Skip to main content
NCBI home page
Molecules logoLink to Molecules
. 2018 Sep 1;23(9):2227. doi: 10.3390/molecules23092227

Heck Transformations of Biological Compounds Catalyzed by Phosphine-Free Palladium

Stanisława Tarnowicz-Ligus 1, Anna M Trzeciak 1,*
PMCID: PMC6225119  PMID: 30200476

Abstract

The development and optimization of synthetic methods leading to functionalized biologically active compounds is described. Two alternative pathways based on Heck-type reactions, employing iodobenzene or phenylboronic acid, were elaborated for the arylation of eugenol and estragole. Cinnamyl alcohol was efficiently transformed to saturated arylated aldehydes in reaction with iodobenzene using the tandem arylation/isomerization sequential process. The arylation of cinnamyl alcohol with phenylboronic acid mainly gave unsaturated alcohol, while the yield of saturated aldehyde was much lower. Catalytic reactions were carried out using simple, phosphine-free palladium precursors and water as a cosolvent, following green chemistry rules as much as possible.

Keywords: palladium, arylation, Heck coupling, cinnamyl alcohol, linalool, eugenol, estragole

1. Introduction

The Heck reaction is one of the most convenient methods for C–C bond formation applied in the preparation of many molecules developed as pharmaceuticals, agrochemicals, and functional materials [1,2,3,4,5]. In particular, it can be applied for allyl alcohol arylation catalyzed by Pd(0) nanoparticles [6]. On the other hand, Heck arylation suffers some drawbacks, such as the application of expensive and toxic aryl halides and the generation of harmful HX waste during the process [7,8]. The halide-free Heck-type reaction, employing arylboronic acid as an aryl source, can be considered an environmentally benign alternative [9,10,11,12]. The direct heteroarylation procedure presents another green pathway leading to arylated organic products [13,14].

Cinnamyl alcohol, eugenol, and estragole are natural compounds. The arylation of these compounds has so far not been intensively developed. Cinnamyl alcohol (3-phenyl-2-propen-1-ol) is used to obtain many cosmetics, perfumes, and detergents [15]. This alcohol has been arylated with iodobenzene to produce α,β-unsatured alcohols by using TBAB (tetrabutylammonium bromide) and NaHCO3 as bases [16]. In analogous reactions performed in the presence of TBAA or without a base, exclusively carbonyl products have been formed [16]. The arylation of cinnamyl alcohol with different aryldiazonium salts under mild conditions in the presence of a Pd2(dba)3 catalyst has been reported [17]. The regio- and stereoselective formation of (Z)-2,3-diarylallylic alcohols has been carried out using a palladium catalyst and the n-Bu4NOAc base in toluene [18]. Arylboronic acid has been used for the arylation of cinnamic phenyl ether in the presence of Pd(OAc)2 and a hydrazone ligand [19].

Eugenol (1-allyl-3-methoxy-4-hydroxybenzene) is extracted from clove oil and marjoram, and it is present in spices such as basil, cinnamon, and nutmeg [20]. Eugenol can be employed in the synthesis of natural products, bioactive compounds, heterocycles, macrocycles, and polymers [21]. A methyl eugenol derivative has been arylated according to the Heck and oxidative Heck procedures to give products showing inhibitory effects on breast cancer cell metathesis [22]. Estragole (p-allylanisole) occurs in basil oil, and it has antioxidative, antimicrobial [23], and anesthetic [24] properties. The arylation of estragole has been performed with bromobenzene and palladium polyether diphosphinite complex anchored in polyethylene glycol [25]. Linalool (3,7-dimethyl-1,6-octadien-3-ol) is a tertiary monoterpene alcohol which is a major component of the Coriandrum sativum essential oil. Moreover, it has very wide applications in the synthesis of fine fragrances, cosmetics, detergents, and other commercial derivatives [26,27,28]. Linalool leads to the corresponding (E)-1-arylalk-1-en-3-ol under the Heck conditions with a Pd-Tedicyp catalyst (Tedicyp = cis, cis, cis, -1,2,3,4-tetrakis(diphenylphosphinomethyl)cyclopentane) [29,30].

