Synthesis of 3-Carbonyl Trisubstituted Furans via Pd-Catalyzed Aerobic Cycloisomerization Reaction: Development and Mechanistic Studies

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Synthesis of 3‑Carbonyl Trisubstituted Furans via Pd-Catalyzed

Aerobic Cycloisomerization Reaction: Development and Mechanistic

Studies

Amanda A. Barboza,^§Attilio Chiavegatti Neto,^§Isac G. Rosset, Guilherme A. M. Jardim,

and Marco A. B. Ferreira *

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ABSTRACT: Herein, we report the synthesis of 3-carbonyl-

trisubstituted furans via Pd-catalyzed oxidative cycloisomerization

reactions of 2-alkenyl-1,3-dicarbonyl scaﬀolds, using molecular

oxygen as the sole oxidant to regenerate active palladium catalytic

species, featuring good functional tolerance and mild reaction

conditions. Deep investigation of intermediates and transition

states of the reaction mechanism were conducted via experimental and DFT studies, providing a detailed mechanistical proﬁle. The

new developed methodology presents a greener alternative to Wacker-type cycloisomerizations and avoids the use of stoichiometric

amounts of oxidants and strong acid additives.

these oxidants,¹⁶and several Pd^IIcatalyzed aerobic oxidative

INTRODUCTION

■

transformations were highlighted in recent reviews.^9,11,13An

Furans represent an important class of electron-rich ﬁve-

membered heterocyclic compounds, which are broadly

important example comprises the aerobic oxidations of

alcohols mediated by Pd^IIchiral diamines by Sigman and co-

workers (Scheme 1A).¹⁷For aerobic asymmetric cyclizations,

the unprecedented work of Stoltz and collaborators describes

the synthesis of substituted benzofuran moieties in excellent

yields and stereoselectivity (Scheme 1B).¹⁸Among Pd-

catalyzed intramolecular cycloisomerization methodologies to

form 3-carbonyl furans, the use of 2-alkynyl-1,3-dicarbonyl

substrates had received considerable attention from the

synthetic community.¹⁹Curiously, although 2-alkenyl-1,3-

dicarbonyl-based compounds are the most structurally

accessible substrates, they were barely explored in the context

of Wacker-type chemistry to access these frameworks. To date,

only two methodologies were found in literature regarding the

Pd-catalyzed aerobic synthesis of 3-carbonyl trisubstituted

furans. The pioneering work described by Han and

Widenhoefer presents a limited scope and the need for an

excessive amount of CuCl₂cooxidant for catalyst regener-

ation.²⁰In subsequent works, Ghorai and co-workers

demonstrated the synthesis of polysubstituted furans and the

oxidative cyclization of o-cinnamyl phenols through the use of

substituted oleﬁns.²¹However, both reactions requires the use

distributed as structural frameworks in natural products¹and

biologically relevant moieties, including important pharma-

ceutical ingredients.²Remarkably, 3-carbonyl-bearing furans

are a common occurrence in current drug prototypes, such as

amiodarone,³sarcofuranocembrenolide B,⁴and wortmannin,⁵

considered important examples of bioactive molecules (Figure

1). In 2017, Dong and co-workers reported the synthesis and

antiviral activity against lethal H5N1 inﬂuenza A viruses of

unprecedented furan-carboxamide derivatives (Figure 1).⁶In

the past few decades, transition-metal-catalyzed reactions

involving oxygen atoms and nonactivated π-bonds comprised

the strategy of choice to synthesize polysubstituted furans.⁷

Palladium-catalyzed reactions embody some of the most

powerful methods for selective oxidative intramolecular

cycloisomerization strategies,^8,9but at the end of the process,

generated Pd⁰requires the use of a stoichiometric oxidant,

such as Cu^II, Ag^I, benzoquinone, or O₂to regenerate Pd^II

species.¹⁰

The use of stoichiometric amounts of molecular oxygen as

reoxidant, allied with catalytic amounts of palladium

complexes, has enormous advantages due to the sustainability

associated with the formation of environmentally benign

byproducts like water and hydrogen peroxide.¹¹However, in

the absence of a cocatalyst, Pd⁰has a tendency to precipitate

into its inactive metallic form.^12,13In some cases, improved

stability of Pd⁰-based catalysts is observed in the presence of

molecular sieves¹⁴and ancillary ligands.¹⁵In this context,

current research has focused on the development of more

environmentally friendly methods in order to avoid the use of

Received: November 19, 2020

Published: February 24, 2021

https://dx.doi.org/10.1021/acs.joc.0c02777

J. Org. Chem. 2021, 86, 3923−3942

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Figure 1. Examples of occurrence of substituted furans in natural products and drug prototypes.

Scheme 1. Summary of Previous Methodologies and Work overview

of stoichiometric quantities of benzoquinone as oxidant and/or

strong acid (p-TsOH) as additive. As part of our interest in

metal-catalyzed aerobic oxidative processes,²²herein we

describe the development, scope, and limitations in the

synthesis of 3-carbonyl trisubstituted furans via Pd-catalyzed

oxidative cycloisomerization reactions of 2-alkenyl-1,3-dicar-

bonyl compounds, using molecular oxygen as the sole oxidant

to regenerate active palladium catalyst species (Scheme 1C).

We also propose a mechanistic rationalization supported by

DFT calculations, NMR experiments, multivariate regression

analysis, and kinetic isotopic eﬀects (KIE) of this trans-

formation.

using K₂CO₃,¹⁸we started our investigation about the

reactivity of 2-alkenyl-β-ketoester 1a by exploring similar

related conditions, using 5 mol % of PdCl₂(CH₃CN)₂as

catalyst in DMF (entry 1, Table 1). This preliminary

experiment led to complete consumption of the starting

material, but a low yield of 2a was observed, together with a

complex mixture of byproducts. No further improvement was

obtained by decreasing the reaction temperature to 40 °C

(entry 2). Next, use of NaOAc resulted in 60% yield of the

expected furan (entry 3), while the use of a bulkier and

stronger base (t-BuOK, entry 4) led to inhibition of the desired

product. The eﬀect of the base stoichiometry (entries 5−7)

and temperature variation (entries 8−9) were also evaluated,

but no improvement in yield was observed. The choice of Pd^II

source was found to impact catalytic eﬃciency (entry 3 versus

entries 11−15), but the investigated options provided

RESULTS AND DISCUSSION

■

Based on a previous report relating the promotion of the Pd-

mediated aerobic heterocyclization reactions in basic medium

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Table 1. Optimization of the Reaction Conditions for the

formation of 2a*

Scheme 2. Scope for Pd-Catalyzed Aerobic

Cycloisomerization of 1,3-Dicabonyl Ester Derivatives

Bearing O-Substituents*

entry

catalyst

base (equiv)

solvent

DMF

yield (%)

a

1

Pd(CH₃CN)₂Cl₂

Pd(C₆H₅CN)₂Cl₂

PdCl₂

K₂CO₃(1.0)

K₂C0₃(1.0)

16

12

60

NR

60

50

17

33

42

43

20

NR

12

27

23

27

38

NR

6

2

3

4

5

6

7

NaOAc (1.0)

^tBuOK (1.0)

NaOAc (2.0)

NaOAc (0.2)

̵

DMF

dioxane

THF

DMAc

DMSO

acetonitrile

PEG 400

toluene

anisole

DMF

b

8

c

NaOAc (1.0)

9

10

11

12

13

14

15

Pd(OAc)₂

Pd(TFA)₂

Pd(Phen)Cl₂

Pd(Quinox)Cl₂

Pd(CH₃CN)₂Cl₂

Pd(CH₃CN)₂Cl2

Pd(CH₃CN)₂Cl₂

d

16

17

18

19

20

21

22

23

24

*

a

Isolated yields are shown. Without 4 A MS.

15

13

3

70

62

particular, p-NO₂benzylic substrate (1e) gave 2e in only 32%

yield. Analysis by GC−MS (Figure S1) showed the presence of

benzyl alcohol, potentially from ester hydrolysis of 2a in which

this result could partially explain the lower yield involving

electron-withdrawing ester substituents. In general, reactions

with diﬀerent substrates were monitored via TLC and total

starting material consumption was observed after 24 h. It was

noted that longer reaction times provided minor yields in

several cases, even when starting material was still detected.

Overall, the yields were usually lower when bulkier ester

moieties were employed (2f−j), possibly due to hindering

eﬀects at cyclization steps. Primary and secondary alkyl esters

aﬀorded high yields (2f−g,i, >80% yield), except for the

sterically bulky isoborneol derivative 1j (2j, 54% yield),

showing similar results with tertiary alkyl ester 1h (2h, 52%

yield). When the structural complexity was increased, such as

the introduction of a cholesterol backbone, a satisfactory yield

of 73% was observed for 2k. The importance of molecular

sieves was evaluated for representative substrates 2a,c,f (yields

in parentheses, Scheme 2), highlighting how the reaction

performance is dramatically aﬀected by this additive.

Next, we explored possibilities of modiﬁcation in the ketone

portion of β-ketoester substrates (4a−h) (Scheme 3).

Evaluating the electronic demand of aromatic groups (4a−

c), a small decrease in yield was observed in the presence of an

electron-withdrawing nitro group (4b). It was noted that

longer reaction times provided minor yields, as exempliﬁed for

products 4a and 4b, which provided yields of 52% and 38%,

respectively, after 40 h of reaction. A variety of alkyl chains,

such as the ethyl (4d), isopropyl (4e), and cyclopropyl (4f) at

the ketone portion, were compatible, providing average to

e

25

26

f

DMF

*

The tests were performed employing 0.3 mmol of 1a in 2 mL of

solvent and O₂atmosphere (1 atm). Variations in reaction conditions

are described in each footnote. 80 °C and 0.1 M. 60 °C. rt. 2.5

mol % of Pd(CH₃CN)₂Cl₂. 80 mg of 4 Å molecular sieves. Addition

of LiCl (1.0 equiv).

a

b

c

d

e

f

unsatisfactory results. When 2.5 mol % of PdCl₂(CH₃CN)₂

was used, 2a was obtained in only 27% yield (entry 16). A brief

examination of the eﬀects of solvents showed that the use of

polar solvents resulted in poorer reaction performance. The

use of dioxane, THF, DMAc, and toluene in place of DMF

aﬀorded low yields (entries 17−20), while DMSO and

acetonitrile (entries 20 and 21) were considerably less

eﬀective. Green solvents such as PEG 400 and anisole (entries

22 and 24) were also tested, showing equal ineﬃciency.

Finally, use of 4 Å molecular sieves provided the desired

product in 70% yield (entry 25), and use of a halogenated

additive (LiCl) resulted in a slight decrease in yield (entry 26).

After establishing the best reactional parameters (entry 25,

Table 1), our eﬀorts continued to provide a scope for the

optimized transformation. The ﬁrst modiﬁcation was carried

out on the ester portion of 1,3-dicarbonyl substrates (Scheme

2). Substitution patterns on the aryl group by electron-

donating and -withdrawing groups displayed average variations

in yield (2a−e). Although reaction with an electron donor p-

OMe substituent (2b, 70% yield) showed no apparent eﬀect,

electron-withdrawing substituents (2c−e) resulted in decreases

in yield, with complete conversion of starting materials. in

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substrate 5b provided derivative 6b in 67% yield. Unfortu-

nately, for cyclic β-diketone 5c and tetrasubstituted substrates

5d−e, the optimized protocol was not suﬃcient to promote

cyclization.

Scheme 3. Scope for Pd-Catalyzed Aerobic

Cycloisomerization of 1,3-Dicarbonyl Ketone Derivatives

Bearing Diﬀerent Groups in the Ketone Portion*

To evaluate the eﬀect of molecular oxygen in the reaction

processing, a control experiment with system deoxygenation

was performed using the freeze−pump−thaw deoxygenation

technique,²⁴resulting in 15% yield of 2a, while the absence of

molecular sieves furnished the same product in 4% yield

(Scheme 5A). This fact may be due to remaining O₂being

Scheme 5. Control Experiments and Scaling Eﬀects for the

Optimized Conditions

*

a

Isolated yields. Addition of LiCl (1 equiv).

good yields, where 4d proved to be volatile, which explains a

decrease in yield. As expected, the tert-butyl derivative

suppressed the formation of products, providing 4g with less

than 2% yield, reﬂecting the severe steric hindrance imposed

by this substituent. When a methoxymethyl side chain

substrate was employed, the desired product 4h was obtained

in low yields (18% and 20% with addition of LiCl), potentially

due to the formation of bidentate complex palladium species.²³

In general, lower yields could be attributed to ester group

decomposition (further details are discussed in the Para-

metrization and Multivariate Regression Analysis section).

Finally, to determine the generality of the cyclization,

substituted β-diketone substrates 5a−e were investigated

(Scheme 4). The optimized established conditions enabled

the use of nonsymmetric acyclic diketone (5a), giving 6a in

50% yield and complete regioselectivity. The symmetrical

strongly adsorbed on the molecular sieves. These yields are

considerably lower than those obtained under the optimized

conditions, corroborating the importance of oxygen in

reactional media. Additionally, the use of atmospheric air as

a source of oxygen was evaluated for substrates 1a, 3c, and 5b

(Scheme 5B). It was observed that reaction was eﬃcient, and

yields for derivatives 2a, 4c, and 6b were close to the ones

obtained using the optimized condition. These results show

that the reactions can be performed in order to avoid the use of

oxygen gas, increasing the safety of procedures at the cost of a

small loss of performance. In terms of applicability, the

reaction was escalated to gram scale, resulting in product 2a

with 68% yield (Scheme 5C).

a

Scheme 4. Scope for More Challenging Substrates

MECHANISTIC INVESTIGATION

■

Initial Considerations. Nucleopalladations are considered

one of the most common mechanisms for palladium-catalyzed

oxidative functionalization of oleﬁns, where the formation of π-

alkene−palladium complexes plays a fundamental role in

stereo- and regioselectivity.²⁵The interactions between a

nucleophile and the π-bond of palladated intermediates are

governed by a combination of steric and electronic eﬀects, such

as orbital interactions,²⁶steric bulky of involved species,²⁷

dispersion forces, and electrostatics.²⁸Recently, Liu and co-

workers analyzed these diﬀerent types of nucleophile−

substrate interactions using a computational approach.²⁹The

a

Isolated yields.

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Scheme 6. Possibilities for Reaction Pathways Investigated in This Work

electronic nature of palladium catalysts, controlled by anionic

coordinated ligand additives,³⁰can alter the polarization of the

electron-density of oleﬁns in the palladated π-alkene complex,

and together with the analysis of the nucleophile, it is possible

to predict Markovnikov selectivity in the transition states as

well as plausible intermediates in intermolecular nucleopalla-

dation processes.

Scheme 7. KIE Experiments

Considered equally important, palladium-catalyzed stereo-

controlled intramolecular nucleophilic attacks on metal

coordinated oleﬁns³¹using oxygen³²or nitrogen³³atoms as

nucleophiles have been heavily investigated in the literature.

Insightful examples can be found in the works of Wolfe³⁴and

Stahl.³⁵Intramolecular Wacker-type oxidative cyclizations,

after the oxypalladation step, can proceed by a most favorable

5-exo-cyclization, with two possibilities of attack (anti and

syn).³⁶Previous works showed that strongly and bulky

coordinated ligands at Pd core like Cl⁻favors anti-oxy-

palladation by hindering the nucleophile attack,³⁷while use of

nonmetal oxidants like molecular oxygen or benzoquinone, in

the absence of salt additives, makes syn-oxypalladation addition

more favorable.^38,39Despite this knowledge, there is a lack of

works aimed at the understanding of the main steps of the

mechanism of 2-alkenyl-1,3-dicarbonyl scaﬀolds in palladium

cycloisomerizations, and the study of such a process is

essential. In this section, we disclose a full mechanistic

rationalization supported by DFT calculations, NMR experi-

ments, multivariate regression analysis, and KIE experiments

(Scheme 6).

NMR and KIE Experiments. The use of a base for the

reaction follows the hypothesis that the oxo-palladation step is

preceded by a tautomerization equilibrium, and the enolic

form would be responsible for the attack.²¹Following this

hypothesis, NMR studies were conducted (see the Supporting

Information, section 4), revealing no α-carbonyl proton

abstraction in 1a after base addition. Additionally, we observe

an absence of deprotonated substrate after addition of

PdCl₂(CH₃CN)₂. These results may indicate no accumulation

of this active specie in reaction media and, therefore, the

involvement of the α-carbonyl proton removal in the rate-

determining step of the process. To support this hypothesis,

kinetic isotopic eﬀect (KIE) experiments were conducted

(Scheme 7 and Supporting Information) resulting in a k_H/k_D=

1.70 0.14, suggesting a rate-limiting step related to the α-

carbonyl proton removal by NaOAc.

tional studies involving Pd-catalyzed cyclizations of 2-alkenyl-

1,3-dicarbonyl scaﬀolds have been nonexistent in the literature.

