Consecutive One-Pot versus Domino Multicomponent Approaches to 3-(Diarylmethylene)oxindoles

Based on consecutive one-pot conditions combining three palladium-catalyzed reactions (Sonogashira, Heck and Suzuki-Miyaura reactions), a more efficient domino multicomponent method has been successfully developed to access a wide variety of 3-(diarylmethylene)oxindoles. Microwave irradiation and use of a silver salt were the most important factors to achieve high yields and stereoselectivity.


Introduction
Multicomponent reactions (MCRs) are generally understood as reactions in which three or more substrates are added at the beginning of the reaction to afford the products via two or more chemical transformations [1]. Inherently, well-designed MCRs can provide an efficient synthetic method for complex skeletons from simple substrates, securing diversity of products in a less time-consuming and more economical manner compared with the corresponding stepwise approaches [2]. These features of MCRs have attracted much interest among synthetic chemists in the pharmaceutical industry aiming to apply MCRs to create a wide variety of small molecule libraries [3][4][5]. Various heterocycles have also been synthesized via MCRs [6], especially utilizing transition metal catalysts [7]. Recently, as part of our ongoing efforts to find efficient synthetic methods for biologically active skeletons, we reported two such methods [8,9] for the preparation of 3-(diarylmethylene)oxindoles (Scheme 1), which are attracting increased interest due to their recently identified biological activities, such as AMPK activation [10] and anti-breast-cancer activity [11]. Both of our methods involve a simple propiolamide 1, and commercially available aryl iodides and arylboronic acids as starting materials to produce 3-(diarylmethylene)oxindoles via three successive palladium-catalyzed reactions: the Sonogashira, Heck, and Suzuki-Miyaura reactions. However, there is a big difference between the two methods in terms of the reaction process. The first method, under thermal conditions, begins with the Sonogashira reaction of propiolamide 1 and aryl iodide at 60 • C to give Sonogashira adduct 2, which then proceeds through Heck and Suzuki-Miyaura reactions upon the addition of arylboronic acid and elevation of the reaction temperature to 90 • C [8]. It is worth noting that the addition of a silver salt (AgOTf) with the arylboronic acid enhances the E/Z stereoselectivity of unsymmetrically substituted 3-(diarylmethylene)oxindoles. In contrast, the second method, under microwave-assisted conditions, requires neither a second addition, nor a temperature change [9]. Although both methods are one-pot reactions, the first method is a consecutive one-pot reaction requiring more than two separate operations, whereas the second method is a domino MCR, which offers a more efficient chemical transformation but makes it harder to achieve optimal conditions. Herein, we report our efforts efforts to develop efficient domino MCRs from consecutive one-pot conditions and wide screening of the substrate scope of the resulting domino MCRs, which contributes to our understanding of the mechanism of the reaction and could inform future studies on MCRs. Scheme 1. Consecutive one-pot versus domino MCR approach to 3-(diarylmethylene)oxindoles.

Results and Discussion
To verify the possibility of domino MCRs, we started with the addition of all three substrates (propiolamide 1, aryl iodide and arylboronic acid) at the beginning of the reaction, which were then exposed to the same reaction conditions for the consecutive one-pot reaction (Pd(PPh3)4, CuI, NaOAc, DMF; 60 °C for 1.5 h, then 90 °C for 24 h) ( Table 1). A silver salt (AgOTf) was not added in this preliminary study because it does not affect reaction progress, but mainly enhances the stereoselectivity of unsymmetrically substituted products. The main concern of this study was possibility of the direct Suzuki-Miyaura reaction between aryl iodide and arylboronic acid, to produce biphenyl byproducts 4. However, the formation of biphenyl compounds 4 was less than 15% for both symmetric (entries 1-3) and unsymmetric products (entries [4][5][6][7][8][9][10]. The yield and E/Z stereoselectivity were also similar to those of consecutive one-pot conditions. These results imply that aryl iodide reacted first with propiolamide 1 rather than arylboronic acid at the initial temperature (60 °C), to produce the corresponding Sonogashira adduct 2 that was then transformed into the desired 3 at a higher temperature (90 °C).
In spite of the promising preliminary results, the E/Z stereoselectivity for unsymmetrically substituted products was still poor without silver salt (Table 1; entries 5-10). Thus, we investigated the ability of silver salt to improve the stereoselectivity of the products ( Table 2). In the initial screening of silver salts, AgOTf showed the best enhancement of stereoselectivity without any compensatory loss of product yield [8]. Subsequently, more intensive screenings for silver salts revealed that Ag3PO4 is a better additive for this purpose, as shown in Table 2. When Ag3PO4 was added at the beginning of the reaction with all substrates, stereoselectivity was enhanced as expected, but yields decreased with the formation of a substantial amount of the biphenyl product 4 (20%-40% yield). Silver salt might hamper the Sonogashira reaction between 1 and aryl iodide, allowing more aryl iodide to undergo the direct Suzuki-Miyaura reaction with arylboronic acid. Scheme 1. Consecutive one-pot versus domino MCR approach to 3-(diarylmethylene)oxindoles.

Results and Discussion
To verify the possibility of domino MCRs, we started with the addition of all three substrates (propiolamide 1, aryl iodide and arylboronic acid) at the beginning of the reaction, which were then exposed to the same reaction conditions for the consecutive one-pot reaction (Pd(PPh 3 ) 4 , CuI, NaOAc, DMF; 60 • C for 1.5 h, then 90 • C for 24 h) ( Table 1). A silver salt (AgOTf) was not added in this preliminary study because it does not affect reaction progress, but mainly enhances the stereoselectivity of unsymmetrically substituted products. The main concern of this study was possibility of the direct Suzuki-Miyaura reaction between aryl iodide and arylboronic acid, to produce biphenyl byproducts 4. However, the formation of biphenyl compounds 4 was less than 15% for both symmetric (entries [1][2][3] and unsymmetric products (entries [4][5][6][7][8][9][10]. The yield and E/Z stereoselectivity were also similar to those of consecutive one-pot conditions. These results imply that aryl iodide reacted first with propiolamide 1 rather than arylboronic acid at the initial temperature (60 • C), to produce the corresponding Sonogashira adduct 2 that was then transformed into the desired 3 at a higher temperature (90 • C).
In spite of the promising preliminary results, the E/Z stereoselectivity for unsymmetrically substituted products was still poor without silver salt (Table 1; entries 5-10). Thus, we investigated the ability of silver salt to improve the stereoselectivity of the products ( Table 2). In the initial screening of silver salts, AgOTf showed the best enhancement of stereoselectivity without any compensatory loss of product yield [8]. Subsequently, more intensive screenings for silver salts revealed that Ag 3 PO 4 is a better additive for this purpose, as shown in Table 2. When Ag 3 PO 4 was added at the beginning of the reaction with all substrates, stereoselectivity was enhanced as expected, but yields decreased with the formation of a substantial amount of the biphenyl product 4 (20%-40% yield). Silver salt might hamper the Sonogashira reaction between 1 and aryl iodide, allowing more aryl iodide to undergo the direct Suzuki-Miyaura reaction with arylboronic acid.
