 1372,

1326, 1262, 1208, 1121, 1084, 856 cm^-1. ¹H NMR (400 MHz, CDCl₃), 

3

ppm: 6.79 – 6.63 (m, 5H), 6.38 – 6.23 (m, 3H), 3.69 (q, J = 7.2 Hz, 2H),

2

3.39 (s, 2H), 0.72 (t, ³J = 7.2 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃),  ppm:

167.8, 163.3 (dd, ¹J = 248.6 Hz and ³J = 13.1 Hz, C-F), 139.1, 138.9 (t, ³J

= 9.1 Hz, C-F), 138.2 (t, ⁴J = 2.0 Hz, C-F), 134.0, 129.0, 128.2, 126.7,

112.2. (dd, ²J = 19.1 Hz and ⁴J = 7.0 Hz, C-F), 104.3 (t, ²J = 25.2 Hz, C-

F), 61.5, 33.4, 14.4. HRMS (EI, m/z): Calcd. for C₁₈H₁₆F₂NaO₂325.1011;

found 325.1031

2

General procedure for the preparation of α-substituted cinnamates

18h-i.

Ethyl

(2E)-3-(3,5-difluorophenyl)-2-[(3,5-difluorophenyl)methyl]prop-2-

To a stirred separated solutions of MBH adducts 19 (0.484 g, 2 mmol) and

20 (0.63 g, 2 mmol) in a mixture of solvents (methanol/toluene or

dioxane/water, see tables for details), at room temperature, was added the

enoate (18c). Yield: 99%, yellowish oil. IR (ATR, _max): 3093, 2987, 1709,

1622, 1592, 1460, 1372, 1322, 1266, 1218, 1119, 847 cm^-1. ¹H NMR (500

MHz, CDCl₃),  ppm: 7.82 (s, 1H), 6.85-6.77 (m, 3H), 6.69-6.63 (m, 3H),

4.23 (q, ³J = 7.0 Hz, 2H), 3.86 (s, 2H), 1.26 (t, ³J = 7.1 Hz, 3H). ¹³C NMR

corresponding

boronic

acids

(4

mmol)

and

chloro(1,5-

cyclooctadiene)rhodium (I) dimer [Rh(cod) Cl]₂(2 – 5 mol%, see tables for

details). For some reactions was added triphenylphosphine. Each resulting

mixtures were heated at 50 °C or at reflux and the evolution of the

reactions were followed by TLC. After completion, the solvents were

removed under reduced pressure and the residues were diluted with ethyl

acetate (50 mL). The organic phases were washed with brine (3 x 15 mL),

dried over anhydrous Na₂SO₄, filtered and the solvent was evaporated

under reduced pressure. The crude products were purified by silica gel

column chromatography using a mixture of ethyl acetate: hexane (12:88)

as eluent to provide the corresponding -substituted cinnamates 18h-i.

(126 MHz, CDCl₃),  ppm: 167.3, 163.5 (dd, J = 248.9 Hz and ³J = 13.8

1

Hz, C-F), 163.4 (dd, ¹J = 250.1 Hz e ³J = 13.8 Hz, C-F), 143.2 (t, ³J = 8.7

Hz, C-F), 139.3, 138.4 (t, ³J = 10.0 Hz, C-F), 132.6, 112.1 (dd, J = 20.1

2

Hz and ⁴J = 6.3 Hz, C-F), 111.1 (dd, ²J = 20.1 Hz and ⁴J = 6.3 Hz, C-F),

104.7 (t, ²J = 25.1 Hz, C-F), 102.4 (t, ²J = 25.1 Hz, C-F), 61.8, 33.2, 14.5.

HRMS (EI, m/z): Calcd. for C₁₈H₁₄F4NaO₂361.0822; found 368.0813

Ethyl

(2E)-3-(3,5-difluorophenyl)-2-[(2-methylphenyl)methyl]prop-2-

enoate (18d). Yield: 99%, light yellow oil. IR (ATR, _max): 3080, 2980, 1709,

1620, 1590, 1434, 1372, 1326, 1262, 1208, 1121, 1084, 856 cm^-1. ¹H NMR

(250 MHz, CDCl₃),  ppm: 7.21 – 7.08 (m, 4H), 7.01 – 6.98 (m, 1H), 6.85

– 6.71 (m, 3H), 4.21 (q, ³J = 7.2 Hz, 2H), 3.81 (s, 2H), 2.30 (s, 3H), 1.24 (t,

³J = 7.2 Hz, 3H). ¹³C NMR (63 MHz, CDCl₃),  ppm: 167.9, 163.2 (dd, ¹J

= 249.0 Hz and ³J = 12.96 Hz, C-F), 138.8 (t, ³J = 9.6 Hz, C-F), 138.4 (t,

⁴J = 2.6 Hz, C-F), 137.1, 136.5, 133.9, 130.6, 126.9, 126.7, 126.5, 112.2

(dd, ²J = 16.6 Hz and ⁴J = 8.7 Hz, C-F), 104.3 (t, ²J = 8.7 Hz, C-F), 61.6,

31.0, 20.0, 14.4. HRMS (EI, m/z): Calcd. C₁₉H₁₈F₂NaO₂⁺339.1167; found

339.1149

Ethyl

(2E)-3-(3,5-difluorophenyl)-2-[(4-sulfamoylphenyl)methyl]prop-2-

enoate (18h). Yield: 55%, colorless oil. IR (Film, _max): 3373, 3264, 3079,

2992, 2900, 1707, 1629, 1331, 1276, 1156, 1156, 1118 cm^-1. ¹H NMR (250

3

MHz, MeOD):  ppm 7.85 (d, ³J = 6.4 Hz, 2H), 7.81 (s, 1H), 7.31 (d, J =

8.3 Hz, 2H), 7.03-6.87 (m, 3H), 4.19 (q, ³J = 7.1 Hz, 2H), 3.97 (s, 2H), 1.22

(t, ³J = 7.1 Hz, 3H). ¹³C NMR (63 MHz, MeOD):  ppm 167.2, 163.1 (dd, J

= 248.1 Hz and ³J = 12.9 Hz, C-F), 162.9 (dd, J = 248.0 Hz and ³J = 12.8

Hz, C-F), 143.7, 141.6, 138.4 (t, ³J = 10.0 Hz, C-F), 138.4 (t, ⁴J = 2.4 Hz,

2

C-F), 132.6, 128.1, 126.1, 111.6 (d, J = 9.2 Hz, C-F), 111.3 (d, J = 8.9

Hz, C-F), 103.6 (t, ²J = 25.7 Hz, C-F), 61.1, 32.4, 13.0. HRMS (ESI, m/z):

Calcd. for C₁₈H₁₈F₂NO₄S [M+H]⁺382.0919; found 382.0992.

10.1002/ejoc.201901850

European Journal of Organic Chemistry

FULL PAPER

Methyl

(2E)-3-(6-bromo-2H-1,3-benzodioxol-5-yl)-2-

[(4-

ppm: 7.17 – 7.13 (m, 4H), 6.81 – 6.64 (m, 4H), 4.12 (s, 2H), 3.61 (s, 2H),

2.21 (s, 3H). ¹³C NMR (63 MHz, CDCl₃),  ppm: 163.2 (dd, ¹J = 247.6 Hz

and J = 13.1 Hz, C-F), 142.1, 140.7 (t, J = 9.6 Hz, C-F), 137.0, 136.6,

130.7, 128.1, 126.9, 126.6, 125.4 (t, ⁴J = 2.4 Hz, C-F), 111.6 (dd, ²J = 16.2

fluorophenyl)methyl]prop-2-enoate (18i). Yield 72%, greenish oil. IR (ATR,

3



_max): 3090, 2982, 2907, 1696, 1618, 1588, 1490, 1434, 1272, 1121, 1087,

860 cm^-1. H NMR (250 MHz, CDCl₃):  ppm 7.80 (s, 1H), 7.13-7.04 (m,

3H), 7.00-6.90 (m, 2H), 6.70 (s, 1H), 5.96 (s, 2H), 3.75 (s, 5H). ¹³C NMR

(62. MHz, CDCl₃):  ppm 167.8, 159.4 (d, J = 243.9 Hz, C-F), 148.7, 147.2,

1

4

2

Hz and J = 8.4 Hz, C-F), 102.5 (t, J = 25.4 Hz, C-F), 66.5, 32.7, 19.9.

HRMS (EI, m/z): Calcd. for C₁₇H₁₅F₂O [M-H]⁺273.1085; found 273.1091

4

140.0, 134.7 (d, J = 3.2 Hz, C-F), 131.8, 129.4, 129.3, 128.5, 115.6 (C-

Br), 115.4, 115.0, 112.9, 109.2, 102.0, 52.2, 32.3. HRMS (ESI, m/z): Calcd.

(2E)-3-(3,5-difluorophenyl)-2-[(3-methylphenyl)methyl]prop-2-en-1-ol

(26e). Yield: 98%, colorless oil. IR (ATR, _max): 3274, 3168, 2896, 2847,

1618, 1583, 1430, 1326, 1240, 1117, 1056, 873 cm^-1. ¹H NMR (250 MHz,

CDCl₃),  ppm: 7.23 – 7.16 (m, 1H), 7.06 – 6.95 (m, 3H), 4.14 (s, 2H), 3.63

(s, 2H), 2.33 (s, 3H). ¹³C NMR (151 MHz, CDCl₃),  ppm: 163.3 (dd, ¹J =

248.1 Hz and ³J = 13.4 Hz, C-F), 142.5, 140.8 (t, ³J = 9.7 Hz, C-F), 138.7,

138.5, 129.5, 129.0, 127.6, 125.6, 128.0 (t, ⁴J = 2.4 Hz, C-F), 111.7 (dd, ²J

= 20.1 Hz and ⁴J = 5.1 Hz, C-F), 102.5 (t, ²J = 25.5 Hz, C-F), 66.4, 34.7,

21.7. HRMS (EI, m/z): Calcd. for C₁₇H₁₅F₂O [M-H]⁺273.1085; found

273.1093

for C₁₈H₁₅BrFO₄[M+H]⁺393.0132; found 393.0175.

General procedure for the preparation of allylic alcohols 26a-i

To a separated stirred solutions of cinnamates 26a-i (1.44 mmol), at -78 °C,

under inert atmosphere, were added, drop by drop, a toluene solution of

diisobutyl aluminium hydride (DIBAL-H, 1 M, 5.0 equiv.). The reactions

were followed by TLC. After completion, a saturated solution of sodium

acetate (NaOAc, 2 mL) was added, followed by the addition of a saturated

solution of ammonium chloride (NH₄Cl, 2.0 ml). The resulting mixture was

vigorously stirred for 1h. After that, the reactions were filtered over a pad

of celite, under reduced pressure, with aid of a Büchner funnel. The filtered

organic solutions were washed with distilled water (20 mL), brine (20 mL)

and evaporated. The residues were diluted with ethyl acetate (50 mL) and

the organic phases were washed again with brine (3 x 15 mL), dried over

anhydrous Na₂SO₄, filtered and the solvent was removed under reduced

pressure. The crude products were then purified by silica gel column

chromatography using a mixture of ethyl acetate : hexane (36:64) to afford

the corresponding allylic alcohols.