Driven by those facts, DFT studies were carried out using 7 as

the model substrate (Scheme 8A). As shown above,

substitution of one acetonitrile in Pd^IIcomplex leads to an

anionic intermediate 7c (anionic path), with a signiﬁcant

reduction in free energy (7c, ΔG = −5.8 kcal/mol). Another

possibility, like direct complexation of 7 with Pd(CH₃CN)₂Cl₂

(neutral path) after an acetonitrile substitution event, provides

intermediate 7k-4 with an energy preference slightly lower

than the previous one (7k-4, ΔG = −2.7 kcal/mol). Direct

enolization of 7 (enolate path) resulted in a higher energy

intermediate (7′′, ΔG = 10.8 kcal/mol), and its formation

should be mediated by the palladium complex and the base. A

detailed description of other reactional intermediates is

described in the Supporting Information. Following the

anionic pathway, π-complexation possibilities between complex

7c and the oleﬁn portion of the model substrate 7 were

calculated, together with several ligand substitution events

between acetonitrile and acetate. Free energy values showed

that monosubstitution of acetonitrile ligand by one acetate,

followed by π-complexation with the oleﬁn portion to generate

intermediate 7d was the most favorable event (ΔG = −11.6

kcal/mol) (Scheme 8B). These complexes present η²-type

complexation with palladium center, with bond lengths of

order of 2.2 Å (see the Supporting Information).

Next, one of the plausible pathways was considered and

calculated, in which the acetate ligand deprotonates the β-

ketoester carbon, resulting in enolization, showing a transition

state with the highest value of free energy (TS-1, ΔΔG = 26.4

kcal/mol) among the lower anionic energy paths, which

corroborates with the k_H/k_Dvalue found in the KIE

experiments. This endergonic step involves the formation of

the unstable enolate intermediate 7e (ΔG = 7.1 kcal/mol).

DFT Calculations. Mechanistic description based on

theoretical methods regarding intramolecular oxypalladations

were thoroughly investigated for alkenol-based substrates.⁴⁰

Until recently, mechanistic interpretations based on computa-

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a

Scheme 8. Possible Reaction Pathways and Initial Ligand Exchanges Involving Pre-complex PdCl₂(MeCN)₂

a

Gibbs free energies in kcal/mol at M06/6-111+g(d,p)-(def2tzvp for Pd) IEF-PCM-[DMF].

The further step comprises a 5-exo-trig cyclization,⁴¹and the

energies of the two possible attacks of the oxygen atom were

measured (syn and anti), in which the anti-attack was strongly

disfavored in terms of free energy barrier (TS-3, ΔΔG = 10.2

kcal/mol). A more favorable path, involving an inner-sphere

syn insertion, was revealed to be less energetic, being initiated

by the departing of AcOH by the oxygen enolate attack

through an associative interchange mechanism (TS-2, ΔΔG =

5.2 kcal/mol), forming the thermodynamically favorable

intermediate 7f (ΔG = −1.2 kcal/mol). The inner-sphere syn

insertion generates the highly strained planar square complex

hydrogen and the palladium core, with a bond length of 1.91 Å

and Pd−H−C angle of 97°. Transition state TS-7 characterizes

a β-hydride elimination (ΔΔG = 2.1 kcal/mol), leading to π-

complex 7j, that suﬀers ligand exchange to aﬀord product 8

and regenerate catalyst (Scheme 9).

We also evaluated a mixed neutral/anionic pathway, in

which the oleﬁn coordinates to the palladium catalyst 7a and

replace an acetonitrile ligand. Both cis (7k-4) and trans (7k-2)

intermediates were explored, and the lowest energy pathway

can be seen in Scheme 10 (see Scheme S2 for the pathway

involving 7k-4). Initially, we evaluated the syn and anti-attack

starting from the 7k-2 intermediate, in which the reaction

could proceed (see Schemes S1 for additional diastereomeric

transition states). The lower energy transition state TS-7d

involves a carbonyl attack opposed to the palladium metal,

showing an energy barrier of ΔΔG = 14.3 kcal/mol, forming a

high energy oxonium intermediate 9b (ΔG = 11.2 kcal/mol).

This intermediate could undergo barrierless steps (see Figure

S172), involving the extrusion of acetonitrile and complexation

of acetate ion, producing the anionic intermediate 13 (ΔG =

9.3 kcal/mol), that precedes the deprotonation of the β-

ketoester carbon. A competitive pathway for these steps would

involve the direct cyclization of intermediate 7d, previously

discussed without prior deprotonation, but stationary points

and transition states could not be located. In subsequent steps,

a low energy transition state TS-10 (ΔΔG = 3.3 kcal/mol)

̌

̀

7g through TS-4 (ΔΔG = 9.9 kcal/mol). In fact, Kocovsky and

̈

Backvall reported that syn-additions are common in the case of

intramolecular oxy- and amido-palladation, when initial

coordination of the internal nucleophile to the metal is

observed.⁴²From 7g, all subsequent steps presented a lower

energy barrier and are thermodynamically favorable. At ﬁrst, 7g

undergoes into a four membered cyclic transition state TS-5

(ΔΔG = 4.3 kcal/mol) to result in less strained intermediate

7h, bearing a η¹-type complexation (bond length of 2.2 Å),

with an exocyclic double bond. This bond length characterizes

a weaker bond, a feature that facilitates the conversion of 7h

into a conformer that enables a β-hydride insertion event. This

event is processed via another four membered transition state

(TS-6, ΔΔG = 1.6 kcal/mol) to generate intermediate 7i,

presenting an agnostic interaction with the recently inserted

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a

Scheme 9. Relative Gibbs Energy Proﬁle for the Anionic Path

a

Gibbs free energies in kcal/mol at M06/6-111+g(d,p)-(def2tzvp for Pd) IEF-PCM-[DMF].

characterizes deprotonation of the β-ketoester carbon by the

coordinated acetate ion, leading to a dramatic decrease in

energy, producing the thermodynamically favorable intermedi-

ate 14 (ΔG = −10.4 kcal/mol). All subsequent steps are

related to ligand exchange events to form the reactive cis-

complex 7g, responsible for the ﬁrst β-H elimination step and

converging to the anionic mechanism previously discussed.

Analyzing the full energy proﬁle connecting both anionic

and neutral pathways, and applying the kinetic model of

Kozuch and Shaik,⁴³we identiﬁed the rate-limiting states 7d

and TS-1 (anionic)/ TS-10 (neutral), deﬁning the energy span

(δE) and kinetic of this reaction (Scheme 11). For both

pathways the energy proﬁle corroborates the conclusions

obtained from the KIE experiments, suggesting the deproto-

nation of the β-ketoester carbon as the turnover determining

states. The experimental KIE value was 1.7, whereas the

calculated KIE from TS-1 and TS-10 geometries were 3.3 and

3.9, respectively. The lower value of the experimental KIE

indicates that some elementary step must have some degree of

rate control in the catalytic cycle.⁴⁴In our scenario, the

theoretical neutral pathway showed elementary steps in the

catalytic cycle presenting TSs of similar energies as the C−H

activation TS-1 (Scheme 11). Considering essentially the free

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a

Scheme 10. Relative Gibbs Energy Proﬁle for Mixed Neutral/Anionic Path

a

Gibbs free energies in kcal/mol at M06/6-111+g(d,p)-(def2tzvp for Pd) IEF-PCM-[DMF].

energies of all the species and energy span (δE), the conclusion

would be that the mixed neutral/anionic path dominates.

Parametrization and Multivariate Regression Anal-

ysis. From the previously theoretical calculations indicating

the deprotonation of the β-ketoester carbon as the rate-limiting

transition state, a better performance involving the electron-

deﬁcient starting materials was expected. However, a possible

dichotomy between acidity and oxygen nucleophilicity in the

nucleopalladation step persists. Lower yields were observed for

strong electron-withdrawing groups, both in the ester and

ketone portions, although no ketoester starting material

remaining at the end of the reaction. In addition, the steric

inﬂuence seems to have greater importance in the ketonic

portion of the ketoester. Considering the lack of an obvious

relationship between reactivity and structural features of the

ketoesters, we decide to apply statistical correlations tools to

interrogate the origin of the reaction eﬃciency and its

relationship with the reaction mechanism.⁴⁵Our general

workﬂow to this study started choosing the product to collect

their molecular descriptors, including calculated electronic and

steric parameters (Figure 2). Initially, a conformational search

of products was initiated using Molecular Mechanics (MM),

followed by DFT geometry optimization (see the Supporting

Information for further details). All used parameters in the

models are values of the Boltzmann averaged conformers. The

electronic feature of each 3-carbonyl-trisubstituted furan was

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a

Scheme 11. Free Energy Network Connecting Rate-Limiting States of Anionic and Neutral Pathways

a

Gibbs free energies in kcal/mol at M06/6-111+g(d,p)-(def2tzvp for Pd) IEFPCM-[DMF].

measured relative to the natural bond orbital (NBO) charges

of oxygens (q_O) and carbons (q_C), NBO energies of lone pairs

of oxygens (E_LP(O)), and δ_COand δ*_COof the ester carbonyl

fragment.^45,46The steric eﬀects caused by the groups attached

in the carbonyl functional group were individually assessed

using Verlop’s Sterimol parameters L, B₁, and B₅.⁴⁷

Next, multivariate regression analysis was carried out to

investigate the cooperative impact of the electronic and steric

parameters in the reaction yield, using the training set (12

samples, including R and R′ variations). The model produced

good internal-validation scores (leave-one-out Q²), k-fold, and

a coeﬃcient of determination (R²) of 0.95 (Figure 3A).

Additionally, this model described reasonably well the test set

(ﬁve samples). The model overestimates the yield for the

outlier 2j, which we attributed to the underestimation of the

size of isoborneol by B_1(R′)descriptor. The multivariate model

was expressed in three interpretable terms, discriminating

diﬀerent aspects of the reaction mechanism (Figure 3A,B).

The partitioning of the yield, according to these terms, helped

the rationalization of their importance according to the

structural features of products, as can be seen in Figure 3C.

The average energy of the π-symmetry lone pair E_{LP2_O6}

describes the electron density of the ester group and is related

to the decomposition of product/starting material. We

assumed this hypothesis after the identiﬁcation of benzylic

alcohol by GC−MS during reaction monitoring analysis. The

decrease in yield of products 2c, 2d, 2e, and 4b followed the

increase of the electron-withdrawing group in the aromatic

portion, with the descriptor E_{LP2_O6}being largely responsible

for this reduction. As illustrated in Figure 3C, this term has a

positive contribution for electron-rich esters 2b,g−i,k,

reﬂecting the increase in stability.

In contrast, the second hybrid stereoelectronic descriptor

q_O1:B_1(R)reﬂects the electronic and steric nature of the R

group, suggesting a direct correlation with the TS-10, and

consequently the β-hydrogen abstraction event. Electron-rich

R groups make this step diﬃcult, featuring negative values for

this descriptor, such as 4f and 4g. In contrast, while electron-

withdrawing R groups increase the yield by this descriptor,

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Figure 2. General modeling workﬂow (A) and structural features correlating with yield (B).

electron-poor R/R′ groups reinforce the drop in yield due to

ester decomposition (E_{LP2_O6}), as pictured for 4b (Figure 3C).

The third descriptor B_1(R):B_1(R′)intercorrelates the sterics

between R/R′ substituents and suggests a decreased yield in

the presence of bulky groups, with higher sensitivity for R

portion. Despite the highest coeﬃcient, and therefore the

greatest signiﬁcance to the model, its values show little

variation over the series of compounds, except for the 2h and

4g, containing very bulky substituents (Figure 3C). Consid-

ering that TS-7d and TS-10 are close in energy, this scenario

may be related to a change in the steric regime and,

consequently, the rate-limiting transition state. Analyzing the

geometries of these transition states, only the TS-10 would

have a greater sensitivity to the inclusion of bulky groups,

especially in the R position, leading to a drastic decrease of

yield and justifying the previous observations.

General Overview of Proposed Reaction Pathways.

Finally, a mechanistic proposal could be illustrated to provide

a general overview of the two main reaction pathways (anionic

and neutral). The anionic cycle begins with ligand exchange

followed by π-complexation to generate 7d, which undergoes

α-hydrogen abstraction, resulting in intermediate 7e. Then the

oxygen atom binds to the Pd core via cis-nucleopalladation

(intermediate 7f), and a syn attack in the endocyclic oleﬁn

carbon leads to 7g. The ﬁnal steps involve a β-hydride

elimination to give 7h, followed by a β-H insertion and another

β-hydride elimination event (intermediates 7h and 7i). After

proton abstraction, an acetonitrile ligand coordinates to

palladium, resulting in product 8a, that after oxidation of

Pd(0) by O₂regenerates the catalyst 7c (Scheme 12). In the

neutral path, 7b undergoes π-complexation to generate 7k-2

and after carbonyl attack generates oxonium intermediate 9b.

After ligand exchange events, anionic intermediate 13 is

produced, and deprotonation of the β-ketoester carbon by the

coordinated acetate ion generates 14. After coordination of a

Cl⁻(intermediate 15) and ligand exchange, intermediate 17

leads to 7g, and the cycle continue via the previous anionic

pathway (Scheme 12).

CONCLUSIONS

■

In summary, we developed a mild, eﬃcient, and greener

reaction for the synthesis of 3-carbonyl-trisubstituted furan

scaﬀolds via Pd-catalyzed Wacker-type cycloisomerization

using O₂as the sole oxidant for the process, constituting a

reliable methodology for the preparation of important building

blocks starting from 2-alkenyl-1,3-dicarbonyl moieties. Fur-

thermore, experimental and computational studies made

possible a detailed and unprecedented description of the

reaction mechanism. This work represents a successful example

of a highly detailed mechanistically aerobic cycloisomerization

strategy to prepare furan-based building blocks and open new

avenues toward the chemistry of potential bioactive structures.

EXPERIMENTAL SECTION

■

General Methods. Reagents, when not synthesized, as well as

solvents were obtained commercially and when necessary were treated

using standard laboratory techniques according to methods published

by Perrin, Armarego, and Perrin (Pergamon Press, 1966).⁴⁸Thin-

layer chromatography analyses (TLC) using ﬂuorescent-treated silica

gel 60 (F₂₅₄) coated aluminum plates and revealed under UV light

and/or vanillin were performed to follow up the reactions. Column

chromatography using silica gel 60 (230−240 mesh) was the

technique of choice for puriﬁcations. The H and ¹³C NMR spectra

1

were recorded using the Bruker Advance 400 brand spectrometer at

400 and 100 MHz, respectively, employing CDCl₃or DMSO-d₆as

solvent, using tetramethylsilane (TMS) for the H NMR spectra as a

1

reference and for the ¹³C spectra the solvent signal was used, with the

chemical displacements (δ) reported in ppm and the coupling

constants (J) in hertz (Hz). The following abbreviations were used to

note signal multiplicities: s, singlet; sl, singlet large; d, doublet; t,

triplet; q, quartet; dd, doublet of doublets; ddd, doublet of doublet of

doublets; dt, doublet of triplets; ddt, doublet of doublet of triplets; dq,

doublet of quartets; m, multiplet; p, pentet; sept, septet; td, triplet of

doublets; tt, triplet of triplets. The Shimadzu IR Prestige-21

spectrophotometer was used to obtain infrared spectra with

wavelength absorbances (cm⁻¹). Melting point analyses were

performed on a melting point M-560 (BUCHI) apparatus, and

high-resolution mass spectra were recorded using a Bruker model

IMPACT HD spectrometer operating in positive mode and

electrospray ionization source with quadrupole time-of-ﬂight analyzer

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Figure 3. Mechanistic investigation by multidimensional regression modeling. (A) and (B) E_{LP2_O6}, descriptor of average energy of the π-symmetry

lone pair; q_O1:B_1(R), second hybrid stereoelectronic descriptor; B_1(R):B_1(R′), descriptor that intercorrelates the sterics between R/R′ substituents.

(C) The partitioning of the yield with positive and negative contributions of descriptors presented in model Y (%) = 65.0 + E_{LP2_O6}− q_O1:B_1(R)

B_1(R):B_1(R′).

+

(ESI-QqTOF). Optical rotations were measured on a PerkinElmer

Polarimeter. Warning: despite the absence of any accidents involving the

use of oxygen gas in the adopted synthetic procedures, all experiments were

conducted in a controlled environment, composed of a fume hood with

appropriate exhaust. All experiments were conducted without pressuriza-

tion.

Preparation of 2-Alkenyl-β-ketoester Derivatives. Method I. The

following procedure was adapted from literature.⁴⁹The β-ketoester

(10.4 mmol, 1.00 equiv), acetone (30 mL), and potassium carbonate

(13.5 mmol, 1.30 equiv) were added in an ace tube, respectively. Allyl

bromide (13.5 mmol, 1.30 equiv) was added, and the mixture was

stirred overnight at 60 °C using a an oil bath. After completion, the

reaction was ﬁltered, and the solvent was evaporated under reduced

pressure. The crude product was puriﬁed by ﬂash silica column

chromatography using a mixture of hexane and ethyl acetate (9:1) as

eluent.

acetylpent-4-enoate (7) (20 mmol, 1.0 equiv), the respective alcohol

(30 mmol, 1.5 equiv), and catalyst (2 mmol, 0.1 equiv, boric acid,⁵⁰or

iron nanoparticle⁵¹), were added in a round-bottom ﬂask with toluene

(100 mL). The mixture was reﬂuxed using a an oil bath under

vigorous stirring for 12 h using a Dean−Stark apparatus. After

completion, the solvent was evaporated under reduced pressure, and

the crude product was puriﬁed by ﬂash silica column chromatography

using a mixture of hexane and ethyl acetate (9:1) as eluent.