To solve the problem of low yield with the addition of silver salt, we screened various phosphine ligands, expecting improvement of yield while maintaining good stereoselectivity ( Table 3, entries [1][2][3][4][5]. Bidentate phosphine ligands are known as effective ligands for the cationic pathway of palladium-catalyzed reactions [12]. Unfortunately, the addition of bidentate ligands (dppp, dppb and dppf) did not afford the desired product 3f (entries [1][2][3]. When P(o-tol) 3 was added, 3f was obtained in poor yield (13%) (entry 4). Addition of PPh 3 showed a promising result (entry 5; Molecules 2017, 22, 503 3 of 20 50% yield, 5:1 E/Z ratio) but was still less effective than the consecutive one-pot conditions with Ag 3 PO 4 ( Table 2, entry 2; 86% yield, 9:1 E/Z ratio). Interestingly, elevation of the initial reaction temperature to 90 • C, which removed the additional temperature change operation, provided 3f in 67% yield with a 7.5:1 E/Z ratio (entry 6). When the reaction temperature was further increased (150 • C), the reaction rate increased but yield and stereoselectivity decreased slightly (entries 6 and 7). These results showed that high reaction temperature reduced the hampering effect of silver salt on the initial Sonogashira reaction.   To solve the problem of low yield with the addition of silver salt, we screened various phosphine ligands, expecting improvement of yield while maintaining good stereoselectivity (    To solve the problem of low yield with the addition of silver salt, we screened various phosphine ligands, expecting improvement of yield while maintaining good stereoselectivity (Table 3, entries 1-5). Bidentate phosphine ligands are known as effective ligands for the cationic pathway of palladiumcatalyzed reactions [12]. Unfortunately, the addition of bidentate ligands (dppp, dppb and dppf) did not afford the desired product 3f (entries 1-3). When P(o-tol)3 was added, 3f was obtained in poor  yield, 9:1 E/Z ratio). Interestingly, elevation of the initial reaction temperature to 90 °C, which removed the additional temperature change operation, provided 3f in 67% yield with a 7.5:1 E/Z ratio (entry 6). When the reaction temperature was further increased (150 °C), the reaction rate increased but yield and stereoselectivity decreased slightly (entries 6 and 7). These results showed that high reaction temperature reduced the hampering effect of silver salt on the initial Sonogashira reaction. Considering the above results, we decided to test microwave irradiation conditions, which are known for accelerating sluggish thermal reactions [13][14][15] (Table 4). Reactions with microwave irradiation at 100 °C, for 10, 30 and 60 min, increased yields from 46% to 80% with increasing reaction time, and the stereoselectivity in all three cases was very high (9:1~18:1 E/Z ratio, entries 1-3). Higher reaction temperatures (110 and 130 °C) made it possible to complete the reaction in a shortest time (10 min) with good yield and stereoselectivity (entries 4 and 5). The best result was obtained at 150 °C, presenting 99% yield and a 13:1 E/Z ratio (entry 6). At 160 °C, the reaction was completed in 5 min to give 3f in 98% yield with slightly lower stereoselectivity (7.5:1 E/Z ratio) (entry 7).
Based on these favorable results under microwave conditions, we decided to investigate the effects of additives on microwave-assisted reactions by performing a blank test. Without phosphine ligand (PPh3), the reaction still proceeded smoothly, to provide 3f in slightly lower yield and stereoselectivity (entry 8; 92% yield, 8:1 E/Z ratio). However, the removal of silver salt (Ag3PO4) dramatically decreased the yield (36%) and stereoselectivity (1:1.2 E/Z ratio) (entry 9). Without both PPh3 and Ag3PO4, the lowest yield (35%) and stereo-inverted selectivity (1:1.5 E/Z ratio) were obtained (entry 10). Interestingly, the addition of two equivalents of Ag3PO4 without base (NaOAc) still provided product 3f in moderate yield and stereoselectivity (entry 11). Thus, under microwave irradiation conditions, silver salt seems to be a crucial additive not only for good stereoselectivity, but also for high yield.
With optimized microwave-assisted conditions in hand, we investigated the substrate scope for the synthesis of symmetrically substituted 3-(diarylmethylene)oxindoles ( Table 5). Regardless of the substituents on the aryl group, all reactions gave the desired products 3a-d in good yield (entries [1][2][3][4]. To verify the effect of silver salt, control experiments without Ag3PO4 were also performed. As expected, the absence of silver salt decreased the yield of all reactions. However, the degree of yield reduction appears to be related to the electronic effect of the substituent on the aryl group. The formation of 3b bearing the electron-donating methoxy group at the 4-position was hardly affected by the absence of Ag3PO4 (75% vs. 55%); whereas the yields for 3d with the electron-withdrawing nitro group at the Considering the above results, we decided to test microwave irradiation conditions, which are known for accelerating sluggish thermal reactions [13][14][15] (Table 4). Reactions with microwave irradiation at 100 • C, for 10, 30 and 60 min, increased yields from 46% to 80% with increasing reaction time, and the stereoselectivity in all three cases was very high (9:1~18:1 E/Z ratio, entries 1-3). Higher reaction temperatures (110 and 130 • C) made it possible to complete the reaction in a shortest time (10 min) with good yield and stereoselectivity (entries 4 and 5). The best result was obtained at 150 • C, presenting 99% yield and a 13:1 E/Z ratio (entry 6). At 160 • C, the reaction was completed in 5 min to give 3f in 98% yield with slightly lower stereoselectivity (7.5:1 E/Z ratio) (entry 7). same position changed dramatically, from 90% to 9%, without addition of Ag3PO4. This suggests that the positive effect of Ag3PO4 on the domino MCRs is due in part to enhancing the last Suzuki-Miyaura reaction step [16].  Based on these favorable results under microwave conditions, we decided to investigate the effects of additives on microwave-assisted reactions by performing a blank test. Without phosphine ligand (PPh 3 ), the reaction still proceeded smoothly, to provide 3f in slightly lower yield and stereoselectivity (entry 8; 92% yield, 8:1 E/Z ratio). However, the removal of silver salt (Ag 3 PO 4 ) dramatically decreased the yield (36%) and stereoselectivity (1:1.2 E/Z ratio) (entry 9). Without both PPh 3 and Ag 3 PO 4 , the lowest yield (35%) and stereo-inverted selectivity (1:1.5 E/Z ratio) were obtained (entry 10). Interestingly, the addition of two equivalents of Ag 3 PO 4 without base (NaOAc) still provided product 3f in moderate yield and stereoselectivity (entry 11). Thus, under microwave irradiation conditions, silver salt seems to be a crucial additive not only for good stereoselectivity, but also for high yield.
