Consecutive One-Pot versus Domino

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Consecutive One-Pot versus Domino Multicomponent Approaches to 3-(Diarylmethylene)oxindoles Sunhwa Park, Jiyun Lee, Kye Jung Shin, Euichaul Oh and Jae Hong Seo * Integrated Research Institute of Pharmaceutical Sciences, College of Pharmacy, The Catholic University of Korea, Bucheon-si, Gyeonggi-do 420-743, Korea; [email protected] (S.P.); [email protected] (J.L.); [email protected] (K.J.S.); [email protected] (E.O.) * Correspondence: [email protected]; Tel.: +82-2-2164-6531; Fax: +82-2-2164-4059 Academic Editor: Richard A. Bunce Received: 27 February 2017; Accepted: 17 March 2017; Published: 22 March 2017

Abstract: 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. Keywords: consecutive one-pot reaction; domino reaction; palladium-catalyzed reaction; microwave irradiation

3-(diarylmethylene)oxindole;

1. 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 [3–5]. 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 Molecules 2017, 22, 503; doi:10.3390/molecules22030503

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to develop efficient domino MCRs fromfrom consecutive one-pot conditions andand wide screening of efforts to develop efficient domino MCRs consecutive one-pot conditions wide screening the substrate understanding of of the the of the substratescope scopeofofthe theresulting resultingdomino dominoMCRs, MCRs,which which contributes contributes to our understanding mechanismof ofthe thereaction reaction and and could could inform inform future future studies studies on on MCRs. MCRs. mechanism

Scheme Scheme1.1.Consecutive Consecutiveone-pot one-potversus versusdomino dominoMCR MCRapproach approachto to3-(diarylmethylene)oxindoles. 3-(diarylmethylene)oxindoles.

2. Results and Discussion 2. Results and Discussion To verify the possibility of domino MCRs, we started with the addition of all three substrates 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 (propiolamide 1, aryl iodide and arylboronic acid) at the beginning of the reaction, which were exposed to the same reaction conditions for the consecutive one-pot reaction (Pd(PPh3)4, CuI, NaOAc, then exposed to the same reaction conditions for the consecutive one-pot reaction (Pd(PPh3 )4 , CuI, DMF; 60 °C for 1.5 h, then 90 °C for 24 h) (Table 1). A silver salt (AgOTf) was not added in this 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 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 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. 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 However, the formation of biphenyl compounds 4 was less than 15% for both symmetric (entries 1–3) unsymmetric products (entries 4–10). The yield and E/Z stereoselectivity were also similar to those of and unsymmetric products (entries 4–10). The yield and E/Z stereoselectivity were also similar to those consecutive one-pot conditions. These results imply that aryl iodide reacted first with propiolamide 1 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 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). 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 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 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 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 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 of product yield [8]. Subsequently, more intensive screenings for silver salts revealed that Ag3 PO4 is a better additive for this purpose, as shown in Table 2. When Ag3PO4 was added at the beginning of a better additive for this purpose, as shown in Table 2. When Ag3 PO4 was added at the beginning of the reaction with all substrates, stereoselectivity was enhanced as expected, but yields decreased with 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 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 hamper the Sonogashira reaction between 1 and aryl iodide, allowing more aryl iodide to undergo the the direct Suzuki-Miyaura reaction with arylboronic acid. 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 1–5). 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 1–3). When P(o-tol)3 was added, 3f was obtained in poor yield (13%) (entry 4). Addition of PPh3 showed a promising result (entry 5;

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50% yield, 5:1 E/Z ratio) but was still less effective than the consecutive one-pot conditions with Ag3 PO4 (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 Molecules 2017, 22, 503 3 of 19 (150 ◦ C), the reaction rate increased but yield and stereoselectivity decreased slightly (entries 6 and 7). These results showed thatTable high 1. reaction temperature the hampering Preliminary results ofreduced thermal domino MCRs 1. effect of silver salt on the initial Sonogashira Molecules 2017, 22, 503 reaction. 3 of 19 Table Table 1. 1. Preliminary Preliminary results results of of thermal thermal domino domino MCRs MCRs 11.

Consecutive One-Pot 4,5 Yield (%) 2 E/Z Ratio 3 4a 3a 1 H H – 68 – 81 – 4,5 Consecutive One-Pot 4b 3b 2 MeO MeO – 50 – 85 – 4,5 1 2 2 2 3 Consecutive One-Pot Entry R1 R2 44 Yield (%) 2 33 Yield (%) 2 E/Z Ratio 3 2 3 Entry Yield (%) Yield (%) E/Z Ratio R R Yield80(%) 2 E/Z Ratio 4c 3c 3 Cl Cl – 86 – Yield (%) E/Z –Ratio 3 4a 3a H 2 NO H 2 4d – 68 – 81 – 3d 415 NO 15 66 67 1 H H 4a 3a 68 81 4b 3b 25 MeO MeO –– 50 –– 85 –– 4e 3e H 14 66 1:2 52 1:1 2 MeO MeO 4b – 3b 50 – 85 – 4c 3c Cl Cl –– 86 –– 80 –– 4f 3f3c H 12 78 2:1 5780 1:1 3 36 Cl Cl 4c 86 5 3d NO 15 66 –– 67 –– 4g 3g H22 NO 515 75 1:1.1 5267 1:1 NO NO222 4d 4d 3d 66 4 475 5 4e 3e H MeO 14 66 1:2 52 1:1 5 58 H MeO 4e 3e 66 1:2 1:1 MeO H –14 59 1.5:1 7052 1.6:1 6 69 H Cl 12 78 2:1 57 1:1 4f4f 3f3f H Cl 12 78 2:1 57 1:1 Cl H – 84 1:2.4 77 1:3.4 H NO22 4g 4g 3g 75 1:1.1 52 1:1 7 75 56 3g H 2 NO 55 75 1:1.1 52 1:1 NO H 10 80 1:13 73 1:10 10 8 MeO H 4e – 3e 59 1.5:1 70 1.6:1 8 MeO H 1 4e – iodide3e(1.1 eq),59 1.5:1 70 1.6:1 %), 1 Reaction (1.0 arylboronic acid 9 Clconditions: H 4f eq), aryl – 3f 84 1:2.4(1.2 eq), Pd(PPh 77 3)4 (10 mol 1:3.4 4f 3f 9 Cl H – 84 1:2.4 77 1:3.4 6 NO%), H (3 4g 1:10 10 (5 mol CuI eq), DMF 10 (0.05 M), 3g 60 °C, 1.5 80 h, then 90 °C,1:13 24 h; 2 Isolated73yield or combined 2 NaOAc 4g 3g NO2 H 10 80 1:13 73 1:10 10 6 3 Ratio between 1yield of isolated E- and isolated E-(1.2 and Z-isomers; Reaction 1 Reaction conditions: 1 (1.0Z-isomers; eq), aryl iodide (1.1 eq), arylboronic acid eq), Pd(PPh3 )4 4(10 mol %), conditions: CuI (5 mol %), 1 Reaction conditions: 1 (1.0 eq),◦ aryl iodide (1.1 eq), ◦ C, 24 2 Isolated arylboronic acid (1.2 eq), Pd(PPh 3)4 (10 mol %), NaOAc (3 eq), DMF (0.05 M), 60 C, 1.5 h, then 90 h; yield or combined yield of isolated (1.0 eq), aryl iodide (1.1 eq), Pd(PPh3)4 (10 mol %), CuI (5 mol %), NaOAc (3 eq), DMF (0.05 M), 60 °C, 3 Ratio between isolated E- and Z-isomers; 4 Reaction conditions: Eand Z-isomers; 1 (1.0 eq),yield aryl iodide (1.1 eq), CuI (5then mol arylboronic %), NaOAc (3 eq), DMF (0.05 M), 60 1.5 h, then ◦90 24 h; 2 Isolated or combined 5°C, Reported in°C, reference [8]; 6 Reaction temperature 1.5 h, (1.2 90 °C, Pd(PPh3 )4 (10 mol %), CuIacid (5 mol %),eq), NaOAc (3 24 eq),h;DMF (0.05 M),data 60 C, 1.5 h, then arylboronic acid (1.2 eq), 90 ◦ C, 3 4 yield of isolated Eand Z-isomers; Ratio between isolated E- and Z-isomers; Reaction conditions: 1 ◦ C. 24 h; 5raised Reported data [8]; 6 Reaction temperature was raised from 60 ◦ C to 110 was from 60 in °Creference to 110 °C. (1.0 eq), aryl iodide (1.1 eq), Pd(PPh3)4 (10 mol %), CuI (5 mol %), NaOAc (3 eq), DMF (0.05 M), 60 °C, 5 Reported data in reference [8]; 6 1.5 h, then arylboronic Table acid (1.2 eq), 90of °C, 24 h;salt 2. silver on Table 2. Effect Effect of silver salt on thermal thermal domino domino MCRs MCRs11. Reaction temperature was raised from 60 °C to 110 °C. Entry