Considering a wide spectrum of biological properties of the above-mentioned compounds, interesting activities of their aryl derivatives can also be expected, as has already been shown for the eugenol derivative [22]. In our work, we focused on the application of phosphine-free palladium precursors (Pd(OAc)2, PdCl2cod, or PdCl2(CH3CN)2) in two Heck-type arylation reactions employing iodobenzene or phenylboronic acid as an arylating agent. The application of phenylboronic acid avoids the formation of halide waste, in agreement with green chemistry rules. We also tested using water as a cosolvent in the reactions studied.

2. Results and Discussion

In order to get arylated derivatives of eugenol and estragole, two methods were tested and optimized. The first one was the Heck coupling with iodobenzene. In the second procedure, based on the Heck-type reaction, phenylboronic acid was employed as an arylating agent (Scheme 1). In this method, the base was eliminated from the system; however, the addition of a Cu(II) salt as an oxidant regenerating the catalytic amount of Pd(II) from Pd(0) was necessary [10,11,12,23]. The Heck-type reaction with the application of phenylboronic acid limits the formation of halide waste materials.

Scheme 1.

Scheme 1

Open in a new tab

Heck and Heck-type arylation of eugenol or estragole.

Table 1 presents the results of the Heck arylation of eugenole with iodobenzene. Three products, 1E, 1Z, and 1b, were identified, and the amount of 1b was below 3% in all cases, while 1E was the main product. The first experiments, carried out for 3 h at 100 °C in DMF as a solvent, resulted in a 100% conversion of PhI with the formation of 81% of 1E and 16% of 1Z. Very similar results were obtained after 1 h (95% conversion). Further studies showed that the Heck arylation can be successfully performed in a DMF:water mixture (DMF:water = 4:1 or 2.5:2.5). The reaction rate slowed down at a higher content of water, and the yield of 1E was only 69% after 1 h. However, after 2 h, the conversion of PhI achieved 100% with a 79% yield of 1E. The conversion of PhI depended on the reaction temperature: it decreased at lower temperatures, 80 °C and 60 °C, to 90% and 74%, respectively, after 3 h (Table 1, entries 1, 11 and 12). On the other hand, product 1b was not formed at lower temperatures. Considering the effect of the catalyst type, PdCl2(CH3CN)2 turned out to be weaker than Pd(OAc)2, resulting in a 16% lower conversion (Table 1, entry 2 and 9).

Table 1.

Results of the Heck arylation of eugenol with iodobenzene.

Entry Catalyst Base DMF:H2O T (°C) Time (h) PhI Conversion (%) Yield (%) a
1E 1Z 1b
1 Pd(OAc)2 K2CO3 DMF 100 3 100 81 16 3
2 DMF 100 1 95 78 15 2
3 4:1 100 3 100 84 14 2
4 4:1 100 2 100 85 15 0
5 4:1 100 1 100 85 13 1
6 2.5:2.5 100 2 100 79 21 0
7 2.5:2.5 100 1 93 69 23 1
9 PdCl2(CH3CN)2 DMF 100 1 79 74 5 0
10 Pd(OAc)2 4:1 100 40 min 74 65 7 2
11 4:1 80 3 90 80 10 0
12 4:1 60 3 74 68 6 0
Open in a new tab

Reaction conditions (method A): PhI (1 mmol), eugenol (1 mmol), K2CO3 (2 mmol), [Pd] (1 × 10−5 mol), DMF or mixture of DMF with H2O (5 cm3). a GC yield.

Next, the Heck arylation of estragole with iodobenzene was studied (Table 2). After 3 h of a reaction carried out at 100 °C, the conversion of iodobenzene reached 96%, and the yields of the main products, 2E and 2Z, were comparable, 47% and 42%, respectively. The presence of water resulted in a decrease in PhI conversion to 61% at the DMF:H2O ratio equal 4:1. In all experiments, the amount of product 2b was as low as 3–7%.

Table 2.

Results of the Heck arylation of estragole with iodobenzene.

Entry Catalyst Base DMF:H2O T (°C) Time (h) PhI Conversion (%) Yield (%) a
2E 2Z 2b
1 Pd(OAc)2 K2CO3 DMF 80 3 71 36 30 5
2 DMF 100 3 96 47 42 7
4 DMF 100 1 77 40 31 6
5 2.5:2.5 100 1 41 24 14 3
3 4:1 100 3 61 35 22 4
6 4:1 100 1 15 11 4 0
7 4:1 80 3 37 28 9 0
Open in a new tab

Reaction conditions (method A): PhI (1 mmol), estragole (1 mmol), K2CO3 (2 mmol), [Pd] (1 × 10−5 mol), DMF or a mixture of DMF and H2O (5 cm3). a GC yield.