With optimized microwave-assisted conditions in hand, we investigated the substrate scope for the synthesis of symmetrically substituted 3-(diarylmethylene)oxindoles ( Table 5). Regardless of the substituents on the aryl group, all reactions gave the desired products 3a-d in good yield (entries [1][2][3][4]. To verify the effect of silver salt, control experiments without Ag 3 PO 4 were also performed. As expected, the absence of silver salt decreased the yield of all reactions. However, the degree of yield reduction appears to be related to the electronic effect of the substituent on the aryl group. The formation of 3b bearing the electron-donating methoxy group at the 4-position was hardly affected by the absence of Ag 3 PO 4 (75% vs. 55%); whereas the yields for 3d with the electron-withdrawing nitro group at the same position changed dramatically, from 90% to 9%, without addition of Ag 3 PO 4 . This suggests that the positive effect of Ag 3 PO 4 on the domino MCRs is due in part to enhancing the last Suzuki-Miyaura reaction step [16]. same position changed dramatically, from 90% to 9%, without addition of Ag3PO4. This suggests that the positive effect of Ag3PO4 on the domino MCRs is due in part to enhancing the last Suzuki-Miyaura reaction step [16].  Next, we tested the effect of our reaction conditions on the synthesis of unsymmetrically substituted 3-(diarylmethylene)oxindoles having electronically different substituents at the 4-position of the phenyl group (Table 6). All reactions provided products 3e-g in good yield (80%-99%). Stereoselectivity for each reaction was more than 8:1, giving the expected stereoisomer as the major product, except in the reaction with 4-methoxyphenyl iodide, in which the E/Z ratio of 1.2:1 resulted in a little more of the stereoinverted E-isomer than the Z-isomer. This exceptional case will be revisited later through extensive screening of the reaction conditions. To confirm the ligand effect on our domino MCRs, all reactions were Next, we tested the effect of our reaction conditions on the synthesis of unsymmetrically substituted 3-(diarylmethylene)oxindoles having electronically different substituents at the 4-position of the phenyl group (Table 6). All reactions provided products 3e-g in good yield (80%-99%). Stereoselectivity for each reaction was more than 8:1, giving the expected stereoisomer as the major product, except in the reaction with 4-methoxyphenyl iodide, in which the E/Z ratio of 1.2:1 resulted in a little more of the stereo-inverted E-isomer than the Z-isomer. This exceptional case will be revisited later through extensive screening of the reaction conditions. To confirm the ligand effect on our domino MCRs, all reactions were tested again without PPh 3 , which resulted in similar but slightly lower yield and stereoselectivity. The addition of PPh 3 did not enhance the reaction as much as silver salt, but nevertheless surely plays a meaningful role in producing good yield and stereoselectivity of the domino MCRs. tested again without PPh3, which resulted in similar but slightly lower yield and stereoselectivity. The addition of PPh3 did not enhance the reaction as much as silver salt, but nevertheless surely plays a meaningful role in producing good yield and stereoselectivity of the domino MCRs. To widen the application of the reaction, a more expanded substrate scope was investigated ( Table 7). The reaction of 4-acetoxyphenylboronic acid showed relatively low yield (45%) but high stereoselectivity (10:1 E/Z ratio) (entry 1). Unlike 4-methoxyphenyl iodide, the reaction of 4-acetoxyphenyl iodide presented good yield and stereoselectivity (entry 2), representing an alternative way to synthesize the Z-isomer with an oxygen atom at the 4-position of the phenyl group. Moreover, 3-(diarylmethylene)oxindoles with substituents at the 3-position of the phenyl group were easily prepared by our domino MCRs, regardless of the electronic effect of the substituent (entries 3-10). When the yield was moderate, addition of two equivalents of arylboronic acid increased the yield up to 94%, accompanied by slightly lower stereoselectivity (entries 5 and 10). It is worth pointing out that the reaction of 3-methoxyphenyl iodide showed good stereoselectivity (1:8 E/Z ratio, entry 7). This result suggests that the position of the methoxy group on the aryl iodide is important for determining the stereoselectivity of the reaction. 2-Chloro and 2-methoxyphenylboronic acids were good substrates for the reaction, providing 3l and 3m in good yield (entries 11 and 12); however, no product was formed in the reaction of 2-nitrophenylboronic acid (entry 13). 2-Methoxyphenyl iodide reiterated the problem of low stereoselectivity, as well as 4-methoxyphenyl iodide (entry 14). The reaction of 2-chlorophenyl iodide resulted in good yield and stereoselectivity (entry 15), while the 2nitrophenyl iodide was a poor substrate for the reaction, giving product 3n in very low yield (entry 16). Taken together, the above results suggest that our domino MCRs have broad substituent tolerance for both aryl iodide and arylboronic acid, producing good yield and stereoselectivity except for 2-or 4-methoxyphenyl iodide and the 2-nitro substituent.
Next, we tried to solve the low stereoselectivity problem for the reaction with 4-methoxyphenyl iodide (Table 8). We focused on the amount of Ag3PO4, which seems to play a crucial role in achieving good stereoselectivity in the domino MCRs. Increasing the amount of Ag3PO4 showed little improvement of stereoselectivity, but rather reduced the yield (entries 2-4). Other silver salts were not as effective as Ag3PO4 (entries 5-8). Then, we lowered the reaction temperature. At 130 °C, stereoselectivity increased slightly (1:1.5 E/Z ratio, entry 9). At 100 °C, the reaction rate was much slower and a longer reaction time was needed to achieve reasonable yield. The reaction for 1 h at 100 °C provided the best stereoselectivity (1:4 E/Z ratio) with good yield (70% entry 10). A longer reaction time (3 h To widen the application of the reaction, a more expanded substrate scope was investigated ( Table 7). The reaction of 4-acetoxyphenylboronic acid showed relatively low yield (45%) but high stereoselectivity (10:1 E/Z ratio) (entry 1). Unlike 4-methoxyphenyl iodide, the reaction of 4-acetoxyphenyl iodide presented good yield and stereoselectivity (entry 2), representing an alternative way to synthesize the Z-isomer with an oxygen atom at the 4-position of the phenyl group. Moreover, 3-(diarylmethylene)oxindoles with substituents at the 3-position of the phenyl group were easily prepared by our domino MCRs, regardless of the electronic effect of the substituent (entries 3-10). When the yield was moderate, addition of two equivalents of arylboronic acid increased the yield up to 94%, accompanied by slightly lower stereoselectivity (entries 5 and 10). It is worth pointing out that the reaction of 3-methoxyphenyl iodide showed good stereoselectivity (1:8 E/Z ratio, entry 7). This result suggests that the position of the methoxy group on the aryl iodide is important for determining the stereoselectivity of the reaction. 2-Chloro and 2-methoxyphenylboronic acids were good substrates for the reaction, providing 3l and 3m in good yield (entries 11 and 12); however, no product was formed in the reaction of 2-nitrophenylboronic acid (entry 13). 2-Methoxyphenyl iodide reiterated the problem of low stereoselectivity, as well as 4-methoxyphenyl iodide (entry 14). The reaction of 2-chlorophenyl iodide resulted in good yield and stereoselectivity (entry 15), while the 2-nitrophenyl iodide was a poor substrate for the reaction, giving product 3n in very low yield (entry 16). Taken together, the above results suggest that our domino MCRs have broad substituent tolerance for both aryl iodide and arylboronic acid, producing good yield and stereoselectivity except for 2-or 4-methoxyphenyl iodide and the 2-nitro substituent.