Preparation of Substituted Dicarbonyl-2-alkenyl Derivatives.

Method III. The following procedure was adapted from the

literature.^21,52,53In a 100 mL round-bottom ﬂask charged with

distilled water (3.0 mL) were slowly added NaOH (0.60 g, 15 mmol,

0.75 equiv) and ethanol (50 mL), a mixture of benzaldehyde (2.1 mL,

20 mmol, 1.0 equiv), and acetophenone (2.4 mL, 20 mmol, 1.0 equiv)

with the temperature being maintained by an ice bath. The reaction

mixture was stirred and allowed to reach room temperature for 4 h.

After the end of the reaction, the product (chalcone) has precipitated,

and it was ﬁltered and washed it with water and ice-cold ethanol. The

Protocol for Transesteriﬁcation Reactions. Method II. The

following procedure was adapted from the literature. Methyl 2-

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Scheme 12. Mechanistic Proposal

resulting chalcone was used without further puriﬁcation. Next,

chalcone (0.30 g, 1.5 mmol, 1.0 equiv) was solubilized in ethanol

(5 mL), and the mixture was cooled to 0 °C. A solution of NaBH₄

(0.12 g, 3.0 mmol, 2.0 equiv) in water (1 mL) was and slowly added.

The reaction was stirred in an ice bath for 1 h and then for another 2

h at room temperature. The reaction was extracted with the addition

of 10 mL of distilled water and ether (5 × 10 mL), and the organic

phase was dried with anhydrous Na₂SO₄. The resulting alcohol was

used without further puriﬁcation. In a 15 mL round-bottom ﬂask

charged with alcohol (0.11 g, 0.50 mmol, 1.0 equiv) were added 1,3-

dicarbonyl (0.60 mmol, 1.2 equiv) and DCM (2 mL), Re₂O₇catalyst

(0.0036 g, 0.0075 mmol, 0.015 equiv), and the reaction was stirred at

room temperature. The complete consumption of the starting

materials was monitored by TLC, and NH₄Cl solution (1.0 mL)

was added. The mixture was extracted with EtOAc (3 × 10 mL) and

the organic phase dried with anhydrous Na₂SO₄. The solvent was

removed, and the crude product was puriﬁed by column

chromatography using silica gel and a hexane/EtOAc gradient.

Pd-Catalyzed Aerobic Cycloisomerization Reactions. Method IV.

In a dry 5 mL round-bottom ﬂask, the previously prepared 2-alkenyl-

β-ketoesters (0.3 mmol, 1.0 equiv), preactivated 4 Å molecular sieves

powder (80 mg), dry sodium acetate (0.3 mmol, 1.0 equiv),

PdCl₂(CH₃CN)₂(5 mol %, 0.0075 mmol), and DMF (2.0 mL)

were added in sequence. An O₂atmosphere was achieved, and the

reaction was stirred at 40 °C using a an oil bath for 24 h. After

completion, the crude product was puriﬁed by ﬂash silica column

chromatography using a mixture of hexane/ethyl acetate (9:1) as

eluent.

Lock). Deuterated DMF (0.7 mL) was added to the tube containing

1a, the mixture was sonicated in an ultrasound bath and transferred to

1

an NMR tube, and a H NMR spectrum was recorded. In sequence,

the reaction solution was transferred to the tube containing the

NaOAc base, sonicated, and transferred to the same NMR tube, in

1

which a second H NMR spectrum was recorded. Finally, the ﬁnal

solution was transferred to the tube containing the Pd catalyst,

1

sonicated, and transferred to the same NMR tube, and a ﬁnal H

NMR spectrum was recorded. Each spectrum was recorded with an

interval of 32 and 24 min between them.

Kinetics. In a 10 mL round-bottom ﬂask were added compound 1a

(105 mg, 0.50 mmol, 1.00 equiv) or deuterated compound 1a′ (71

mg, 0.40 mmol, 1.00 equiv), dry NaOAc (1.00 equiv), Pd-

(CH₃CN)₂Cl₂(5 mol %), and the internal standard hexadecane

(0.50 equiv). Then DMF was added to complete a 0.15 M solution of

the respective β-ketoester (1a or 1a′), and the reaction ﬂask was kept

open under stirring at 40 °C using a an oil bath for 24 h. At every 30 s

for the ﬁrst 3 min of reaction and then for every 5 min (see the

Supporting Information), a 70 μL aliquot of the reaction was collected

using a micropipette, which was diluted with HPLC grade ethyl

acetate in a suﬃcient amount to complete 1000 μL of solution. Three

runs were performed on the CG−MS equipment, each with an

injection volume of 1 μL of the resulting solution, and the relative

number of analytes were obtained. Details of the procedure for

performing GC analysis were described in the Supporting

Information.

Computational Methods. All DTF calculations were performed

using the ultraﬁne grid in Gaussian 16.⁵⁵Geometry optimization and

single-point calculations of intermediates and transition states were

conducted with M06 functional⁵⁶using mixed basis-set of

def2TZVP⁵⁷for palladium e 6-311+g(d,p)⁵⁸for other atoms.

Vibrational analysis was performed at all calculated points to conﬁrm

they either as a transition state (only one imaginary frequency) or as a

local minimum (zero imaginary frequencies), furnishing also the zero-

point vibrational energies, the thermal and entropic correction from

which the Gibbs free energies were determined. Solvent eﬀects were

accounted for all optimizations using IEF-PCM (N,N-dimethylforma-

mide). Transition states were submitted to intrinsic reaction

coordinate (IRC) calculation to conﬁrm the desired connection

between reactants and products. Where relevant, conformational

search of intermediates was performed using SPMC (Systematic

Preparation of Deuterated Compound 1a′. Method V. The

following procedure was adapted from the literature.⁵⁴The β-

ketoester 1a (0.23 g, 1.00 mmol) was weighed in a 5 mL round-

bottom ﬂask in which was added a volume of 1.0 mL of a 50 mg/mL

(0.40 mol/L) K₂CO₃solution prepared in D₂O. The resulting

solution was stirred at room temperature for 24 h. The crude product

was extracted with diethyl ether (3 × 5 mL), and the organic phase

was dried with anhydrous Na₂SO₄. The product (2-D-benzyl 2-

acetylpent-4-enoate (1a′)) was obtained after simple ﬁltration and

solvent removal.

NMR Experiments. Substrate 1a (0.020 mmol, 0.0046 g), NaOAc

(0.020 mmol, 0.0016 g), and PdCl₂(CH₃CN)₂(0.020 mmol, 0.0052

g), were weighed separately in 1.5 mL microtubes (Eppendorf, Safe-

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Pseudo Monte Carlo) with OPLS_2005 force ﬁeld as implemented in

Maestro 9.6 software.⁵⁹Visualizations were done using GaussView 5⁶⁰

and CYLView 2.0.⁶¹See the Supprting Information for detailed

information on the parametrization process.

2.53−2.39 (m, 2H), 2.18−2.17 (m, 3H), 1.61−1.49 (m, 2H), 1.27

(m, 10H), 0.86 (t, J = 6.9 Hz, 3H). ¹³C{¹H} NMR (100 MHz,

DMSO): δ 202.6, 169.0, 134.8, 117.0, 64.7, 58.0, 39.5, 31.6, 31.2,

29.0, 28.6, 28.5, 28.0, 25.3, 22.1, 13.9. IR (NaCl, thin ﬁlm, cm⁻¹):

3080, 2957, 2928, 2857, 1746, 1715, 1643, 1468, 1435, 1358, 1231,

1184, 1152, 1061, 993, 918. HRMS (ESI-TOF) m/z: [M + H]⁺Calcd

for C₁₅H₂₇O₃, 255.1960; Found, 255.1959.

Decan-2-yl 2-Acetylpent-4-enoate (1g). Synthesized according to

method II, furnishing the new compound in 95% (4.6 mmol, 1.4 g)

isolated yield as a translucent oil, R_f0.22 (10% ethyl acetate in

hexane). ¹H NMR (400 MHz, CDCl₃): δ 5.73 (m, 1H), 5.08 (dq, J =

17.1, 1.5 Hz, 1H), 5.03 (dq, J = 10.2, 1.2 Hz, 1H), 4.98−4.89 (m,

1H), 3.47 (t, J = 7.4 Hz, 1H), 2.60−2.54 (m, 2H), 2.21 (s, 3H),

1.31−1.18 (m, 17H), 0.86 (t, J = 6.9 Hz, 3H). ¹³C{¹H} NMR (100

MHz, CDCl₃): δ 202.5, 169.0, 134.4, 117.5, 72.6, 59.6, 35.9, 32.2,

32.0, 29.7, 29.4, 29.1, 25.5, 22.8, 19.9, 14.2. IR (NaCl, thin ﬁlm,

cm⁻¹): 3080, 2926, 2855, 1740, 717, 1643, 1466, 1439, 1379, 1358,

1327, 1246, 1231, 1186, 1155, 1121, 1061, 995, 916. HRMS (ESI-

TOF) m/z: [M + Na]⁺Calcd for C₁₇H₃₀O₃Na 305.2088; Found,

305.2096.

Benzyl 2-Acetylpent-4-enoate (1a).⁶²Synthesized according to

method I, furnishing the known compound in 48% (4.9 mmol, 1.2 g)

isolated yield as a pale-yellow oil, R_f0.27 (10% ethyl acetate in

1

hexane). H NMR (400 MHz, CDCl₃): δ 7.39−7.30 (m, 5H), 5.73

(ddt, J = 17.0, 10.2, 6.8 Hz, 1H), 5.16 (d, J = 1.2 Hz, 2H), 5.07 (dq, J

= 17.1, 1.5 Hz, 1H), 5.03 (dq, J = 10.2, 1.3 Hz, 1H), 3.57 (t, J = 7.4

Hz, 1H), 2.63−2.58 (m, 2H), 2.18 (s, 3H). ¹³C{¹H} NMR (100

MHz, CDCl₃): δ 202.3, 169.1, 135.3, 134.1, 128.7, 128.6, 128.4,

117.6, 67.2, 59.2, 32.2, 29.2. IR (NaCl, thin ﬁlm, cm⁻¹): 3218, 3185,

3131, 3108, 3073, 1893, 1866, 1793, 1650, 1606, 1509, 1415, 1378,

1335, 1301, 1145, 1071, 901, 849.

4-Methoxybenzyl 2-acetylpent-4-enoate (1b). Synthesized ac-

cording to method II, furnishing the new compound in 72% (3.6

mmol, 0.93 g) isolated yield as a yellow oil, R_f0.44 (20% ethyl acetate

1

in hexane). H NMR (400 MHz, CDCl₃): δ 7.33−7.22 (m, 2H),

6.92−6.83 (m, 2H), 5.72 (ddt, J = 17.0, 10.2, 6.8 Hz, 1H), 5.10 (d, J =

2.3 Hz, 2H), 5.09−5.00 (m, 2H), 3.80 (s, 3H), 3.54 (t, J = 7.4 Hz,

1H), 2.61−2.56 (m, 2H), 2.16 (s, 3H). ¹³C{¹H} NMR (100 MHz,

CDCl₃): δ 202.4, 169.2, 159.9, 134.2, 130.4, 127.5, 117.6, 114.1, 67.1,

59.3, 55.4, 32.2, 29.2. IR (NaCl, thin ﬁlm, cm⁻¹): 3078, 3003, 2959,

2938, 2837, 1742, 1715, 1643, 1614, 1587, 1516, 1464, 1443, 1360,

1304, 1250, 1175, 1150, 1113, 1034, 922, 827. HRMS (ESI-TOF) m/

z: [M + Na]⁺Calcd for C₁₅H₁₈O₄Na 285.1098; Found, 285.1087.

Methyl 4-(((2-Acetylpent-4-enoyl)oxy)methyl)benzoate (1c). Syn-

thesized according to method II, furnishing the new compound in

23% (0.8 mmol, 0.2 g) isolated yield as a pale-yellow oil, R_f0.24 (10%

tert-Butyl 2-Acetylpent-4-enoate (1h).⁶³Synthesized according to

method II, furnishing the known compound in 15% (0.7 mmol, 0.1 g)

isolated yield as a translucent oil, R_f0.48 (10% ethyl acetate in

hexane). ¹H NMR (400 MHz, CDCl₃): δ 5.72 (ddt, J = 17.0, 10.2, 6.8

Hz, 1H), 5.07 (dq, J = 17.1, 1.6 Hz, 1H), 5.02 (dq, J = 10.2, 1.1 Hz,

1H), 3.40 (t, J = 7.4 Hz 1H), 2.53 (m, 2H), 2.21−2.20 (m, 3H), 1.44

(s, 9H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 202.9, 168.5, 134.6,

117.3, 82.1, 60.4, 32.3, 29.1, 28.0. IR (NaCl, thin ﬁlm, cm⁻¹): 3080,

3003, 2980, 2934, 1738, 1715, 1643, 1479, 1456, 1435, 1393, 1369,

1339, 1252, 1146, 997, 918, 845.

1

ethyl acetate in hexane). H NMR (400 MHz, CDCl₃): δ 8.05−8.00

(1RS,2SR,5RS)-2-Isopropyl-5-methylcyclohexyl 2-Acetylpent-4-

enoate (1i). Synthesized according to method II, furnishing the

new compound in 13% (0.34 mmol, 0.094 g) isolated yield as a pale-

(m, 2H), 7.44−7.37 (m, 2H), 5.73 (ddt, J = 17.0, 10.2, 6.8 Hz, 1H),

5.21 (d, J = 0.9 Hz, 2H), 5.12−5.01 (m, 2H), 3.91 (s, 3H), 3.59 (t, J =

7.4 Hz, 1H), 2.63−2.58 (m, 2H), 2.19 (s, 3H). ¹³C{¹H} NMR (100

MHz, CDCl₃): δ 202.2, 169.0, 166.7, 140.3, 134.0, 130.3, 130.0,

128.0, 117.8, 66.4, 59.2, 52.3, 32.3, 29.3. IR (KBr, thin ﬁlm, cm⁻¹):

3078, 3003, 2981, 2953, 2843, 1745, 1728, 1714, 1643, 1614, 1577,

1512, 1435, 1417, 1359, 1311, 1282, 1226, 1180, 1149, 1111, 1056,

1020, 993, 966, 921, 854, 802, 758, 704. HRMS (ESI-TOF) m/z: [M

+ H]⁺Calcd for C₁₆H₁₉O₅291.1227; Found, 291.1217.

1

orange oil, R_f0.63 (10% ethyl acetate in hexane). H NMR (400

MHz, CDCl₃): δ 5.79−5.68 (m, 1H), 5.24 (m, 1H), 5.13−5.01 (m,

2H), 3.52 (td, J = 7.5, 2.0 Hz, 1H), 2.62−2.57 (m, 2H), 2.23 (d, J =

1.6 Hz, 3H), 2.01−1.89 (m, 1H), 1.79−1.70 (m, 2H), 1.60−1.47 (m,

1H), 1.33 (m, 2H), 1.11−0.90 (m, 3H), 0.86 (m, 9H). ¹³C{¹H} NMR

(100 MHz, CDCl₃): δ 202.5, 168.8, 134.4, 117.5, 72.7, 59.8, 46.9,

39.1, 34.8, 32.2, 29.2, 26.7, 25.3, 22.2, 21.2, 20.8. IR (NaCl, thin ﬁlm,

cm⁻¹): 3080, 2949, 2924, 2870, 2847, 1736, 1717, 1643, 1476, 1456,

1445, 1389, 1369, 1358, 1321, 1246, 1233, 1192, 1144, 1063, 1024,

1009, 993, 918. HRMS (ESI-TOF) m/z: [M + Na]⁺Calcd for

C₁₇H₂₈O₃Na 303.1931; Found, 303.1934.

4-Chlorobenzyl 2-Acetylpent-4-enoate (1d). Synthesized accord-

ing to method II, furnishing the new compound in 20% (0.4 mmol,

0.2 g) isolated yield as a yellow oil, R_f0.57 (20% ethyl acetate in

hexane). ¹H NMR (400 MHz, CDCl₃): δ 7.35−7.31 (m, 2H), 7.29−

7.25 (m, 2H), 5.72 (ddt, J = 17.0, 10.2, 6.8 Hz, 1H), 5.14−5.11 (m,

2H), 5.09−5.00 (m, 2H), 3.57 (t, J = 7.4 Hz, 1H), 2.63−2.57 (m,

2H), 2.19 (s, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 202.2,

169.0, 134.4, 134.0, 133.9, 129.8, 128.9, 117.7, 66.3, 59.2, 32.2, 29.3.

IR (NaCl, thin ﬁlm, cm⁻¹): 3080, 3003, 2982, 2957, 2924, 1746,

1715, 1643, 1601, 1495, 1435, 1360, 1227, 1184, 1150, 1094, 1016,

993, 922, 806. HRMS (ESI-TOF) m/z: [M + H]⁺Calcd for

C₁₄H₁₆ClO₃267.0782; Found, 267.0773.