In the alternative Heck-type procedure with phenylboronic acid used instead of iodobenzene, the base was eliminated and copper salts, Cu(OAc)2 or Cu(OAc)2.·H2O, were added (Scheme 1, Table 3). The best result, 92% conversion of eugenol, was achieved after 4 h at 100 °C (Table 3, entry 8). Two products, 1E and 1Z, were formed in comparable amounts, 46 and 39%, respectively. In almost all experiments performed according to this procedure, the yields of 1E and 1Z were similar. This is different from the Heck method with iodobenzene, which favored product 1E over 1Z. Only in one case, in a shorter reaction of 3 h, was the excess of 1E over 1Z significant (26%) (Table 3, entry 7). However, the prolongation of this reaction to 4 h resulted in an increase in the yield of 1E. The Heck-type procedure with phenylboronic acid was successful only when copper salts were employed as palladium oxidants. In contrast, arylation products were not formed in reactions performed in air (Table 3).

Table 3.

Results of the Heck-type arylation of eugenol with phenylboronic acid.

Entry Catalyst Base Modification T (°C) Time (h) Eugenol Conversion (%) Yield (%) a
1E 1Z 1b
1 Pd(OAc)2 KOH Air 50 3 0 0 0 0
2 Na2CO3 Air 50 3 0 0 0 0
3 K2CO3 Air 50 3 0 0 0 0
3 PdCl2cod ˗ Cu(OAc)2 120 4 55 21 21 7
4 ˗ 100 4 25 9 6 10
5 ˗ Cu(OAc)2.·H2O 100 4 53 26 17 9
6 ˗ Cu(OAc)2 120 4 57 26 25 6
7 Pd(OAc)2 ˗ 100 3 81 51 26 4
8 ˗ 100 4 92 46 39 4
Open in a new tab

Reaction conditions (method B): eugenol (1 mmol), phenylboronic acid (1.5 mmol), base (2 mmol), Cu2+ salt (2 mmol), [Pd] (1 × 10−5 mol), DMF (5 cm3). a GC yield.

Eugenol reacted faster according to the Heck procedure, and the conversion of PhI was 100% already after 1 h (Table 1, entry 5). In the Heck-type reaction, a conversion of 92% was achieved in 4 h (Table 3, entry 8).

Estragole was efficiently arylated with phenylboronic acid under the same conditions (Table 4). In this case, the positive effect of copper salts on the reaction course was also noted, while products were not formed in air atmosphere without copper. The best result, 92% conversion of estragole, was obtained after 4 h at 100 °C. Both products, 2E and 2Z, were formed in comparable amounts, 47 and 41%, respectively. In general, this method gave similar results to that with iodobenzene.

Table 4.

Results of the Heck-type reaction of estragole with phenylboronic acid.

Entry Catalyst Base Modification T (°C) Time (h) Estragole Conversion (%) Yield (%) a
2E 2Z 2b
1 Pd(OAc)2 KOH Air 50 3 0 0 0 0
2 Na2CO3 Air 50 3 0 0 0 0
3 PdCl2cod ˗ Cu(OAc)2 120 4 64 34 28 2
4 ˗ 100 4 34 22 12 0
5 ˗ Cu(OAc)2.·H2O 100 4 59 32 24 3
6 Pd(OAc)2 ˗ Cu(OAc)2 100 2.5 89 46 39 4
7 ˗ 100 3 90 49 37 4
8 ˗ 100 4 92 47 41 4
Open in a new tab

Reaction conditions (method B): estragole (1 mmol), phenylboronic acid (1.5 mmol), base (2 mmol), Cu2+ salt (2 mmol), [Pd] (1 × 10−5 mol), DMF (5 cm3). a GC yield.

The arylation of cinnamyl alcohol with iodobenzene produced a mixture of products with saturated aldehydes 3 and 4 being the main ones (Scheme 2). The formation of these products can be explained by a tandem process involving the isomerization of the Heck-reaction product, namely di-arylated allylic alcohol, produced in the first step [16]. The small amounts of unsaturated aldehydes 5 and 6 were probably formed by the Pd(II)-catalyzed dehydrogenation of 3 and 4 [31].