Next, we tried to solve the low stereoselectivity problem for the reaction with 4-methoxyphenyl iodide (Table 8). We focused on the amount of Ag 3 PO 4 , which seems to play a crucial role in achieving good stereoselectivity in the domino MCRs. Increasing the amount of Ag 3 PO 4 showed little improvement of stereoselectivity, but rather reduced the yield (entries 2-4). Other silver salts were not as effective as Ag 3 PO 4 (entries 5-8). Then, we lowered the reaction temperature. At 130 • C, stereoselectivity increased slightly (1:1.5 E/Z ratio, entry 9). At 100 • C, the reaction rate was much slower and a longer reaction time was needed to achieve reasonable yield. The reaction for 1 h at 100 • C provided the best stereoselectivity (1:4 E/Z ratio) with good yield (70% entry 10). A longer reaction time (3 h) at 100 • C increased the yield to 79% but decreased stereoselectivity (1:3 E/Z ratio, entry 11). Thus, in the case of poor stereoselectivity, modification of the reaction temperature and time of the reaction can offer a solution. yield to 79% but decreased stereoselectivity (1:3 E/Z ratio, entry 11). Thus, in the case of poor stereoselectivity, modification of the reaction temperature and time of the reaction can offer a solution.   yield to 79% but decreased stereoselectivity (1:3 E/Z ratio, entry 11). Thus, in the case of poor stereoselectivity, modification of the reaction temperature and time of the reaction can offer a solution.  Our next challenge was to expand the substrate scope to heteroaryl groups ( Table 9). The 3-or 4-pyridinyl group was introduced by our domino MCRs in good yield and high stereoselectivity (entries 1 and 2). The reaction with 3-benzothiophenylboronic acid provided the desired product in 52% yield and 16:1 E/Z ratio (entry 3). Interestingly, in this reaction, unexpected byproduct 5 was isolated; the structure of 5 was elucidated by intensive one-dimensional (1D) and two-dimensional (2D) nuclear magnetic resonance (NMR) experiments. The formation of tricyclic compound 5 would be explained by insertion of an acetyl group originating from the base (NaOAc). The formation of 5 was easily removed by the use of the more heteroarylboronic acid (2 eq, entry 4); 2-benzothiophenylboronic acid and 3-furanylboronic acid showed similar activity in domino MCRs (entries 5-8), although the stereoselectivity of the reaction with 2-benzothiophenylboronic acid was much lower than for the others (entries 5 and 6). Table 9. Substrate scope with heteroarylboronic acids 1 .
Molecules 2017, 22, 503 8 of 19 Our next challenge was to expand the substrate scope to heteroaryl groups ( Table 9). The 3-or 4-pyridinyl group was introduced by our domino MCRs in good yield and high stereoselectivity (entries 1 and 2). The reaction with 3-benzothiophenylboronic acid provided the desired product in 52% yield and 16:1 E/Z ratio (entry 3). Interestingly, in this reaction, unexpected byproduct 5 was isolated; the structure of 5 was elucidated by intensive one-dimensional (1D) and two-dimensional (2D) nuclear magnetic resonance (NMR) experiments. The formation of tricyclic compound 5 would be explained by insertion of an acetyl group originating from the base (NaOAc). The formation of 5 was easily removed by the use of the more heteroarylboronic acid (2 eq, entry 4); 2-benzothiophenylboronic acid and 3-furanylboronic acid showed similar activity in domino MCRs (entries 5-8), although the stereoselectivity of the reaction with 2-benzothiophenylboronic acid was much lower than for the others (entries 5 and 6). Next, we investigated the possibility of derivatization of propiolamide 1 (Table 10). When the N-substituent of propiolamide 1 was changed to a H or a Bn group, the reactions showed good yield and moderate stereoselectivity (entries 1 and 2). Under standard conditions, one carbon-extended substrate 6c showed low yield (35%, entry 3). The yield increased to 45% at higher reaction temperature (180 °C) but almost no stereoselectivity was observed (1.1:1 E/Z ratio, entry 4). Propiolate ester 6d turned out to be a poor substrate for our domino MCRs, giving both a low yield and poor stereoselectivity (entry 5). All results implied that applying our microwave-assisted domino MCRs to the synthesis of other heterocycles is possible, but needs further study for optimization of each reaction.
In all of the above results, the stereoselectivity of the domino MCRs varied depending on the substrate. One of the reasons for this could be the isomerization of product 3 under the reaction conditions. Thus, we exposed pure (Z)-and (E)-isomers of 3e to the standard reaction conditions (Table 11). Both (Z)and (E)-3e showed very low isomerization rates (<15%), regardless of the addition of Ag3PO4. This suggests that isomerization of the product would not be a main reason for low stereoselectivity, and the Our next challenge was to expand the substrate scope to heteroaryl groups ( Table 9). The 3-or 4-pyridinyl group was introduced by our domino MCRs in good yield and high stereoselectivity (entries 1 and 2). The reaction with 3-benzothiophenylboronic acid provided the desired product in 52% yield and 16:1 E/Z ratio (entry 3). Interestingly, in this reaction, unexpected byproduct 5 was isolated; the structure of 5 was elucidated by intensive one-dimensional (1D) and two-dimensional (2D) nuclear magnetic resonance (NMR) experiments. The formation of tricyclic compound 5 would be explained by insertion of an acetyl group originating from the base (NaOAc). The formation of 5 was easily removed by the use of the more heteroarylboronic acid (2 eq, entry 4); 2-benzothiophenylboronic acid and 3-furanylboronic acid showed similar activity in domino MCRs (entries 5-8), although the stereoselectivity of the reaction with 2-benzothiophenylboronic acid was much lower than for the others (entries 5 and 6). Next, we investigated the possibility of derivatization of propiolamide 1 (Table 10). When the N-substituent of propiolamide 1 was changed to a H or a Bn group, the reactions showed good yield and moderate stereoselectivity (entries 1 and 2). Under standard conditions, one carbon-extended substrate 6c showed low yield (35%, entry 3). The yield increased to 45% at higher reaction temperature (180 °C) but almost no stereoselectivity was observed (1.1:1 E/Z ratio, entry 4). Propiolate ester 6d turned out to be a poor substrate for our domino MCRs, giving both a low yield and poor stereoselectivity (entry 5). All results implied that applying our microwave-assisted domino MCRs to the synthesis of other heterocycles is possible, but needs further study for optimization of each reaction.
In all of the above results, the stereoselectivity of the domino MCRs varied depending on the substrate. One of the reasons for this could be the isomerization of product 3 under the reaction conditions. Thus, we exposed pure (Z)-and (E)-isomers of 3e to the standard reaction conditions (Table 11). Both (Z)and (E)-3e showed very low isomerization rates (<15%), regardless of the addition of Ag3PO4. This suggests that isomerization of the product would not be a main reason for low stereoselectivity, and the Our next challenge was to expand the substrate scope to heteroaryl groups ( Table 9). The 3-or 4-pyridinyl group was introduced by our domino MCRs in good yield and high stereoselectivity (entries 1 and 2). The reaction with 3-benzothiophenylboronic acid provided the desired product in 52% yield and 16:1 E/Z ratio (entry 3). Interestingly, in this reaction, unexpected byproduct 5 was isolated; the structure of 5 was elucidated by intensive one-dimensional (1D) and two-dimensional (2D) nuclear magnetic resonance (NMR) experiments. The formation of tricyclic compound 5 would be explained by insertion of an acetyl group originating from the base (NaOAc). The formation of 5 was easily removed by the use of the more heteroarylboronic acid (2 eq, entry 4); 2-benzothiophenylboronic acid and 3-furanylboronic acid showed similar activity in domino MCRs (entries 5-8), although the stereoselectivity of the reaction with 2-benzothiophenylboronic acid was much lower than for the others (entries 5 and 6). Next, we investigated the possibility of derivatization of propiolamide 1 (Table 10). When the N-substituent of propiolamide 1 was changed to a H or a Bn group, the reactions showed good yield and moderate stereoselectivity (entries 1 and 2). Under standard conditions, one carbon-extended substrate 6c showed low yield (35%, entry 3). The yield increased to 45% at higher reaction temperature (180 °C) but almost no stereoselectivity was observed (1.1:1 E/Z ratio, entry 4). Propiolate ester 6d turned out to be a poor substrate for our domino MCRs, giving both a low yield and poor stereoselectivity (entry 5). All results implied that applying our microwave-assisted domino MCRs to the synthesis of other heterocycles is possible, but needs further study for optimization of each reaction.