R1

R2

4

Yield (%) 2

3

Yield (%) 2

E/Z Ratio 3

Table 2. Effect of silver salt on thermal domino MCRs 1.

Entry Entry

1 1 RR

RR2 2

4

Yield Yield (%) (%)22

33

Yield Yield (%) (%)2 2

E/Z E/Z Ratio Ratio3 3

Consecutive OneConsecutive 4 4 Pot (Ag 3PO One-Pot (Ag PO 3 4)4 )

Consecutive OneConsecutive Pot (AgOTf) One-Pot (AgOTf)4,54,5

Yield Yield E/Z E/Z Yield E/Z Yield E/Z 2 2 2 2 Consecutive OneConsecutive OneRatio (%) Ratio (%) (%) Ratio Ratio 4,5 Pot (Ag 3PO4) 4 Pot (AgOTf) Yield Yield E/Z 4e 3e 1 H MeO 45 42 3.5:1 63 10:1 70 2.5:1 2 1 MeO 4e 45 3e 42 3.5:1 63 10:1 70 2.5:1 Entry R1H R 4 3 2 2 3 (%) (%) Ratio Yield Yield E/Z E/Z 4f 3f 22 HH ClCl 39 4.5:1 86 9:1 45 7:1 20 3f 39 4.5:1 86 9:1 7:1 2 2 6 6 Ratio (%) Ratio (%) H NO 4g 25 3g 50 4:1 66 3:1 56 5.2:1 3 3g 3 H NO2 2 50 4:1 66 3:1 5.2:1 4e H conditions: MeO 1 (1.0 45 42(1.1 703)4CuI 2.5:1 11Reaction eq), eq), aryl iodide (1.1 eq), arylboronic acid (1.263 eq), Pd(PPh mol %), mol %), Reaction conditions: 1 (1.0 aryl3eiodide eq),3.5:1 arylboronic acid (1.210:1 eq), Pd(PPh (10(5mol %), 3 )4 (10 ◦ C, 1.5 h, ◦ C, 24 2 Isolated 4f 3f 2 H Cl 20 39 4.5:1 86 9:1 45 7:1of NaOAc (3 eq), Ag PO (1.1 eq), DMF (0.05 M), 60 then 90 h; yield or combined yield 3 4 2 Isolated 3 PO 4 (1.1 eq), DMF (0.05 M), 60 °C, 1.5 h, then 90 °C, 24 h; CuI (5 mol %), NaOAc (3 eq), Ag 3 4 Reaction conditions: 1 (1.0 eq), aryl iodide 6 E- and NO Z-isomers; 4g Ratio25between 3g isolated 3isolated H 2 50 E- and Z-isomers; 4:1 3 66 3:1 56 5.2:1 Ratio between isolated E- and Z-isomers; yield orPd(PPh combined of CuI isolated and Z-isomers; (1.1 eq), )4 (10yield mol %), (5 molE-%), NaOAc (3 eq), DMF (0.05 M), 60 ◦ C, 1.5 h, then arylboronic acid 3 1 Reaction conditions: 1 (1.0 6acid eq), aryl iodide (1.1 eq), arylboronic (1.2 eq), Pd(PPh 3)4 (10 mol %), 4 Reaction (1.2 eq), silver salt (1.1 eq), 90 ◦eq), C, 24 h; 5iodide Reported data in reference [8]; mol Reaction temperature raised conditions: 1 (1.0 aryl (1.1 eq), Pd(PPh 3)4 (10 %), CuI (5 mol %),was NaOAc (3from eq), ◦ C to 110 ◦ C. 60 3PO4 (1.1 eq), DMF (0.05 M), 60 °C, 1.5 h, then 90 °C, 24 h;5 2 Isolated CuI (5 mol %), NaOAc (3 eq), Ag DMF (0.05 M), 60 °C, 1.5 h, then arylboronic acid (1.2 eq), silver salt (1.1 eq), 90 °C, 24 h; Reported 3 Ratio between isolated E- and Z-isomers; yield combined of isolated E- and was Z-isomers; 6 Reaction temperature raised from 60 °C to 110 °C. data inorreference [8];yield 4 Reaction conditions: 1 (1.0 eq), aryl iodide (1.1 eq), Pd(PPh3)4 (10 mol %), CuI (5 mol %), NaOAc (3 eq), DMF (0.05the M),problem 60 °C, 1.5ofh,low thenyield arylboronic (1.2 eq),ofsilver (1.1 eq), 90 °C, 24various h; 5 Reported To solve with theacid addition silversalt salt, we screened phosphine 6 raised from 60 °Cstereoselectivity to 110 °C. dataexpecting in reference [8]; Reactionoftemperature ligands, improvement yield whilewas maintaining good (Table 3, entries 1–5).

Bidentate phosphine ligands are known as effective ligands for the cationic pathway of palladiumTo solve the problem of low yield with the addition of silver salt, we screened various phosphine catalyzed reactions [12]. Unfortunately, the addition of bidentate ligands (dppp, dppb and dppf) did ligands, expecting improvement of yield while maintaining good stereoselectivity (Table 3, entries 1–5). 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 Molecules 2017, 22, 503 4 of 20 reduced the hampering effect of silver salt on the initial Sonogashira reaction. Table 3. 3. Phosphine ligand ligand effect effect and and further further optimization optimization 11. Table

Entry Phosphine PhosphineLigand Ligand Entry 1 dppp 1 dppp 2 dppb 2 dppb dppf 33 dppf P(o-tol)3 3 44 P(o-tol) PPh3 3 55 PPh 66 PPh PPh3 3 77 PPh PPh3 3 88 PPh PPh3 3

Conditions Conditions 60 °C, 1.5 h then 90 °C, 24 h 60 ◦ C, 1.5 h then 90 ◦ C, 24 h 60 ◦°C, 1.5 hh then then90 90◦°C, 24hh 60 C, 1.5 C, 24 60 ◦°C, 1.5 hh then then90 90◦°C, 24hh 60 C, 1.5 C, 24 60 ◦°C, 1.5 hh then then90 90◦°C, 24hh 60 C, 1.5 C, 24 60 ◦°C, 1.5 hh then then90 90◦°C, 24hh 60 C, 1.5 C, 24 90 C, 24 90◦°C, 24 hh ◦ C, 1.5 h 150 150 °C, 1.5 h ◦ C, 3 h 150 150 °C, 3h