Scheme 2.

Scheme 2

Open in a new tab

Heck coupling of cinnamyl alcohol.

The data collected in Table 5 indicate the positive effect of water on the reaction course. For example, the yield of product 3 was 13%, and that of product 4 was 29%, after a 6 h reaction in DMF. When the same reaction was carried out in DMF:H2O (1:1), the yield of products 3 and 4 increased to 34 and 57%, respectively. Moreover, in the presence of water, the formation of a biphenyl side product was completely suppressed (Table 5, entry 3). Unfortunately, attempts to increase the amount of water to the DMF:H2O ratio of 1:4 resulted in a biphenyl yield increase to 19%, although the conversion of iodobenzene was quite high (93%) (Table 5, entry 4). Good results were also obtained in the presence of a TBAB additive (Table 5, entry 2). The formation of side products 5 and 6 was noted in few cases.

Table 5.

Results of the Heck reaction of cinnamyl alcohol with iodobenzene.

Entry Catalyst Base Modification Time (h) PhI Conversion (%) Yield (%) b
Bif. 3 4 5 6
1 PdCl2cod NaOAc ˗ 6 68 15 13 29 7 2
2 PdCl2cod TBAB a 6 91 5 28 52 3 3
3 PdCl2cod DMF:H2O
(1:1)		 6 93 ˗ 34 57 ˗ ˗
4 PdCl2cod DMF:H2O
(4:1)		 6 93 19 14 53 ˗ ˗
5 PdCl2cod K2HPO4 ˗ 6 30 ˗ 11 19 ˗ ˗
6 PdCl2cod DMF:H2O
(1:1)		 6 56 10 18 28 ˗ ˗
7 24 96 2 8 72 ˗ 11
8 PdCl2cod DMF:H2O
(1:4)		 6 68 10 13 40 ˗ ˗
9 PdCl2cod Et3N ˗ 6 68 24 22 18 ˗ ˗
10 DMF:H2O
(1:1)		 6 67 5 26 36 ˗ ˗
Open in a new tab

Reaction conditions (method C): PhI (1 mmol), cinnamyl alcohol (1 mmol), base (2 mmol), [Pd] (1 × 10−5 mol), DMF or DMF mixed with H2O (5 cm3), 100 °C; a 1 g of TBAB was added. b GC yield.

Next, the reaction of cinnamyl alcohol with phenylboronic acid was studied (Scheme 3). In these conditions, PdCl2cod was not active, and Pd(OAc)2 and Pd2(dba)3 were used as catalysts. Interestingly, the unsaturated alcohol 7, which was not obtained in reaction with iodobenzene, was formed as the main product in this case (Table 6). Arylation with phenylboronic acid was rather fast, and, already after 1 h at 50 °C, 100% of the alcohol was converted to afford 74% of 7 together with 20% and 6% of products 3 and 4, respectively. At a higher temperature, 100 °C, the yield of the side product, biphenyl, increased.

Scheme 3.

Scheme 3

Open in a new tab

The Heck-type arylation of cinnamyl alcohol with phenylboronic acid.

Table 6.

Results of the Heck-type arylation of cinnamyl alcohol with phenylboronic acid.

Entry Catalyst Salt Cu2+ T (°C) Time (h) Cinnamyl Alcohol Conversion (%) Yield (%) b
3 4 7
1 Pd(OAc)2 Air 100 4 0 0 0 0
2 Cu(OAc)2 100 6 100 37 14 49
3 100 4 100 40 16 44
4 50 1 90 18 6 63
5 Pd2(dba)3 50 4 100 19 6 75
6 50 1 100 20 6 74
7 a 50 1 63 13 5 45
8 50 0.5 90 25 8 56
Open in a new tab

Reaction conditions (method B): cinnamyl alcohol (1 mmol), phenylboronic acid (1.5 mmol), Cu2+ salt (2 mmol), [Pd] (1 × 10−5 mol), DMF (5 cm3), a [Pd] (0.5 × 10−5 mol). b GC yield.