In all of the above results, the stereoselectivity of the domino MCRs varied depending on the substrate. One of the reasons for this could be the isomerization of product 3 under the reaction conditions. Thus, we exposed pure (Z)-and (E)-isomers of 3e to the standard reaction conditions (Table 11). Both (Z)and (E)-3e showed very low isomerization rates (<15%), regardless of the addition of Ag3PO4. This suggests that isomerization of the product would not be a main reason for low stereoselectivity, and the Our next challenge was to expand the substrate scope to heteroaryl groups ( Table 9). The 3-or 4-pyridinyl group was introduced by our domino MCRs in good yield and high stereoselectivity (entries 1 and 2). The reaction with 3-benzothiophenylboronic acid provided the desired product in 52% yield and 16:1 E/Z ratio (entry 3). Interestingly, in this reaction, unexpected byproduct 5 was isolated; the structure of 5 was elucidated by intensive one-dimensional (1D) and two-dimensional (2D) nuclear magnetic resonance (NMR) experiments. The formation of tricyclic compound 5 would be explained by insertion of an acetyl group originating from the base (NaOAc). The formation of 5 was easily removed by the use of the more heteroarylboronic acid (2 eq, entry 4); 2-benzothiophenylboronic acid and 3-furanylboronic acid showed similar activity in domino MCRs (entries 5-8), although the stereoselectivity of the reaction with 2-benzothiophenylboronic acid was much lower than for the others (entries 5 and 6). Table 9. Substrate scope with heteroarylboronic acids 1 . Next, we investigated the possibility of derivatization of propiolamide 1 (Table 10). When the N-substituent of propiolamide 1 was changed to a H or a Bn group, the reactions showed good yield and moderate stereoselectivity (entries 1 and 2). Under standard conditions, one carbon-extended substrate 6c showed low yield (35%, entry 3). The yield increased to 45% at higher reaction temperature (180 °C) but almost no stereoselectivity was observed (1.1:1 E/Z ratio, entry 4). Propiolate ester 6d turned out to be a poor substrate for our domino MCRs, giving both a low yield and poor stereoselectivity (entry 5). All results implied that applying our microwave-assisted domino MCRs to the synthesis of other heterocycles is possible, but needs further study for optimization of each reaction.

Entry Het-Ar-B(OH)2 3 Yield (%) 2 E/Z
In all of the above results, the stereoselectivity of the domino MCRs varied depending on the substrate. One of the reasons for this could be the isomerization of product 3 under the reaction conditions. Thus, we exposed pure (Z)-and (E)-isomers of 3e to the standard reaction conditions (Table 11). Both (Z)and (E)-3e showed very low isomerization rates (<15%), regardless of the addition of Ag3PO4. This suggests that isomerization of the product would not be a main reason for low stereoselectivity, and the Our next challenge was to expand the substrate scope to heteroaryl groups ( Table 9). The 3-or 4-pyridinyl group was introduced by our domino MCRs in good yield and high stereoselectivity (entries 1 and 2). The reaction with 3-benzothiophenylboronic acid provided the desired product in 52% yield and 16:1 E/Z ratio (entry 3). Interestingly, in this reaction, unexpected byproduct 5 was isolated; the structure of 5 was elucidated by intensive one-dimensional (1D) and two-dimensional (2D) nuclear magnetic resonance (NMR) experiments. The formation of tricyclic compound 5 would be explained by insertion of an acetyl group originating from the base (NaOAc). The formation of 5 was easily removed by the use of the more heteroarylboronic acid (2 eq, entry 4); 2-benzothiophenylboronic acid and 3-furanylboronic acid showed similar activity in domino MCRs (entries 5-8), although the stereoselectivity of the reaction with 2-benzothiophenylboronic acid was much lower than for the others (entries 5 and 6). Table 9. Substrate scope with heteroarylboronic acids 1 . Next, we investigated the possibility of derivatization of propiolamide 1 (Table 10). When the N-substituent of propiolamide 1 was changed to a H or a Bn group, the reactions showed good yield and moderate stereoselectivity (entries 1 and 2). Under standard conditions, one carbon-extended substrate 6c showed low yield (35%, entry 3). The yield increased to 45% at higher reaction temperature (180 °C) but almost no stereoselectivity was observed (1.1:1 E/Z ratio, entry 4). Propiolate ester 6d turned out to be a poor substrate for our domino MCRs, giving both a low yield and poor stereoselectivity (entry 5). All results implied that applying our microwave-assisted domino MCRs to the synthesis of other heterocycles is possible, but needs further study for optimization of each reaction.

Entry Het-Ar-B(OH)2 3 Yield (%) 2 E/Z
In all of the above results, the stereoselectivity of the domino MCRs varied depending on the substrate. One of the reasons for this could be the isomerization of product 3 under the reaction conditions. Thus, we exposed pure (Z)-and (E)-isomers of 3e to the standard reaction conditions (Table 11). Both (Z)and (E)-3e showed very low isomerization rates (<15%), regardless of the addition of Ag3PO4. This suggests that isomerization of the product would not be a main reason for low stereoselectivity, and the Our next challenge was to expand the substrate scope to heteroaryl groups ( Table 9). The 3-or 4-pyridinyl group was introduced by our domino MCRs in good yield and high stereoselectivity (entries 1 and 2). The reaction with 3-benzothiophenylboronic acid provided the desired product in 52% yield and 16:1 E/Z ratio (entry 3). Interestingly, in this reaction, unexpected byproduct 5 was isolated; the structure of 5 was elucidated by intensive one-dimensional (1D) and two-dimensional (2D) nuclear magnetic resonance (NMR) experiments. The formation of tricyclic compound 5 would be explained by insertion of an acetyl group originating from the base (NaOAc). The formation of 5 was easily removed by the use of the more heteroarylboronic acid (2 eq, entry 4); 2-benzothiophenylboronic acid and 3-furanylboronic acid showed similar activity in domino MCRs (entries 5-8), although the stereoselectivity of the reaction with 2-benzothiophenylboronic acid was much lower than for the others (entries 5 and 6). Table 9. Substrate scope with heteroarylboronic acids 1 . Next, we investigated the possibility of derivatization of propiolamide 1 (Table 10). When the N-substituent of propiolamide 1 was changed to a H or a Bn group, the reactions showed good yield and moderate stereoselectivity (entries 1 and 2). Under standard conditions, one carbon-extended substrate 6c showed low yield (35%, entry 3). The yield increased to 45% at higher reaction temperature (180 °C) but almost no stereoselectivity was observed (1.1:1 E/Z ratio, entry 4). Propiolate ester 6d turned out to be a poor substrate for our domino MCRs, giving both a low yield and poor stereoselectivity (entry 5). All results implied that applying our microwave-assisted domino MCRs to the synthesis of other heterocycles is possible, but needs further study for optimization of each reaction.