Yield Yield (%) (%) 22 0 0 00 00 13 13 50 50 67 67 45 45 61 61

E/Z E/ZRatio Ratio3 3 - - 3.5:1 3.5:1 5:15:1 7.5:1 7.5:1 3.5:1 3.5:1 3.5:1 3.5:1

1 Reaction conditions: 1 (1.0 eq), phenyl iodide (1.1 eq), 4-chlorophenylboronic acid (1.2 eq), Pd(PPh ) (10 mol %), CuI 1 Reaction 3 4eq), Pd(PPh3)4 conditions: 1 (1.0 eq), phenyl iodide (1.1 eq), 4-chlorophenylboronic acid (1.2 (5 mol %), NaOAc (3 eq), Ag3 PO4 (1.1 eq), phosphine ligand (30 mol %), DMF (0.05 M), conditions; 2 Combined yield (10 mol %), (5 mol %),3 NaOAc (3 eq),isolated Ag3POE4 (1.1 eq), phosphine ligand (30 mol %), DMF (0.05 M), of isolated E- CuI and Z-isomers; Ratio between and Z-isomers. dppp: 1,3-bis(diphenylphosphino)propane; 0 -bis(diphenylphosphino)ferrocene. 2 Combined yield of isolated E3 Ratio between isolated E- and Z-isomers. dppp: dppb: 1,4-bis(diphenylphosphino)-butane; dppf: conditions; and1,1 Z-isomers;

1,3-bis(diphenylphosphino)propane; dppb: 1,4-bis(diphenylphosphino)-butane; dppf: 1,1′-bis (diphenylphosphino)ferrocene. Considering the above results, we decided to test microwave irradiation conditions, which are

known for accelerating sluggish thermal reactions [13–15] (Table 4). Reactions with microwave Considering results, we60 decided to test microwave irradiation which are ◦ C,above irradiation at 100the for 10, 30 and min, increased yields from 46% to conditions, 80% with increasing known for accelerating sluggish thermal reactions [13–15] (Table 4). Reactions with microwave irradiation reaction time,22,and Molecules 2017, 503 the stereoselectivity in all three cases was very high (9:1~18:1 E/Z ratio, entries5 1–3). of 19 at 100 °C, for 10,temperatures 30 and 60 min, increased fromit46% to 80% increasing reaction and ◦ C) made Higher reaction (110 and 130yields possible to with complete the reaction in atime, shortest the stereoselectivity in all threeand cases was very high (9:1~18:1 E/Z ratio, entries 1–3). Higher reaction same position changed dramatically, from 90% to 9%, without addition of Ag3PO 4. This suggests that time (10 min) with good yield stereoselectivity (entries 4 and 5). The best result was obtained at temperatures (110 and 130 °C) made it possible to complete the reaction in a shortest time (10 min) ◦ ◦ the positive effect of99% Ag3yield PO4 on thea domino is due in to enhancing the lastwas Suzuki-Miyaura 150 C, presenting and 13:1 E/ZMCRs ratio (entry 6).part At 160 C, the reaction completed in yield (entries and 5). The best result reaction [16]. 5with mingood to step give 3f inand 98%stereoselectivity yield with slightly lower 4stereoselectivity (7.5:1 E/Zwas ratio)obtained (entry 7).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 11. (entry 7). give 3f in 98% yield with slightly stereoselectivity (7.5:1reactions E/Z ratio) Tablelower 4. Optimization Optimization of microwave microwave reactions Table 4. of 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)3 still provided product Entry Temp Temp(◦(°C) Time (min) Yield Ratio Entry C) Yield(%) (%)2 2 E/Z E/Z Ratio 3 3f in moderate yield and stereoselectivity (entry 11). Thus, under microwave irradiation conditions, 1 100 10 46 12:1 100 10 for good stereoselectivity, 46 12:1but also for high yield. silver salt seems to be a1 crucial additive not only 100 30 67 18:1 2 2 100 30 67 18:1 With optimized microwave-assisted conditions in hand, we investigated 100 60 80 9:19:1 the substrate scope for 3 3 100 60 80 the synthesis of symmetrically substituted 3-(diarylmethylene)oxindoles 5). Regardless of the 110 10 54 7:1(Table 4 4 110 54 7:1 substituents on the aryl5group, all130 reactions gave10the desired 92 products 3a–d in good yield (entries 1–4). 92 13:1 5 130 13:1 6 6 salt, control 150 10 without Ag 993PO4 were13:1 13:1 performed. As expected, 150 experiments 99 To verify the effect of silver also 7 7 160 7.5:1 160 the absence of silver salt decreased the yield of 55all reactions.9898 However,7.5:1 the degree of yield reduction 150 10 92 8:1 8 48 4 150 10 92 8:1 appears to be related to the electronic effect of the group. The formation of 3b 150 10 substituent 36on the aryl 1:1.2 9 59 5 150 10 36 1:1.2 6 bearing the electron-donating methoxy group at the 4-position was hardly affected by the absence of 150 10 35 1:1.5 10 6 150 10 35 1:1.5 10 7 Ag3PO4 (75% vs. 55%); the yields for 10 3d with the electron-withdrawing nitro group at the 150 79 10:1 11 whereas 7 1

11

150

10

79

10:1

Reaction conditions: 1 (1.0 eq), phenyl iodide (1.1 eq), 4-chlorophenylboronic acid (1.2 eq), Pd(PPh3 )4 (10 mol %), 1 Reaction conditions: 1 (1.0 eq), phenyl iodide (1.1 eq), 4-chlorophenylboronic acid (1.2 eq), Pd(PPh3)4 CuI (5 mol %), NaOAc (3 eq), Ag3 PO4 (1.1 eq), PPh3 (30 mol %), DMF (0.05 M), microwave irradiation, temperature (10time molon%), CuI2 (5 mol %),yield NaOAc (3 eq), EAgand 3POZ-isomers; 4 (1.1 eq), 3PPh 3 (30 mol %), DMFE-(0.05 microwave and table; Combined of isolated Ratio between isolated and M), Z-isomers; 4 Reaction without PPh ; 5 Reaction without Ag PO 6 Reaction without PPh and Ag PO ; 7 Two equivalents 2 3 Ratio between ; of 3 4 3 3 4 yield of isolated E- and Z-isomers; irradiation, temperature and time on table;3 Combined Ag3 PO4 were used without NaOAc. 4 5 6

isolated E- and Z-isomers; Reaction without PPh3; Reaction without Ag3PO4; Reaction without PPh3 and Ag3PO4; 7 Two equivalents of Ag3PO4 were used without NaOAc. Table 5. Substrate scope for symmetric products and the effect of silver salt 1.

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]. Table 4. Optimization of microwave reactions 1.