4-Nitrobenzyl 2-Acetylpent-4-enoate (1e). Synthesized according

to method II, furnishing the new compound in 24% (0.5 mmol, 0.1 g)

isolated yield as a yellow oil, R_f0.57 (20% ethyl acetate in hexane). ¹H

NMR (400 MHz, CDCl₃): δ 8.26−8.20 (m, 2H), 7.50 (m, 2H), 5.74

(ddt, J = 17.0, 10.2, 6.8 Hz, 1H), 5.27−5.24 (m, 2H), 5.12−5.04 (m,

2H), 3.63 (t, J = 7.4 Hz, 1H), 2.65−2.60 (m, 2H), 2.23 (s, 3H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ 202.2, 169.0, 148.0, 142.6,

133.9, 128.7, 124.0, 118.0, 65.7, 59.1, 32.4, 29.5. IR (NaCl, thin ﬁlm,

cm⁻¹): 3113, 3082, 2982, 2951, 2859, 1746, 1715, 1643, 1607, 1520,

1435, 1348, 1265, 1227, 1182, 1150, 1113, 1057, 995, 924, 853, 739.

HRMS (ESI-TOF) m/z: [M + H]⁺Calcd for C₁₄H₁₆NO₅278.1023;

Found, 278.1015.

(1RS,2RS,4SR)-7,7-Dimethylbicyclo[2.2.1]heptan-2-yl 2-Acetyl-

pent-4-enoate (1j). Synthesized according to method II, furnishing

the new compound in 8% (0.28 mmol, 0.080 g) isolated yield as a

1

translucent oil, R_f0.55 (10% ethyl acetate in hexane). H NMR (400

MHz, CDCl₃): δ 5.81−5.69 (m, 1H), 5.01 (dq, J = 17.0, 1.5 Hz, 1H),

5.07−5.03 (m, 1H), 4.94−4.89 (m, 1H), 3.54 (td, J = 7.4, 1.5 Hz,

1H), 2.63−2.57 (m, 2H), 2.24 (s, 3H), 1.91−1.66 (m, 3H), 1.36−

1.16 (m, 2H), 0.90−0.82 (m, 9H). ¹³C{¹H} NMR (100 MHz,

CDCl₃): δ 202.6, 169.6, 134.4, 117.6, 81.4, 59.6, 48.0, 44.9, 36.7, 32.3,

29.2, 28.1, 27.2, 19.8, 18.9, 13.6. IR (NaCl, thin ﬁlm, cm⁻¹): 3078,

2955, 2880, 1740, 1717, 1643, 1481, 1454, 1439, 1391, 1358, 1304,

1248, 1233, 1188, 1155, 1115, 1047, 1018, 993, 916. HRMS (ESI-

TOF) m/z: [M + Na]⁺Calcd for C₁₇H₂₆O₃Na 301.1775; Found,

301.1762.

(3S,8S,9S,10R,13R,14S,17R)-10,13-Dimethyl-17-((R)-6-methyl-

heptan-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-

1H-cyclopenta[a]phenanthren-3-yl 2-Acetylpent-4-enoate (1k).

Synthesized according to method II, furnishing the new compound

in 25% (0.9 mmol, 0.4 g) isolated yield as a white solid, mp 75.8−77.7

25

°C, R_f0.63 (10% ethyl acetate in hexane), [α]_D−16.9 (c 0.5,

AcOEt). ¹H NMR (400 MHz, CDCl₃): δ 5.80−5.68 (m, 1H), 5.40−

5.35 (m, 1H), 5.09 (dq, J = 17.1, 1.5 Hz, 1H), 5.06−5.02 (m, 1H),

4,71−4.72 (m, 1H), 3.48 (t, J = 7.4 Hz, 1H), 2.60−2.55 (m, 2H),

2.23 (s, 3H), 2.05−1.76 (m, 6H), 1.70−0.89 (m, 30H), 0.86 (dd, J =

6.6, 1.8 Hz, 6H), 0.67 (s, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ

202.6, 168.8, 139.4, 134.4, 123.1, 117.5, 75.3, 59.6, 56.8, 56.3, 50.1,

Octyl 2-Acetylpent-4-enoate (1f). Synthesized according to

method II, furnishing the new compound in 40% (1.4 mmol, 0.36

g) isolated yield as an orange oil, R_f0.47 (20% ethyl acetate in

1

hexane). H NMR (400 MHz, DMSO): δ 5.72 (ddt, J = 17.0, 10.2,

6.7 Hz, 1H), 5.08 (dq, J = 17.1, 1.6 Hz, 1H), 5.00 (dq, J = 10.2, 1.2

Hz, 1H), 4.07 (td, J = 6.6, 1.4 Hz, 2H), 3.74 (dd, J = 6.6, 6.5 Hz, 1H),

3935

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42.4, 39.6, 38.0, 37.0, 36.7, 36.3, 35.9, 32.3, 32.0, 29.1, 28.4, 27.8,

24.4, 23.0, 21.2, 19.4, 18.8, 12.0. IR (KBr pellet, cm⁻¹): 2967, 2947,

2889, 2868, 2855, 1746, 1717, 1643, 1468, 1381, 1360, 1244, 1196,

1138, 1026, 995, 918. HRMS (ESI-TOF) m/z: [M + NH₄]⁺Calcd for

C₃₄H₅₈O₃N 528.4412; Found, 528.4425.

28.9, 26.2, 22.8, 14.2, 13.8, 13.3. IR (KBr, thin ﬁlm, cm⁻¹): 2955,

2926, 2857, 1715, 1624, 1589, 1456, 1420, 1404, 1366, 1281, 1231,

1204, 1132, 1084, 777. HRMS (ESI-TOF) m/z: [M + H]⁺Calcd for

C₁₅H₂₅O₃, 253.1804; Found, 253.1813.

Decan-2-yl 2,5-Dimethylfuran-3-carboxylate (2g). Synthesized

according to method IV, furnishing the new compound in 83% (0.25

mmol, 0.069 g) isolated yield as a yellow oil, R_f0.66 (10% ethyl

Benzyl 2,5-Dimethylfuran-3-carboxylate (2a). Synthesized ac-

cording to method IV, furnishing the new compound in 70% (0.21

mmol, 0.055 g) isolated yield as a yellow oil, R_f0.45 (10% ethyl

1

acetate in hexane). H NMR (400 MHz, CDCl₃): δ 6.21 (d, J = 1.1

1

acetate in hexane). H NMR (400 MHz, CDCl₃): δ 7.44−7.30 (m,

Hz, 1H), 5.11−4.99 (m, 1H), 2.52 (s, 3H), 2.24 (dd, J = 1.1, 0.5 Hz,

3H), 1.65−1.52 (m, 2H), 1.30−1.23 (m, 15H), 0.90−0.85 (m, 3H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ 164.2, 157.5, 14.9, 114.5, 106.4,

70.7, 36.2, 32.0, 29.7, 29.5, 25.6, 22.8, 20.3, 14.3, 13.9, 13.3. IR (NaCl,

thin ﬁlm, cm⁻¹): 2951, 2924, 2855, 1713, 1624, 1589, 1462, 1416,

1400, 1371, 1281, 1231, 1207, 1126, 1078, 1007, 986, 926, 814, 777.

HRMS (ESI-TOF) m/z: [M + H]⁺Calcd for C₁₇H₂₉O₃281.2111;

Found, 281.2117.

5H), 6.27 (s, 1H), 5.28 (s, 2H), 2.54 (s, 3H), 2.24 (s, 3H). ¹³C{¹H}

NMR (100 MHz, CDCl₃): δ 164.1, 158.0, 150.1, 136.5, 128.6, 128.1,

128.1, 113.8, 106.3, 65.8, 13.8, 13.2. IR (NaCl, thin ﬁlm, cm⁻¹): 3123,

3090, 3065, 3034, 2953, 2924, 2891, 2857, 1722, 1715, 1622, 1587,

1499, 1454, 1418, 1402, 1362, 1279, 1233, 1198, 1132, 1074, 1030,

988, 926, 814, 775, 752, 745, 735, 696. HRMS (ESI-TOF) m/z: [M +

H]⁺Calcd for C₁₄H₁₅O₃231.1016; Found, 231.1006.

tert-Butyl 2,5-Dimethylfuran-3-carboxylate (2h).⁶⁴Synthesized

according to method IV, furnishing the known compound in 52%

(0.16 mmol, 0.031 g) isolated yield as a yellow oil, R_f0.78 (10% ethyl

4-Methoxybenzyl 2,5-Dimethylfuran-3-carboxylate(2b). Synthe-

sized according to method IV, furnishing the new compound in 70%

(0.22 mmol, 0.054 g) isolated yield as a white solid, mp 38.7−39.4

°C, R_f0.47 (10% ethyl acetate in hexane). ¹H NMR (400 MHz,

CDCl₃): δ 7.36−7.30 (m, 2H), 6.93−6.86 (m, 2H), 6.22 (d, J = 0.8

Hz, 1H), 5.19 (s, 2H), 3.81 (s, 3H), 2.51 (s, 3H), 2.22 (d, J = 0.5 Hz,

3H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 164.3, 159.6, 158.0, 150.0,

130.0, 128.6, 114.0, 113.9, 106.3, 65.7, 55.4, 13.9, 13.3. IR (KBr pellet,

cm⁻¹): 3123, 3073, 3048, 2994, 2974, 2961, 2938, 2920, 2839, 1709,

1612, 1585, 1516, 1450, 1400, 1371, 1306, 1281, 1258, 1244, 1202,

1188, 1072, 1038, 982, 922, 833, 820, 779. HRMS (ESI-TOF) m/z:

[M + Na]⁺Calcd for C₁₅H₁₆O₄Na 283.0941; Found, 283.0928.

4-(Methoxycarbonyl)benzyl 2,5-Dimethylfuran-3-carboxylate

(2c). Synthesized according to method IV, furnishing the new

compound in 54% (0.16 mmol, 0.047 g) isolated yield as a white

1

acetate in hexane). H NMR (400 MHz, CDCl₃): δ 6.15 (d, J = 0.7

Hz, 1H), 2.48 (s, 3H), 2.21 (d, J = 0.5 Hz, 3H), 1.53 (s, 9H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ 163.9, 157.0, 149.6, 115.5,

106.5, 80.3, 28.4, 13.8, 13.3. IR (NaCl, thin ﬁlm, cm⁻¹): 3005, 2976,

2926, 1713, 1624, 1589, 1479, 1454, 1416, 1396, 1366, 1290, 1277,

1231, 1215, 1173, 1080, 1036, 1007, 986, 926, 843, 779.

(1RS,2SR,5RS)-2-Isopropryl-5-methylcyclohexyl 2,5-Dimethylfur-

an-3-carboxylate (2i). Synthesized according to method IV, furnish-

ing the new compound in 80% (0.12 mmol, 0.034 g) isolated yield as

1

a yellow oil, R_f0.79 (10% ethyl acetate in hexane). H NMR (400

MHz, CDCl₃): δ 6.22 (d, J = 0.9 Hz, 1H), 5.36 (d, J = 2.3 Hz, 1H),

2.54 (s, 3H), 2.24 (d, J = 0.6 Hz, 3H), 2.05−1.97 (m, 1H), 1.83−1.74

(m, 2H), 1.71−1.57 (m, 1H), 1.52−1.35 (m, 2H), 1.14−0.91 (m,

3H), 0.91−0.83 (m, 9H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ

163.9, 157.3, 150.0, 115.0, 106.5, 70.8, 47.0, 39.4, 35.0, 29.5, 26.9,

25.6, 22.3, 21.0, 14.1, 13.3. IR (NaCl, thin ﬁlm, cm⁻¹): 3125, 2949,

2922, 2868, 2847, 1713, 1624, 1589, 1454, 1445, 1418, 1402, 1369,

1281, 1231, 1207, 1150, 1076, 1007, 988, 957, 924, 893, 835, 814,

777. HRMS (ESI-TOF) m/z: [M + H]⁺Calcd for C₁₇H₂₇O₃

279.1955; Found, 279.1959.

1

solid, mp 72−74.4 °C, R_f0.43 (10% ethyl acetate in hexane). H

NMR (400 MHz, CDCl₃): δ 8.06−8.00 (m, 2H), 7.47−7.43 (m, 2H),

6.24 (d, J = 1.0 Hz, 1H), 5.30 (s, 2H), 3.91 (s, 3H), 2.52 (s, 3H), 2.24

(sl, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 166.9, 164.0, 158.4,

150.3, 141.6, 130.0, 129.9, 127.6, 113.5, 106.2, 65.1, 52.3, 13.9, 13.3.

IR (KBr pellet, cm⁻¹): 2999, 2955, 2930, 1728, 1701, 1614, 1585,

1449, 1435, 1406, 1368, 1279, 1227, 1200, 1117, 1107, 1084, 1020,

995, 964, 843, 814, 773, 750. HRMS (ESI-TOF) m/z: [M + H]⁺

Calcd for C₁₆H₁₇O₅289.1070; Found, 289.1062.

(1RS,2RS,4SR)-1,7,7-Dimethylbicyclo[2.2.1]heptan-2-yl 2,5-Di-

methylfuran-3-carboxylate (2j). Synthesized according to method

IV, furnishing the new compound in 54% (0.08 mmol, 0.02 g)

isolated yield as a yellow oil, R_f0.38 (20% ethyl acetate in hexane). ¹H

NMR (400 MHz, CDCl₃): δ 6.23 (d, J = 1.0 Hz, 1H), 5.01 (ddd, J =

10.0, 3.5, 2.2 Hz, 1H), 2.54 (s, 3H), 2.43 (dddd, J = 13.6, 9.9, 4.7, 3.3

Hz, 1H), 2.25 (t, J = 0.8 Hz, 3H), 2.06−1.98 (m, 1H), 1.82−1.68 (m,

1H), 1.71 (t, J = 4.5 Hz, 1H), 1.40−1.22 (m, 2H), 1.06 (dd, J = 13.0,

3.6 Hz, 1H), 0.94 (s, 3H), 0.88 (d, J = 6.6 Hz, 6H). ¹³C{¹H} NMR

(100 MHz, CDCl₃): δ 164.8, 157.4, 150.0, 114.5, 106.4, 79.8, 49.0,

47.9, 45.1, 37.1, 28.2, 27.5, 19.9, 19.0, 13.7, 13.3. IR (NaCl, thin ﬁlm,

cm⁻¹): 3123, 2953, 2926, 2880, 1722, 1713, 1705, 1626, 1589, 1454,

1416, 1402, 1393, 1362, 1300, 1285, 1231, 1207, 1140, 1115, 1076,

1007, 989, 926, 812, 777. HRMS (ESI-TOF) m/z: [M + H]⁺Calcd

for C₁₇H₂₅O₃277.1798; Found, 277.1787.

(3S,8S,9S,10R,13R,14S,17R)-10,13-Dimethyl-17-((R)-6-methyl-

heptan-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-

1H-cyclopenta[a]phenanthren-3-yl 2,5-Dimethylfuran-3-carboxy-

late (2k). Synthesized according to method IV, furnishing the new

compound in 73% (0.22 mmol, 0.11 g) isolated yield as a white solid,

melting point: 135.1−137.4 °C, R_f0.9 (10% ethyl acetate in hexane),

[α]_D²⁵−7.7 (c 0.5, AcOEt). ¹H NMR (400 MHz, CDCl₃): δ 6.21 (d, J

= 1.0 Hz, 1H), 5.40 (d, J = 5.0 Hz, 1H), 4.79−4.69 (m, 1H), 2.51 (s,

3H), 2.23 (s, 3H), 2.10−1.60 (m, 8H), 1.55−0.95 (m, 23H), 0.92 (d,

J = 6.5 Hz, 3H), 0.86 (dd, J = 6.6, 1.8 Hz, 6H), 0.68 (s, 3H). ¹³C{¹H}

NMR (100 MHz, CDCl₃): δ 163.9, 157.6, 149.9, 139.9, 122.8, 114.4,

106.4, 73.7, 56.9, 56.3, 50.2, 42.5, 39.9, 39.7, 38.5, 37.2, 36.8, 36.3,

36.0, 32.1, 32.0, 28.4, 28.2, 24.4, 24.0, 23.0, 22.7, 22.2, 19.5, 18.9,

13.9, 13.3, 12.0. IR (KBr pellet, cm⁻¹): 2961, 2945, 2920, 2886, 2870,

2839, 1717, 1584, 1468, 1418, 1377, 1362, 1267, 1229, 1200, 1132,

4-Chlorobenzyl 2,5-Dimethylfuran-3-carboxylate (2d). Synthe-

sized according to method IV, furnishing the new compound in 55%

(0.08 mmol, 0.02 g) isolated yield as a yellow oil, R_f0.88 (20% ethyl

1

acetate in hexane). H NMR (100 MHz, CDCl₃): δ 7.34−7.32 (m,

4H), 6.22 (d, J = 0.8 Hz, 1H), 5.21 (s, 2H), 2.52 (s, 3H), 2.23 (d, J =

0.6 Hz, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 164.1, 158.3,

150.2, 135.0, 134.2, 129.5, 128.9, 113.6, 106.2, 65.0, 13.9, 13.9, 13.3,

13.3. IR (NaCl, thin ﬁlm, cm⁻¹): 3125, 2953, 2924, 2889, 2855, 1722,

1715, 1622, 1587, 1495, 1445, 1398, 1362, 1279, 1233, 1198, 1132,

1076, 1016, 988, 928, 816, 775. HRMS (ESI-TOF) m/z: [M + H]⁺

Calcd for C₁₄H₁₄ClO₃265.0626; Found, 265.0618.