(2E)-3-(3,5-difluorophenyl)-2-[(4-chlorophenyl)methyl]prop-2-en-1-ol (26f).

Yield: 97%, colorless oil. IR (ATR, _max): 3261, 2920, 2851, 1620, 1588,

1491, 1430, 1326, 1117, 895 cm^-1. ¹H NMR (400 MHz, CDCl₃),  ppm: 7.26

(d, ³J = 8.4 Hz, 2H), 7.09 (d, ³J = 7.8 Hz, 2H), 6.79 – 6.77 (m, 2H), 6.71 –

6.68 (m, 2H), 4.12 (s, 2H), 3.62 (s, 2H). ¹³C NMR (101 MHz, CDCl₃), 

ppm: 163.3 (dd, ¹J = 248.2 Hz and ³J = 13.2 Hz, C-F), 141.9, 140.5 (t, ³J

= 9.7 Hz, C-F), 137.1, 132.7, 130.0, 129.2, 125.5 (t, ⁴J = 2.2 Hz, C-F),

111.6 (dd, ²J = 18.4 Hz and ⁴J = 6.8 Hz, C-F), 102.8 (t, ²J = 25.3 Hz, C-F),

66.2, 34.1. HRMS (EI, m/z): Calcd. for C₁₆H₁₂ClF₂O [M-H]⁺293.0539;

found 293.0542

(2E)-3-(3,5-difluorophenyl)-2-[(4-fluorophenyl)methyl]prop-2-en-1-ol (26a).

Yield: 91%, colorless oil. IR (Film, _max): 3406, 1620, 1588, 1508, 1117,

(2E)-3-(3,5-Difluorophenyl)-2-[(4-methanesulfonylphenyl)methyl]prop-2-

en-1-ol (26g). Yield: 67%, pale yellow oil. IR (Film, _max): 3431, 2922, 1619,

1588, 1301, 1148, 1117 cm^-1. ¹H NMR (250 MHz, CDCl₃):  ppm 7.80 (d,

³J = 8.3 Hz, 2H), 7.32 (d, ³J = 8.4 Hz, 2H), 6.79-6.59 (m, 4H), 4.07 (s, 2H),

3.70 (s, 2H), 3.01 (s, 3H). ¹³C NMR (63 MHz, CDCl₃):  ppm 163.0 (dd, ¹J

= 248.2 Hz and ³J = 13.3 Hz, C-F), 162.8 (dd, ¹J = 248.2 Hz and ³J = 13.3

Hz, C-F), 145.3, 140.6, 140.0 (t, ³J = 9.4 Hz, C-F), 138.4, 129.3, 127.6,

125.7 (t, ⁴J = 2.3 Hz, C-F), 111.3 (d, ²J = 8.5 Hz, C-F), 111.1 (d, ²J = 8.4

1

1048 cm^-1. H NMR (250 MHz, CDCl₃),  ppm: 7.14-7.08 (m, 2H), 7.01-

6.95 (m, 2H), 6.81-6.77 (m, 2H), 6.74-6.65 (m, 2H), 4.12 (s, 2H), 3.63 (s,

2H). ¹³C NMR (63 MHz, CDCl₃),  ppm: 163.0 (dd, ¹J = 248.1 Hz and ³J =

13.1 Hz, C-F), 161.9 (d, ¹J = 244.6 Hz, C-F), 142.2, 140.6 (t, ³J = 9.6 Hz,

C-F), 134.2 (d, ⁴J = 3.3 Hz, C-F), 130.1 (d, ³J = 7.9 Hz, CF), 125.3 (t, ⁴J =

2.4 Hz, C-F), 115.9 (d, ²J = 21.3 Hz, C-F), 111.7 (dd, ²J = 16.2 Hz and ⁴J

2

= 8.5 Hz, C-F), 102.7 (t, J = 25.4 Hz, C-F), 66.2, 33.9. HRMS (EI, m/z):

Calcd. for C₁₆H₁₂F₃[M-H₂O]⁺261.0886; found 261.0865

Hz, C-F), 102.4 (t, J = 25.6 Hz, C-F), 65.5, 44.4, 34.2. HRMS (EI, m/z):

2

Calcd. for C₁₇H₁₆F₂O₃S 338.0788; found 338.0800.

(2E)-2-benzyl-3-(3,5-difluorophenyl)prop-2-en-1-ol (26b). Yield: 93%,

colorless oil. IR (ATR, _max): 3369, 3086, 3026, 1620, 1586, 1495, 1450,

1430, 1383, 1326, 1240, 1117, 1041, 987, 849 cm^-1. ¹H NMR (250 MHz,

CDCl₃),  ppm: 7.31 – 7.15 (m, 5H), 6.84 – 6.66 (m, 3H), 4.14 (s, 2H), 3.67

(s, 2H). ¹³C NMR (126 MHz, CDCl₃),  ppm: 163.3 (dd, ¹J = 247.9 Hz and

³J = 13.1, C-F), 142.4, 140.8 (t, ³J = 9.8 Hz, C-F), 138.6, 129.1, 128.7,

126.8, 125.1 (t, ⁴J = 2.1 Hz, C-F), 111.7 (dd, ²J = 19.5 Hz and ⁴J = 5.9 Hz,

C-F), 102.6 (t, ²J = 25.4 Hz, C-F), 66.3, 34.8. HRMS (EI, m/z): Calcd. for

C₁₆H₁₄F₂NaO [M+Na]⁺283.0905; found 283.0927

4-{2-[(3,5-Difluorophenyl)methyl]-3-hydroxypropyl}benzene-1-

sulfonamide (26h). Yield: 70%, brownish oil. IR (Film, _max): 3375, 3269,

3089, 2924, 1620, 1588, 1324, 1160, 1117cm^-1. ¹H NMR (250 MHz,

3

MeOD):  ppm 7.83 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.3 Hz, 2H), 6.89-

6.72 (m, 4H), 4.05 (d, J = 1.1 Hz, 2H), 3.71 (s, 2H). ¹³C NMR (63 MHz,

2

MeOD):  ppm 163.3 (dd, J = 246.7 Hz and ³J = 13.3 Hz, C-F), 163.1 (dd,

J = 246.8 Hz and ³J = 13.3 Hz, C-F), 143.5, 141.7, 141.6, 140.8 (t, ³J = 9.8

Hz, C-F), 128.5, 126.1, 124.6 (t, ⁴J = 2.3 Hz, C-F), 111.0 (d, ²J = 8.6 Hz,

C-F), 110.7 (d, ²J = 8.7 Hz, C-F), 101.5 (t, ²J = 25.7 Hz, C-F), 64.6, 33.5.

HRMS (ESI, m/z): Calcd. for C₁₆H₁₄F₂NO₂S [M-H₂O]⁺322.0713; found

322.0738.

(2E)-3-(3,5-difluorophenyl)-2-[(3,5-difluorophenyl)methyl]prop-2-en-1-ol

(26c). Yield: 98%, colorless oil. IR (ATR, _max): 3274, 3160, 2894, 2846,

1618, 1585, 1456, 1314, 1061, 1115, 841 cm^-1. ¹H NMR (500 MHz, CDCl₃),

 ppm: 6.79-6.68 (m, 7H), 4.14 (d, ²J = 4.7 Hz, 2H), 3.64 (s, 2H), 1.56 (t,

²J = 5.7 Hz, 1H). ¹³C NMR (126 MHz, CDCl₃),  ppm: 163.6 (dd, ¹J = 248.7

Hz and ³J = 12.8 Hz, C-F), 163.3 (dd, ¹J = 248.7 Hz and ³J = 13.2 Hz, C-

F), 142.7 (t, ³J = 8.7 Hz, C-F), 140.9, 140.2 (t, ³J = 9.5 Hz, C-F), 126.3 (t,

⁴J = 2.1 Hz, C-F), 111.6 (m, C-F), 103.0 (t, ²J = 25.3 Hz, C-F), 102.5 (t, ²J

= 25.4 Hz, C-F), 66.2, 34.4. HRMS (EI, m/z): Calcd. for C₁₆H₁₁F₄O [M-H]⁺

295.0741; found 295.0743

2-[(6-Bromo-2H-1,3-benzodioxol-5-yl)methyl]-3-(4-fluorophenyl)propan-1-

ol (26i). Yield: 87%, yellow oil. IR (Film, _max): 3397, 1601, 1507, 1475,

1

1411, 1265, 1223, 1157, 1114, 1038 cm^-1. H NMR (250 MHz, CDCl₃): 

ppm 7.12-7.04 (m, 3H), 7.00-6.90 (m, 2H), 6.73 (s, 1H), 6.59 (s, 1H), 5.95

(s, 2H), 4.10 (d, ²J = 1.1 Hz, 2H), 3.50 (s, 2H). ¹³C NMR (63 MHz, CDCl₃):

 ppm 159.5 (d, J = 244.3 Hz, C-F), 147.4, 147.0, 140.7, 134.3 (d, ⁴J = 3.2

Hz, C-F), 130.2, 129.9, 129.8, 126.6, 115.4, 115.1, 114.9 (C-Br), 112.6,

109.9, 101.7, 65.5, 33.6. HRMS (EI, m/z): Calcd. for C₁₇H₁₄BrFO₃

364.0110; found 364.0125.

(2E)-3-(3,5-difluorophenyl)-2-[(2-methylphenyl)methyl]prop-2-en-1-ol

(26d). Yield: 95%, colorless oil. IR (ATR, _max): 3313, 3077, 3019, 2920,

1620, 1588, 1432, 1326, 1117, 845 cm^-1. ¹H NMR (250 MHz, CDCl₃), 

General procedure for the preparation of allylic bromides 27a-i

10.1002/ejoc.201901850

European Journal of Organic Chemistry

FULL PAPER

To a stirred solution of allylic alcohols (26a-26i, 1.26 mmol) in anhydrous

dichloromethane, under argon atmosphere, at 0 °C, was added carbon

tetrabromide (1.89 mmol, 1.5 equiv.) and triphenylphoshine (1.64 mmol,

1.3 equiv.) The resulting mixture was maintained under stirring and TLC

followed the evolution of the reaction. After completion, the solvent was

partially removed under reduced pressure until 30% of the original volume.

To this concentrated solution was added hexane to precipitate the

triphenylphosphine oxide formed. After filtration, the resulting solution was

diluted with ethyl acetate and the organic phase was washed with brine (3

x 30.0 mL), dried over anhydrous Na₂SO₄, filtered and the solvent was

evaporated under reduced pressure. The crude was purified by silica gel

column chromatography using ethyl acetate: hexane (15:85) as eluent to

afford the corresponding allylic bromides.