Considering the activity of the catalysts used, it is worth noting that the activity of the Pd(0) complex was similar to that of the Pd(II) compound. The conversion of the substrate was high for both catalysts; however, Pd2(dba)3 preferably produced product 7, due to slow isomerization to 4. According to the well-accepted mechanism of the oxidative Heck coupling, Pd(II) is assumed to be catalytically active [10,11,23]. However, we have no evidence of the oxidation of Pd2(dba)3 in our system.

The last substrate studied was linalool (Scheme 4). It reacted smoothly with iodobenzene forming products 8 and 9.

Scheme 4.

Scheme 4

Open in a new tab

Heck coupling of linalool.

As shown in Table 6, the conversion of iodobenzene after 3 h was 42–47%, while it increased significantly, to 61–95%, after a change of the solvent from DMF alone to a DMF/water mixture (Table 7, entries 2 and 4). Considering the base, NaOAc was found the most efficient, enabling the formation of 66% of product 8 and 29% of product 9. Unfortunately, linalool did not react with phenylboronic acid under Heck-type conditions with Pd(OAc)2 as a catalyst.

Table 7.

Results of the Heck arylation of linalool with iodobenzene.

Entry Catalyst Base Modification Time (h) PhI Conversion (%) Yield (%) a
8 9
1 PdCl2cod NaOAc ˗ 3 47 33 14
2 DMF:H2O
(4:1)		 3 95 66 29
3 K2HPO4 ˗ 3 42 21 21
4 DMF:H2O
(4:1)		 3 65 48 17
5 Et3N ˗ 3 42 29 12
6 DMF:H2O
(4:1)		 3 61 45 12
Open in a new tab

Reaction conditions (method C): PhI (1 mmol), linalool (1 mmol), base (2 mmol), [Pd] (1 × 10−5 mol), 100 °C, DMF or mixed DMF with H2O (5 cm3). a GC yield.

3. Materials and Methods

3.1. Reactants

Iodobenzene, eugenol, estragole, cinnamyl alcohol, linalool, and phenylboronic acid (Sigma Aldrich, Poznań, Poland) were used without purification or drying.

3.2. General Procedures

3.2.1. Heck Reaction (Method A)

The reaction was carried out in a 50 cm3 Schlenk tube. The solid substrates, the base (2 mmol), and the Pd catalyst (1 × 10−5 mol) were weighed and placed in the Schlenk tube under an N2 atmosphere. Next, olefin (1 mmol), iodobenzene (1 mmol), and 5 cm3 of the solvent (DMF alone or DMF mixed with water) were added with a pipette. The Schlenk tube was closed with a rubber plug, and the reaction mixture was stirred at 60–100 °C in oil bath. After the given reaction time, the Schlenk tube was cooled down, and the organic products were separated by extraction with diethyl ether (three times with 5, 4, and 2 cm3). For better phase separation, 5 cm3 of water was added, and the products were GC–MS analyzed (Hewlett Packard 8454A (Palo Alto, CA, USA)) with mesitylene (0.1 cm3) as the internal standard. The GC yield given in the Table means the substrate conversion to a given product. Physicochemical data of reaction products can be found in Supplementary Materials.

3.2.2. Heck-Type Reaction (Method B)

The reaction was carried out in a 50 cm3 Schlenk tube. The solid substrates, copper (II) acetate (2 mmol), phenylboronic acid (1.5 mmol), and the Pd catalyst (1 × 10−5 mol) were weighed and placed in the Schlenk tube under an N2 atmosphere. Next, olefin (1 mmol) and 5 cm3 of the solvent (DMF alone or DMF mixed with water) were added with a pipette. The Schlenk tube was closed with a rubber plug, and the reaction mixture was stirred at 50–120 °C in oil bath. After the given reaction time, the Schlenk tube was cooled down, and the organic products were separated by extraction with diethyl ether (three times with 5, 4, and 2 cm3). For better phase separation, 5 cm3 of water was added, and the products were GC–MS analyzed (Hewlett Packard 8454A) with mesitylene (0.1 cm3) as the internal standard. The GC yield given in the Table means the substrate conversion to a given product. Physicochemical data of reaction products can be found in Supplementary Materials.