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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 (Ag3 PO4 ) dramatically decreased the yield (36%) and stereoselectivity (1:1.2 E/Z ratio) (entry 9). Without both 3 Entry yield Temp (°C) and Time (min) Yieldselectivity (%) 2 E/Z(1:1.5 RatioE/Z PPh3 and Ag3 PO4 , the lowest (35%) stereo-inverted ratio) were obtained 1 addition 100of two equivalents 10 12:1 (entry 10). Interestingly, the of Ag46 PO without base (NaOAc) still provided 3 4 2 100 30 67 18:1 product 3f in moderate yield and stereoselectivity (entry 11). Thus, under microwave irradiation 3 100 60 80 9:1 conditions, silver salt seems to be a crucial additive not only for good stereoselectivity, but also for 4 110 10 54 7:1 high yield. 5 130 10 92 13:1 With optimized microwave-assisted conditions in hand, the substrate scope for 6 150 10 99we investigated 13:1 the synthesis of symmetrically substituted 3-(diarylmethylene)oxindoles (Table 5). Regardless of the 7 160 5 98 7.5:1 8:1 in good yield (entries 1–4). 84 substituents on the aryl group, all 150 reactions gave10the desired92 products 3a–d 5 9 150 10 36 1:1.2 To verify the effect of silver salt, control experiments without Ag3 PO4 were also performed. 150salt decreased 10 the yield 35 of all reactions. 1:1.5 10 6of silver As expected, the absence However, the degree 150 10 79 10:1 11 7 of yield reduction appears to be related to the electronic effect of the substituent on the aryl group. 1 Reaction conditions: 1 (1.0 eq), phenyl iodide (1.1 eq), 4-chlorophenylboronic acid (1.2 eq), Pd(PPh3)4 The formation of 3b bearing the electron-donating methoxy group at the 4-position was hardly affected mol %), CuI (5 mol %), NaOAc (3 eq), Ag3PO4 (1.1 eq), PPh3 (30 mol %), DMF (0.05 M), microwave by the (10 absence of Ag3 PO4 (75% vs. 55%); whereas the yields for 3d with the electron-withdrawing irradiation, temperature and time on table; 2 Combined yield of isolated E- and Z-isomers; 3 Ratio between nitro group at the same position changed dramatically, from 90% to 9%, without addition of Ag3 PO4 . isolated E- and Z-isomers; 4 Reaction without PPh3; 5 Reaction without Ag3PO4; 6 Reaction without PPh3 This suggests that 7the positive effect of Ag3 PO4 on the domino MCRs is due in part to enhancing the and Ag3PO4; Two equivalents of Ag3PO4 were used without NaOAc. last Suzuki-Miyaura reaction step [16]. Table 5. Substrate scope for symmetric products and the effect of silver salt 1. Table 5. Substrate scope for symmetric products and the effect of silver salt 1 .

WithAg Ag3 PO 3PO4 22 Without 3PO4 Without AgAg With 3 PO4 4 3 Yield (%) Yield (%) 3 Yield (%) 3 Yield (%) 3 3a 1 H 75 27 H 3a 75 2755 3b 21 MeO 75 MeO 3b 75 5515 3c 32 Cl 72 3 Cl 3c 72 15 3d 4 NO2 90 9 4 NO2 3d 90 9 1 Reaction conditions: 1 (1.0 eq), aryl iodide (1.1 eq), arylboronic acid (1.2 eq), Pd(PPh3)4 (10 mol %), CuI 1 Reaction conditions: 1 (1.0 eq), aryl iodide (1.1 eq), arylboronic acid (1.2 eq), Pd(PPh ) (10 mol %), CuI (5 mol %), 3 4 (5 mol %), NaOAc (3 eq), 3 (30 or mol %), with or 4without 3PO 4 (1.1 eq), DMF (0.05 M), microwave NaOAc (3 eq), PPh3 (30 mol PPh %), with without Ag3 PO (1.1 eq),Ag DMF (0.05 M), microwave irradiation, 150 ◦ C, 2 3 2 3 10 min; Reported data reference [9]; Isolated irradiation, 150 °C, 10inmin; Reported data inyield. reference [9]; Isolated yield. Entry Entry

RR

33

Next, we thethe effect of our conditions on the synthesis of unsymmetrically substituted Next, wetested tested effect of reaction our reaction conditions on the synthesis of unsymmetrically 3-(diarylmethylene)oxindoles having electronically different substituents at the 4-position of the substituted 3-(diarylmethylene)oxindoles having electronically different substituents at the 4-position phenyl group (Table All reactions 3e–g in good yield Stereoselectivity of the phenyl group6).(Table 6). Allprovided reactionsproducts provided products 3e–g (80%–99%). in good yield (80%–99%). for each reaction was more than 8:1, giving the expected stereoisomer as the major product, except in the Stereoselectivity for each reaction was more than 8:1, giving the expected stereoisomer as the major reaction with 4-methoxyphenyl iodide, in which the E/Ziodide, ratio ofin1.2:1 resulted in aratio little of more ofresulted the stereoproduct, except in the reaction with 4-methoxyphenyl which the E/Z 1.2:1 in inverted E-isomer than the Z-isomer. This exceptional case will be revisited later through extensive a little more of the stereo-inverted E-isomer than the Z-isomer. This exceptional case will be revisited screening of the reactionscreening conditions. ligand effect on our domino MCRs, allon reactions were later through extensive of To theconfirm reactionthe conditions. To confirm the ligand effect our domino MCRs, all reactions were 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.

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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 Molecules 2017, 22, 503 6 of 20 meaningful role in producing good yield and stereoselectivity of the domino MCRs. Table Table 6. 6. Basic substrate substrate scope scope for for unsymmetric unsymmetric products products and and the the ligand ligand effect effect11.

2 With Without PPh 3 Without PPh With PPh PPh33 2 3 3 4 3 Yield (%) 3 E/Z Ratio 4 Yield (%) 3 E/Z Ratio 4 4 Yield (%) E/Z Ratio Yield (%) E/Z Ratio 1 H MeO 3e 85 8:1 88 8:1 1 2 H H MeOCl 3e3f 85 8:1 99 13:1 92 88 8:1 8:1 2 3 H H ClNO2 3f3g 99 13:1 92 89 9.5:1 86 9:1 8:1 3 H NO2 3g 89 9.5:1 86 9:1 3e 4 MeO H 80 1.2:1 68 1.6:1 4 MeO H 3e 80 1.2:1 68 1.6:1 3f 5 Cl H 85 1:15 81 1:18 5 Cl H 3f 85 1:15 81 1:18 3g 2 H 88 1:>20 84 1:>20 6 NO 6 NO2 H 3g 88 1:>20 84 1:>20 1 Reaction conditions: 1 (1.0 eq), aryl iodide (1.1 eq), arylboronic acid (1.2 eq), Pd(PPh3)4 (10 mol %), CuI 1 Reaction conditions: 1 (1.0 eq), aryl iodide (1.1 eq), arylboronic acid (1.2 eq), Pd(PPh3 )4 (10 mol %), CuI (5 mol %), (5 mol %), NaOAc (3without eq), with or3 (30 without PPh 3 3(30 3PO 4 (1.1 eq), DMF (0.05 M), microwave NaOAc (3 eq), with or PPh mol %), Ag PO4mol (1.1%), eq),Ag DMF (0.05 M), microwave irradiation, 150 ◦ C, 2 Reported data in reference 3 Isolated yield or combined 10 min; [9]; yield of isolated Eand Z-isomers; 2 3 irradiation, 150 °C, 10 min; Reported data in reference [9]; Isolated yield or combined yield of 4 Ratio between isolated E- and Z-isomers. isolated E- and Z-isomers; 4 Ratio between isolated E- and Z-isomers.