4-Nitrobenzyl 2,5-Dimethylfuran-3-carboxylate (2e). Synthesized

according to method IV, furnishing the new compound in 32% (0.05

mmol, 0.01 g) isolated yield as a white solid, melting point: 94.8−96.5

°C, R_f0.6 (20% ethyl acetate in hexane). ¹H NMR (400 MHz,

CDCl₃): δ 8.26−8.20 (m, 2H), 7.58−7.52 (m, 2H), 6.24 (d, J = 0.9

Hz, 1H), 5.34 (s, 2H), 2.53 (s, 3H), 2.25 (d, J = 0.6 Hz, 3H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ 163.8, 158.7, 150.5, 147.8,

143.9, 128.3, 124.0, 113.3, 106.1, 64.4, 13.9, 13.3. IR (KBr pellet,

cm⁻¹): 3111, 3076, 2926, 2851, 1707, 1624, 1605, 1589, 1520, 1495,

1447, 1404, 1364, 1346, 1292, 1234, 1213, 1094, 999, 841, 775, 739.

HRMS (ESI-TOF) m/z: [M + H]⁺Calcd for C₁₄H₁₄NO₅276.0866;

Found, 276.0858.

Octyl 2,5-Dimethylfuran-3-carboxylate (2f). Synthesized accord-

ing to method IV, furnishing the new compound in 85% (0.26 mmol,

0.065 g) isolated yield as a yellow oil, R_f0.67 (20% ethyl acetate in

hexane). ¹H NMR (400 MHz, CDCl₃): δ 6.21 (s, 1H), 4.19 (t, J = 6.7

Hz, 2H), 2.52 (s, 3H), 2.23 (s, 3H), 1.74−1.64 (m, 2H), 1.44−1.22

(m, 10H), 0.88 (t, J = 6.9 Hz, 3H). ¹³C{¹H} NMR (100 MHz,

CDCl₃): δ 164.6, 157.6, 150.0, 114.2, 106.4, 64.3, 31.9, 29.4, 29.3,

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1078, 1070, 995, 820, 773. HRMS (ESI-TOF) m/z: [M + NH₄]⁺

Calcd for C₃₄H₅₆O₃N 526.4255; Found, 526.4268.

= 10.2, 1.1 Hz, 1H), 4.26−4.13 (m, 2H), 3.65 (t, J = 7.4 Hz, 1H),

2.64−2.59 (m, 2H), 2.06 (tt, J = 7.8, 4.5 Hz, 1H), 1.25 (t, J = 7.1 Hz,

3H), 1.09−1.05 (m, 2H), 0.95−0.89 (m, 2H). ¹³C{¹H} NMR (100

MHz, CDCl₃): δ 204.8, 169.5, 134.5, 117.4, 61.4, 59.6, 32.3, 20.0,

14.3, 12.0. IR (NaCl, thin ﬁlm, cm⁻¹): 3080, 3007, 2982, 2938, 1738,

1703, 1643, 1445, 1420, 1383, 1337, 1298, 1263, 1229, 1180, 1132,

1078, 1045, 1011, 918, 856.

Ethyl 2-Benzoylpent-4-enoate (3a).⁴⁰Synthesized according to

method I, furnishing the known compound in 60% (3 mmol, 0.7 g)

isolated yield as a translucent oil, R_f0.49 (10% ethyl acetate in

hexane). ¹H NMR (400 MHz, CDCl₃): δ 8.00−7.96 (m, 2H), 7.60−

7.54 (m, 1H), 7.50−7.42 (m, 2H), 5.81 (ddt, J = 17.0, 10.2, 6.9 Hz,

1H), 5.10 (dq, J = 17.1, 1.5 Hz, 1H), 5.02 (dq, J = 10.2, 1.1 Hz, 1H),

4.39 (t, J = 7.2 Hz, 1H), 4.19−4.06 (m, 2H), 2.81−2.68 (m, 2H),

1.15 (t, J = 7.1 Hz, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 194.6,

169.5, 136.3, 134.6, 133.6, 128.8, 128.7, 117.5, 61.5, 54.0, 33.1, 14.1.

IR (NaCl, thin ﬁlm, cm⁻¹): 3078, 2982, 2936, 2909, 2872, 1738,

1682, 1643, 1597, 1582, 1449, 1368, 1269, 1236, 1196, 1165, 1117,

1026, 1001, 920, 856, 779, 737, 691.

Ethyl 2-Pivaloyl Pent-4-enoate(3g). Synthesized according to

method I, furnishing the new compound in 35% (1.8 mmol, 0.37 g)

isolated yield as a pale-yellow oil, R_f0.61 (10% ethyl acetate in

hexane). ¹H NMR (400 MHz, CDCl₃): δ 5.70 (ddt, J = 17.1, 10.1, 7.0

Hz, 1H), 5.07 (dq, J = 17.1, 1.5 Hz, 1H), 5.02−4.98 (m, 1H), 4.17−

4.07 (m, 2H), 3.94 (t, J = 7.2 Hz, 1H), 2.64−2.56 (m, 1H), 2.53−

2.44 (m, 1H), 1.22 (t, J = 7.1 Hz, 3H), 1.15 (s, 9H). ¹³C{¹H} NMR

(100 MHz, CDCl₃): δ 209.4, 169.3, 134.9, 117.5, 61.4, 52.4, 45.3,

34.1, 26.2, 14.2. IR (NaCl, thin ﬁlm, cm⁻¹): 3080, 2976, 2938, 2909,

2874, 1746, 1709, 1643, 1479, 1466, 1441, 1395, 1368, 1327, 1271,

1225, 1182, 1119, 1059, 1026, 997, 959, 918. HRMS (ESI-TOF) m/

z: [M + H]⁺Calcd for C₁₂H₂₁O₃213.1485; Found, 213.1483.

2-(2-Methoxyacetyl) Methyl Pent-4-enoate (3h). Synthesized

according to method I, furnishing the new compound in 43% (1.1

mmol, 0.19 g) isolated yield as a translucent oil, R_f0.24 (10% ethyl

2-(4-Nitrobenzoyl) Ethyl Pent-4-enoate (3b). Synthesized accord-

ing to method I, furnishing the new compound in 56% (2.8 mmol,

0.76 g) isolated yield as a yellow solid, melting point: 40.4−43.6 °C,

R_f0.63 (10% ethyl acetate in hexane). ¹H NMR (400 MHz, DMSO):

δ 8.40−8.33 (m, 2H), 8.23−8.16 (m, 2H), 5.79 (ddt, J = 17.0, 10.2,

6.8 Hz, 1H), 5.09−4.97 (m, 2H), 4.85 (t, J = 7.0 Hz, 1H), 4.05 (q, J =

7.1 Hz, 2H), 2.62 (t, J = 7.1 Hz, 2H), 1.06 (t, J = 7.1 Hz, 3H).

¹³C{¹H} NMR (100 MHz, DMSO): δ 194.6, 168.8, 150.2, 140.5,

134.5, 129.9, 124.1, 117.6, 61.2, 53.0, 39.5, 32.4, 13.9. IR (KBr pellet,

cm⁻¹): 3117, 3090, 2978, 2926, 2870, 1717, 1697, 1636, 1607, 1530,

1470, 1437, 1410, 1369, 1352, 1329, 1300, 1265, 1234, 1213, 1173,

1159, 1119, 1026, 1007, 916, 854, 723. HRMS (ESI-TOF) m/z: [M +

H]⁺Calcd for C₁₄H₁₆NO₅278.1023; Found, 278.1018.

1

acetate in hexane). H NMR (400 MHz, CDCl₃): δ 5.71 (ddt, J =

17.1, 10.1, 6.9 Hz, 1H), 5.06 (dq, J = 17.0, 1.6 Hz, 1H), 5.01 (dq, J =

10.2, 1.1 Hz, 1H), 4.09 (d, J = 17.0 Hz, 1H), 4.04 (d, J = 17.0 Hz,

1H), 3.70−3.65 (m, 4H), 3.37 (s, 3H), 2.60−2.55 (m, 2H). ¹³C{¹H}

NMR (100 MHz, CDCl₃): δ 202.9, 169.3, 134.0, 117.6, 76.7, 59.3,

54.1, 52.3, 31.7. IR (NaCl, thin ﬁlm, cm⁻¹): 3080, 2986, 2953, 2828,

1748, 1732, 1717, 1643, 1454, 1435, 1339, 1269, 1233, 1200, 1121,

995, 922. HRMS (ESI-TOF) m/z: [M + H]⁺Calcd for

C₉H₁₅O₄187.0965; Found, 187.0965.

2-(3-Methoxybenzoyl) Ethyl Pent-4-enoate (3c). Synthesized

according to method I, furnishing the new compound in 97% (1.9

mmol, 0.51 g) isolated yield as a yellow oil, R_f0.55 (10% ethyl acetate

1

in hexane). H NMR (400 MHz, CDCl₃): δ 7.58−7.55 (m, 1H),

Ethyl 5-Methyl-2-phenylfuran-3-carboxylate(4a).⁶⁷Synthesized

according to method IV, furnishing the known compound in 67%

(0.20 mmol, 0.044 g) isolated yield as a translucent oil, R_f0.62 (10%

7.50−7.49 (m, 1H), 7.39−7.34 (m, 1H), 7.11 (ddd, J = 8.2, 2.7, 0.9

Hz, 1H), 5.80 (ddt, J = 17.1, 10.2, 6.9 Hz, 1H), 5.01 (dq, J = 17.1, 1.6

Hz, 1H), 5.02 (dq, J = 10.3, 1.1 Hz, 1H), 4.36 (t, J = 7.2 Hz, 1H),

4.19−4.07 (m, 2H), 3.83 (s, 3H), 2.76−2.71 (m, 2H), 1.16 (t, J = 7.1

Hz, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 194.4, 169.5, 160.0,

137.6, 134.6, 129.8, 121.3, 120.3, 117.5, 112.8, 61.5, 55.5, 54.1, 33.1,

14.1. IR (NaCl, thin ﬁlm, cm⁻¹): 3078, 2980, 2940, 2837, 1738, 1688,

1643, 1597, 1584, 1487, 1464, 1450, 1431, 1368, 1323, 1265, 1229,

1182, 1117, 1042, 995, 922, 789. HRMS (ESI-TOF) m/z: [M + H]⁺

Calcd for C₁₅H₁₉O₄263.1278; Found, 263.1275.

1

ethyl acetate in hexane). H NMR (400 MHz, CDCl₃): δ 7.98−7.94

(m, 2H), 7.45−7.34 (m, 3H), 6.44 (q, J = 1.0 Hz, 1H), 4.28 (q, J =

7.1 Hz, 2H), 2.35 (d, J = 1.1 Hz, 3H), 1.32 (t, J = 7.1 Hz, 3H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ 163.9, 156.0, 151.2, 130.2,

129.0, 128.2, 128.1, 114.6, 108.9, 60.5, 14.4, 13.5. IR (NaCl, thin ﬁlm,

cm⁻¹): 3075, 3057, 3032, 2982, 2924, 2905, 2872, 1722, 1715, 1614,

1603, 1580, 1557, 1493, 1447, 1412, 1379, 1290, 1273, 1209, 1134,

1096, 1040, 1024, 1003, 986, 918, 831, 781, 762, 692.

Ethyl 2-Propionylpent-4-enoate (3d).⁶⁵Synthesized according to

method I, furnishing the known compound in 25% (1.2 mmol, 0.22 g)

isolated yield as a translucent oil, R_f0.49 (10% ethyl acetate in

hexane). ¹H NMR (400 MHz, CDCl₃): δ 5.71 (ddt, J = 17.1, 10.2, 6.9

Hz, 1H), 5.06 (dq, J = 17.1, 1.6 Hz, 1H), 5.01 (dq, J = 10.1, 1.2 Hz,

1H), 4.16 (q, J = 7.0 Hz, 2H), 3.52 (t, J = 7.4 Hz, 1H), 2.64−2.42 (m,

4H), 1.24 (t, J = 7.1 Hz, 3H), 1.04 (t, J = 7.2 Hz, 3H). ¹³C{¹H} NMR

(100 MHz, CDCl₃): δ 205.7, 169.8, 134.8, 117.8, 61.8, 58.7, 35.9,

32.7, 14.5, 8.0. IR (NaCl, thin ﬁlm, cm⁻¹): 3080 2982, 2940, 2909,

2882, 1746, 1715, 1643, 1462, 1445, 1412, 1369, 1335, 1267, 1229,

1182, 1126, 1103, 1032, 999, 920, 856.

Ethyl 5-Methyl-2-(4-nitrophenyl)furan-3-carboxylate(4b).⁶⁸Syn-

thesized according to method IV, furnishing the known compound in

47% (0.14 mmol, 0.038 g) isolated yield as a yellow solid, mp 77,3−

79,2 °C, R_f0.63 (20% ethyl acetate in hexane). ¹H NMR (400 MHz,

DMSO): δ 8.21−8.26 (m, 2H), 8.18−8.14 (m, 2H), 6.59 (d, J = 0.9

Hz, 1H), 4.24 (q, J = 7.1 Hz, 2H), 2.37 (s, 3H), 1.26 (t, J = 7.1 Hz,

3H). ¹³C{¹H} NMR (100 MHz, DMSO): δ 162.6, 153.6, 151.9,

147.0, 135.1, 128.5, 123.6, 117.2, 109.7, 60.7, 39.5, 14.0, 13.1. IR (KBr

pellet, cm⁻¹): 3100, 3076, 3011, 2988, 1722, 1715, 1597, 1568, 1516,

1489, 1449, 1404, 1379, 1354, 1300, 1281, 1260, 1215, 1132, 1094,

1028, 999, 991, 854, 829, 812, 773, 752, 694.

Ethyl 2-Isobutyrylpent-4-enoate (3e). Synthesized according to

method I, furnishing the new compound in 45% (1.1 mmol, 0.22 g)

isolated yield as a pale-yellow oil, R_f0.66 (10% ethyl acetate in

hexane). ¹H NMR (400 MHz, CDCl₃): δ 5.70 (ddt, J = 17.0, 10.1, 6.8

Hz, 1H), 5.07 (dq, J = 17.0, 1.5 Hz, 1H), 5.01 (dq, J = 10.1, 1.1 Hz,

1H), 4.18−4.13 (m, 2H), 3.68 (t, J = 7.4 Hz, 1H), 2.77 (sept, J = 6.9

Hz, 1H), 2.59−2.54 (m, 2H), 1.24 (t, J = 7.1 Hz, 3H), 1.12−1.06 (m,

6H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 208.5, 169.3, 134.6, 117.5,

61.4, 56.7, 40.8, 32.6, 18.4, 14.2. IR (NaCl, thin ﬁlm, cm⁻¹): 3080,

2976, 2936, 2876, 1744, 1715, 1643, 1468, 1447, 1385, 1368, 1335,

1298, 1258, 1229, 1184, 1126, 1096, 1032, 1003, 920, 858. HRMS

(ESI-TOF) m/z: [M + H]⁺Calcd for C₁₁H₁₉O₃199.1329; Found,

199.1326.

Ethyl 2-(3-Methoxyphenyl)-5-methylfuran-3-carboxylate (4c).

Synthesized according to method IV, furnishing the new compound

in 67% (0.20 mmol, 0.051 g) isolated yield as a white oil, R_f0.53 (10%

1

ethyl acetate in hexane). H NMR (400 MHz, CDCl₃): δ 7.62−7.54

(m, 2H), 7.32 (t, J = 8.0 Hz, 1H), 6.92 (ddd, J = 8.3, 2.6, 0.9 Hz, 1H),

6.44 (q, J = 1.0 Hz, 1H), 4.28 (q, J = 7.1 Hz, 2H), 3.86 (s, 3H), 2.35

(d, J = 1.0 Hz, 3H), 1.33 (t, J = 7.1 Hz, 3H). ¹³C{¹H} NMR (100

MHz, CDCl₃): δ 163.9, 159.4, 155.7, 151.1, 131.3, 129.1, 120.6,

115.1, 114.8, 113.4, 109.0, 60.5, 55.5, 14.4 13.5. IR (NaCl, thin ﬁlm,

cm⁻¹): 3121, 3080, 2980, 2957, 2940, 2907, 2835, 1721, 1715, 1605,

1557, 1493, 1464, 1454, 1435, 1377, 1317, 1292, 1281, 1256, 1211,

1180, 1134, 1098, 1047, 1032, 860, 820, 775, 698. HRMS (ESI-TOF)

m/z: [M + H]⁺Calcd for C₁₅H₁₇O₄261.1121; Found, 261.1109.