1-[(1E)-3-bromo-2-[(4-chlorophenyl)methyl]prop-1-en-1-yl]-3,5-

difluorobenzene (27f). Yield: 91%, light yellow oil. IR (ATR, _max): 3088,

2922, 2851, 1620, 1588, 1491, 1430, 1326, 1216, 1119, 1091, 847 cm^-1.

¹H NMR (250 MHz, CDCl₃),  ppm: 7.28 (d, ³J = 8.2 Hz, 2H), 7.10 (d, ³J =

8.5 Hz, 2H), 6.82-6.70 (m, 4H), 3.95 (s, 2H), 3.77 (s, 2H). ¹³C NMR (63

MHz, CDCl₃),  ppm: 163.3 (dd, ¹J = 249.1 Hz and ³J = 13.2 Hz, C-F),

3

4

139.6 (t, J = 9.4 Hz, C-F), 139.2, 136.4, 133.0, 130.3, 130.0 (t, J = 2,5

Hz, C-F), 129.3, 111.8 (dd, ²J = 16.3 Hz and ⁴J = 8.8 Hz, C-F), 103.4 (t, ²J

= 25.2 Hz, C-F), 37.6, 34.2.

1-[(1E)-3-Bromo-2-[(4-methanesulfonylphenyl)methyl]prop-1-en-1-yl]-3,5-

difluorobenzene (27g). Yield: 90%, tinged yellow oil. IR (Film, _max): 3423,

2928, 1618, 1588, 1430, 1304, 1149, 1118 cm-1. ¹H NMR (250 MHz,

3

CDCl₃):  ppm 7.87 (d, J = 8.3 Hz, 2H), 7.36 (d, J = 8.3 Hz, 2H), 6.87-

6.66 (m, 4H), 3.93 (s, 2H), 3.87 (s, 2H), 3.04 (s, 3H). NMR ¹³C (63 MHz,

CDCl₃):  ppm 163.1 (dd, ¹J = 249.2 Hz and ³J = 13.3 Hz, C-F), 162.8 (dd,

¹J = 249.1 Hz and ³J = 13.0 Hz, C-F), 144.2, 139.1, 139.0 (t, ³J = 9.6 Hz,

C-F), 137.8, 130.5 (t, ⁴J = 2.5 Hz, C-F), 129.5, 127.8, 111.5 (d, ²J = 8.6 Hz,

C-F), 111.3 (d, ²J = 8.7 Hz, C-F), 103.2 (t, ²J = 25.2 Hz, C-F), 44.4, 37.1,

34.4. HRMS (ESI, m/z): Calcd. for C₁₇H₁₆BrF₂O₂S 401.0017; found

401.0111.

1-[(1E)-3-bromo-2-[(4-fluorophenyl)methyl]prop-1-en-1-yl]-3,5-

difluorobenzene (27a). Yield: 97%, light yellow oil. IR (Film, _max): 3041,

2927, 2859, 1626, 1596, 1509, 1461, 1315, 1257, 1223, 1158, 1117 cm^-1.

¹H NMR (500 MHz, CDCl₃),  ppm: 7.14-7.11 (m, 2H), 7.01-6.98 (m, 2H),

6.84-6.72 (m, 4H), 3.95 (s, 2H), 3.77 (s, 2H). ¹³C NMR (126 MHz, CDCl₃),

 ppm: 163.4 (dd, ¹J = 248.9 Hz and ³J = 13.1 Hz, C-F), 162.1 (d, ¹J =

245.2 Hz, C-F), 139.7 (t, ³J = 9.4 Hz, C-F), 139.6, 133.6 (d, ⁴J = 3.1 Hz, C-

F), 130.4 (d, ³J = 7.9 Hz, C-F), 129.8. (t, ⁴J = 2.1 Hz, C-F), 116.0 (d, ²J =

21.4 Hz, C-F), 111.8 (dd, ²J = 19.6 Hz and ⁴J = 6.2 Hz, C-F), 103.4 (t, ²J =

25.1 Hz, C-F), 37.7, 34.0. HRMS (ESI, m/z): Calcd. for C₁₆H₁₂F3BrLi

347.0234; found 347.0195

4-[(2E)-2-bromethyl-3-(3,5-difluorophenyl)prop-2-en-1-yl]benzene-1-

sulfonamide (27h). Yield: 96%, brownish oil. IR (Film, _max): 3381, 3272,

1620, 1590, 1325, 1162, 1119 cm^-1. ¹H NMR (250 MHz, CDCl₃):  ppm

7.86 (d, ³J = 8.5 Hz, 2H), 7.30 (d, ³J = 8.5 Hz, 2H), 6.85-6.67 (m, 4H), 5.27

(s, 2H – NH₂) 3.93 (s, 2H), 3.85 (s, 2H). ¹³C NMR (63 MHz, CDCl₃):  ppm

1-[(1E)-2-benzyl-3-bromoprop-1-en-1-yl]-3,5-difluorobenzene

(27b).

3

Yield: 96%, light yellow oil. IR (ATR, _max): 3064, 3028, 2924, 1620, 1588,

1497, 1454, 1430, 1326, 1216, 1119, 990, 847 cm^-1. ¹H NMR (600 MHz,

CDCl₃),  ppm: 7.33 – 7.17 (m, 5H), 6.85 – 6.72 (m, 4H), 3.98 (s, 2H), 3.81

(s, 2H). ¹³C NMR (151 MHz, CDCl₃),  ppm: 162.7 (dd, ¹J = 248.7 Hz and

³J = 13.3, C-F), 139.8 (t, ³J = 9.8 Hz, C-F), 139.7, 137.9, 129.7, 129.1,

128.8, 127.0, 111.7 (dd, ²J = 20.1 Hz and ⁴J = 5.1 Hz, C-F), 103.2 (t, ²J =

25.6 Hz, C-F), 37.8, 34.6.

163.0 (dd, J = 249.1 Hz and J = 13.3 Hz, C-F), 162.8 (dd, J = 249.1 Hz

3

and J = 13.3 Hz, C-F), 143.1, 140.5, 139.0 (t, J = 9.6 Hz, C-F), 137.9,

130.3 (t, ⁴J = 2.5 Hz, C-F), 129.3, 126.9, 111.5 (d, ²J = 8.7 Hz, C-F), 111.3

(d, ²J = 8.6 Hz, C-F), 103.2 (t, ²J = 25.3 Hz, C-F), 37.1, 34.4. HRMS (ESI,

m/z): Calcd. for C₁₆H₁₄BrF₂NNaO₂S⁺423.9789; found 423.9818.

5-Bromo-6-[(1E)-3-bromo-2-[(4-fluorophenyl)methyl]prop-1-en-yl]-2H-1,3-

benzodioxole (27i). Yield: 81%, colorless oil. IR (Film, _max): 1713, 1601,

1

1-[(1E)-3-bromo-2-[(3,5-difluorophenyl)methyl]prop-1-en-1-yl]-3,5-

difluorobenzene (27c). Yield: 95%, light yellow oil. IR (ATR, _max): 1620,

3100 – 2859, 1592, 1460, 1432, 1322, 1216, 1117, 847 cm^-1. ¹H NMR (500

MHz, CDCl₃),  ppm: 6.81-6.68 (m, 7H), 3.97 (s, 2H), 3.78 (s, 2H). ¹³C

1507, 1477, 1436, 1412 1265, 1038 cm^-1. H NMR (250 MHz, CDCl₃): 

ppm 7.79 (s, 1H), 7.12-7.04 (m, 3H), 7.00-6.90 (m, 2H), 6.70 (s, 1H), 5.97

(s, 2H), 3.75 (s, 4H). ¹³C NMR (63 MHz, CDCl₃):  ppm 159.4 (d, J = 244.1

4

Hz, C-F), 148.6, 147.2, 140.0, 134.7 (d, J = 3.2 Hz, C-F), 131.8, 129.4,

1

NMR (126 MHz, CDCl₃),  ppm: 163.61 (dd, J = 249.4 Hz and ³J = 13.1

129.3, 128.6, 115.6 (C-Br), 115.4, 115.0, 112.9, 109.2, 102.0, 52.1, 32.3.

HRMS (ESI, m/z): Calcd. for C₁₇H₁₃Br₂FO₂Li 432.9426; found 432.9352.

1

3

Hz, C-F), 163.4 (dd, J = 249.3 Hz and J = 13.1 Hz, C-F), 141.9 (t, ³J =

8.9 Hz, C-F), 139.35 (t, ³J = 9.4 Hz, C-F), 138.3 (s), 130.8 (t, ⁴J = 2.5 Hz,

C-F), 111.9-111.7 (m, C-F), 103.6 (t, ²J = 25.3 Hz, C-F), 102.8 (t, ²J = 25.3

Hz, C-F), 37.4, 34.6.

Malonate alkylation reaction. Preparation of ,-unsaturated diesters

28a-28i

1-[(1E)-3-bromo-2-[(2-methylphenyl)methyl]prop-1-en-1-yl]-3,5-

difluorobenzene (27d). Yield: 90%, light yellow oil. IR (ATR, _max): 3067,

3017, 2922, 1620, 1588, 1430, 1328, 1214, 1119, 849 cm^-1. ¹H NMR (250

MHz, CDCl₃),  ppm: 7.19 – 7.11 (m, 4H), 6.85 – 6.67 (m, 4H), 3.97 (s,

2H), 3.76 (s, 2H), 2.19 (s, 3H). ¹³C NMR (63 MHz, CDCl₃),  ppm: 163.2

(dd, ¹J = 248.6 Hz and ³J = 13.2 Hz, C-F), 139.9 (t, ³J = 9.6 Hz, C-F), 139.4,

137.3, 136.1, 130.9, 130.3 (t, ⁴J = 2.4 Hz, C-F), 128.5, 127.2, 126.6, 111.8

(dd, ²J = 16.3 Hz and ⁴J = 8.5 Hz, C-F), 103.3 (t, ²J = 25.3 Hz, C-F), 38.2,

32.6, 19.2.

To a stirred solution of allylic bromides (27a-27f, 1.23 mmol) in anhydrous

tetrahydrofuran (THF), at 0 °C, under nitrogen atmosphere, was added a

suspension of ethyl malonate (1.35 mmol, 1.1 equiv.) and sodium hydride

(1.48 mmol, 1.1 mmol) in anhydrous THF (2 mL). The resulting mixture

was vigorously stirred and TLC was used to follow the reaction evolution.