3.2.3. Heck-Type Reaction (Method C)

The reaction was carried out in a 50 cm3 Schlenk tube. The solid substrates, the base (2 mmol), and the PdCl2cod (1 × 10−5 mol) were weighed and placed in the Schlenk tube under an N2 atmosphere. Next, iodobenzene (1 mmol), cinnamyl alcohol or linalool (1 mmol), and 5 cm3 of the solvent (DMF alone or DMF mixed with water) were added with a pipette. The Schlenk tube was closed with a rubber plug, and the reaction mixture was stirred at 50–100 °C in oil bath. After the given reaction time, the Schlenk tube was cooled down, and the organic products were separated by extraction with diethyl ether (three times with 7, 3, and 2 cm3). For better phase separation, 5 cm3 of water was added, and the products were GC–MS analyzed (Hewlett Packard 8454A) with mesitylene (0.1 cm3) as the internal standard. The GC yield given in the Table means the substrate conversion to a given product. Physicochemical data of reaction products can be found in Supplementary Materials.

4. Conclusions

We presented two efficient methods based on palladium-catalyzed Heck procedures, leading to arylated products of biological importance. In particular, it was discovered that water serving as a co-solvent significantly enhanced product yield.

The Heck-type reaction employing phenylboronic acid and Cu2+ salts was tested for the first time in the arylation of eugenol and estragole, and the obtained results were very promising. In this procedure, the iodobenzene substrate was substituted by phenylboronic acid, which improved the economic and environmental aspects. The same method applied to cinnamyl alcohol enabled the preparation of arylated unsaturated alcohol in 1 h at 50 °C.

In the Heck coupling of cinnamyl alcohol with iodobenzene, diarylated saturated aldehydes were obtained. Also in this case, the addition of water resulted in an increase in iodobenzene conversion by over 20%, and 57% of 2,3-diphenylpropanal was formed. Similarly, the arylation of linalool in a DMF:H2O mixture gave better results (66% of product 8 and 29% of product 9) than a reaction carried out in the absence of water (33% of product 8 and 14% of product 9).

Supplementary Materials

Supplementary materials are available on line.

Click here for additional data file. (671.2KB, pdf)

Author Contributions

S.T.-L. performed experiments, analyzed the obtained results and prepared the manuscript. A.M.T. defined the work plan and the research methodology, elaborated the final version of the manuscript.

Funding

Financial support of National Science Centre (NCN, Poland) with grant 2014/15/B/ST5/02101 is gratefully acknowledged.

Conflicts of Interest

The authors declare no conflict of interest.

Footnotes

Sample Availability: Samples of the compounds are not available from the authors.