Entry 1 R1 2 R2 Entry R R

33

To To widen widen the the application application of of the the reaction, reaction, aa more more expanded expanded substrate substrate scope scope was was investigated investigated (Table 7). The reaction of 4-acetoxyphenylboronic acid showed relatively low but (Table 7). The reaction of 4-acetoxyphenylboronic acid showed relatively low yieldyield (45%)(45%) but high high stereoselectivity (entry Unlike4-methoxyphenyl 4-methoxyphenyliodide, iodide,the the reaction reaction of stereoselectivity (10:1 (10:1 E/Z E/Z ratio)ratio) (entry 1). 1). Unlike of 4-acetoxyphenyl iodide presented good yield and stereoselectivity (entry 2), representing an alternative 4-acetoxyphenyl iodide presented good yield and stereoselectivity (entry 2), representing an way to synthesize the Z-isomer with anwith oxygen atomatom at the 4-position ofofthe group. alternative way to synthesize the Z-isomer an oxygen at the 4-position thephenyl phenyl group. Moreover, group were were Moreover, 3-(diarylmethylene)oxindoles 3-(diarylmethylene)oxindoleswith with substituents substituents at at the the 3-position 3-position of of the the phenyl phenyl group easily prepared by our domino MCRs, regardless of the electronic effect of the substituent (entries 3–10). easily prepared by our domino MCRs, regardless of the electronic effect of the substituent (entries 3–10). When acid increased thethe yield upup to When the the yield yieldwas wasmoderate, moderate,addition additionofoftwo twoequivalents equivalentsofofarylboronic arylboronic acid increased yield 94%, accompanied by slightly lower stereoselectivity (entries 5 and 10). It is worth pointing out that the to 94%, accompanied by slightly lower stereoselectivity (entries 5 and 10). It is worth pointing out reaction 3-methoxyphenyl iodide showed stereoselectivity (1:8 E/Z ratio, 7). This result that the of reaction of 3-methoxyphenyl iodidegood showed good stereoselectivity (1:8 entry E/Z ratio, entry 7). suggests that the position methoxy on the aryl iodide is important for is determining This result suggests that of thethe position of group the methoxy group on the aryl iodide important the for stereoselectivity the reaction. 2-Chloro and 2-methoxyphenylboronic acids were good substrates for determining theof stereoselectivity of the reaction. 2-Chloro and 2-methoxyphenylboronic acids were the reaction, providing 3l and 3m in good yield (entries 11 and 12); however, no product was formed good substrates for the reaction, providing 3l and 3m in good yield (entries 11 and 12); however, no in the reaction of 2-nitrophenylboronic acid (entry 13). 2-Methoxyphenyl iodide reiterated the problem product was formed in the reaction of 2-nitrophenylboronic acid (entry 13). 2-Methoxyphenyl iodide of low stereoselectivity, as well as 4-methoxyphenyl iodide (entry 14). The reaction of 2-chlorophenyl reiterated the problem of low stereoselectivity, as well as 4-methoxyphenyl iodide (entry 14). The iodide resulted in good yieldiodide and stereoselectivity (entry the 2-nitrophenyl was athe poor reaction of 2-chlorophenyl resulted in good yield15), andwhile stereoselectivity (entryiodide 15), while 2substrate foriodide the reaction, giving product very low yieldproduct (entry 16). together, above nitrophenyl was a poor substrate for3n theinreaction, giving 3n inTaken very low yield the (entry 16). results suggest that our domino have substituent tolerance for both aryl iodide and Taken together, the above resultsMCRs suggest thatbroad our domino MCRs have broad substituent tolerance arylboronic producing good yield and stereoselectivity except 2- or 4-methoxyphenyl iodide for both arylacid, iodide and arylboronic acid, producing good yield andfor stereoselectivity except for 2- or and the 2-nitro substituent. 4-methoxyphenyl iodide and the 2-nitro substituent. Next, solve the low stereoselectivity stereoselectivity problem Next, we we tried tried to to solve the low problem for for the the reaction reaction with with 4-methoxyphenyl 4-methoxyphenyl iodide (Table8). 8).We Wefocused focused amount of3PO Ag4,3which PO4 , which seems play arole crucial role in iodide (Table onon thethe amount of Ag seems to play to a crucial in achieving achieving good stereoselectivity in the domino MCRs. Increasing the amount of Ag PO showed 4 good stereoselectivity in the domino MCRs. Increasing the amount of Ag3PO4 showed little3improvement little improvementbut of stereoselectivity, but rather reduced yield (entries 2–4). not Other silver salts of stereoselectivity, rather reduced the yield (entries 2–4).the Other silver salts were as effective as were not as effective Ag3we POlowered 5–8). Then,temperature. we lowered the reaction temperature. At 130 ◦ C, 4 (entriesthe Ag3PO 4 (entries 5–8). as Then, reaction At 130 °C, stereoselectivity increased ◦ C, the reaction rate was much stereoselectivity (1:1.5 E/Zreaction ratio, entry 9). At 100 slower slightly (1:1.5 E/Z increased ratio, entryslightly 9). At 100 °C, the rate was much and a longer reaction time slower and a time wasThe needed to achieve yield. the Thebest reaction for 1 h at was needed tolonger achievereaction reasonable yield. reaction for 1 h atreasonable 100 °C provided stereoselectivity ◦ C provided the best stereoselectivity (1:4 E/Z ratio) with good yield (70% entry 10). A longer 100 (1:4 E/Z ratio) with good yield (70% entry 10). A longer reaction time (3 h) at 100 °C increased the 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.

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Molecules 2017, 22, 503 of 19 yield to 79% but decreased stereoselectivity (1:3 E/Z ratio, entry 11). Thus, in the case of 7poor 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 Molecules 2017, 22, 503 7 of 20 stereoselectivity, modification of the reaction temperature and time of the reaction can offer a solution. 1

Table 7. Expanded substrate scope for unsymmetric products .

Table 7. 7. Expanded Expanded substrate substrate scope scope for for unsymmetric unsymmetric products products11. Table

Entry R1 R2 3 Yield (%) 2 E/Z Ratio 3 1 H 4-AcO 3h 45 10:1 3 Entry R1R1 R22 3 Yield (%) 2 2E/Z Ratio Entry R Yield E/Z Ratio 3 3h3 2 4-AcO H 82 (%) 1:8 1 H 4-AcO 3h 45 10:1 3i3h 3-MeO 98 9:1 10:1 1 3 HH 4-AcO 45 3h 2 4-AcO H 82 1:8 3j3h H 3-Cl 72 82 10:1 2 4 4-AcO H 1:8 3i 3 H 3-MeO 98 9:1 9:1 4 3 5 HH 3-MeO 3j3i 3-Cl 94 98 7.5:1 3j3j H 3-Cl 72 72 10:1 10:1 4 64 HH 3-Cl 2 3k 93 12:1 3-NO 4 3j H 3-Cl 94 7.5:1 H 3-Cl 3j 94 5 4 57 3i 3-MeO H 85 1:8 7.5:1 3k 2 93 12:1 H 6 86 H 3-NO 3k 93 2 3j 3-Cl H 81 1:13 12:1 7 97 3-MeO 3i 85 3i 3-MeO H 85 1:8 1:8 3k 3-NO2 H 65 1:>20 8 84 3-Cl H 3j 81 1:13 3j 3-Cl 81 1:13 3k 3-NO2 H 94 1:>20 10 9 9 3-NO H 3k 65 1:>20 2 2 3k 3-NO H 65 1:>20 11 H 2-MeO 3l 81 6.5:1 H 1:>20 10 4 10 4 3-NO 2 2 3k3k 3-NO H 94 94 1:>20 3m 12 H 2-Cl 84 8:1 6.5:1 11 11 HH 2-MeO 3l 81 3l 2-MeO 81 6.5:1 0 84 - 8:1 2-NO 12 13 HH 2-Cl 2 3n3m 3m 12 H 2-Cl 84 8:1 3l3n 2-MeO H 2 57 0 1.2:1 13 14 H 2-NO 3n3l 0 57 - 1.2:1 13 2-MeO H 2-NO 2-Cl H 2 3m 85 1:14 14 15 3l3m 14 2-MeO H 57 85 1.2:1 1:14 15 16 2-Cl 3n H 17 1:>20 2-NO2 3m 15 2-Cl H 85 1:141:>20 16 1 (1.0 2-NO H (1.1 eq), 3narylboronic 17 acid (1.2 1 Reaction conditions: 2 eq), aryl iodide eq), Pd(PPh3)4 (10 mol %), 3n 2 H 17 1:>20 16 2-NO 1 Reaction conditions: 1 (1.0 eq), aryl iodide (1.1 eq), arylboronic acid (1.2 eq), Pd(PPh ) (10 mol %), CuI (5 mol %), 3 4 microwave irradiation, CuI (5 mol %), PPh3 (30 mol %), NaOAc (3 eq), Ag3PO4 (1.1 eq), DMF (0.05 M), ◦ C, mol 1 Reaction PPh %), NaOAc (3 eq), DMFarylboronic (0.05 M), microwave irradiation, 10 min; conditions: 1 (1.0 eq),Ag aryl iodide (1.1 eq), acid (1.2 eq), Pd(PPh150 3)4 (10 %), 3 (30 mol 3 PO 4 (1.1 eq), 2 Isolated yield or combined 3 Ratio between isolated °C, 10 min; yield of isolated Eand Z-isomers; 2150 3 Isolated yield or combined yield of isolated Eand Z-isomers; Ratio between isolated Eand Z-isomers; CuI (5 mol %), PPh 3 (30 mol %), NaOAc (3 eq), Ag3PO4 (1.1 eq), DMF (0.05 M), microwave irradiation, 4ETwo of 4arylboronic acid were Two equivalents ofused. arylboronic acid were used. andequivalents Z-isomers; 150 °C, 10 min; 2 Isolated yield or combined yield of isolated E- and Z-isomers; 3 Ratio between isolated E- and Z-isomers; 4 Two equivalents of arylboronic acid were used. Table 8. 8. Further optimization optimization for for the the reaction reaction with with 4-methoxyphenyl 4-methoxyphenyl iodide iodide 11. Table Table 8. Further optimization for the reaction with 4-methoxyphenyl iodide 1.

