**Figure 32.**

*Synthesis of 4,6-disubstituted coumarins.*

**Figure 33.** *Synthesis of 3, and 4-substituted and 3,4-disubstituted coumarins.*

**125**

**Figure 37.**

*One-Pot Synthesis of Coumarin Derivatives DOI: http://dx.doi.org/10.5772/intechopen.89013*

= R3

hand, both 3- and 4-substituted coumarins **114** (R2

, R3 ≠ H) [125].

reactivity of *E*-enoates **112c** and **112d** than *E*-enoate **112a**.

synthesized from *o*-iodophenols **111** and terminal alkynes **110** (R2

= CH3) having CH2CHMe2 and CH3 group, respectively,

= H) and **115** (R2

= H;

= H) have been

= n

= H; R3

at the β-carbon, and their double bonds are therefore less sterically hindered than that in *E*-enoate **112a.** This reduced hindering is a major factor for the higher

Palladium-catalyzed carbonylative annulation of terminal alkynes **110** (R<sup>2</sup>

C4H9, n C8H17) bearing long alkyl chain. In addition, a wide variety of 3,4-disubstituted

(43–78%) via carbonylative annulation between *o*-iodophenols **111** and internal

The suggested mechanism of the carbonylative annulation is presented in **Figure 34**. The carbonylative annulation process is believed to proceed via (a) oxidative addition of *o*-iodophenol **111** to Pd(0), (b) insertion of alkyne **110** into the aryl-palladium complex **116**, (c) CO insertion into the resulting vinylic palladium species **118**, and (d) nucleophilic attack of the phenolic oxygen on the carbonyl carbon of the acylpalladium complex **119** with simultaneous regeneration of the

3,4-Disubstituted coumarins **121** are also isolated in good to excellent yields from readily available 2-(1-hydroxyprop-2-ynyl)phenols **120** via palladium-catalyzed

Pr, Ph, SiMe3, SiEt3, CO2Et, etc.) with *o*-iodophenols **111** affords 3-substituted

= H) in poor yields (18–36%) (**Figure 33**) [124]. On the other

, R3 ≠ H) have also been achieved in moderate to good yields

= CH3) and **112d** (R2

coumarins **114** (R2

coumarins **114/115** (R<sup>2</sup>

alkynes **110** (R<sup>2</sup>

Pd(0) catalyst.

**Figure 35.**

**Figure 36.**

*Synthesis of 4-arylcoumarins.*

*Synthesis of 4-arylcoumarins.*

*Synthesis of 3,4-disubstituted coumarins.*

R3

R3 = n

**Figure 34.** *Possible mechanism for the synthesis of coumarins via carbonylative annulation.*

#### *One-Pot Synthesis of Coumarin Derivatives DOI: http://dx.doi.org/10.5772/intechopen.89013*

*Phytochemicals in Human Health*

**Figure 32.**

**Figure 33.**

*Synthesis of 4,6-disubstituted coumarins.*

*Synthesis of 3, and 4-substituted and 3,4-disubstituted coumarins.*

*Possible mechanism for the synthesis of coumarins via carbonylative annulation.*

**124**

**Figure 34.**

R3 = CH3) and **112d** (R2 = R3 = CH3) having CH2CHMe2 and CH3 group, respectively, at the β-carbon, and their double bonds are therefore less sterically hindered than that in *E*-enoate **112a.** This reduced hindering is a major factor for the higher reactivity of *E*-enoates **112c** and **112d** than *E*-enoate **112a**.

Palladium-catalyzed carbonylative annulation of terminal alkynes **110** (R<sup>2</sup> = H; R3 = n Pr, Ph, SiMe3, SiEt3, CO2Et, etc.) with *o*-iodophenols **111** affords 3-substituted coumarins **114** (R2 = H) in poor yields (18–36%) (**Figure 33**) [124]. On the other hand, both 3- and 4-substituted coumarins **114** (R2 = H) and **115** (R2 = H) have been synthesized from *o*-iodophenols **111** and terminal alkynes **110** (R2 = H; R3 = n C4H9, n C8H17) bearing long alkyl chain. In addition, a wide variety of 3,4-disubstituted coumarins **114/115** (R<sup>2</sup> , R3 ≠ H) have also been achieved in moderate to good yields (43–78%) via carbonylative annulation between *o*-iodophenols **111** and internal alkynes **110** (R<sup>2</sup> , R3 ≠ H) [125].

The suggested mechanism of the carbonylative annulation is presented in **Figure 34**. The carbonylative annulation process is believed to proceed via (a) oxidative addition of *o*-iodophenol **111** to Pd(0), (b) insertion of alkyne **110** into the aryl-palladium complex **116**, (c) CO insertion into the resulting vinylic palladium species **118**, and (d) nucleophilic attack of the phenolic oxygen on the carbonyl carbon of the acylpalladium complex **119** with simultaneous regeneration of the Pd(0) catalyst.

3,4-Disubstituted coumarins **121** are also isolated in good to excellent yields from readily available 2-(1-hydroxyprop-2-ynyl)phenols **120** via palladium-catalyzed

**Figure 35.** *Synthesis of 3,4-disubstituted coumarins.*

**Figure 37.** *Synthesis of 4-arylcoumarins.*

dicarbonylation process in the presence of KI in MeOH at room temperature (**Figure 35**) [126].

Furthermore, electrophilic palladium-catalyzed cycloisomerization of brominated arylpropiolates **122** followed by Suzuki coupling with arylboronic acids furnishes 4-arylcoumarins **123** in moderate to good yields (**Figure 36**) [127]. This strongly suggests that a single loading of catalyst Pd(OAc)2 could be used to conduct sequential reactions for the synthesis of substituted coumarins.