After completion, the solvent was removed under reduced pressure and to

the residue was added carefully distilled water (10 mL). The aqueous

phase was extracted with diethyl ether (3 x 30 mL). The combined organic

phases were washed with brine (3 x 15 mL), dried over anhydrous Na₂SO₄,

filtered and the solvente was removed under reduced pressure. The

residue was purified by silica gel column chromatography using a mixture

of ethyl acetate: hexane (12:88) as eluent to give the corresponding

diesters

1-[(1E)-3-bromo-2-[(3-methylphenyl)methyl]prop-1-en-1-yl]-3,5-

difluorobenzene (27e). Yield: 93%, light yellow oil. IR (ATR, _max): 3017,

2920, 2853, 1612, 1588, 1430, 1326, 1216, 1119, 849 cm^-1. ¹H NMR (250

MHz, CDCl₃),  ppm: 7.24 – 6.80 (m, 8H), 3.98 (s, 2H), 3.77 (s, 2H), 2.34

(s, 3H). ¹³C NMR (151 MHz, CDCl₃),  ppm: 163.3 (dd, ¹J = 248.4 Hz and

³J = 13.0 Hz, C-F), 139.9 (t, ³J = 11.6 Hz, C-F), 138.8, 137.9, 129.8 (t, ⁴J

1,3-Diethyl 2-[(2Z)-3-(3,5-difluorophenyl)-2-[(4-fluorophenyl)methyl]prop-

2-en-1-yl]propanedioate (28a). Yield: 76%, colorless oil. IR (Film, _max):

3457, 2983, 1749, 1732, 1619, 1588, 1508, 1223, 1118, 1095 cm^-1.¹H

NMR (250 MHz, CDCl₃):  ppm 7.12-7.05 (m, 2H), 7.03-6.93 (m, 2H), 6.74-

2

= 2.1 Hz, C-F), 129.7, 129.0, 127.8, 125.9, 111.8 (dd, J = 20.1 Hz, C-F

and ⁴J = 5.1 Hz, C-F), 103.3 (t, ²J = 25.6 Hz, C-F), 38.0, 34.6, 21.8.

10.1002/ejoc.201901850

European Journal of Organic Chemistry

FULL PAPER

3

6.62 (m, 3H), 6.46 (s, 1H), 4.18 (q, J = 7.1 Hz, 4H), 3.57 (t, J = 8.0 Hz,

1,3-Diethyl 2-[(2Z)-3-(3,5-difluorophenyl)-2-[(4-chlorophenyl)methyl]prop-

2-en-1-yl]propanedioate (28f). Yield: 76%, colorless oil. IR (ATR, _max):

2985, 2931, 1735, 1735, 1726, 1620, 1585, 1491, 1441, 1368, 1324, 1156,

1H), 3.57 (s, 2H), 2.66 (d, J = 7.8 Hz, 2H), 1.24 (t, J = 7.1 Hz, 6H). ¹³

C

3

1

3

NMR (63 MHz, CDCl₃):  ppm 168.6, 163.0 (dd, J = 248.2 Hz and J =

13.2 Hz, C-F), 162.7 (dd, ¹J = 248.3 Hz and ³J = 13.0 Hz, C-F), 161.6 (d,

¹J = 244.7 Hz, C-F), 140.3 (t, ³J = 9.4 Hz, C-F), 139.1, 133.6 (d, ⁴J = 3.2

Hz, C-F), 129.8, 129.7, 127.5 (t, ⁴J = 2.2 Hz, C-F), 115.7, 115.3, 111.3 (d,

²J = 8.5 Hz, C-F), 111.1 (d, ²J = 8.7 Hz, C-F), 102.2 (t, ²J = 25.7 Hz, C-F),

61.5, 50.5, 35.6, 35.3, 14.0. HRMS (ESI, m/z): Calcd. for C₂₃H₂₄F₃O₄

[M+H)⁺421.1627; found 421.1610.

3

1117, 840 cm^-1. ¹H NMR (250 MHz, CDCl₃),  ppm: 7.27 (d, J = 8.5 Hz,

2H), 7.06 (d, ³J = 8.2 Hz, 2H), 6.71 – 6.64 (m, 3H), 6.47 (s, 1H), 4.19 (q,

3

³J = 7.0 Hz, 4H), 3.57 (t, J = 8.2 Hz, 1H), 3.57 (s, 2H), 2.66 (d, ³J = 8.5

Hz, 2H), 1.25 (t, ³J = 7.2 Hz, 6H). ¹³C NMR (101 MHz, CDCl₃),  ppm:

169.0, 163.3 (dd, ¹J = 248.6 Hz and ³J = 13.2 Hz, C-F), 140.7 (t, ³J = 9.6

Hz, C-F), 139.2, 137.0, 132.7, 130.1, 129.2, 128.1 (t, ⁴J = 2.0 Hz, C-F),

111.6 (dd, ²J = 18.3 Hz and ⁴J = 6.7 Hz, C-F), 102.7 (t, ²J = 25.3 Hz, C-F),

+

61.9, 50.9, 36.2, 35.7, 14.4. HRMS (EI, m/z): Calcd. for C₂₃H₂₃ClF₂NaO₄

1,3-Diethyl

2-[(2Z)-2-benzyl-3-(3,5-difluorophenyl)prop-2-en-1-

459.1145; found 459.1122

yl]propanedioate (28b). Yield: 77%, colorless oil. IR (ATR, _max): 3086,

2982, 2939, 1730, 1620, 1586, 1497, 1434, 1326, 1229, 1145, 1119, 1033,

990, 849 cm^-1. ¹H NMR (500 MHz, CDCl₃),  ppm: 7.31 – 7.13 (m, 5H),

1,3-Diethyl

2-[(2Z)-3-(3,5-difluorophenyl)-2-[(4-

3

6.74 – 6.65 (m, 3H), 6.47 (s, 1H), 4.19 (q, J = 7.5 Hz, 4H), 3.61 (s, 2H),

methanesulfonylphenyl)methyl]prop-2-en-1-yl]propanedioate (28g). Yield:

70%, yellow tinged oil. IR (Film, _max): 3410, 2981, 2928, 1743, 1729, 1619,

1587, 1306, 1150, 1117 cm^-1. ¹H NMR (250 MHz, CDCl₃):  ppm 7.85 (d,

³J = 8.2 Hz, 2H), 7.32 (d, ³J = 8.2 Hz, 2H), 6.75-6.57 (m, 3H), 6.51 (s, 1H),

3.59 (t, ³J = 8.0 Hz, 1H), 2.69 (d, ³J = 8.0 Hz, 2H), 1.25 (t, ³J = 7.0 Hz, 6H).

NMR ¹³C (126 MHz, CDCl₃),  ppm: 169.1, 163.2 (dd, ¹J = 248.0 Hz and

³J = 13.1, C-F), 140.9 (t, ³J = 9.4 Hz, C-F), 139.6, 138.4, 129.1, 128.8,

127.8 (t, ⁴J = 1.9 Hz, C-F), 126.9, 111.6 (dd, ²J = 19.3 Hz and ⁴J = 5.8 Hz,

C-F), 102.6 (t, ²J = 25.5 Hz, C-F), 61.9, 50.9, 36.7, 35.9, 14.4. HRMS (EI,

m/z): Calcd. for C₂₃H₂₄F₂NaO₄⁺425.1535; found 425.1540

3

4.17 (q, J = 7.0 Hz, 4H), 3.68 (s, 2H), 3.58 (t, J = 8.0 Hz, 1H), 3.03 (s,

3H), 2.64 (d, ³J = 7.8 Hz, 2H), 1.23 (t, ³J = 7.1 Hz, 6H). ¹³C NMR (63 MHz,

CDCl₃):  ppm 168.5, 163.0 (dd, ¹J = 248.6 Hz and ³J = 13.2 Hz, C-F),

1

3

162.8 (dd, J = 248.6 Hz and J= 13.2 Hz, C-F), 144.8, 140.0 (t, J= 9.6

Hz, C-F), 138.9, 137.8, 129.3, 128.3 (t, ⁴J = 2,3 Hz, C-F), 127.8, 111.3 (d,

²J = 8.4 Hz, C-F), 111.0 (d, ²J = 8.5 Hz, C-F), 102.5 (t, ²J = 25.3 Hz, C-F),

61.6, 50.5, 44.4, 36.4, 35.2, 14.0. HRMS (ESI, m/z): Calcd. for

C₂₄H₂₇F₂O₆S [M+H]⁺481.1496; found 481.1477.

1,3-Diethyl

2-[(2Z)-3-(3,5-difluorophenyl)-2-[(3,5-

difluorophenyl)methyl]prop-2-en-1-yl]propanedioate (28c). Yield: 71%,

colorless oil. IR (ATR, _max): 2983, 2935, 1730, 1620, 1588, 1462, 1434,

1370, 1322, 1283, 1147, 1117, 847 cm^-1. ¹H NMR (250 MHz, CDCl₃), 

ppm: 6.71-6.65 (m, 6H), 6.52 (s, 1H), 4.19 (q, ³J = 7.5 Hz, 4H), 3.58 (t, ³J

= 7.5 Hz, 1H), 3.58 (s, 2H), 2.67 (d, ³J = 7.5 Hz, 2H), 1.25 (t, ³J = 7.5 Hz,

6H). ¹³C NMR (126 MHz, CDCl₃),  ppm: 168.9 (s), 163.6 (dd, ¹J = 248.9

Hz and ³J = 13.8 Hz, C-F), 163.3 (dd, ¹J = 248.9 Hz and ³J = 13.8 Hz, C-

1,3-Diethyl

2-[(2Z)-3-(3,5-difluorophenyl)-2-[(4-

sulfamoylphenyl)methyl]prop-2-en-1-yl]propanedioate (28h). Yield: 72%,

colorless oil. IR (Film, _max): 3372, 3262, 2985, 1742, 1728, 1619, 1587,

1332, 1266, 1162, 1118 cm^-1. ¹H NMR (250 MHz, MeOD):  ppm 7.84 (d,

³J = 8.3 Hz, 1H), 7.33 (d, ³J = 8.3 Hz, 1H), 6.83-6.73 (m, 3H), 6.56 (s, 1H),

4.17 (q, ³J = 7.1 Hz, 4H), 3.74 (t, ³J = 7.8 Hz, 1H), 3.70 (s, 2H), 2.64 (d, ³J

= 7.8 Hz, 2H), 1.21 (t, ³J = 7.0 Hz, 6H). ¹³C NMR (63 MHz, MeOD):  ppm

168.9, 163.1 (dd, J = 247.2 Hz and ³J = 13.3 Hz, C-F), 162.8 (dd, J = 247.2

Hz and ³J = 13.3 Hz, C-F), 143.1, 140.6 (t, ³J = 9.6 Hz, C-F), 138.5, 131.8,

128.7, 127.7 (t, ⁴J = 2.2 Hz, C-F), 126.2, 111.0 (d, ²J = 8.7 Hz, C-F), 110.8

3

F), 142.5 (t, J = 8.8 Hz, C-F), 140.4 (t, J = 8.8 Hz, C-F), 138.2, 128.8,

111.7, 111.5 (m, C-F), 102.9 (t, ²J = 25.1 Hz, C-F), 102.5 (t, ²J = 17.6 Hz,

C-F), 62.0, 50.9, 36.5, 35.7, 14.4. HRMS (EI, m/z): Calcd. for C₂₃H₂₂F₄O₄

[M+H]⁺439.1527; found 439.1531

1,3-Diethyl 2-[(2Z)-3-(3,5-difluorophenyl)-2-[(2-methylphenyl)methyl]prop-

2-en-1-yl]propanedioate (28d). Yield: 75%, colorless oil. IR (ATR, _max):

2983, 2941, 1730, 1620, 1588, 1434, 1370, 1326, 1231, 1145, 1119, 1035,

862 cm^-1. ¹H NMR (250 MHz, CDCl₃),  ppm: 7.16 – 7.10 (m, 4H), 6.69 –

(d, ²J = 8.3 Hz, C-F), 101.8 (t, J = 25.7 Hz, C-F), 61.3, 50.2, 35.7, 35.2,

13.0. HRMS (ESI, m/z): Calcd. for C₂₃H₂₆F₂NO₆S [M + H]⁺482.1449; found

482.1541.