2 2 E/Z 3 3 Entry Silver Salt (eq) (eq) Temp (°C) Time Time (min) Yield Yield E/Z Ratio Entry Silver Salt Temp (◦ C) (min) (%)(%) Ratio 1 Ag3PO4 (1.1) 150 10 80 1.2:1 1 Ag3 PO 150 (°C) 10 (min) 80 (%) 2 E/Z 1.2:1Ratio 3 Entry Silver Salt(1.1) (eq) Temp Time Yield 2 Ag3PO44 (1.5) 150 10 85 1:1 2 Ag (1.5) 150 10 10 85 80 1:1 Ag333PO PO444 (2.0) (1.1) 150 1.2:1 PO 150 10 61 1:1.3 31 3 Ag Ag (2.0) 150 10 10 61 85 1:1.3 Ag333PO PO444 (4.0) (1.5) 150 1:1 4244 4 Ag PO 150 1:1.5 Ag PO (4.0) 150 10 10 41 41 1:1.5 3 4 3PO4 (2.0) 150 10 61 1:1.3 3 Ag 150 1.3:1 55 Ag22CO Ag CO3 (1.1) (1.1) 150 10 10 56 56 1.3:1 464 Ag3PO443(1.1) (4.0) 150 10 41 1:1.5 150 6 AgBF4 150 10 10 12 12 3:13:1 2CO3 (1.1) 150 10 56 1.3:1 5 Ag 150 10 10 25 25 2.3:1 77 AgOTf (1.1) 150 2.3:1 4 (1.1) 150 10 12 6 AgBF 150 10 10 0 0 - 3:1 88 AgOAc (1.1) 150 7 AgOTf (1.1) 150 10 25 2.3:1 Ag (1.1) 130 10 10 70 70 1:1.5 PO44 (1.1) 130 1:1.5 99 Ag33PO 810 AgOAc (1.1) 150 10 0 Ag 100 60 60 70 70 1:41:4 33PO 10 Ag PO44 (1.1) 100 11 Ag PO 100 180 79 1:3 3 4 (1.1) 130 10 70 1:1.5 9 Ag 100 180 79 1:3 11 Ag33PO44 (1.1) 1 Reaction 10 3PO 4 (1.1) 100 60 1:4 conditions: 1Ag (1.0 eq), 4-methoxylphenyl iodide (1.1 eq), phenylboronic acid70(1.2 eq), Pd(PPh mol %), 3 )4 (10 1 Reaction conditions: 1 (1.0 eq), 4-methoxylphenyl iodide (1.1 eq), phenylboronic acid (1.2 eq), CuI (5 mol (303PO mol4 (1.1) %), NaOAc (3 eq), irradiation, 100silver salt, DMF 180(0.05 M), microwave 79 1:3 indicated 11%), PPh3 Ag 2 3 Pd(PPh 3 ) 4 (10 mol %), CuI (5 mol %), PPh 3 (30 mol %), NaOAc (3 eq), silver salt, DMF (0.05 M), temperature and time in table; Combined yield of isolated E- and Z-isomers; Ratio between isolated E- and 1 Reaction conditions: 1 (1.0 eq), 4-methoxylphenyl iodide (1.1 eq), phenylboronic acid (1.2 eq), 4 Z-isomers; base (NaOAc) was used. microwaveNo irradiation, indicated temperature and time in table; 2 Combined yield of isolated E- and Pd(PPh3)4 (10 mol %), CuI (5 mol %), PPh3 (30 mol %), NaOAc (3 eq), silver salt, DMF (0.05 M), Z-isomers; 3 Ratio between isolated E- and Z-isomers; 4 No base (NaOAc) was used. microwave irradiation, indicated temperature and time in table; 2 Combined yield of isolated E- and Our next challenge was to expand the substrate scope to heteroaryl groups (Table 9). The 3- or Z-isomers; 3 Ratio between isolated E- and Z-isomers; 4 No base (NaOAc) was used.

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

Molecules 2017, 22, 503 8 of 19 Molecules 2017, 22, 503 8 of 19 Molecules 2017, 22, 503 8 of 19 Molecules 2017, 22, 503 8 of 19 challenge was to expand the substrate scope to heteroaryl groups (Table 9). The MoleculesOur 2017,next 22, 503 8 of3-19or Molecules 2017, 503 of Our2017, next challenge was to expand the substrate scope to heteroaryl groups (Table 9). The 83-of8 or Molecules 22,22, 503 1920 4-pyridinyl waswas introduced bythe oursubstrate domino scope MCRstoinheteroaryl good yield and high stereoselectivity Our2017, next challenge to expand groups (Table 9). The 83-of or Molecules 22,group 503 19 Our2017, next was to expand the domino substrateMCRs scope in to good heteroaryl (Table 9). The83-of or 4-pyridinyl group by our yield groups and high stereoselectivity Molecules 22,challenge 503 was introduced 19 Our next challenge was to expand the substrate scope to heteroaryl groups (Table 9). The 3or (entries 1 and 2). The reaction with 3-benzothiophenylboronic acid provided the desired product 4-pyridinyl group was introduced by our domino MCRs in good yield and high stereoselectivity Molecules 2017, 22, 503 8 of 19in