Entry Het-Ar-B(OH)2 3 Yield (%) 2 E/Z
In all of the above results, the stereoselectivity of the domino MCRs varied depending on the substrate. One of the reasons for this could be the isomerization of product 3 under the reaction conditions. Thus, we exposed pure (Z)-and (E)-isomers of 3e to the standard reaction conditions (Table 11). Both (Z)and (E)-3e showed very low isomerization rates (<15%), regardless of the addition of Ag3PO4. This suggests that isomerization of the product would not be a main reason for low stereoselectivity, and the Molecules 2017, 22, 503 8 of 19 Our next challenge was to expand the substrate scope to heteroaryl groups ( Table 9). The 3-or 4-pyridinyl group was introduced by our domino MCRs in good yield and high stereoselectivity (entries 1 and 2). The reaction with 3-benzothiophenylboronic acid provided the desired product in 52% yield and 16:1 E/Z ratio (entry 3). Interestingly, in this reaction, unexpected byproduct 5 was isolated; the structure of 5 was elucidated by intensive one-dimensional (1D) and two-dimensional (2D) nuclear magnetic resonance (NMR) experiments. The formation of tricyclic compound 5 would be explained by insertion of an acetyl group originating from the base (NaOAc). The formation of 5 was easily removed by the use of the more heteroarylboronic acid (2 eq, entry 4); 2-benzothiophenylboronic acid and 3-furanylboronic acid showed similar activity in domino MCRs (entries 5-8), although the stereoselectivity of the reaction with 2-benzothiophenylboronic acid was much lower than for the others (entries 5 and 6). Next, we investigated the possibility of derivatization of propiolamide 1 (Table 10). When the N-substituent of propiolamide 1 was changed to a H or a Bn group, the reactions showed good yield and moderate stereoselectivity (entries 1 and 2). Under standard conditions, one carbon-extended substrate 6c showed low yield (35%, entry 3). The yield increased to 45% at higher reaction temperature (180 °C) but almost no stereoselectivity was observed (1.1:1 E/Z ratio, entry 4). Propiolate ester 6d turned out to be a poor substrate for our domino MCRs, giving both a low yield and poor stereoselectivity (entry 5). All results implied that applying our microwave-assisted domino MCRs to the synthesis of other heterocycles is possible, but needs further study for optimization of each reaction.
In all of the above results, the stereoselectivity of the domino MCRs varied depending on the substrate. One of the reasons for this could be the isomerization of product 3 under the reaction conditions. Thus, we exposed pure (Z)-and (E)-isomers of 3e to the standard reaction conditions (Table 11). Both (Z)and (E)-3e showed very low isomerization rates (<15%), regardless of the addition of Ag3PO4. This suggests that isomerization of the product would not be a main reason for low stereoselectivity, and the Our next challenge was to expand the substrate scope to heteroaryl groups ( Table 9). The 3-or 4-pyridinyl group was introduced by our domino MCRs in good yield and high stereoselectivity (entries 1 and 2). The reaction with 3-benzothiophenylboronic acid provided the desired product in 52% yield and 16:1 E/Z ratio (entry 3). Interestingly, in this reaction, unexpected byproduct 5 was isolated; the structure of 5 was elucidated by intensive one-dimensional (1D) and two-dimensional (2D) nuclear magnetic resonance (NMR) experiments. The formation of tricyclic compound 5 would be explained by insertion of an acetyl group originating from the base (NaOAc). The formation of 5 was easily removed by the use of the more heteroarylboronic acid (2 eq, entry 4); 2-benzothiophenylboronic acid and 3-furanylboronic acid showed similar activity in domino MCRs (entries 5-8), although the stereoselectivity of the reaction with 2-benzothiophenylboronic acid was much lower than for the others (entries 5 and 6). Next, we investigated the possibility of derivatization of propiolamide 1 (Table 10). When the N-substituent of propiolamide 1 was changed to a H or a Bn group, the reactions showed good yield and moderate stereoselectivity (entries 1 and 2). Under standard conditions, one carbon-extended substrate 6c showed low yield (35%, entry 3). The yield increased to 45% at higher reaction temperature (180 °C) but almost no stereoselectivity was observed (1.1:1 E/Z ratio, entry 4). Propiolate ester 6d turned out to be a poor substrate for our domino MCRs, giving both a low yield and poor stereoselectivity (entry 5). All results implied that applying our microwave-assisted domino MCRs to the synthesis of other heterocycles is possible, but needs further study for optimization of each reaction.
In all of the above results, the stereoselectivity of the domino MCRs varied depending on the substrate. One of the reasons for this could be the isomerization of product 3 under the reaction conditions. Thus, we exposed pure (Z)-and (E)-isomers of 3e to the standard reaction conditions (Table 11). Both (Z)and (E)-3e showed very low isomerization rates (<15%), regardless of the addition of Ag3PO4. This suggests that isomerization of the product would not be a main reason for low stereoselectivity, and the Our next challenge was to expand the substrate scope to heteroaryl groups ( Table 9). The 3-or 4-pyridinyl group was introduced by our domino MCRs in good yield and high stereoselectivity (entries 1 and 2). The reaction with 3-benzothiophenylboronic acid provided the desired product in 52% yield and 16:1 E/Z ratio (entry 3). Interestingly, in this reaction, unexpected byproduct 5 was isolated; the structure of 5 was elucidated by intensive one-dimensional (1D) and two-dimensional (2D) nuclear magnetic resonance (NMR) experiments. The formation of tricyclic compound 5 would be explained by insertion of an acetyl group originating from the base (NaOAc). The formation of 5 was easily removed by the use of the more heteroarylboronic acid (2 eq, entry 4); 2-benzothiophenylboronic acid and 3-furanylboronic acid showed similar activity in domino MCRs (entries 5-8), although the stereoselectivity of the reaction with 2-benzothiophenylboronic acid was much lower than for the others (entries 5 and 6). Table 9. Substrate scope with heteroarylboronic acids 1 . Next, we investigated the possibility of derivatization of propiolamide 1 (Table 10). When the N-substituent of propiolamide 1 was changed to a H or a Bn group, the reactions showed good yield and moderate stereoselectivity (entries 1 and 2). Under standard conditions, one carbon-extended substrate 6c showed low yield (35%, entry 3). The yield increased to 45% at higher reaction temperature (180 °C) but almost no stereoselectivity was observed (1.1:1 E/Z ratio, entry 4). Propiolate ester 6d turned out to be a poor substrate for our domino MCRs, giving both a low yield and poor stereoselectivity (entry 5). All results implied that applying our microwave-assisted domino MCRs to the synthesis of other heterocycles is possible, but needs further study for optimization of each reaction.