2

3

6.1 (m, 3H), 6.49 (s, 1H), 4.18 (q, J = 7.0 Hz, 4H), 3.56 (t, J = 10.0 Hz,

1H), 3.56 (s, 2H), 2.68 (d, ³J = 8.0 Hz, 2H), 2.18 (s, 3H), 1.25 (t, ³J = 7.2

Hz, 6H). ¹³C NMR (101 MHz, CDCl₃),  ppm: 169.1, 163.2 (dd, ¹J = 248.0

Hz and ³J = 13.2 Hz, C-F), 142.0 (t, ³J = 9.6 Hz, C-F), 139.4, 137.0, 136.51,

130.8, 128.4, 128.0 (t, ⁴J = 2.2 Hz, C-F), 127.0, 126.6, 111.6 (dd, ²J = 18.4

1,3-Diethyl

2-[(2Z)-3-(6-bromo-2H-1,3-benzodioxol-5-yl)-2-[(4-

fluorophenyl)methyl]prop-2-en-1-yl]propanedioate (28i). Yield: 83%,

yellow tinged oil. IR (Film, _max): 2982, 2917, 1747, 1731, 1601, 1507, 1475,

1411, 1369, 1266, 1156, 1037 cm^-1. ¹H NMR (250 MHz, CDCl₃):  ppm

7.12-7.01 (m, 3H), 7.01-6.90 (m, 2H), 6.65 (s, 1H) 6.36 (s, 1H) 5.95 (s, 2H),

4.13 (q, ³J = 7.1 Hz, 4H), 3.60 (t, ³J = 7.7 Hz, 1H), 3.45 (s, 2H), 2.64 (d, ³J

= 7.7 Hz, 2H), 1.25 (t, ³J = 7.0 Hz, 6H). ¹³C NMR (63 MHz, CDCl₃):  ppm

168.8, 160.7 (d, J = 244.4 Hz, C-F), 147.4, 147.0, 137.8, 134.1 (d, ⁴J = 3.3

Hz, C-F), 130.6, 130.0, 129.9, 128.6, 115.4, 115.2, 114.8 (C-Br), 112.6,

110.0, 101.7, 61.5, 50.6, 35.8, 34.4, 14.0. HRMS (ESI, m/z): Calcd. for

C₂₄H₂₅BrFO₆[M + H]⁺507.0818; found 507.0891.

4

2

Hz and J = 6.7 Hz, C-F), 102.5 (t, J = 25.4 Hz, C-F), 61.9, 51.1, 36.1,

34.7, 19.9, 14.4. HRMS (EI, m/z): Calcd. for C₂₄H₂₆F₂NaO₄⁺439.1691;

found 439.1696

1,3-Diethyl 2-[(2Z)-3-(3,5-difluorophenyl)-2-[(3-methylphenyl)methyl]prop-

2-en-1-yl]propanedioate (28e). Yield: 73%, colorless oil. IR (ATR, _max):

2983, 2933, 1730, 1620, 1586, 1434, 1370, 1229, 1145, 1119, 866 cm^-1.

¹H NMR (250 MHz, CDCl₃),  ppm: 7.22 – 7.16 (m, 1H), 7.05 – 6.93 (m,

3H), 6.75 – 6.62 (m, 3H), 6.47 (s, 1H), 4.19 (q, ³J = 6.5 Hz, 4H), 3.60 (t, ³J

= 8.0 Hz, 1H), 3.58 (s, 2H), 4.69 (d, ³J = 8.0 Hz, 2H), 2.33 (s, 3H), 1.25 (t,

³J = 7.0 Hz, 6H). ¹H NMR (250.13 MHz, C₆D₆),  ppm: 7.06-7.00 (m, 1H),

General procedure for the preparation of the ,-unsaturated

carboxylic acids 17a-f

3

6.86 (m, 3H), 6.71-6.67 (m, 2H), 6.43-6.35 (m, 2H), 3.90 (q, J = 7.0 Hz,

4H), 3.68 (t, ³J = 7.7 Hz, 1H), 3.47 (s, 2H), 2.85 (d, ³J = 8.7 Hz, 2H), 2.06

(s, 3H), 0.87 (t, ³J = 7.2 Hz, 6H). ¹³C NMR (151 MHz, CDCl₃),  ppm: 169.1,

163.2 (dd, ¹J = 247.9 Hz and ³J = 13.0 Hz, C-F), 140.9 (t, ³J = 9.7 Hz, C-

F), 139.7, 138.7, 138.3, 129.5, 128.9, 127.8, 127.6, 125.7, 111.6 (dd, ²J =

19.9 Hz and ⁴J = 5.1 Hz, C-F), 102.5 (t, ²J = 25.5 Hz, C-F), 61.8, 50.9, 36.6,

35.9, 21.7, 14.4. HRMS (EI, m/z): Calcd. for C₂₄H₂₆F₂NaO₄⁺439.1691;

found 439.1692

Suspensions of the diethyl esters 28a-28f (0.62-0.65 mmol) in 20% HCl

aqueous solution (8.5-10 mL) were refluxed for 120 h and were allowed to

warm to room temperature. The final solutions were extracted with ethyl

acetate (3 x 10 mL). The organic portions were washed with distilled water

(3 x 20 mL), saturated NaCl solution (3 x 20 mL) and dried with anhydrous

Na₂SO₄. The solvents were evaporated under vaccum and the residues

were purified by flash silica gel column chromatography using ethyl

10.1002/ejoc.201901850

European Journal of Organic Chemistry

FULL PAPER

acetate:hexane (40:60) as eluent to provide the corresponding ,-

unsaturated carboxylic acids.

(4Z)-5-(3,5-difluorophenyl)-4-[(4-chlorophenyl)methyl]pent-4-enoic acid

(17f). Yield: 65% (85%, based on recovered starting material), amorphous

yellowish solid. M.p. 94 – 95 ^oC. IR (ATR, _max): 3088, 2920, 2853, 1700,

1618, 1586, 1491, 1303, 1216, 1117, 1093, 847 cm^-1. ¹H NMR (250 MHz,

CDCl₃),  ppm: 7.24 (d, ³J = 8.2 Hz, 2H), 7.04 (d, ³J = 8.2 Hz, 2H), 6.71 –

6.61 (m, 3H), 6.43 (s, 1H), 3.54 (s, 2H), 2.54 – 2.45 (m, 2H), 2.43 – 2.35

(4Z)-5-(3,5-difluorophenyl)-4-[(4-fluorophenyl)methyl]pent-4-enoic

acid

(17a). Yield: 64% (86%, based on recovered starting material), amorphous

white solid. M. p. 90-91 ºC. IR (Film, _max): 3086, 3037, 2925, 2861, 1710,

1619, 1588, 1508, 1431, 1322, 1222, 1117 cm^-1. ¹H NMR (250 MHz,

CDCl₃),  ppm: 7.13-7.07 (m, 2H), 7.02-6.95 (m, 2H), 6.76-6.64 (m, 3H),

6.45 (s, 1H), 3.58 (s, 2H), 2.58-2.51 (m, 2H), 2.44-2.38 (m, 2H). ¹³C NMR

(63 MHz, CDCl₃),  ppm: 179.5, 163.2 (dd, ¹J = 248.4 Hz and ³J = 13.2 Hz,

C-F), 161.9 (d, ¹J = 244.7 Hz, C-F), 141.4, 141.0 (t, ³J = 9.4 Hz, C-F), 134.3

(d, ⁴J = 3.1 Hz, C-F), 130.1 Hz (d, ³J = 7.5 Hz, C-F), 126.3 (t, ⁴J = 2.5 Hz,

C-F), 115.9 (d, ²J = 20.8 Hz, C-F), 111.6 (dd, ²J = 16.3 Hz and ⁴J = 8.2 Hz ,

C-F), 102.5 (t, ²J = 25.2 Hz, C-F), 36.3, 32.8, 31,6. HRMS (EI, m/z): Calcd.

for C₁₈H₁₄F₃O₂⁺[M-H]⁺319.0940; found 319.0972

1

(m, 2H). ¹³C NMR (63 MHz, CDCl₃),  ppm: 178.8, 163.3 (dd, J = 248.4

Hz and ³J = 13.2 Hz, C-F), 141.0, 140.9 (t, ³J = 9.4 Hz, C-F), 137.2, 132.7,

130.7, 130.1, 129.2, 126.6 (t, ⁴J = 2.5 Hz, C-F), 111.6 (t, ²J = 16.3 Hz and

⁴J = 8.8 Hz, C-F), 102.6 (t, ²J = 25.2 Hz, C-F), 36.5, 32.7, 31.6. HRMS (EI,

m/z): Calcd. for C₁₈H₁₃ClF₂NaO₂⁺359.0621; found 359.0652

Preparation of ,-unsaturated mono-esters 29g-i

To a stirred solution of di-esters 28g-i (0.94 mmol) in a mixture of

dimethylsulfoxide (DMSO) and water (3:1) was added NaCl (1.16 mmol).

The resulting solution was heated at 190 °C and the evolution of the

reactions were followed by TLC. After completion, the reaction mixture was

poured into a separating funnel containing distilled water (30 mL). The

mixture was then extracted with diethyl ether (6 x 30 mL). The combined

organic phases were washed with brine (3 x 15 mL), dried over anhydrous

Na₂SO₄, filtered and the solvent was removed under reduced pressure.

The crude residue was purified by silica gel column chromatography using

a mixture of ethyl acetate:hexane (20:80) to furnish the required mono-

ester.

(4Z)-4-benzyl-5-(3,5-difluorophenyl)pent-4-enoic acid (17b). Yield: 69%

(88%, based on recovered starting material), amorphous yellowish solid.