Ethyl 2-Ethyl-5-methylfuran-3-carboxylate(4d). Synthesized ac-

cording to method IV, furnishing the new compound in 56% (0.17

mmol, 0.030 g) isolated yield as a yellow oil, R_f0.68 (10% ethyl

Ethyl 2-(Cyclopropanocarbonyl) Pent-4-enoate (3f).⁶⁶Synthe-

sized according to method I, furnishing the known compound in 10%

(0.46 mmol, 0.091 g) isolated yield as a pale-yellow oil, R_f0.46 (10%

ethyl acetate in hexane). ¹H NMR (400 MHz, CDCl₃): δ 5.75 (ddt, J

= 17.0, 10.2, 6.8 Hz, 1H), 5.09 (dq, J = 17.1, 1.6 Hz, 1H), 5.03 (dq, J

1

acetate in hexane). H NMR (400 MHz, CDCl₃): δ 6.20 (d, J = 1.1

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Hz, 1H), 4.25 (q, J = 7.1 Hz, 2H), 2.94 (q, J = 7.6 Hz, 2H), 2.23 (d, J

= 1.1 Hz, 3H), 1.32 (t, J = 7.1 Hz, 3H), 1.22 (t, J = 7.6 Hz, 3H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ 164.4, 162.7, 150.0, 113.2,

106.3, 60.0, 21.3, 14.5, 13.3, 12.5. IR (NaCl, thin ﬁlm, cm⁻¹): 2980,

2938, 2928, 2880, 1715, 1620, 1584, 1464, 1418, 1402, 1385, 1304,

1252, 1204, 1136, 1088, 1043, 962, 945, 837, 779. HRMS (ESI-TOF)

m/z: [M + H]⁺Calcd for C₁₀H₁₅O₃183.1016; Found, 183.1017.

Ethyl 2-Isopropyl-5-methylfuran-3-carboxylate(4e).⁴⁷Synthe-

sized according to method IV, furnishing the known compound in

74% (0.22 mmol, 0.044 g) isolated yield as a yellow oil, R_f0.70 (10%

ethyl acetate in hexane). ¹H NMR (400 MHz, CDCl₃): δ 6.19 (d, J =

1.1 Hz, 1H), 4.25 (q, J = 7.1 Hz, 2H), 3.70 (sept, J = 7.0 Hz, 1H),

2.23 (d, J = 1.0 Hz, 3H), 1.32 (t, J = 7.1 Hz, 3H), 1.24 (d, J = 7.0 Hz,

6H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 165.8, 164.4, 149.7, 119.3,

106.2, 60.0, 27.2, 20.9, 14.5, 13.3.

g) isolated yield as a yellow oil, R_f0.33 (20% ethyl acetate in hexane).

¹H NMR (400 MHz, DMSO-d₆): δ 5.97 (ddt, J = 16.4, 10.6, 5.4 Hz,

1H), [5.76−5.59 (m, 0.20H)]*, 5.44−5.12 (m, 3H), [4.86 (dd, J =

24.2, 13.6 Hz, 0.41H)]*, [4.64 (d, J = 3.8 Hz, 0.43H)]*, 4.51−4.37

(m, 2H), [3.50 (s, 0.04H)]*, [2.91 (d, J = 6.2 Hz, 0.42H)]*, [2.64 (t,

J = 6.2 Hz, 0.43H)]*, 2.40 (t, J = 6.2 Hz, 2H), 2.20 (t, J = 6.4 Hz,

2H), 1.87 (p, J = 6.3 Hz, 2H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ

198.1, 176.9, 132.3, 118.4, 102.7, 68.7, 36.4, 28.3, 20.9. IR (KBr, thin

ﬁlm, cm⁻¹): 3082, 2947, 2893, 2878, 1651, 1605, 1458, 1427, 1373,

1350, 1331, 1223, 1184, 1138, 991, 961, 930, 864, 826, 760, 498,

467.* refers to the minor stereoisomer.

Benzyl (E)-2-Acetyl-3,5-diphenylpent-4-enoate (5d). Synthesized

according to method III, furnishing the new compound in 66% (0.3

mmol, 0.1 g) isolated yield as a white solid, mp 78.2−79.8 °C, R_f0.69

(20% ethyl acetate in hexane). ¹H NMR (400 MHz, CDCl₃): δ 7.39−

7.16 (m, 28 H), 7.07−6.99 (m, 2H), 6.44−6.38 (m, 2H), 6.30−6.20

(m, 2 H), 5.17 (d, J = 12.2 Hz, 1H), [5.07 (d, J = 12.1 Hz, 1H)]*,

4.96−4.84 (m, 2 H), 4.35−4.25 (m, 2 H), 4.20−4.10 (m, 2 H), 2.26

(s, 3H), [2.00 (s, 3H)]*. ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 201.6,

201.4, 168.0, 167.6, 140.4, 140.2, 136.8, 136.7, 135.2, 132.0, 131.7,

129.4, 129.2, 129.1, 128.9, 128.7, 128.6, 128.4, 128.3, 128.1, 127.8,

127.7, 127.3, 127.3, 126.5, 67.5, 67.3, 65.6, 65.3, 49.2, 48.9, 30.2, 30.0.

IR (KBr pellet, cm⁻¹): 3080, 3059, 3026, 2963, 2953, 1734, 1711,

1597, 1495, 1454, 1381, 1366, 1288, 1279, 1211, 1186, 1148, 1092,

970, 949, 768, 748, 696. HRMS (ESI-TOF) m/z: [M + Na]⁺Calcd

for C₂₆H₂₄O₃Na 407.1623; Found, 407.1617.*the indicated signals

appear duplicated in the spectrum but integrate for the correct amount of

hydrogens of only one molecule and are therefore referring only to one of

the diastereoisomers. The other signs correspond to twice the expected

amount of hydrogens.

Ethyl 2-Cyclopropyl-5-methylfuran-3-carboxylate (4f). Synthe-

sized according to method IV, furnishing the new compound in 60%

(0.20 mmol, 0.041 g) isolated yield as an oﬀ-white solid, mp 54,7−58

°C, R_f0.68 (10% ethyl acetate in hexane). ¹H NMR (400 MHz,

DMSO): δ 6.22 (s, 1H), 4.20 (q, J = 7.1 Hz, 2H), 2.68−2.61 (m,

1H), 2.16 (s, 3H), 1.25 (t, J = 7.1 Hz, 3H), 1.05−0.87 (m, 4H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ 163.5, 160.8, 149.0, 113.1,

106.3, 59.6, 14.3, 12.8, 8.9, 8.2. IR (KBr pellet, cm⁻¹): 3123, 3098,

3063, 3017, 2992, 2978, 2949, 2924, 2907, 1697, 1645, 618, 1584,

1479, 1408, 1387, 1339, 1285, 1244, 1202, 1180, 1067, 1057, 1024,

947, 887, 826, 808, 783. HRMS (ESI-TOF) m/z: [M + H]⁺Calcd for

C₁₁H₁₅O₃195.1016; Found, 195.1017.

Ethyl 2-(tert-Butyl)-5-methylfuran-3-carboxylate (4g).⁶⁹Synthe-

sized according to method IV, furnishing the known compound in

<2% isolated yield as a yellow oil, R_f0.75 (10% ethyl acetate in

(E)-3-(1,3-Diphenylallyl)pentane-2,4-dione (5e).¹⁷Synthesized

according to method III, furnishing the known compound in 84%

(0.4 mmol, 0.1 g) isolated yield as a white solid, mp 76.9−78.1 °C, R_f

1

hexane). H NMR (400 MHz, CDCl₃): δ 6.26 (d, J = 1.0 Hz, 1H),

4.25 (q, J = 7.1 Hz, 2H), 2.23 (d, J = 1.1 Hz, 3H), 1.40 (s, 9H), 1.33

(t, J = 7.1 Hz, 3H). IR (NaCl, thin ﬁlm, cm⁻¹): 2976, 2959, 2930,

2907, 2872, 1721, 1715, 1557, 1481, 1464, 1373, 1267, 1221, 1204,

1155, 1111, 1063, 1026, 781.

1

0.22 (10% ethyl acetate in hexane). H NMR (400 MHz, CDCl₃): δ

7.35−7.18 (m, 10H), 6.43 (d, J = 15.8 Hz, 1H), 6.19 (ddd, J = 15.8,

5.6, 2.3 Hz, 1H), 4.38−4.29 (m, 2H), 2.25 (s, 3H), 1.92 (s, 3H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ 203.0, 202.9, 140.2, 136.6,

131.8, 129.3, 129.1, 128.6, 128.0, 127.8, 127.4, 126.5, 74.6, 49.3, 30.2,

29.9. IR (KBr pellet, cm⁻¹): 3082, 3059, 3024, 2916, 1722, 1697,

1599, 1495, 1452, 1416, 1377, 1360, 1287, 1271, 1248, 1173, 1140,

1070, 1030, 988, 974, 766, 745, 704.

Methyl 2-(Methoxymethyl)-5-methylfuran-3-carboxylate (4h).

Synthesized according to method IV, furnishing the new compound

in 18% (0.05 mmol, 0.01 g) isolated yield as a yellow oil, R_f0.39 (10%

ethyl acetate in hexane). ¹H NMR (400 MHz, CDCl₃): δ 6.28 (d, J =

1.1 Hz, 1H), 4.69 (s, 2H), 3.82 (s, 3H), 3.40 (s, 3H), 2.29 (d, J = 1.0

Hz, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 164.1, 155.4, 152.5,

117.1, 106.6, 64.9, 58.5, 51.6, 13.5. IR (NaCl, thin ﬁlm, cm-¹) 3123,

3098, 3063, 3017, 2992, 2949, 2924, 2907, 1697, 1645, 1618, 1584,

1479, 1408, 1387, 1379, 1339, 1285, 1244, 1202, 1180, 1067, 1057,

1024, 947, 887, 833, 783. HRMS (ESI-TOF) m/z: [M + H]⁺Calcd

for C₉H₁₃O₄185.0814; Found, 185.0820.

1-(5-Methyl-2-phenylfuran-3-yl)ethan-1-one (6a).⁷³Synthesized

according to method IV, furnishing the known compound in 50%

(0.06 mmol, 0.01 g) isolated yield as a yellow oil, R_f0.72 (10% ethyl

1

acetate in hexane). H NMR (400 MHz. CDCl₃): δ 7.74−7.68 (m,

2H), 7.50−7.44 (m, 1H), 7.38 (dd, J = 8.2, 6.8 Hz, 2H), 6.09 (s, 1H),

2.41 (s, 3H), 2.21 (s, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ

171.3, 158.1, 149.9, 139.5, 132.1, 129.1, 128.4, 121.3, 107.6, 60.5,

29.8, 21.2, 14.3, 13.3. IR (NaCl, thin ﬁlm, cm⁻¹): 3206, 3170, 3137,

3110, 3075, 3004, 1849, 1802, 1750, 1719, 1598, 1546, 1517, 1438,

1416, 1386, 1370, 1160, 1054, 890, 855.

2-Allyl-1-phenylbutane-1,3-dione (5a).⁷⁰Synthesized according

to method I, furnishing the known compound in 68% (0.24 mmol,

0.049 g) isolated yield as an orange oil, R_f0.44 (10% ethyl acetate in

1

hexane). H NMR (400 MHz, CDCl₃): δ 7.98 (m, 2H), 7.62−7.56

(m, 1H), 7.50−7.45 (m, 2H), 5.75 (ddt, J = 17.0, 10.2, 6.8 Hz, 1H),

5.08 (dq, J = 17.1, 1.5 Hz, 1H), 5.02 (dq, J = 10.2, 1.2 Hz, 1H), 4.54

(t, J = 7.2 Hz, 1H), 2.81−2.66 (m, 2H), 2.14 (s, 3H). ¹³C{¹H} NMR

(100 MHz, CDCl₃): δ 203.7, 195.9, 136.4, 134.5, 133.9, 129.0, 128.8,

117.6, 62.8, 33.1, 28.2. IR (NaCl, thin ﬁlm, cm⁻¹): 3230, 3154, 3131,

3071, 1874, 1829, 1793, 1746, 1731, 1600, 1509, 1488, 1407, 1380,

1355, 1334, 1152, 1119, 1073, 930, 901, 844.

(5-Methyl-2-phenylfuran-3-yl)(phenyl)methanone (6b).¹⁶Syn-

thesized according to method IV, furnishing the known compound

in 67% (0.2 mmol, 0.05 g) isolated yield as a yellow oil, R_f0.68 (10%

ethyl acetate in hexane). ¹H NMR (400 MHz. CDCl₃): δ 7.83 (d, J =

8.1 Hz, 2H), 7.66 (d, J = 7.6 Hz, 2H), 7.48 (t, J = 7.4 Hz, 1H), 7.36

(t, J = 7.6 Hz, 2H), 7.27 (m, 3H), 6.29 (s, 1H), 2.39 (s, 3H). ¹³C{¹H}

NMR (100 MHz, CDCl₃): δ 192.1, 154.6, 151.3, 138.3, 132.8, 130.1,

129.8, 128.7, 128.4, 127.4, 121.9, 109.9, 13.6. IR (KBr, thin ﬁlm,

cm⁻¹): 3059, 3028, 2955, 2920, 1655, 1597, 1578, 1551, 1489, 1447,

1373, 1315, 1277, 1223, 1177, 1126, 1072, 1015, 999, 887, 768, 725,

691, 675, 467.

2-Allyl-1,3-diphenylpropane-1,3-dione (5b).⁷¹Synthesized ac-

cording to method I, furnishing the known compound in 54% (0.8

mmol, 0.2 g) isolated yield as a white solid, R_f0.49 (10% ethyl acetate

in hexane). ¹H NMR (400 MHz, CDCl₃): δ 7.99−7.93 (m, 4H), 7.57

(td, J = 7.5, 1.3 Hz, 2H), 7.49−7.42 (m, 4H), 5.93−5.82 (m, 1H),

5.29 (dd, J = 7.3, 6.2 Hz, 1H), 5.10 (dt, J = 17.1, 1.5 Hz, 1H), 5.03 (d,

J = 10.2 Hz, 1H), 2.88 (td, J = 6.8, 1.3 Hz, 2H). ¹³C{¹H} NMR (100

MHz, CDCl₃): δ 195.7, 136.1, 135.2, 133.7, 129.0, 128.8, 117.4, 56.9,

33.7. IR (KBr pellet, cm⁻¹): 3082, 3063, 2932, 2913, 1694, 1667,

1593, 1578, 1447, 1331, 1269, 1234, 1207, 1173, 1003, 926, 907, 799,

760, 694, 687.

Methyl 2-Acetylpent-4-enoate (7).⁷⁴Synthesized according to

method I, furnishing the known compound in 30% (6 mmol, 1 g)

isolated yield as a pale-yellow oil, R_f0 .47 (10% ethyl acetate in

hexane). ¹H NMR (400 MHz, CDCl₃): δ 5.74 (ddt, J = 17.0, 10.2, 6.8

Hz, 1H), 5.10 (dq, J = 17.1, 1.5 Hz, 1H), 5.05 (dq, J = 10.2, 1.2 Hz,

1H), 3.76−3.73 (m, 3H), 3.55 (t, J = 7.4 Hz, 1H), 2.63−2.57 (m,

2H), 2.24 (s, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 202.5,

169.8, 134.3, 117.7, 59.2, 52.6, 32.3, 29.3. IR (NaCl, thin ﬁlm, cm⁻¹):

2-Allylcyclohexane-1,3-dione (5c).⁷²Synthesized according to

method I, furnishing the known compound in 30% (0.58 mmol, 0.089

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3080, 3005, 2982, 2955, 2924, 2847, 1746, 1715, 1643, 1435, 1360,

1269, 1233, 1198, 1152, 1121, 1059, 995, 922, 847.

ACKNOWLEDGMENTS

■

The authors gratefully acknowledge FAPESP (Grant Nos.

2014/50249-8, 2020/10246-0, and 2020/01255-6), GlaxoS-

mithKline, CAPES (Finance Code 001), and PNPD/CAPES

and CNPq for funding and fellowships. We thank Prof.

d₁-Benzyl 2-Acetylpent-4-enoate (1a′). Synthesized according to

method V, furnishing the compound in 63% (0.63 mmol, 0.15 g)

isolated yield (78% of deuterium incorporated) as a yellow oil, R_f0.33

(10% ethyl acetate in hexane) ¹H NMR (400 MHz. CDCl₃): δ 7.34−

7.21 (m, 5H), 5.65 (ddt, J = 17.1, 10.2, 6.8 Hz, 1H), 5.10 (s, 2H),

5.03−4.92 (m, 2H), 3.5 (t, J = 7.4 Hz, 0.22H), 2.53 (d, J = 6.7 Hz,

2H), 2.11 (s, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 202.4,

169.2, 135.4, 134.2, 128.7, 128.7, 128.6, 128.5, 117.7, 67.3, 59.3, 32.2,

29.3. IR (KBr, thin ﬁlm, cm⁻¹): 3078, 3067, 3036, 2982, 2959, 2924,

1740, 1713, 1643, 1497, 1454, 1435, 1358, 1265, 1231, 1192, 1142,

1107, 1061, 995, 918, 826, 748, 698, 644, 594, 471.

́

Claudio F. Tormena for the computational facilities.