References

  • 1.Heck R.F. Palladium-catalyzed reactions of organic halides with olefins. Acc. Chem. Res. 1979;12:146–151. doi: 10.1021/ar50136a006. [DOI] [Google Scholar]
  • 2.Beletskaya I.P., Cheprakov A.V. The Heck Reaction as a Sharpening Stone of Palladium Catalysis. Chem. Rev. 2000;100:3009–3066. doi: 10.1021/cr9903048. [DOI] [PubMed] [Google Scholar]
  • 3.Dounay A.B., Overman L.E. The Asymmetric Intramolecular Heck Reaction in Natural Product Total Synthesis. Chem. Rev. 2003;103:2945–2964. doi: 10.1021/cr020039h. [DOI] [PubMed] [Google Scholar]
  • 4.Nicolaou K.C., Bulger P.G., Sarlah D. Palladium-Catalyzed Cross−Coupling Reactions in Total Synthesis. Angew. Chem. Int. Ed. 2005;44:4442–4489. doi: 10.1002/anie.200500368. [DOI] [PubMed] [Google Scholar]
  • 5.Torborg C., Beller M. Recent Applications of Palladium−Catalyzed Coupling Reactions in the Pharmaceutical, Agrochemical, and Fine Chemical Industries. Adv. Synth. Catal. 2009;351:3027–3043. doi: 10.1002/adsc.200900587. [DOI] [Google Scholar]
  • 6.Tarnowicz S., Alsalahi W., Mieczynska E., Trzeciak A.M. Heck arylation of allyl alcohol catalyzed by Pd(0) nanoparticles. Tetrahedron. 2017;73:5605–5612. doi: 10.1016/j.tet.2017.03.034. [DOI] [Google Scholar]
  • 7.Heravi M.M., Fazeli A. Recent Advances in the Application of the Heck Reaction in the Synthesis of Heterocyclic Compounds. Heterocycles. 2010;81:1979–2026. doi: 10.3987/REV-10-675. [DOI] [Google Scholar]
  • 8.Mazuela J., Tolstoy P., Pamies O., Andersson P.G., Dieguez M. Phosphite-oxazole/imidazole ligands in asymmetric intermolecular Heck reaction. Org. Biomol. Chem. 2011;9:941–946. doi: 10.1039/C0OB00656D. [DOI] [PubMed] [Google Scholar]
  • 9.Enquist P.-A., Lindh J., Larhed M. Open-air oxidative Heck reactions at room temperature. Green Chem. 2006;8:338–343. doi: 10.1039/b517152k. [DOI] [PubMed] [Google Scholar]
  • 10.Du X.L., Suguro M., Hirabayashi K., Mori A., Nishikata T., Hagiwara N., Kawata K., Okeda T., Wang H.F., Fugami K., et al. Mizoroki−Heck Type Reaction of Organoboron Reagents with Alkenes and Alkynes. A Pd(II)-Catalyzed Pathway with Cu(OAc)2 as an Oxidant. Org. Lett. 2001;3:3313–3316. doi: 10.1021/ol016529y. [DOI] [PubMed] [Google Scholar]
  • 11.Liu Y., Li D., Park C.-M. Stereoselective Synthesis of Highly Substituted Enamides by an Oxidative Heck Reaction. Angew. Chem. Int. Ed. 2011;50:7333–7336. doi: 10.1002/anie.201101550. [DOI] [PubMed] [Google Scholar]
  • 12.Inamoto K., Kawasaki J., Hiroya K., Kondo Y., Doi T. Tandem-type Pd(II)-catalyzed oxidative Heck reaction/intramolecular C–H amidation sequence: A novel route to 4-aryl-2-quinolinones. Chem. Commun. 2012;48:4332–4334. doi: 10.1039/c2cc30600j. [DOI] [PubMed] [Google Scholar]
  • 13.Nitti A., Bianchi G., Po R., Swager M., Pasini D. Domino Direct Arylation and Cross-Aldol for Rapid Construction of Extended Polycyclic π-Scaffolds. J. Am. Chem. Soc. 2017;139:8788–8791. doi: 10.1021/jacs.7b03412. [DOI] [PubMed] [Google Scholar]
  • 14.Nitti A., Po R., Bianchi G., Pasini D. Direct Arylation Strategies in the Synthesis of π-Extended Monomers for Organic Polymeric Solar Cells. Molecules. 2017;22:21. doi: 10.3390/molecules22010021. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Letizia C.S., Cocchiara J., Lalko J., Lapczynski A., Api A.M. Review Fragrance material review on cinnamyl alcohol. Food Chem. Toxicol. 2005;43:837–866. doi: 10.1016/j.fct.2004.09.012. [DOI] [PubMed] [Google Scholar]
  • 16.Calo V., Nacci A., Monopoli A., Ferola V. Palladium−Catalyzed Heck Arylations of Allyl Alcohols in Ionic Liquids: Remarkable Base Effect on the Selectivity. J. Org. Chem. 2007;72:2596–2601. doi: 10.1021/jo070005f. [DOI] [PubMed] [Google Scholar]
  • 17.Yusub C.T., Hossian A., Manna M.K., Jana R. Chemo-, Regio- and Stereoselective Heck-Matsuda Arylation of Allylic Alcohols under Mild Conditions. Org. Biomol. Chem. 2015;13:4841–4845. doi: 10.1039/C50B00235D. [DOI] [PubMed] [Google Scholar]