M. p. 95 – 97 ^oC. IR (ATR, _max): 3078, 3024, 2905, 2851, 2628, 2551,

1694, 1618, 1586, 1495, 1426, 1324, 1294, 1294, 1212, 1149, 1117, 1078,

1

985, 841 cm^-1. H NMR (400 MHz, CDCl₃),  ppm: 7.34 – 7.13 (m, 5H),

6.77 – 6.64 (m, 3H), 6.45 (s, 1H), 3.61 (s, 2H), 2.55 – 2.50 (m, 2H), 2.46 –

1

2.40 (m, 2H). ¹³C NMR (101 MHz, CDCl₃),  ppm: 178.6, 163.3 (dd, J =

3

247.9 Hz and J = 13.2, C-F), 141.6, 141.2 (t, J = 9.6 Hz, C-F), 138.7,

4

2

129.1, 128.8, 126.9, 126.2 (t, J = 2.2 Hz, C-F), 111.7 (dd, J = 18.4 Hz

and ⁴J = 6.7 Hz, C-F), 102.4 (t, ²J = 25.6 Hz, C-F), 37.1, 32.7, 31.8. HRMS

(EI, m/z): Calcd. for C₁₈H₁₆F₂NaO₂⁺325.1011; found 325.0979

Ethyl

(4Z)-5-(3,5-difluorophenyl)-4-[(4-

methanesulfonylphenyl)methyl]pent-4-enoate (29g). Yield: 82%, yellow

tinged oil. IR (Film, max): 3410, 2923, 1727, 1619, 1586, 1432, 1305,

1148, 1116 cm^-1. ¹H NMR (250 MHz, CDCl₃):  ppm 7.86 (d, J = 8.2 Hz,

2H), 7.33 (d, J = 8.2 Hz, 2H), 6.75-6.60 (m, 3H), 6.49 (s, 1H), 4.11 (q, ³J =

7.0 Hz, 2H), 3.68 (s, 2H), 3.04 (s, 3H), 2.55-2.44 (m, 2H), 2.44-2.32 (m,

4Z)-5-(3,5-difluorophenyl)-4-[(3,5-difluorophenyl)methyl]pent-4-enoic

acid (17c). Yield: 61% (84%, based on recovered starting material),

amorphous white solid. M. p. 93 – 94 ^oC. IR (ATR, _max): 3103, 2913, 1698,

1620, 1590, 1432, 1318, 1290, 1117, 975, 843 cm^-1. ¹H NMR (250 MHz,

CDCl₃),  ppm: 6.73-6.65 (m, 6H), 6.50 (s, 1H), 3.58 (s, 2H), 2.60-2.54 (m,

2H), 2.45-2.39 (m, 2H). ¹³C NMR (126 MHz, CDCl₃),  ppm: 178.5, 163.6

(dd, ¹J = 248.9 Hz and ³J = 12.8 Hz, C-F), 163.3 (dd, ¹J = 248.5 Hz and ³J

= 13.1 Hz, C-F), 142.8 (t, J = 8.8 Hz, C-F), 140.6 (t, J = 9.5 Hz, C-F),

140.1, 127.2, 111.7 – 111.5 (m, C-F), 102.8 (t, ²J = 25.4 Hz, C-F), 102.5 (t,

²J = 25.4 Hz, C-F), 36.8, 32.6, 31.6. HRMS (EI, m/z): Calcd. for

C₁₈H₁₃F₄O₂⁺[M-H] 337.0846; found 337.0855

3

2H), 1.23 (t, J = 7.1 Hz, 3H). ¹³C NMR (63 MHz, CDCl₃):  ppm 172.5,

163.0 (dd, ¹J = 248.4 Hz and ³J = 13.1 Hz, C-F), 162.8 (dd, ¹J = 248.4 Hz

3

and J = 13.1 Hz, C-F), 145.2, 140.4 (t, J = 9.5 Hz, C-F), 140.0, 138.8,

129.3, 127.7, 126.6 (t, ⁴J = 2.2 Hz, C-F), 111.3 (d, ²J = 8.3 Hz, C-F), 111.0

3

(d, ²J = 8.4 Hz, C-F), 102.3 (t, J = 25.4 Hz, C-F), 60.5, 44.5, 36.7, 32.5,

31.6, 14.2. HRMS (ESI, m/z): Calcd. for C₂₁H₂₃F₂O₄S [M + H]⁺409.1285;

2

found 409.1227.

(4Z)-5-(3,5-difluorophenyl)-4-[(2-methylphenyl)methyl]pent-4-enoic acid

(17d). Yield: 59% (81%, based on recovered starting material), amorphous

yellowish solid. M. p. 87 – 88 ^oC. IR (ATR, _max): 3080, 3017, 2918, 1700,

1620, 1586, 1430, 1298, 1212, 1117, 845 cm^-1. ¹H NMR (250 MHz, CDCl₃),

 ppm: 10.11 (s, 1H), 7.21 – 7.10 (m, 4H), 6.77 – 6.63 (m, 3H), 6.49 (s,

1H), 3.57 (s, 2H), 2.61 – 2.52 (m, 2H), 2.47 – 2.41 (m, 2H), 2.20 (s, 3H).

¹³C NMR (63 MHz, CDCl₃),  ppm: 179.5, 163.2 (dd, ¹J = 247.8 Hz and ³J

Ethyl

(4Z)-5-(3,5-difluorophenyl)-4-[(4-sulfamoylphenyl)methyl]pent-4-

enoate (29h). Yield: 69%, colorless oil. IR (Film, max): 3378, 3271, 3057,

2985, 1728, 1620, 1588, 1325, 1266, 1164, 1117 cm^-1. ¹H NMR (250 MHz,

CDCl₃):  ppm 7.85 (d, J = 8.3 Hz, 2H), 7.27 (d, J = 8.7 Hz, 2H), 6.77-

6,61 (m, 3H), 6.48 (s, 1H), 5.11 (s, 2H – NH₂), 4.11 (q, J = 7.1 Hz, 2H),

3.66 (s, 2H), 2.54-2.44 (m, 2H), 2.44-2.33 (m, 2H), 1.23 (t, ³J = 7.1 Hz, 3H).

¹³C NMR (63 MHz, CDCl₃):  ppm 172.7, 163.0 (dd, J = 247.9 Hz and ³J=

13.1 Hz, C-F), 162.9 (dd, J = 248.0 Hz and ³J = 13.2 Hz, C-F), 144.1, 140.5

(t, ³J = 9.5 Hz, C-F), 140.2, 129.1, 126.8, 126.5 (t, ⁴J = 2.1 Hz, C-F), 111.3

(d, ²J = 7.2 Hz, C-F), 111.1 (d, ²J = 7.0 Hz, C-F), 102.3 (t, ²J = 24.9 Hz, C-

F), 60.6, 36.6, 32.6, 31.6, 14.2. HRMS (ESI, m/z): Calcd. for C₂₀H₂₂F₂NO₄S

[M+H]⁺410.1237; found 410.1240.

3

= 13.3 Hz, C-F), 141.4, 141.1 (t, J = 9.6 Hz, C-F), 137.0, 136.8, 130.7,

4

2

128.3, 126.9, 126.5, 126.4 (t, J = 2.4 Hz, C-F), 111.5 (dd, J = 16.2 Hz

and ⁴J = 8.5 Hz, C-F), 102.3 (t, ²J = 25.3 Hz, C-F), 41.0, 34.9 32.1, 19.9.

HRMS (EI, m/z): Calcd. for C₁₉H₁₈F₂NaO₂⁺339.1167; found 339.1191

(4Z)-5-(3,5-difluorophenyl)-4-[(3-methylphenyl)methyl]pent-4-enoic acid

(17e). Yield: 57% (80%, based on recovered starting material), amorphous

yellowish solid. M.p. 88 – 89 ^oC. IR (ATR, _max): 2922, 1707, 1602, 1586,

1430, 1324, 1117, 873, 841 cm^-1. ¹H NMR (250 MHz, CDCl₃),  ppm: 9.98

(s, 1H), 7.26 – 7.17 (m, 1H), 7.06 – 6.94 (m, 3H), 6.79 – 6.64 (m, 3H), 6.45

(s, 1H), 3.58 (s, 2H), 2.56 – 2.51 (m, 2H), 2.46 – 2.43 (m, 2H), 2.34 (s, 3H).

¹³C NMR (101 MHz, CDCl₃),  ppm: 179.1, 163.2 (dd, ¹J = 247.9 Hz and

³J = 13.2 Hz, C-F), 141.7, 141.2 (t, ³J = 9.7 Hz, C-F), 138.7, 138.6, 129.5,

Ethyl

(4Z)-5-(6-bromo-2H-1,3-benzodioxol-5-yl)-4-[(4-

fluorophenyl)methyl]pent-4-enoate (29i). Yield: 78%, yellow tinged oil. IR

(Film, max): 3055, 2916, 2849, 1729, 1601, 1507, 1475, 1411, 1370,

1265, 1038 cm^-1. ¹H NMR (250 MHz, CDCl₃):  ppm 7.10-7.04 (m, 3H),

6.99-6.92 (m, 2H), 6.69 (s, 1H), 6.32 (s, 1H), 5.95 (s, 2H), 4.12 (q, ³J = 7.2

Hz, 2H), 3.44 (s, 2H), 2.53-2.47 (m, 5H), 2.40-2.34 (m, 2H), 1.24 (t, J =

7.1 Hz, 3H). ¹³C NMR (63 MHz, CDCl₃):  ppm 172.8, 161.4 (d, J = 244.0

3

4

2

4

128.9, 127.6, 126.2 (t, J = 2.2 Hz, C-F), 125.7, 111.7 (dd, J = 18.4 Hz

and ⁴J = 6.7 Hz, C-F), 102.4 (t, ²J = 25.5 Hz, C-F), 37.0, 32.8, 31.9, 21.8.

HRMS (ESI, m/z): Calcd. for C₁₉H₁₈F₂NaO₂⁺339.1167; found 339.1194

Hz, C-F), 147.3, 147.0, 140.0, 134.5 (d, J = 3.2 Hz, C-F), 130.8, 129.9,

129.8, 126.9, 115.4, 115.1, 114.9 (C-Br), 112.5, 110.0, 101.6, 60.4, 36.0,

32.8, 30.7, 14.2. HRMS (EI, m/z): Calcd. for C₂₁H₂₀BrFO₄434.0529; found

434.0481.

10.1002/ejoc.201901850

European Journal of Organic Chemistry

FULL PAPER

Esters basic hydrolysis. Synthesis of ,-unsaturated acids 17g-i

was slowly added to the reaction medium. During the addition of the acid

aqueous solution the reaction temperature was rigorously controlled in

order to not overcome 5 °C. The organic phase was separated and washed

with distilled water (3 x 50 mL), dried over anhydrous Na₂SO₄, filtered and

the solvent was removed under reduced pressure. The residue was

purified by silica gel column chromatography using a mixture of ethyl

acetate: hexane (36:64) to give the required substituted cyclopentenones.