REFERENCES

■

(1) A critical review of the 2002 literature preceded by three

chapters on current heterocyclic topics: Hou, X.-L.; Yang, Z.; Wong,

H. N. C. Chapter 5.3 Five-Membered Ring Systems: Furans and

Benzofurans. In Progress in Heterocyclic Chemistry; Gribble, G. W.,

Joule, J. A., Eds.; Elsevier, 2003; Vol. 15, pp 167−205.

(2) Lipshutz, B. H. Five-Membered Heteroaromatic Rings as

Intermediates in Organic Synthesis. Chem. Rev. 1986, 86, 795−819.

(3) Baumann, M.; Baxendale, I. R.; Ley, S. V.; Nikbin, N. An

overview of the key routes to the bestselling 5-membered ring

heterocyclic pharmaceuticals. Beilstein J. Org. Chem. 2011, 7, 442−

495.

(4) Kapojos, M. M.; Lee, J.-S.; Oda, T.; Nakazawa, T.; Takahashi,

O.; Ukai, K.; Mangindaan, R. E. P.; Rotinsulu, H.; Wewengkang, D.

S.; Tsukamoto, S.; Kobayashi, H.; Namikoshi, M. Two unprecedented

cembrene-type terpenes from an indonesian soft coral sarcophyton sp.

Tetrahedron 2010, 66, 641−645.

(5) Guo, Y.; Quan, T.; Lu, Y.; Luo, T. Enantioselective Total

Synthesis of (+)-Wortmannin. J. Am. Chem. Soc. 2017, 139, 6815−

6818.

(6) Yu, Y.; Zheng, J.; Cao, L.; Li, S.; Li, X.; Zhou, H.-B.; Liu, X.; Wu,

S.; Dong, C. Furan-carboxamide derivatives as novel inhibitors of

lethal H5N1 influenza A viruses. RSC Adv. 2017, 7, 9620−9627.

(7) (a) Ma, S.; Yu, Z. Oxidative Cyclization-Dimerization Reaction

of 2,3-Allenoic Acids and 1,2-Allenyl Ketones: An Efficient Synthesis

of 4-(3 ′-Furanyl)butenolide Derivatives. Angew. Chem. 2002, 114,

1853−1856. (b) Ma, S.; Zhang, J.; Lu, L. Pd(0)-Catalyzed Coupling

Cyclization Reaction of Aryl or Alkenyl Halides with 1,2-Allenyl

Ketones: Scope and Mechanism. Chem. - Eur. J. 2003, 9 (11), 2447−

2456. (c) Xiao, Y.; Zhang, J. Palladium(II)-Catalyzed Domino

Reaction of 2-(1-Alkynyl)-2-alken-1-ones with Nucleophiles: Scope,

Mechanism and Synthetic Application in the Synthesis of 3,4-Fused

Bicyclic Tetrasubstituted Furans. Adv. Synth. Catal. 2009, 351, 617−

629. (d) Cheng, C.; Liu, S.; Zhu, G. Palladium-Catalyzed Cyclo-

isomerization and Aerobic Oxidative Cycloisomerization of Homo-

allenyl Amides: A Facile and Divergent Approach to 2-Aminofurans.

Org. Lett. 2015, 17, 1581−1584. (e) Duc, D. X. Recent Progress in

the Synthesis of Furan. Mini-Rev. Org. Chem. 2019, 16, 422−452.

(8) Zeni, G.; Larock, R. C. Synthesis of Heterocycles via Palladium

π -Olefin and π -Alkyne Chemistry. Chem. Rev. 2004, 104, 2285−2310.

(9) McDonald, R. I.; Liu, G.; Stahl, S. S. Palladium(II)-Catalyzed

Alkene Functionalization via Nucleopalladation: Stereochemical

Pathways and Enantioselective Catalytic Applications. Chem. Rev.

2011, 111, 2981−3019.

ASSOCIATED CONTENT

* Supporting Information

The Supporting Information is available free of charge at

https://pubs.acs.org/doi/10.1021/acs.joc.0c02777.

■

sı

1

Copies of H, ¹³C, and IV spectra, additional computa-

tional discussions, optimized geometries, and energies

corresponding to all stationary points (PDF)

FAIR data, including the primary NMR FID ﬁles, for

compounds 1a−k, 1a′, 2a−k, 3a−h, 4a−h, 5a−e, 6a,b,

7, and experimental compounds (ZIP)

AUTHOR INFORMATION

Corresponding Author

■

Marco A. B. Ferreira − Centre for Excellence for Research in

Sustainable Chemistry (CERSusChem), Department of

Chemistry, Federal University of São Carlos - UFSCar, São

Carlos, São Paulo 13565-905, Brazil; orcid.org/0000-

0002-4954-6691; Email: marco.ferreira@ufscar.br

Authors

Amanda A. Barboza − Centre for Excellence for Research in

Sustainable Chemistry (CERSusChem), Department of

Chemistry, Federal University of São Carlos - UFSCar, São

Carlos, São Paulo 13565-905, Brazil; orcid.org/0000-

0001-5606-911X

Attilio Chiavegatti Neto − Centre for Excellence for Research

in Sustainable Chemistry (CERSusChem), Department of

Chemistry, Federal University of São Carlos - UFSCar, São

Carlos, São Paulo 13565-905, Brazil; orcid.org/0000-

0002-4266-4409

Isac G. Rosset − Centre for Excellence for Research in

Sustainable Chemistry (CERSusChem), Department of

Chemistry, Federal University of São Carlos - UFSCar, São

Carlos, São Paulo 13565-905, Brazil; Universidade Federal

do Paraná - Departamento de Engenharias e Exatas,

Palotina, Paraná 85950-000, Brazil; orcid.org/0000-

0003-2989-7854

Guilherme A. M. Jardim − Centre for Excellence for Research

in Sustainable Chemistry (CERSusChem), Department of

Chemistry, Federal University of São Carlos - UFSCar, São

Carlos, São Paulo 13565-905, Brazil; orcid.org/0000-

0002-9882-3085

(10) Campbell, A. N.; Stahl, S. S. Overcoming the “Oxidant

Problem ”: Strategies to Use O2 as the Oxidant in Organometallic C-

H Oxidation Reactions Catalyzed by Pd (and Cu). Acc. Chem. Res.

2012, 45, 851−863.

(11) Barton, D. H. R; Martell, A. E.; Sawyer, D. T. The Activation of

Dioxygen and Homogeneous Catalytic Oxidation; Plenum Press: New

York, 1993.

(12) Konnick, M. M.; Gandhi, B. A.; Guzei, I. A.; Stahl, S. S.

Reaction of Molecular Oxygen with a PdII- Hydride to Produce a

PdII-Hydroperoxide: Acid Catalysis and Implications for Pd-

Catalyzed Aerobic Oxidation Reactions. Angew. Chem., Int. Ed.

2006, 45, 2904−2907.

(13) Beccalli, E. M.; Broggini, G.; Martinelli, M.; Sottocornola, S. C-

C, C-O, C-N Bond Formation on sp2 Carbon by Pd(II)-Catalyzed

Reactions Involving Oxidant Agents. Chem. Rev. 2007, 107, 5318−

5365.

Complete contact information is available at:

https://pubs.acs.org/10.1021/acs.joc.0c02777

Author Contributions

^§A.A.B. and A.C.N. contributed equally to this work.

Notes

The authors declare no competing ﬁnancial interest.

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The Journal of Organic Chemistry

pubs.acs.org/joc

Article

(14) (a) Steinhoff, B. A.; King, A. E.; Stahl, S. S. Unexpected Roles

of Molecular Sieves in Palladium-Catalyzed Aerobic Alcohol

Oxidation. J. Org. Chem. 2006, 71, 1861−1868. (b) Nishimura, T.;

Maeda, Y.; Kakiuchi, N.; Uemura, S. Palladium(II)-catalysed

oxidation of alcohols under an oxygen atmosphere in a fluorous

biphase system (FBS). J. Chem. Soc., Perkin Trans. 1 2000, 4301−

4305.

(15) Wang, D.; Weinstein, A. B.; White, P. B.; Stahl, S. S. Ligand-

Promoted Palladium-Catalyzed Aerobic Oxidation Reactions. Chem.

Rev. 2018, 118, 2636−2679.

(16) Gligorich, K. M.; Sigman, S. S. Recent advancements and

challenges of palladium(II)-catalyzed oxidation reactions with

molecular oxygen as the sole oxidant. Chem. Commun. 2009, 3854−

3867.

(17) Jensen, D. R.; Pugsley, J. S.; Sigman, M. S. Palladium-Catalyzed

Enantioselective Oxidations of Alcohols Using Molecular Oxygen. J.

Am. Chem. Soc. 2001, 123, 7475−7476.

(25) Keith, J. A.; Henry, P. M. The Mechanism of the Wacker

Reaction: A Tale of Two Hydroxypalladations. Angew. Chem., Int. Ed.

2009, 48, 9038−9049.

(26) (a) Eisenstein, O.; Hoffmann, R. Activation of a coordinated

olefin toward nucleophilic attack. J. Am. Chem. Soc. 1980, 102, 6148−

6149. (b) Eisenstein, O.; Hoffmann, R. Transition-metal complexed

olefins: how their reactivity toward a nucleophile relates to their

electronic structure. J. Am. Chem. Soc. 1981, 103, 4308−4320.

̈

(27) (a) Åkermark, B.; Backvall, J. E.; Hegedus, L. S.; Zetterberg, K.;

̈

Siirala-Hansén, K.; Sjoberg, K. Palladium-promoted addition of

amines to isolated double bonds. J. Organomet. Chem. 1974, 72,

127−138. (b) Timokhin, V. I.; Stahl, S. S. Bronsted base-modulated

regioselectivity in the aerobic oxidative amination of styrene catalyzed

by palladium. J. Am. Chem. Soc. 2005, 127, 17888−17893.

(28) Lyngvi, E.; Sanhueza, I. A.; Schoenebeck, F. Dispersion Makes

the Difference: Bisligated Transition States Found for the Oxidative

Addition of Pd(PtBu3)2 to Ar-OSO2R and Dispersion Controlled

Chemoselectivity in Reactions with Pd[P(iPr)(tBu2)]2. Organo-

metallics 2015, 34, 805−812.

(29) Qi, X.; Kohler, D. G.; Hull, K. L.; Liu, P. Energy

Decomposition Analyses Reveal the Origins of Catalyst and

Nucleophile Effects on Regioselectivity in Nucleopalladation of

Alkenes. J. Am. Chem. Soc. 2019, 141, 11892−11904.

(30) Kohler, D. G.; Gockel, S. N.; Kennemur, J. L.; Waller, P. J.;

Hull, K. L. Palladium-catalysed anti-Markovnikov selective oxidative

amination. Nat. Chem. 2018, 10, 333−340.

(18) Trend, R. M.; Ramtohul, Y. K.; Ferreira, E. M.; Stoltz, B. M.

Palladium-Catalyzed Oxidative Wacker Cyclizations in Nonpolar

Organic Solvents with Molecular Oxygen: A Stepping Stone to

Asymmetric Aerobic Cyclizations. Angew. Chem., Int. Ed. 2003, 42,

2892−2895.

(19) (a) Arcadi, A.; Rossi, E. A Palladium - Catalyzed Domino

Reaction of 3-Acetyl-5-hexyn-2-one with Aryl Iodides under Carbon

Monoxide. Tetrahedron Lett. 1996, 37, 6811−6814. (b) Arcadi, A.;

Cacchi, S.; Fabrizi, G.; Marinelli, F.; Parisi, L. M. Highly substituted

furans from 2-propynyl-1,3-dicarbonyls and organic halides or triflates

via the oxypalladation-reductive elimination domino reaction.

Tetrahedron 2003, 59, 4661−4671. (c) Saito, A.; Enomoto, Y.;

Hanzawa, Y. Pd-catalyzed cycloisomerization-allylation of 4-alky-

nones: synthesis of 5-homoallylfuran derivatives. Tetrahedron Lett.

2011, 52, 4299−4302. (d) Ruengsangtongkul, S.; Chaisan, N.;

Thongsornkleeb, C.; Tummatorn, J.; Ruchirawat, S. Rate Enhance-

ment in CAN-Promoted Pd(PPh3)2Cl2-Catalyzed Oxidative Cycliza-

tion: Synthesis of 2-Ketofuran-4-carboxylate Esters. Org. Lett. 2019,

21, 2514−2517.

(20) Han, X.; Widenhoefer, R. A. Palladium-Catalyzed Oxidative

Alkoxylation of α -Alkenyl β -Diketones to Form Functionalized

Furans. J. Org. Chem. 2004, 69, 1738−1740.

(21) (a) Nallagonda, R.; Reddy, R. R.; Ghorai, P. Palladium-

Catalyzed Oxidative Cycloisomerization of 2-Cinnamyl-1,3-Dicarbon-

yls: Synthesis of Functionalized 2-Benzyl Furans. Chem. - Eur. J. 2015,

21, 14732−14736. (b) Rehan, M.; Nallagonda, R.; Das, B. G.; Meena,

T.; Ghorai, P. Synthesis of Functionalized Benzo[b]furans via

Oxidative Cyclization of o-Cinnamyl Phenols. J. Org. Chem. 2017,

82, 3411−3424.

(31) (a) Hegedus, L. S. Transition Metals in the Synthesis of Complex

Organic Molecules; University Science Books: Mill Valley, 1994.

(b) Negishi, E. Organopalladium Chemistry for Organic Synthesis;

Wiley: New York, 2002; Vol. 2, p 2119.

(32) (a) Semmelhack, M. F.; Bodurow, C. Intramolecular

alkoxypalladation/carbonylation of alkenes. J. Am. Chem. Soc. 1984,

106, 1496−1498. (b) Hayashi, T.; Yamasaki, K.; Mimura, M.;

Uozumi, Y. Deuterium-Labeling Studies Establishing Stereochemistry

at the Oxypalladation Step in Wacker-Type Oxidative Cyclization of

an o-Allylphenol. J. Am. Chem. Soc. 2004, 126, 3036−3037. (c) Ward,

A. F.; Xu, Y.; Wolfe, J. P. Synthesis of chromans via Pd-catalyzed

alkene carboetherification reactions. Chem. Commun. 2012, 48, 609−

611.

(33) (a) Isomura, K.; Okada, N.; Saruwatari, M.; Yamasaki, H.;

Taniguchi, H. Firm evidence for cis-aminopalladation in the reactions

of 1-aminohexatrienes with palladium dichloride. Chem. Lett. 1985,

14, 385−388. (b) Ye, X.; White, P. B.; Stahl, S. S. Mechanistic Studies

of Wacker-Type Amidocyclization of Alkenes Catalyzed by (IMes)-

Pd(TFA)2(H2O): Kinetic and Stereochemical Implications of Proton

Transfer. J. Org. Chem. 2013, 78, 2083−2090. (c) Weinstein, A. B.;

Stahl, S. S. Reconciling the Stereochemical Course of Nucleopalla-

diation with the Development of Enantioselective Wacker-Type

Cyclizations. Angew. Chem., Int. Ed. 2012, 51, 11505−11509.

(34) (a) Babij, N. R.; Boothe, J. R.; McKenna, G. M.; Fornwald, R.

M.; Wolfe, J. P. Stereocontrolled synthesis of bicyclic ureas and

sulfamides via Pd-catalyzed alkene carboamination reactions.

Tetrahedron 2019, 75, 4228−4243. (b) Hinds, E. M.; Wolfe, J. P. A

Cross-Metathesis/Aza-Michael Reaction Strategy for the Synthesis of

Cyclic and Bicyclic Ureas. J. Org. Chem. 2018, 83, 10668−10676.

(c) White, D. R.; Herman, M. I.; Wolfe, J. P. Palladium-Catalyzed

Alkene Carboalkoxylation Reactions of Phenols and Alcohols for the

Synthesis of Carbocycles. Org. Lett. 2017, 19, 4311−4314.

(35) (a) Weinstein, A. B.; Schuman, D. P.; Tan, Z. X.; Stahl, S. S.

Synthesis of Vicinal Aminoalcohols by Stereoselective Aza-Wacker

Cyclizations: Access to (−)-Acosamine by Redox Relay. Angew.

Chem., Int. Ed. 2013, 52, 11867−11870. (b) Redford, J. E.;

McDonald, R. I.; Rigsby, M. L.; Wiensch, J. D.; Stahl, S. S.

Stereoselective Synthesis of cis-2,5-Disubstituted Pyrrolidines via

Wacker-Type Aerobic Oxidative Cyclization of Alkenes with tert-

Butanesulfinamide Nucleophiles. Org. Lett. 2012, 14, 1242−1245.

(c) McDonald, R. I.; Stahl, S. S. Modular Synthesis of 1,2-Diamine

Derivatives by Palladium-Catalyzed Aerobic Oxidative Cyclization of

Allylic Sulfamides. Angew. Chem., Int. Ed. 2010, 49, 5529−5532.

(22) (a) Ali, S.; Milanezi, H.; Alves, T. M. F.; Tormena, C. F.;

Ferreira, M. A. B. Cobalt-catalysed Stereoselective Synthesis of 2,5-

trans-THF Nitrile Derivatives as a Platform for Diversification:

Development and Mechanistic Studies. J. Org. Chem. 2018, 83, 7694−

7713. (b) Alves, T. M. F.; Costa, M. O.; Bispo, B. A. D.; Pedrosa, F.