  • 18.Ambrogio I., Cacchi S., Fabrizi G., Goggiamani A., Sgalla S. Regio- and Stereoselective Heck α-Arylation of Cinnamyl Alcohols. Synlett. 2009;4:620–624. doi: 10.1055/s-0028-1087912. [DOI] [Google Scholar]
  • 19.Mino T., Kogure T., Abe T., Koizumi T., Fujita T., Sakamoto M. Palladium-Catalyzed Allylic Arylation of Allylic Ethers with Arylboronic Acids Using Hydrazone Ligands. Eur. J. Org. Chem. 2013:1501–1505. doi: 10.1002/ejoc.201201276. [DOI] [Google Scholar]
  • 20.Maralhas A., Monteiro A., Martins C., Kranendonk M., Laires A., Rueff J., Rodrigues A.S. Genotoxicity and endoreduplication inducing activity of the food flavouring eugenol. Mutagenesis. 2006;21:199–204. doi: 10.1093/mutage/gel017. [DOI] [PubMed] [Google Scholar]
  • 21.Kaufman T.S. The Multiple Faces of Eugenol. A Versatile Starting Material and Building Block for Organic and Bio−Organic Synthesis and a Convenient Precursor toward Bio−Based Fine Chemicals. J. Braz. Chem. Soc. 2015;26:1055–1085. doi: 10.5935/0103-5053.20150086. [DOI] [Google Scholar]
  • 22.Abdel Bar F.M., Khanfar M.A., Elnagar A.Y., Badria F.A., Zaghloul A.M., Ahmad K.F., Sylvester P.W., El Sayed K.A. Design and pharmacophore modeling of biaryl methyl eugenol analogs as breast cancer invasion inhibitors. Bioorg. Med. Chem. 2010;18:496–507. doi: 10.1016/j.bmc.2009.12.019. [DOI] [PubMed] [Google Scholar]
  • 23.Penn L., Shpruhman A., Gelman D. Enantio− and Regioselective Heck−Type Reaction of Arylboronic Acids with 2,3-Dihydrofuran. J. Org. Chem. 2007;72:3875–3879. doi: 10.1021/jo070170v. [DOI] [PubMed] [Google Scholar]
  • 24.Dallmeir K., Carlini E.A. Anesthetic, hypothermic, myorelaxant and anticonvulsant effects of synthetic eugenoderivates and natural analogues. Pharmacology. 1981;22:113–127. doi: 10.1159/000137479. [DOI] [PubMed] [Google Scholar]
  • 25.Sawant D., Wagh Y., Kushal B., Panda A., Bhanage B. Palladium polyether diphosphinite complex anchored in polyethylene glycol as an efficient homogeneous recyclable catalyst for the Heck reactions. Tetrahedron Lett. 2011;52:2390–2393. doi: 10.1016/j.tetlet.2011.02.100. [DOI] [Google Scholar]
  • 26.Bakkali F., Averbeck S., Averbeck D., Idaomar M. Biological effects of essential oils—A review. Food Chem. Toxicol. 2008;46:446–475. doi: 10.1016/j.fct.2007.09.106. [DOI] [PubMed] [Google Scholar]
  • 27.Letizia C.S., Cocchiara J., Lalko J., Api A.M. Review Fragrance material review on linalool. Food Chem. Toxicol. 2003;41:943–964. doi: 10.1016/S0278-6915(03)00015-2. [DOI] [PubMed] [Google Scholar]
  • 28.Raguso R.A., Pichersky E. New perspectives in pollination biology: Floral fragrances A day in the life of a linalool molecule: Chemical communication in a plant-pollinator system. Part 1: Linalool biosynthesis in flowering plants. Plant Species Biol. 1999;14:95–120. doi: 10.1046/j.1442-1984.1999.00014.x. [DOI] [Google Scholar]
  • 29.Berthiol F., Doucet H., Santelli M. Synthesis of β-aryl ketones by tetraphosphine/palladium catalysed Heck reactions of 2- or 3-substituted allylic alcohols with aryl bromides. Tetrahedron. 2006;62:4372–4383. doi: 10.1016/j.tet.2006.02.061. [DOI] [Google Scholar]
  • 30.Berthiol F., Doucet H., Santelli M. Heck reactions of aryl halides with alk-1-en-3-ol derivatives catalysed by a tetraphosphine-palladium complex. Appl. Organometal. Chem. 2006;20:855–868. doi: 10.1002/aoc.1143. [DOI] [Google Scholar]
  • 31.Calo V., Nacci A., Monopoli A., Cotugno A. Palladium-nanoparticle-catalysed Ullmann reactions in ionic liquids with aldehydes as the reductants: Scope and mechanism. Chem. Eur. J. 2009;15:1272–1279. doi: 10.1002/chem.200801621. [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Click here for additional data file. (671.2KB, pdf)

Articles from Molecules : A Journal of Synthetic Chemistry and Natural Product Chemistry are provided here courtesy of Multidisciplinary Digital Publishing Institute (MDPI)

RESOURCES