A stirred methanolic solution of mono-esters 29g-i (0.75 mmol) was added

an aqueous solution of sodium hydroxide (NaOH, 5mL, 2 mol/L). The

resulting solution was heated under reflux and TLC followed the reaction

evolution. After completion, the mixture was cooled at room temperature

and the solvent was removed under reduced pressure. The residue was

washed with chloroform (50 mL). The aqueous solution was acidified with

a cooled aqueous solution of HCl (0 °C, 12 mol/L) until pH 2. After, the

acidified aqueous mixture was extracted with chloroform (3 x 30 mL). The

combined organic phases were dried over anhydrous Na₂SO₄, filtered and

the solvent was removed under reduced pressure. The residue was

purified by silica gel column chromatography using a mixture of ethyl

acetate: hexane (20:80) to provide the corresponding ,-unsaturated

acids.

2-(3,5-Difluorophenyl)-3-[(4-fluorophenyl)methyl]cyclopent-2-en-1-one (8).

Yield: 92%, brownish oil. IR (Film, _max): 3410, 2924, 1703, 1617, 1590,

1508, 1358, 1272, 1118 cm^-1. ¹H NMR (250 MHz, C₆D₆):  ppm 6.93-6.84

(m, 2H), 6.75-6.67 (m, 2H), 6.58-6.40 (m, 3H), 3.11 (s, 2H), 1.96-1.86 (m,

2H), 1.69-1.58 (m, 2H). ¹³C NMR (63 MHz, CDCl₃):  ppm 206.6, 174.0,

163.0 (dd, ¹J = 248.7 Hz and ³J = 13.2 Hz, C-F), 162.9 (dd, ¹J = 248.4 Hz

and ³J = 12.8 Hz, C-F), 161.8 (d, ¹J = 245.3 Hz, C-F), 139.3, 134.7 (t, ³J =

9.6 Hz, C-F), 132.4, 130.3, 130.2, 115.9, 115.7, 112.3 (d, ²J = 6.5 Hz, C-

2

F), 112.1 (d, J = 6.2 Hz, C-F), 103.4 (t, J = 24.9 Hz, C-F), 37.0, 34.6,

29.1. HRMS (ESI, m/z): Calcd. for C₁₈H₁₄F₃O [M+H]⁺303.0997; found

303.0966.

(4Z)-5-(3,5-difluorophenyl)-4-[(4-methanesulfonylphenyl)methyl]pent-4-

enoic acid (17h). Yield: 90%, yellow tinged oil. IR (Film, _max): 3415, 2922,

1

1705, 1620, 1438, 1303, 1148, 1116 cm^-1. H NMR (250 MHz, CDCl₃): 

ppm 7.96-7.84 (m, 3H), 7.51 (d, ³J = 8.3 Hz, 2H), 7.22-7.19 (m, 1H), 7.18-

7.15 (m, 1H), 7.00 (tt, ⁵J = 2.1 Hz and ³J = 9.1 Hz, 1H), 3.11 (s, 4H), 3.09-

3.05 (m, 2H), 3.00 (s, 3H). ¹³C NMR (63 MHz, CDCl₃):  ppm 176.1, 163.0

(dd, ¹J = 249.9 Hz and ³J = 12.4 Hz, C-F), 162.8 (dd, ¹J = 249.9 Hz and ³J

3-Benzyl-2-(3,5-difluorophenyl)cyclopent-2-en-1-one (9). Yield: 74%,

colorless oil. IR (ATR, _max): 3067, 3028, 2920, 2855, 1700, 1618, 1590,

1497, 1432, 1357, 1272, 1117, 998, 856 cm^-1. ¹H NMR (600 MHz, C₆D₆),

 ppm: 7.06 – 7.02 (m, 3H), 6.94 – 6.91 (m, 2H), 6.76 – 6.75 (m, 1H), 6.52

– 6.49 (m, 1H), 3.28 (s, 2H), 1.92 – 1.90 (m, 2H), 1.76 (m, 2H). ¹³C NMR

(151 MHz, C₆D₆),  ppm: 205.2, 173.2, 163.9 (dd, ¹J = 247.8 Hz and ³J =

12.8 Hz, C-F), 139.5, 137.8, 136.4 (t, ³J = 10.0 Hz, C-F), 129.6, 127.7,

113.1 (dd, ²J = 20.2 Hz and ⁴J = 5.1 Hz, C-F), 104.0 (t, ²J = 25.2 Hz, C-F),

38.2, 35.0, 29.5. HRMS (EI, m/z): Calcd. for C₁₈H₁₅F₂O⁺[M+H]⁺285.1085;

found 285.1072

3

= 12.7 Hz, C-F), 142.2 (t, J = 8.6 Hz, C-F), 141.1, 139.6, 131.7, 131.7,

127.6, 127.5 (t, ⁴J = 2.2 Hz, C-F), 110.8 (d, ²J = 8.7 Hz, C-F), 110.5 (d, ²J

= 8.7 Hz, C-F), 104.1 (t, ²J = 25.2 Hz, C-F), 44.4, 41.0, 28.8, 25.2. HRMS

(ESI, m/z): Calcd. for C₁₉H₁₉F₂O₄S [M+H]⁺381.0972; found 381.0995.

(4Z)-5-(3,5-Difluorophenyl)-4-[(4-sulfamoylphenyl)methyl]pent-4-enoic

acid (17i). Yield: 73%, yellow tinged oil. IR (Film, _max): 3386, 3279, 2924,

2852, 1717, 1622, 1594, 1438, 1322, 1266, 1161, 1117 cm^-1. ¹H NMR

(500 MHz, Methanol-D₄):  ppm 7.86 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.5

Hz, 2H), 6.91-6.87 (m, 2H), 6.85 (tt, 1H), 6.82 (s, 1H), 4.09 (s, 2H), 3.76

(s, 2H), 2.13-2.07 (m, 1H), 1.39-1.34 (m, 1H). ¹³C NMR (125 MHz,

Methanol-D₄):  ppm 196.7, 164.6 (dd, J = 247.2 Hz and ³J = 13.6 Hz, C-

2-(3,5-difluorophenyl)-3-[(3,5-difluorophenyl)methyl]cyclopent-2-en-1-one

(10). Yield: 86%, yellowish oil. IR (ATR, _max): 3103, 2924, 2853, 1689,

1618, 1590, 1465, 1434, 1355, 1324, 1115, 844 cm^-1. ¹H NMR (250 MHz,

C₆D₆),  ppm: 6.81-6.73 (m, 2H), 6.52-6.32 (m, 2H), 6.20-6.12 (m, 2H),

2.96 (s, 2H), 1.90-1.86 (m, 2H), 1.55-1.51 (m, 2H). ¹³C NMR (100 MHz,

C₆D₆),  ppm: 204.7, 170.7, 164.0 (dd, ¹J = 249.3 Hz and ³J = 10.5 Hz, C-

F), 163.9 (dd, ¹J = 249.3 Hz and ³J = 10.8 Hz, C-F), 141.6 (t, ³J = 8.8 Hz,

C-F), 140.1 (t, ⁴J = 2.1 Hz, C-F), 135.8 (t, ³J = 10.2 Hz, C-F), 113.2 – 112.4

3

F), 164.5 (dd, J = 246.7 Hz and J = 13.4 Hz, C-F), 145.0, 143.4, 143.3,

142.4 (t, ³J = 9.4 Hz, C-F), 130.0, 127.6, 126.1 (t, ⁴J = 2.3 Hz, C-F), 112.5

(d, ²J = 6.0 Hz, C-F), 112.3 (d, ²J = 6.1 Hz, C-F), 103.1 (t, ²J = 25.6 Hz, C-

F), 66.1, 49.7, 35.1. HRMS (ESI, m/z): Calcd. for C₁₈H₁₆F₂NO₄S [M-H]

380.0768; found 380.0761.

2

(m, C-F), 104.2 (t, J = 25.2 Hz, C-F), 103.2 (t, J = 25.3 Hz, C-F), 37.5,

34.9, 29.2. HRMS (EI, m/z): Calcd. for C₁₈H₁₃F₃O⁺[M+H]⁺321.0897; found

321.0921

(4Z)-5-(6-Bromo-2H-1,3-benzodioxol-5-yl)-4-[(4-

fluorophenyl)methyl]pent-4-enoic acid (17h). Yield: 88%, brownish oil. IR

(Film, _max): 3056, 2907,1709, 1603, 1507, 1475, 1411, 1306, 1266, 1222,

1146, 1038 cm^-1. ¹H NMR (250 MHz, CDCl₃):  ppm 7.10-7.04 (m, 3H),

6.99-6.92 (m, 2H), 6.69 (s, 1H), 6.34 (s, 1H), 5.95 (s, 2H), 3.44 (s, 2H),

2.58-2.52 (m, 2H), 2.42-2.36 (m, 2H). ¹³C NMR (63 MHz, CDCl₃):  ppm

177.1, 161.5 (d, J = 245.7 Hz, C-F), 147.3, 147.0, 139.6, 134.4 (d, ⁴J = 3.2

Hz, C-F), 130.7, 129.9, 129.8, 127.3, 115.4, 115.2, 114.9 (C-Br), 112.6,

110.0, 101.7, 36.0, 32.2, 30.5. HRMS (ESI, m/z); Calcd. for C₁₉H₁₅BrFO₄

[M-H] 405.0138; found 405.0120.