Next, we investigated the possibility of derivatization of propiolamide 1 (Table 10). When the N-substituent of propiolamide 1 was changed to a H or a Bn group, the reactions showed good yield and moderate stereoselectivity (entries 1 and 2). Under standard conditions, one carbon-extended substrate 6c showed low yield (35%, entry 3). The yield increased to 45% at higher reaction temperature (180 • C) but almost no stereoselectivity was observed (1.1:1 E/Z ratio, entry 4). Propiolate ester 6d turned out to be a poor substrate for our domino MCRs, giving both a low yield and poor stereoselectivity (entry 5). All results implied that applying our microwave-assisted domino MCRs to the synthesis of other heterocycles is possible, but needs further study for optimization of each reaction. enhancing effect of the silver salt on stereoselectivity is not caused by suppressing the isomerization of the initial products. 1 Reaction conditions: 6 (1.0 eq), phenyl iodide (1.1 eq), 4-chlorophenylboronic acid (1.2 eq), Pd(PPh3)4 (10 mol %), CuI (5 mol %), PPh3 (30 mol %), NaOAc (3 eq), Ag3PO4 (1.1 eq), DMF (0.05 M), microwave irradiation, 150 °C, 10 min; 2 Combined yield of isolated E-and Z-isomers; 3 Ratio between isolated Eand Z-isomers; 4 Reaction was run at 180 °C. Table 11. Isomerization studies 1 .

Entry Starting Material Silver Salt Conversion Rate (%)
Based on all of the above results, we propose a mechanism for our domino MCRs and isomerization (Scheme 2). The domino reaction begins with the Sonogashira reaction of propiolamide 1 with aryl iodide to afford adduct 2. The fact that the biphenyl byproduct 4 was not detected under microwaveassisted conditions demonstrates that the Sonogashira reaction is more favorable than the Suzuki-Miyaura reaction between aryl iodide and arylboronic acid. In the second step, the bromo substituent of 2 reacts with Pd catalyst to produce vinyl palladium intermediate I, the stereochemistry of which would be the E-configuration due to the syn-addition mechanism of the migratory insertion step [17]. Without the silver salt, isomerization of I to IV probably occurred via a zwitterionic palladium carbenoid intermediate II/III [18,19]. This isomerization mechanism is supported by low stereoselectivity of the reaction with 2-methoxy-and 4-methoxyphenyl iodide. Both substrates could have additional resonance structures (IIa or IIb), which increase the stability of II to facilitate the isomerization rate between I and IV. The last step of the reaction is a Suzuki-Miyaura reaction of I or IV with arylboronic enhancing effect of the silver salt on stereoselectivity is not caused by suppressing the isomerization of the initial products. 1 Reaction conditions: 6 (1.0 eq), phenyl iodide (1.1 eq), 4-chlorophenylboronic acid (1.2 eq), Pd(PPh3)4 (10 mol %), CuI (5 mol %), PPh3 (30 mol %), NaOAc (3 eq), Ag3PO4 (1.1 eq), DMF (0.05 M), microwave irradiation, 150 °C, 10 min; 2 Combined yield of isolated E-and Z-isomers; 3 Ratio between isolated Eand Z-isomers; 4 Reaction was run at 180 °C. Table 11. Isomerization studies 1 . Based on all of the above results, we propose a mechanism for our domino MCRs and isomerization (Scheme 2). The domino reaction begins with the Sonogashira reaction of propiolamide 1 with aryl iodide to afford adduct 2. The fact that the biphenyl byproduct 4 was not detected under microwaveassisted conditions demonstrates that the Sonogashira reaction is more favorable than the Suzuki-Miyaura reaction between aryl iodide and arylboronic acid. In the second step, the bromo substituent of 2 reacts with Pd catalyst to produce vinyl palladium intermediate I, the stereochemistry of which would be the E-configuration due to the syn-addition mechanism of the migratory insertion step [17]. Without the silver salt, isomerization of I to IV probably occurred via a zwitterionic palladium carbenoid intermediate II/III [18,19]. This isomerization mechanism is supported by low stereoselectivity of the reaction with 2-methoxy-and 4-methoxyphenyl iodide. Both substrates could have additional resonance structures (IIa or IIb), which increase the stability of II to facilitate the isomerization rate between I and IV. The last step of the reaction is a Suzuki-Miyaura reaction of I or IV with arylboronic 7a 85 2.2:1 2 6b

Entry Starting Material Silver Salt Conversion Rate (%)
Molecules 2017, 22, 503 9 of 19 enhancing effect of the silver salt on stereoselectivity is not caused by suppressing the isomerization of the initial products.  Based on all of the above results, we propose a mechanism for our domino MCRs and isomerization (Scheme 2). The domino reaction begins with the Sonogashira reaction of propiolamide 1 with aryl iodide to afford adduct 2. The fact that the biphenyl byproduct 4 was not detected under microwaveassisted conditions demonstrates that the Sonogashira reaction is more favorable than the Suzuki-Miyaura reaction between aryl iodide and arylboronic acid. In the second step, the bromo substituent of 2 reacts with Pd catalyst to produce vinyl palladium intermediate I, the stereochemistry of which would be the E-configuration due to the syn-addition mechanism of the migratory insertion step [17]. Without the silver salt, isomerization of I to IV probably occurred via a zwitterionic palladium carbenoid intermediate II/III [18,19]. This isomerization mechanism is supported by low stereoselectivity of the reaction with 2-methoxy-and 4-methoxyphenyl iodide. Both substrates could have additional resonance structures (IIa or IIb), which increase the stability of II to facilitate the isomerization rate between I and IV. The last step of the reaction is a Suzuki-Miyaura reaction of I or IV with arylboronic enhancing effect of the silver salt on stereoselectivity is not caused by suppressing the isomerization of the initial products.  Based on all of the above results, we propose a mechanism for our domino MCRs and isomerization (Scheme 2). The domino reaction begins with the Sonogashira reaction of propiolamide 1 with aryl iodide to afford adduct 2. The fact that the biphenyl byproduct 4 was not detected under microwaveassisted conditions demonstrates that the Sonogashira reaction is more favorable than the Suzuki-Miyaura reaction between aryl iodide and arylboronic acid. In the second step, the bromo substituent of 2 reacts with Pd catalyst to produce vinyl palladium intermediate I, the stereochemistry of which would be the E-configuration due to the syn-addition mechanism of the migratory insertion step [17]. Without the silver salt, isomerization of I to IV probably occurred via a zwitterionic palladium carbenoid intermediate II/III [18,19]. This isomerization mechanism is supported by low stereoselectivity of the reaction with 2-methoxy-and 4-methoxyphenyl iodide. Both substrates could have additional resonance structures (IIa or IIb), which increase the stability of II to facilitate the isomerization rate between I and IV. The last step of the reaction is a Suzuki-Miyaura reaction of I or IV with arylboronic 7c 35 2.5:1

6c