Our1 next challenge was towith expand the domino substrateMCRs scope in to good heteroaryl (Table 9).product The 3- or 4-pyridinyl group was introduced by our yield groups andthe high stereoselectivity (entries and 2). The reaction 3-benzothiophenylboronic acid provided desired in Our challenge was towith expand the substrateMCRs scope to good heteroaryl groups (Table 9).product The 3or 4-pyridinyl group was introduced by 3). our domino in yieldunexpected andthe high stereoselectivity 52% E/Z ratio (entry Interestingly, in reaction, byproduct 5 was (entries 1 next and 2). The reaction 3-benzothiophenylboronic acid provided desired in yield and 16:1 E/Z ratio (entry 3). Interestingly, in this unexpected byproduct Our challenge was to expand the substrateMCRs scope toreaction, heteroaryl groups (Table 9).product The5 3or 4-pyridinyl group was introduced by domino good yield andthe high stereoselectivity (entries 1 next and 2). The reaction with 3-benzothiophenylboronic acid provided desired in 52% yield and 16:1 E/Z ratio (entry 3).our Interestingly, in thisin unexpected byproduct was Our challenge was to expand the substrate scope toreaction, heteroaryl groups (Table 9).product The53or 4-pyridinyl group was introduced by domino MCRs in good yield and high stereoselectivity (entries 1 next and 2). The reaction with 3-benzothiophenylboronic acid provided the desired in isolated; the structure of 5 5was elucidated by intensive (1D) and two-dimensional (2D) 52% yield and 16:1 E/Z ratio (entry 3).our Interestingly, inone-dimensional this unexpected byproduct was isolated; the structure of was elucidated by intensive one-dimensional (1D) and two-dimensional 4-pyridinyl group was introduced by inreaction, good yield and high stereoselectivity (entries 1the and 2). The reaction with 3-benzothiophenylboronic acid provided desired product in 52% yield and 16:1 E/Z 3).our Interestingly, in this unexpected byproduct 5 (2D) was isolated; structure of 5ratio was (entry elucidated by domino intensiveMCRs one-dimensional (1D) andthe two-dimensional 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 inbe 52% yield and 16:1 E/Z ratio (entry 3). Interestingly, in this reaction, unexpected byproduct 5 was nuclear magnetic resonance (NMR) experiments. The formation of tricyclic compound 5 would isolated; the structure of 5 was elucidated by intensive one-dimensional (1D) and two-dimensional (2D) (2D) nuclear magnetic resonance experiments. The formation of tricyclic compound 5 wouldin (entries 1magnetic and 2). The reaction with(NMR) 3-benzothiophenylboronic acid the desired 52% yield and 16:1 E/Z (entry 3). Interestingly, in this reaction, unexpected byproduct 5 (2D) was isolated; the structure of 5ratio was(NMR) elucidated by intensive (1D) and two-dimensional nuclear resonance experiments. Theone-dimensional formation of provided tricyclic compound 5product would be (entries 1magnetic and 2). The reaction with 3-benzothiophenylboronic acid the desired in 52% yield and 16:1 E/Z ratio (entry 3). Interestingly, in thisthe reaction, unexpected byproduct 5 (2D) was isolated; the structure of 5of elucidated byoriginating intensive (1D) and two-dimensional explained by insertion an(NMR) group originating from base (NaOAc). The formation of 5 be nuclear resonance experiments. Theone-dimensional formation of provided tricyclic compound 5product would explained insertion ofwas acetyl from (NaOAc). formation of was 52% yield and 16:1 E/Z (entry 3). Interestingly, in this unexpected byproduct was isolated; the structure ofof5ratio was elucidated by intensive one-dimensional (1D) and two-dimensional nuclear magnetic resonance (NMR) experiments. Thefrom formation tricyclic compound 5 would be explained by insertion an acetyl group originating thereaction, baseof(NaOAc). The formation of 5 (2D) 52% yield and 16:1 E/Z (entry 3). heteroarylboronic Interestingly, in this unexpected byproduct was isolated; the structure ofofuse 5ratio was elucidated by intensive one-dimensional (1D) and two-dimensional nuclear magnetic resonance (NMR) experiments. Thefrom formation of(NaOAc). tricyclic compound 5 would be explained by insertion an acetyl group originating thereaction, base The formation of 5 (2D) easily removed by the more more heteroarylboronic (2 eq, eq, entry 4); 2-benzothiophenylboronic the of the acid (2 entry 4); 2-benzothiophenylboronic isolated; the was elucidated by intensive one-dimensional (1D) two-dimensional nuclearremoved magnetic (NMR) experiments. Thefrom formation tricyclic compound 5 would be explained bystructure insertion of5 an group originating the(2base (NaOAc). The formation of 5 (2D) was easily by resonance theof use of acetyl the more heteroarylboronic acid eq,of entry 4); and 2-benzothiophenylboronic isolated; the structure was elucidated by intensive one-dimensional (1D) two-dimensional nuclear magnetic (NMR) experiments. Thefrom formation tricyclic compound would be explained by insertion of5 an group originating the(2 base (NaOAc). The formation of 5 (2D) was acid removed and acid showed similar activity in easily by resonance theof use of acetyl the more heteroarylboronic acid eq,of entry 4); and 2-benzothiophenylboronic 3-furanylboronic domino MCRs (entries 5–8),55although the nuclear magnetic (NMR) experiments. Thefrom formation tricyclic compound would be explained by insertion of an acetyl group originating (NaOAc). The formation of 5 was easily removed by resonance the use of the more heteroarylboronic acid (2base eq,of entry 4);(entries 2-benzothiophenylboronic acid and 3-furanylboronic acid showed similar activity in the domino MCRs 5–8), although the nuclear magnetic (NMR) experiments. Thefrom formation tricyclic compound 5 than would be explained by insertion of an acetyl group originating (NaOAc). The formation of 5for was easily removed by resonance the use of the more heteroarylboronic acid (2base eq,of entry 4); 2-benzothiophenylboronic stereoselectivity of the reaction 2-benzothiophenylboronic acid was much lower acid and 3-furanylboronic acid showed similar activity in the domino MCRs (entries 5–8), although the stereoselectivity with 2-benzothiophenylboronic acid was the explained by insertion ofreaction an acetyl group originating from (NaOAc). The lower formation 5 was easilyand removed byofthe of theshowed more heteroarylboronic acid (2base eq,acid entry 4);(entries 2-benzothiophenylboronic acid 3-furanylboronic acid similar activity in the domino MCRs 5–8), although stereoselectivity theuse with 2-benzothiophenylboronic was much thanoffor the explained by insertion of an acetyl group originating from (NaOAc). The formation 5 was easily removed by the of theshowed more heteroarylboronic acid (2base eq,acid entry 4);(entries 2-benzothiophenylboronic acid and 3-furanylboronic acid similar activity in the domino MCRs 5–8), although others (entries 5ofand 6). stereoselectivity theuse reaction with 2-benzothiophenylboronic was much lower thanoffor the easily removed use ofacid the showed more (2 eq,acid entry 4);(entries 2-benzothiophenylboronic acid and 3-furanylboronic similar activity acid in domino MCRs 5–8), although stereoselectivity ofthe the reaction with heteroarylboronic 2-benzothiophenylboronic was much lower than for the others (entries 5by and 6). 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 dominoacid MCRs 5–8), although stereoselectivity of the with 2-benzothiophenylboronic was(entries much lower than for the others (entries 5 and 6). reaction acid and 3-furanylboronic acid showed similar activity in dominoacid MCRs 5–8), although stereoselectivity of the with 2-benzothiophenylboronic was(entries much lower than for the others (entries 5 and 6). reaction 11. Tableshowed 9. scopeactivity with heteroarylboronic acids Table 9. Substrate heteroarylboronic acids acid and 3-furanylboronic acid similar in dominoacid MCRs (entries 5–8), although stereoselectivity of the with 2-benzothiophenylboronic was much lower than for the others (entries 5 and 6). reaction 1. Table 9. Substrate scope with heteroarylboronic acids stereoselectivity of the others (entries 5 and 6). reaction with 2-benzothiophenylboronic acid was1 much lower than for the Table 9.with Substrate scope with heteroarylboronic stereoselectivity of the 2-benzothiophenylboronic acidacids was1.much lower than for the others (entries 5 and 6). reaction others (entries 5 and 6). Table 9. Substrate scope with heteroarylboronic acids . others (entries 5 and 6). Table 9. Substrate scope with heteroarylboronic acids 11. Table 9. Substrate scope with heteroarylboronic acids 1. Table 9. Substrate scope with heteroarylboronic acids . Table 9. Substrate scope with heteroarylboronic acids 11. Table 9. Substrate scope with heteroarylboronic acids .