2-(3,5-Difluorophenyl)-3-[(2-methylphenyl)methyl]cyclopent-2-en-1-one

(11). Yield: 67%, yellowish oil. IR (ATR, _max): 3075, 3017, 2922, 1700,

1618, 1590, 1432, 1357, 1272, 1117, 858 cm^-1. ¹H NMR (250 MHz, C₆D₆),

 ppm: 7.02 – 6.88 (m, 5H), 6.76 – 6.72 (m, 1H), 6.54 – 6.45 (m, 1H), 3.28

(s, 2H), 1.94 – 1.90 (m, 2H), 1.73 – 1.68 (m, 5H). ¹³C NMR (125 MHz,

C₆D₆),  ppm: 205.2, 173.4, 163.9 (dd, ¹J = 247.9 Hz and ³J = 12.9 Hz, C-

F), 139.3 (t, J = 2.5 Hz, C-F), 137.1, 136.4 (t, J = 10.0 Hz, C-F), 136.2,

131.3, 130.2, 128.0, 127.1, 113.1 (dd, ²J = 19.9 Hz and ⁴J = 6.0 Hz, C-F),

103.9 (t, ²J = 25.3 Hz, C-F), 36.2, 35.0, 29.5, 19.9. HRMS (EI, m/z): Calcd.

for C₁₉H₁₇F₂O⁺[M+H]⁺299.1242; found 299.1245

4

3

Synthesis of 2,3-substituted cyclopentenones 8-16

2-(3,5-Difluorophenyl)-3-[(3-methylphenyl)methyl]cyclopent-2-en-1-one

(12). Yield: 69%, yellowish oil. IR (ATR, _max): 2985, 2939, 1730, 1620,

1588, 1434, 1374, 1324, 1236, 1164, 1119, 1069, 1020, 843 cm^-1. ¹H NMR

(250 MHz, C₆D₆),  ppm: 7.04 – 6.85 (m, 4H), 6.64 – 6.46 (m, 3H), 3.29 (s,

2H), 2.07 (s, 3H), 1.93 – 1.89 (m, 2H), 1.81 – 1.77 (m, 2H). ¹³C NMR (125

MHz, C₆D₆),  ppm: 205.2, 173.3, 164.0 (dd, ¹J = 248.0 Hz and ³J = 12.9

Hz, C-F), 139.4, 139.1, 137.7, 136.4 (t, ³J = 9.9 Hz, C-F), 130.4, 129.5,

126.7, 113.2 (dd, J = 19.9 Hz and ⁴J = 6.2 Hz, C-F), 104.0 (t, J = 25.3

Hz, C-F), 38.3, 35.0, 29.6, 21.9. HRMS (EI, m/z): Calcd. for C₁₉H₁₇F₂O⁺

299.1242; found 299.1226

To a stirred solution of ,-unsaturated acids 17a-h (0.69 mmol) in

anhydrous dichloromethane (10 mL), under inert atmosphere, at 0 °C, was

added a drop of dry N,N-dimethylformamide (DMF). To this solution was

slowly added, for 15 minutes, oxalyl chloride (0.07 mmol, 0.07 ml). The

resulting solution was maintained under vigorous stirring for 1h. After that,

the reaction temperature was warmed to the room temperature and then a

solution of aluminum chloride (AlCl₃) in anhydrous dichloromethane was

transferred with aid of cannula. The resulting reaction was cooled to 0 °C

and stirred for 10 minutes. After, an aqueous solution of HCl (1N, 30 mL)

2

10.1002/ejoc.201901850

European Journal of Organic Chemistry

FULL PAPER

3-[(4-chlorophenyl)methyl]-2-(3,5-difluorophenyl]ciclopent-2-en-1-one

(13). Yield: 71%, yellowish oil. IR (ATR, _max): 3080, 2931, 2853, 1698,

1618, 1590, 1491, 1421, 1357, 1277, 1121, 1091, 849 cm^-1. NMR ¹H (250

MHz, C₆D₆),  ppm: 7.01 (d, J = 8.5 Hz, 2H), 6.86 (d, J = 8.2 Hz, 2H),

6.54 – 6.41 (m, 3H), 3.08 (s, 2H), 1.94 – 1.90 (m, 2H), 1.65 – 1.61 (m, 2H).

NMR ¹³C (151 MHz, C₆D₆),  ppm: 204.9, 172.1, 163.9 (dd, ¹J = 248.1 Hz

and ³J = 12.8 Hz, C-F), 139.6 (t, ⁴J = 2.3 Hz, C-F), 136.1, 136.1 (t, ³J = 9.4

Hz, C-F), 133.7, 130.9, 129.7, 113.1 (dd, ²J = 20.2 Hz and ⁴J = 5.1 Hz, C-

F), 104.1 (t, ²J = 25.0 Hz, C-F), 37.4, 34.9, 29.3. HRMS (EI, m/z): Calcd.

for C₁₈H₁₄ClF₂O⁺319.0696; found 319.0729

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3

[2]

[3]

[4]

[5]

2-(3,5-Difluorophenyl)-3-[(4-methanesulfonylphenyl)methyl]cyclopent-2-

en-1-one (14). Yield: 79%, yellow oil. IR (Film, _max): 3418, 2922, 1700,

1623, 1559, 1310, 1151, 1117 cm^-1. ¹H NMR (250 MHz, C₆D₆):  ppm 7.89

5

(d, ³J = 8.3 Hz, 2H), 6.48 (tt, J = 2.2 Hz and ³J = 9.3 Hz, 1H), 6.35-6.31

P. D. Storer, J. Xu, J. A. Chavis. P. D. Drew, J. Neuroscience Res. 2005,

80, 66-74 and references cited therein.

(m, 1H) 6.31-6.27 (m, 1H), 3.09 (s, 2H), 2.37 (s, 3H), 2.06-1.95 (m, 2H),

1.75-1.65 (m, 2H). ¹³C NMR (63 MHz, CDCl₃):  ppm 206.4, 172.3, 163.3

(dd, ¹J = 250.0 Hz and ³J = 12.9 Hz, C-F), 163.1 (dd, ¹J = 250.0 Hz and ³J

T. S.-L. Banchelin, S. Carret, A. Giannini, J. –P. Deprés, Eur. J. Org.

Chem. 2009, 3678-3682; For the biological activity of (+)-achalensolide,

see: T. Hirose, N. Miyakoshi, C. Mukai, J. Org. Chem. 2008, 73, 1061-

1066.

3

= 12.8 Hz, C-F), 140.5, 140.2 (t, J = 8.9 Hz, C-F), 140.0, 137.0, 130.0,

127.6, 111.8 (d, ²J = 8.4 Hz, C-F), 111.5 (d, ²J = 8.4 Hz, C-F), 102.8 (t, ²J

= 25.3 Hz, C-F), 44.4, 37.3, 34.6, 29.3. HRMS (ESI, m/z): Calcd. for

C₁₉H₁₇F₂O₃S [M+H]⁺363.0866; found 363.0828.

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a) R. Yokayama, J. M. Huang, C. S. Yang, Y. Fukuyama, J. Nat. Prod.

2002, 65, 527-531; b) L. Trzoss, J. Xu, M. H. Lacoske, W. C. Mobley, E.

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G. Goel, H. P. S. Makkar, G. Francis, K. Becker, Int. J. Toxicology 2007,

26, 279-288.

4-{[2-(3,5-Difluorophenyl)-3-oxocyclopent-1-en-1-yl]methyl}benzene-1-

sulfonamide (15). Yield: 78%, white solid. M. p. 181 – 182°C. IR (Film,

a) J. Wang, Y. H. Shen, H. Z. Jun, J. J. Fu, X. J. Hu, J. J. Qin, J. H. Liu,

M. Chen, S. K. Yan, W. D. Zhang, Org. Lett. 2008, 10, 5517-5520; b) C.

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

_max): 3292, 3200, 1684, 1621, 1593, 1339, 1160, 1117 cm^-1. ¹H NMR (250

3

MHz, MeOD):  ppm 7.96 (d, J = 8.5 Hz, 2H), 7.46 (d, J = 8.5 Hz, 2H),

6.89-6.72 (m, 3H), 3.92 (s, 2H), 2.68-2.60 (m, 2H), 2.60-2.51 (m, 2H). ¹³

C

[9]

For some reviews concerning a comprehensive discussion about

NMR (63 MHz, MeOD):  ppm 208.2, 174.0, 163.3 (dd, J = 247.9 Hz and

³J = 13.2 Hz, C-F), 163.1 (dd, J = 247.6 Hz and ³J = 12.8 Hz, C-F), 143.0,

inflammation, see: a) J. N. Fullerton, D. W. Gilroy, Nat. Rev. Drug

Discovery 2016, 15, 551-567; b) S. Shalapour, M. Karin, J. Clin. Invest.

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Res. 2004, 22, 913-922.

2

141.3 (t, ³J = 8.9 Hz, C-F), 140.0, 135.5, 129.5, 125.8, 111.6 (d, J = 8.5

2

Hz, C-F), 111.3 (d, J = 8.5 Hz, C-F), 101.7 (t, J = 25.7 Hz, C-F), 36.6,

34.2, 28.9. HRMS (ESI, m/z): Calcd. for C₁₈H₁₆F₂NO₃S [M+H]⁺364.0819;

found 364.0823.

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1929-1933.

2-(6-Bromo-2H-1,3-benzodioxol-5-yl)-3-[(4-

fluorophenyl)methyl]cyclopent-2-en-1-one (16). Yield: 90%, viscous

brownish oil. IR (Film, _max): 3054, 2905, 1659, 1617, 1506, 1479, 1375,

1265, 1242, 1040 cm^-1. ¹H NMR (250 MHz, C₆D₆):  ppm 7.26-7.16 (m,

2H), 7.03-6.96 (m, 2H), 6.61 (s, 1H), 6.22 (s, 1H), 6.00 (s, 2H), 3.53 (s,

2H), 2.77-2.72 (m, 2H), 2.31-2.26 (m, 2H). ¹³C NMR (63 MHz, CDCl₃): 

ppm 199.8, 161.7 (d, J = 244.9 Hz, C-F), 151.3, 146.6, 144.8, 134.3 (d, ⁴J

= 3.2 Hz, C-F), 133.8, 130.4, 130.3, 127.7, 115.5, 115.2, 114.8 (C-Br),

110.3, 109.3, 101.7, 45.3, 42.6, 26.1. HRMS (EI, m/z): Calcd. for

C₁₉H₁₄BrFO₃388.0110; found 388.0124

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Acknowledgments

The authors thank the São Paulo Research Foundation

(FAPESP) for financial support. Specifically, LGSF and MVR are

grateful to the FAPESP for fellowships (processes nr

2017/08229-8 and 2008/08438-7). In addition, FC thanks the

Brazilian National Council for Scientific and Technological

Development (CNPq) for a research fellowship (processes nr#

301330/2018-2 and 307840/2014-0) and financial support

(422890/2016-2)

#

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Keywords: Cyclopentenones • Morita-Baylis-Hillman • rhodium

• anti-inflammatory • Friedel-Crafts acylation

10.1002/ejoc.201901850

European Journal of Organic Chemistry

FULL PAPER

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10.1002/ejoc.201901850

European Journal of Organic Chemistry

FULL PAPER

Organic Synthesis*

M. V. Roldão, L. G. Souza-Filho, W. P.

Almeida and Fernando Coelho*

Page No. – Page No.

A straightforward approach to the

synthesis of disubstituted

cyclopentenones

We described an approach to di-substituted cyclopentenones with potential anti-

inflammatory activity, using MBH adducts as building blocks. The synthesis is

based on a rhodium mediated 1,4-addition and an intramolecular Friedel-Crafts

type reaction.

* Synthesis of di-substituted cyclopentenones

Article Doi

A Straightforward Approach to the Synthesis of Disubstituted Cyclopentenones

DOI: 10.1002/ejoc.201901850

Source and publish data:

Authors:

Article abstract of DOI:10.1002/ejoc.201901850

Full text of DOI:10.1002/ejoc.201901850

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