Molecules 2017, 22, 503 9 of 19 enhancing effect of the silver salt on stereoselectivity is not caused by suppressing the isomerization of the initial products.  Based on all of the above results, we propose a mechanism for our domino MCRs and isomerization (Scheme 2). The domino reaction begins with the Sonogashira reaction of propiolamide 1 with aryl iodide to afford adduct 2. The fact that the biphenyl byproduct 4 was not detected under microwaveassisted conditions demonstrates that the Sonogashira reaction is more favorable than the Suzuki-Miyaura reaction between aryl iodide and arylboronic acid. In the second step, the bromo substituent of 2 reacts with Pd catalyst to produce vinyl palladium intermediate I, the stereochemistry of which would be the E-configuration due to the syn-addition mechanism of the migratory insertion step [17]. Without the silver salt, isomerization of I to IV probably occurred via a zwitterionic palladium carbenoid intermediate II/III [18,19]. This isomerization mechanism is supported by low stereoselectivity of the reaction with 2-methoxy-and 4-methoxyphenyl iodide. Both substrates could have additional resonance structures (IIa or IIb), which increase the stability of II to facilitate the isomerization rate between I and IV. The last step of the reaction is a Suzuki-Miyaura reaction of I or IV with arylboronic 7c 45 1.1:1

6d
Molecules 2017, 22, 503 9 of 19 enhancing effect of the silver salt on stereoselectivity is not caused by suppressing the isomerization of the initial products.  Based on all of the above results, we propose a mechanism for our domino MCRs and isomerization (Scheme 2). The domino reaction begins with the Sonogashira reaction of propiolamide 1 with aryl iodide to afford adduct 2. The fact that the biphenyl byproduct 4 was not detected under microwaveassisted conditions demonstrates that the Sonogashira reaction is more favorable than the Suzuki-Miyaura reaction between aryl iodide and arylboronic acid. In the second step, the bromo substituent of 2 reacts with Pd catalyst to produce vinyl palladium intermediate I, the stereochemistry of which would be the E-configuration due to the syn-addition mechanism of the migratory insertion step [17]. Without the silver salt, isomerization of I to IV probably occurred via a zwitterionic palladium carbenoid intermediate II/III [18,19]. This isomerization mechanism is supported by low stereoselectivity of the reaction with 2-methoxy-and 4-methoxyphenyl iodide. Both substrates could have additional resonance structures (IIa or IIb), which increase the stability of II to facilitate the isomerization rate between I and IV. The last step of the reaction is a Suzuki-Miyaura reaction of I or IV with arylboronic In all of the above results, the stereoselectivity of the domino MCRs varied depending on the substrate. One of the reasons for this could be the isomerization of product 3 under the reaction conditions. Thus, we exposed pure (Z)-and (E)-isomers of 3e to the standard reaction conditions (Table 11). Both (Z)-and (E)-3e showed very low isomerization rates (<15%), regardless of the addition of Ag 3 PO 4 . This suggests that isomerization of the product would not be a main reason for low stereoselectivity, and the enhancing effect of the silver salt on stereoselectivity is not caused by suppressing the isomerization of the initial products. enhancing effect of the silver salt on stereoselectivity is not caused by suppressing the isomerization of the initial products.  Table 11. Isomerization studies 1 .

Entry Starting Material Silver Salt Conversion Rate (%)
Based on all of the above results, we propose a mechanism for our domino MCRs and isomerization (Scheme 2). The domino reaction begins with the Sonogashira reaction of propiolamide 1 with aryl iodide to afford adduct 2. The fact that the biphenyl byproduct 4 was not detected under microwaveassisted conditions demonstrates that the Sonogashira reaction is more favorable than the Suzuki-Miyaura reaction between aryl iodide and arylboronic acid. In the second step, the bromo substituent of 2 reacts with Pd catalyst to produce vinyl palladium intermediate I, the stereochemistry of which would be the E-configuration due to the syn-addition mechanism of the migratory insertion step [17]. Without the silver salt, isomerization of I to IV probably occurred via a zwitterionic palladium carbenoid intermediate II/III [18,19]. This isomerization mechanism is supported by low stereoselectivity of the reaction with 2-methoxy-and 4-methoxyphenyl iodide. Both substrates could have additional substituent of 2 reacts with Pd catalyst to produce vinyl palladium intermediate I, the stereochemistry of which would be the E-configuration due to the syn-addition mechanism of the migratory insertion step [17]. Without the silver salt, isomerization of I to IV probably occurred via a zwitterionic palladium carbenoid intermediate II/III [18,19]. This isomerization mechanism is supported by low stereoselectivity of the reaction with 2-methoxy-and 4-methoxyphenyl iodide. Both substrates could have additional resonance structures (IIa or IIb), which increase the stability of II to facilitate the isomerization rate between I and IV. The last step of the reaction is a Suzuki-Miyaura reaction of I or IV with arylboronic acid to give product 3A or 3B, respectively. Addition of the silver salt changes the catalytic pathway of the palladium-catalyzed reaction from neutral to cationic to give the cationic vinyl palladium intermediate V [16,20]. The cationic character on the palladium of V decreases the possibility of isomerization from V to VI, probably due to the instability of the corresponding zwitterionic palladium carbenoid species. Thus, 3A would mainly be obtained by Suzuki-Miyaura reaction of V. Another benefit achieved by the addition of silver salt is the enhancing effect on reaction rate. We already discussed that the silver salt seems to facilitate the last Suzuki-Miyaura step (Table 5). In addition, our previous work proved that the silver salt was an effective additive to also increase the rate of Sonogashira reaction [9]. Thus, microwave irradiation and the silver salt are key factors for the current domino MCRs.
Molecules 2017, 22, 503 10 of 19 acid to give product 3A or 3B, respectively. Addition of the silver salt changes the catalytic pathway of the palladium-catalyzed reaction from neutral to cationic to give the cationic vinyl palladium intermediate V [16,20]. The cationic character on the palladium of V decreases the possibility of isomerization from V to VI, probably due to the instability of the corresponding zwitterionic palladium carbenoid species. Thus, 3A would mainly be obtained by Suzuki-Miyaura reaction of V. Another benefit achieved by the addition of silver salt is the enhancing effect on reaction rate. We already discussed that the silver salt seems to facilitate the last Suzuki-Miyaura step (Table 5). In addition, our previous work proved that the silver salt was an effective additive to also increase the rate of Sonogashira reaction [9]. Thus, microwave irradiation and the silver salt are key factors for the current domino MCRs.

General Information
Microwave reactions were conducted in a Biotage Initiator + microwave reactor (Biotage AB, Uppsala, Sweden). The wattage was automatically adjusted to maintain the desired temperature for the desired period of time. All reactions were performed under an argon atmosphere with dry solvents, unless otherwise stated. Dry methylene chloride (CH2Cl2) tetrahydrofuran (THF) and acetonitrile (CH3CN) were obtained from an Ultimate Solvent Purification System (JC Meyer Solvent System, Laguna Beach, CA, USA). All commercially available reagents were purchased and used without further purification. Reactions were monitored by thin-layer chromatography (TLC) on silica gel plates (Merck TLC Silica Gel 60 F254, Darmstadt, Germany) using UV light, PMA (an ethanolic solution of phosphomolybdic acid) or ANIS (an ethanolic solution of p-anisaldehyde) as visualizing agent. Purification of products was conducted by column chromatography through silica gel 60 (0.060-0.200 mm). NMR spectra were obtained on Bruker AVANCE III 500 MHz (Bruker Corporation, Billerica, MA, USA) using residual Scheme 2. Proposed mechanisms of domino multicomponent reactions (MCRs) and isomerization.