L.; Ferreira, M. A. B. Cobalt-catalyzed oxidative cyclization of gem-

disubstituted conjugated alkenols. Tetrahedron Lett. 2016, 57, 3334−

3338.

(23) (a) Shanker, K.; Reddy, P. M.; Rohini, R.; Ho, Y.; Ravinder, V.

Encapsulation of Pd(II) by N4 and N2O2 macrocyclic ligands: their

use in catalysis and biology. J. Coord. Chem. 2009, 62, 3040−3049.

(b) Aghayee, M.; Zolfigol, M. A.; Keypour, H.; Yarie, M.;

Mohammadi, L. Synthesis and characterization of a novel magnetic

nano-palladium Schiff base complex: application in cross-coupling

reactions. Appl. Organomet. Chem. 2016, 30, 612−618. (c) Movassagh,

B.; Ranjbari, S. Kryptofix 5 as an inexpensive and efficient ligand for

the palladium-catalyzed Mizoroki-Heck reaction. Appl. Organomet.

Chem. 2018, 32, 1−12.

(24) Luyckx, G.; Ceulemans, J. Deoxygenation, Deaeration and

Degassing: A Survey and Evaluation of Methods. Bull. Soc. Chim. Belg.

1987, 96, 151−163.

3940

https://dx.doi.org/10.1021/acs.joc.0c02777

J. Org. Chem. 2021, 86, 3923−3942

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

(36) (a) Tamaru, Y.; Hojo, M.; Yoshida, Z. Inter- and intramolecular

di-alkoxycarbonylation of 3-butenols catalyzed by palladium(II).

Tetrahedron Lett. 1987, 28, 325−328. (b) Tamaru, Y.; Hojo, M.;

Yoshida, Z. Palladium(II)-catalyzed carbonylation of 3-buten-1-ols

and 3-butyn-1-ols: an efficient synthesis of. gamma.-butyrolactones. J.

Org. Chem. 1991, 56, 1099−1105. (c) Ferguson, J.; Zeng, F.; Alper,

H. Synthesis of Coumarins via Pd-Catalyzed Oxidative Cyclo-

carbonylation of 2-Vinylphenols. Org. Lett. 2012, 14, 5602−5605.

catalysts by combining surface organometallic chemistry, high

throughput experimentation, and data analysis. Chem. Sci. 2020, 11,

6717−6723.

(46) (a) Santiago, C. B.; Milo, A.; Sigman, M. S. Developing a

Modern Approach To Account for Steric Effects in Hammett-Type

Correlations. J. Am. Chem. Soc. 2016, 138, 13424. (b) Hollingsworth,

C. A.; Seybold, P. G.; Hadad, C. M. Substituent effects on the

electronic structure and pKa of benzoic acid. Int. J. Quantum Chem.

2002, 90, 1396.

(47) Verloop, A. In Drug Design; Ariens, E. J., Ed.; Academic Press,

1976; Vol. 3, pp 133−187.

(48) Perrin, D. D.; Armarego, W. L. F.; Perrin, D. R. In Puriﬁcation

of laboratory chemicals; Oxford, Pergamon Press: New York, 1966; 1st

Edition.

̈

(37) (a) Andersson, P. G.; Backvall, J.-E. C-O and C-N Bond

Formation Involving Conjugated Dienes and Allylpalladium Inter-

mediates. In Handbook of Organopalladium Chemistry for Organic

Synthesis; Negish, E.-i., Ed.; Wiley: New York, 2002; pp 1859−1874.

̈

(b) Backvall, J.-E.; Granberg, K. L.; Andersson, P. G.; Gatti, R.;

Gogoll, A. Stereocontrolled lactonization reactions via palladium-

(49) Kalaitzakis, D.; Rozzell, J. D.; Smonou, I. K. Synthesis of

Valuable Chiral Intermediates by Isolated Ketoreductases: Applica-

tion in the Synthesis of α -Alkyl-β -hydroxy Ketones and 1,3-Diols. Adv.

Synth. Catal. 2006, 348, 1958−1969.

(50) Kondaiah, G. C. M.; Reddy, L. A.; Babu, K. S.; Gurav, V. M.;

Huge, K. G.; Bandichhor, R.; Reddy, P. P.; Bhattacharya, A.; Anand,

R. V. Boric acid: an efficient and environmentally benign catalyst for

transesterification of ethyl acetoacetate. Tetrahedron Lett. 2008, 49,

106−109.

(51) Gohain, M.; Kumar, V.; Van Tonder, J. H.; Swart, H. C.;

Ntwaeabowa, O. M.; Bezuidenhoudt, B. C. B. Nano CuFe2O4: an

efficient, magnetically separable catalyst for transesterification of β -

ketoesters. RSC Adv. 2015, 5, 18972−18976.

(52) Parveen, N.; Saha, R.; Sekar, G. Stable and Reusable Palladium

Nanoparticles-Catalyzed Conjugate Addition of Aryl Iodides to

Enones: Route to Reductive Heck Products. Adv. Synth. Catal.

2017, 359, 3741−3751.

(53) Gładkowski, W.; Skrobiszewski, A.; Mazur, M.; Siepka, M.;

Pawlak, A.; Obminska-Mrukowicz, B.; Białonska, A.; Poradowski, D.;

Drynda, A.; Urbaniak, M. Synthesis and anticancer activity of novel

halolactones with β -aryl substituents from simple aromatic aldehydes.

Tetrahedron 2013, 69, 10414−10423.

(54) Bowie, J. H.; Eichinger, P. C. H. J. Org. Mass Spectrom. 1987,

22, 103−108.

(55) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;

Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Petersson,

G. A.; Nakatsuji, H.; Li, X.; Caricato, M.; Marenich, A. V; Bloino, J.;

Janesko, B. G.; Gomperts, R.; Mennucci, B.; Hratchian, H. P.; Ortiz, J.

V; Izmaylov, A. F.; Sonnenberg, J. L.; Williams Ding, F.; Lipparini, F.;

Egidi, F.; Goings, J.; Peng, B.; Petrone, A.; Henderson, T.;

Ranasinghe, D.; Zakrzewski, V. G.; Gao, J.; Rega, N.; Zheng, G.;

Liang, W.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.;

Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.;

Throssell, K.; Montgomery, J. A., Jr.; Peralta, J. E.; Ogliaro, F.;

Bearpark, M. J.; Heyd, J. J.; Brothers, E. N.; Kudin, K. N.; Staroverov,

V. N.; Keith, T. A.; Kobayashi, R.; Normand, J.; Raghavachari, K.;

Rendell, A. P.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.;

Millam, J. M.; Klene, M.; Adamo, C.; Cammi, R.; Ochterski, J. W.;

Martin, R. L.; Morokuma, K.; Farkas, O.; Foresman, J. B.; Fox, D. J.

Gaussian 16 Rev. C.01.; Gaussian, Inc.: Wallingford, CT, 2016.

(56) Zhao, Y.; Truhlar, D. G. The M06 Suite of Density Functionals

for Main Group Thermochemistry, Thermochemical Kinetics,

Noncovalent Interactions, Excited States, and Transition Elements:

Two New Functionals and Systematic Testing of Four M06-Class

Functionals and 12 Other Function. Theor. Chem. Acc. 2008, 120,

215−241.

(57) (a) Weigend, F.; Ahlrichs, R. Balanced Basis Sets of Split

Valence, Triple Zeta Valence and Quadruple Zeta Valence Quality for

H to Rn: Design and Assessment of Accuracy. Phys. Chem. Chem.

Phys. 2005, 7, 3297−3305. (b) Weigend, F. Accurate Coulomb-

Fitting Basis Sets for H to Rn. Phys. Chem. Chem. Phys. 2006, 8,

1057−1065.

(58) (a) Krishnan, R.; Binkley, J. S.; Seeger, R.; Pople, J. A. Self-

Consistent Molecular Orbital Methods. XX. A Basis Set for

Correlated Wave Functions. J. Chem. Phys. 1980, 72, 650−654.

catalyzed 1,4-addition to conjugated dienes. J. Org. Chem. 1993, 58

̈

(20), 5445−5451. (c) Backvall, J.-E.; Bystrom, S. E.; Nordberg, R. E.

Stereo- and regioselective palladium-catalyzed 1,4-diacetoxylation of

̈

1,3-dienes. J. Org. Chem. 1984, 49, 4619−4631. (d) Backvall, J.-E.;

Nordberg, R. E.; Wilhelm, D. Dual stereoselectivity in the

nucleophilic attack on (π -allyl)palladium complexes. J. Am. Chem.

Soc. 1981, 107, 6892−6898.

(38) Trend, R. M.; Ramtohul, Y. K.; Stoltz, B. M. Oxidative

Cyclizations in a Nonpolar Solvent Using Molecular Oxygen and

Studies on the Stereochemistry of Oxypalladation. J. Am. Chem. Soc.

2005, 127, 17778−17788.

(39) Nielsen, R. J.; Keith, J. M.; Stoltz, B. M.; Goddard, W. A. A

Computational Model Relating Structure and Reactivity in

Enantioselective Oxidations of Secondary Alcohols by (−)-Spar-

teine-PdII Complexes. J. Am. Chem. Soc. 2004, 126, 7967−7974.

(40) (a) Brooks, J. L.; Xu, L.; Wiest, O.; Tan, D. S.

Diastereoselective Synthesis of Highly Substituted Tetrahydrofurans

by Pd-Catalyzed Tandem Oxidative Cyclization-Redox Relay

Reactions Controlled by Intramolecular Hydrogen Bonding. J. Org.

Chem. 2017, 82, 57−75. (b) Ammann, S. E.; Rice, G. T.; White, M. C.

Terminal Olefins to Chromans, Isochromans, and Pyrans via Allylic

C-H Oxidation. J. Am. Chem. Soc. 2014, 136, 10834−10837.

(c) Ghebreghiorgis, T.; Kirk, B. H.; Aponick, A.; Ess, D. H. Multiple

Mechanisms in Pd(II)-Catalyzed Sn2 ′ Reactions of Allylic Alcohols. J.

Org. Chem. 2013, 78, 7664−7673. (d) Jensen, K. H.; Webb, J. D.;

Sigman, M. S. Advancing the Mechanistic Understanding of an

Enantioselective Palladium-Catalyzed Alkene Difunctionalization

Reaction. J. Am. Chem. Soc. 2010, 132, 17471−17482.

(41) Baldwin, J. E. Rules for Ring Closure. J. Chem. Soc., Chem.

Commun. 1976, 18, 734−736.

̌

́

̈

(42) Kocovsky, P.; Backvall, J. E. The syn/anti-dichotomy in the

palladium catalyzed addition of nucleophiles to alkenes. Chem. - Eur. J.

2015, 21, 36−56.

(43) Kozuch, S.; Shaik, S. A Combined Kinetic-Quantum

Mechanical Model for Assessment of Catalytic Cycles: Application

to Cross-Coupling and Heck Reactions. J. Am. Chem. Soc. 2006, 128,

3355−3365.

(44) (a) Engelin, C.; Jensen, T.; Rodriguez-Rodriguez, S.; Fristrup,

P. Mechanistic Investigation of Palladium-Catalyzed Allylic C-H

Activation. ACS Catal. 2013, 3, 294−302. (b) Simmons, E. M.;

Hartwig, J. F. On the Interpretation of Deuterium Kinetic Isotope

Effects in C-H Bond Functionalizations by Transition-Metal

Complexes. Angew. Chem., Int. Ed. 2012, 51, 3066−3072.

(45) (a) Guo, J.-Y.; Minko, Y.; Santiago, C. B.; Sigman, M. S.

Developing Comprehensive Computational Parameter Sets To

Describe the Performance of Pyridine-Oxazoline and Related Ligands.

ACS Catal. 2017, 7, 4144−XXX. (b) Santiago, C. B.; Guo, J.-Y.;

Sigman, M. S. Predictive and mechanistic multivariate linear

regression models for reaction development. Chem. Sci. 2018, 9,

2398−XXXX. (c) Ferreira, M. A. B.; De Jesus Silva, J.; Grosslight, S.;

Fedorov, A.; Sigman, M. S.; Coperet, C. Non-Covalent Interactions

Drive the Efficiency of Molybdenum Imido Alkylidene Catalysts for

Olefin Metathesis. J. Am. Chem. Soc. 2019, 141, 10788−10800.

(d) De Jesus Silva, J.; Ferreira, M. A. B.; Fedorov, A.; Sigman, M. S.;

Coperet, C. Molecular-level insight in supported olefin metathesis

3941

https://dx.doi.org/10.1021/acs.joc.0c02777

J. Org. Chem. 2021, 86, 3923−3942

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

(b) McLean, A. D.; Chandler, G. S. Contracted Gaussian Basis Sets

for Molecular Calculations. I. Second Row Atoms, Z = 11 −18. J.

Chem. Phys. 1980, 72, 5639−5648.

̈

(59) Maestro, version 9.6; Schrodinger, LLC, New York, NY.

(60) Dennington, R.; Keith, T.; Millam, J. GaussView, version 5;

Semichem, Inc., Shawnee Mission, KS. 2009.

(61) Legault, C. Y. CYLview version 20; Universite de Sherbrooke:

́

Quebec, 2020.

(62) Sweeney, J. B.; Ball, A. K.; Smith, L. J. Catalytic C-C Bond

Formation Using a Simple Nickel Precatalyst System: Base- and

Activator-Free Direct C-Allylation by Alcohols and Amines. Chem. -

Eur. J. 2018, 24, 7354−7357.

(63) King, J. F.; Rathore, R.; Lam, J. Y. L.; Guo, Z. R.; Klassen, D. F.

pH optimization of nucleophilic reactions in water. J. Am. Chem. Soc.

1992, 114, 3028−3033.

(64) Murphy, P. V.; O’Sullivan, T. J.; Kennedy, B. D.; Geraghty, N.

W. A. The reactions of diazo compounds with lactones. Part 2. The

reaction of cyclic 2-diazo-1,3-dicarbonyl compounds with diketene:

benzofuran formation. J. Chem. Soc., Perkin Trans. 1 2000, 2121−

2126.

̌

(65) Smit, B. M.; Pavlovic, R. Z. Three-step synthetic pathway to

fused bicyclic hydantoins involving a selenocyclization step.

Tetrahedron 2015, 71, 1101−1108.

(66) Mori, K.; Mitsui, T.; Fukami, J.; Ohtaki, T. Synthesis of

Compounds with Juvenile Hormone Activity Part VII. A Convenient

Non-stereoselective Synthesis of the C18-Cecropia Juvenile Hormone

and its Analogues; Effect of the Terminal Alkyl Substituents on

Biological Activity. Agric. Biol. Chem. 1971, 35, 1116−1127.

(67) Imagawa, H.; Kurisaki, T.; Nishizawa, M. Mercuric Triflate-

Catalyzed Synthesis of 2-Methylfurans from 1-Alkyn-5-ones. Org. Lett.

2004, 6, 3679−3681.

(68) Chen, P.; Meng, Y.; Yang, Q.; Wu, J.; Xiao, Y.; Gorja, D. R.;

Song, C.; Chang, J. Selective synthesis of 2,5-disubstituted furan-3-

carboxylates and the isomeric 2,4-disubstituted furan-3-carboxylates.

RSC Adv. 2015, 5, 79906−79914.

(69) Tsuji, H.; Yamagata, K.-I.; Ueda, Y.; Nakamura, E. Indium-

Catalyzed Synthesis of Furans and Pyrroles via Cyclization of α -

Propargyl-β -keto Esters. Synlett 2011, 1015−1017.

(70) Noda, H.; Motokura, K.; Miyaji, A.; Baba, T. Efficient

Allylation of Nucleophiles Catalyzed by a Bifunctional Heterogeneous

Palladium Complex-Tertiary Amine System. Adv. Synth. Catal. 2013,

355, 973−980.

(71) Yang, N. Y.; Li, Z. L.; Ye, L.; Tana, B.; Liu, X. Y. Organic base-

catalysed solvent-tuned chemoselective carbotrifluoromethylation and

oxytrifluoromethylation of unactivated alkenes. Chem. Commun. 2016,

52, 9052−9055.

(72) Deschamp, J.; Riant, O. Efficient Construction of Polycyclic

Derivatives via a Highly Selective CuI-Catalyzed Domino Reductive-

Aldol Cyclization. Org. Lett. 2009, 11, 1217−1220.

(73) Tang, E.; Huang, X.; Xu, W.-M. Polymer-supported selenium-

induced electrophilic cyclization: solid-phase synthesis of poly-

substituted dihydrofurans and tetrahydrofurans. Tetrahedron 2004,

60, 9963−9969.

(74) Senthilkumar, S.; Thangapriya, C.; Alagumurugayee, R.;

Kumarraja, M. MMZNiY-Catalyzed Tsuji-Trost Type of Reaction:

A Selective Mono/Bis Allylation of Dicarbonyl Compounds. Catal.

Lett. 2017, 147, 2755−2763.

3942

https://dx.doi.org/10.1021/acs.joc.0c02777

J. Org. Chem. 2021, 86, 3923−3942

Article Doi

Synthesis of 3-Carbonyl Trisubstituted Furans via Pd-Catalyzed Aerobic Cycloisomerization Reaction: Development and Mechanistic Studies

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