2 2 E/Z Ratio 3 3 5 (%) 2 2 Entry Het-Ar-B(OH) Het-Ar-B(OH)2 33 Yield (%) Entry Yield E/Z Ratio 2 3 Entry Het-Ar-B(OH)22 3 Yield (%)(%) E/Z Ratio 5 (%) 522 (%) 2 3 Entry Het-Ar-B(OH) 2 3 Yield (%) E/Z Ratio 5 (%) 3o 1 77 2 >20:1 3 02 Entry Het-Ar-B(OH)2 3o 33o Yield Ratio 5 (%) 77(%) >20:1 0 2 0 11 77 2 E/Z >20:1 3 Entry Het-Ar-B(OH)2 3o 3 Yield (%) E/Z Ratio 5 (%) 1 77 >20:1 0 2 Entry 2 3 3p Yield 86 2 E/Z Ratio 14:1 3 5 (%) 3o 1 2 Het-Ar-B(OH) 77(%) 00 Entry Het-Ar-B(OH)2 3p 3 Yield (%) 22 E/Z>20:1 Ratio 33 5 (%) 21 86 14:1 0 22 3o 77(%) >20:1 Entry Het-Ar-B(OH) 2 3 Yield E/Z Ratio 5 (%) 3p 86 14:1 14:1 0 2 21 3p 86 2 0 3o 77(%) Entry Het-Ar-B(OH)2 3p 3 Yield E/Z>20:1 Ratio 3 5 (%) 21 86 14:1 0 2 3o 77 >20:1 16:1 3p 8652 14:1 3o3q 12 3 77 >20:1 0 25 3q 312 52 16:1 25 3p 86 14:1 3o 77 >20:1 0 3q 32 52 16:1 25 3p 86 14:1 0 3q3q 52 52 16:1 16:1 25 3 23 25 3p 86 14:1 0 3q 3 52 16:1 25 3p3q 24 4 8683 14:1 0 0 8.5:1 3q 3 52 16:1 25 3q 4344 83 8.5:1 0 3q 52 16:1 25 3q 43 83 8.5:1 0 3q 52 16:1 25 3q 44344 83 8.5:1 0 3q3r 5256 16:1 25 1.3:1 3q3q 83 83 8.5:1 0 19 0 8.5:1 44 45 3r 56 1.3:1 19 3q 454 83 8.5:1 0 3r 56 1.3:1 19 3q 454 4 83 8.5:1 0 3r3r 5697 1.3:1 19 1.3:1 3q 4546 83 8.5:1 0 0 3r 5 56 1.3:1 19 64 97 0 3q 83 8.5:1 56 56 19 56544 19 3r3r 97 1.3:11.3:1 0 5668 19 3r3s 654 7 97 1.3:1 0 10 9:1 3r 5 56 1.3:1 19 674 97 0 3s 68 9:1 10 3r 56 1.3:1 19 65 97 0 3s 68 9:1 1.3:1 10 3r 97 1.3:1 0 3r 97 0 6 647744 3s 68 9:1 10 3r 6748 4 97 1.3:1 0 3s 0 3s 6897 9:16:1 10 3r 6 97 1.3:1 0 4 3s 874 97 6:1 0 68 9:1 10 3s 87 97 6:1 0 68 9:1 10 1 Reaction conditions: 3s3s (1.1 68 9:1 10 97eq), 6:1 9:1 0 78744 68 heteroarylboronic 10 eq), Pd(PPh3)4 1 (1.0 eq), phenyl iodide acid (1.2 1 Reaction conditions: 3s (1.1 eq), 68 9:1 10 874 1 (1.0 eq), phenyl iodide 97 heteroarylboronic 6:1 0 (1.2 eq), Pd(PPh3)4 acid 1 Reaction 3s 8 97 6:1 0 mol %), NaOAc eq), Ag3PO4 (1.1 eq), DMF (0.05eq), M),Pd(PPh microwave (10 mol %), CuI (5 mol conditions: 1 %), (1.0PPh eq),3 (30 phenyl iodide (1.1 (3 eq), heteroarylboronic acid (1.2 3)4 1 Reaction 3s (1.1 8 4 %), 97 6:1 eq), DMF 0(0.05 3 (30 mol %),iodide NaOAc (3 eq), eq), heteroarylboronic Ag3PO4 (1.1 (10 mol %),conditions: CuI (5 mol PPheq), 1 (1.0 phenyl acid (1.2M), eq),microwave Pd(PPh 3)4 2 Isolated yield 3 Ratio 1 Reaction 3sor (1.1 84 44 10 97 6:1 0and combined yield isolated EZ-isomers; irradiation, 150 °C, min; 3 (30 mol %), NaOAc (3 eq), Ag 3PO4of (1.1 eq), DMF (0.05 M), microwave (10 mol %), CuI (5 mol %), PPh conditions: 1 (1.0 eq), phenyl iodide eq), heteroarylboronic acid (1.2 eq), Pd(PPh 3)4 2 eq), 3 Ratio 1 Reaction 3s 810 %), 6:1 eq), 0(0.05 6:1 DMF 0M), 8mol Isolated yield or3scombined yield of4 (1.1 isolated E-acid and Z-isomers; irradiation, 150 (5 °C, min; 1 (1.0 phenyl (1.1 eq), heteroarylboronic (1.2 eq),microwave Pd(PPh 3)4 3 (30 mol %),iodide NaOAc (3 97 eq),97 Ag3PO (10 mol %),conditions: CuI PPh 4 Two equivalents of heteroarylboronic acid were used. 3 2 eq), 1(10 between isolated Eand Z-isomers; Isolated yield or combined yield of isolated Eand Z-isomers; Ratio irradiation, 150 °C, 10 min; Reaction conditions: 1 (1.0 phenyl iodide (1.1 eq), heteroarylboronic acid (1.2 eq), Pd(PPh 3)4 3 (30 mol %), NaOAc (3 eq), Ag 3PO 4 (1.1 eq), DMF (0.05 M), microwave mol %), CuI (5 mol %), PPh 4 Two 1irradiation, 2 eq), 3 Ratio equivalents of heteroarylboronic acid were used. between isolated Eand Z-isomers; Reaction conditions: 1 (1.0 phenyl iodide (1.1 eq), heteroarylboronic acid (1.2 eq), Pd(PPh 3)4 3 (30 mol %), NaOAc (3 eq), Ag 3PO 4 (1.1 eq), DMF (0.05 M), microwave (10 mol %), CuI (5 mol %), PPh Isolated yield or combined yield of isolated Eand Z-isomers; 150 °C, 10 min; 4 2 3 1between 1 Two equivalents of heteroarylboronic acid were used. isolated Eand Z-isomers; 3 (30 mol %),iodide NaOAc (3 eq), eq), Ag3PO eq), DMF (0.05 M), (10 mol %), CuI mol %), PPh Isolated yield or(1.1 combined yield of4 (1.1 isolated Eand Z-isomers; Ratio irradiation, 150 (5 °C, 10 min; Reaction conditions: (1.0 eq), phenyl (1.1 heteroarylboronic acid (1.2 eq),microwave Pd(PPh Reaction conditions: 11 (1.0 phenyl iodide eq), acid DMF (1.2 eq), Pd(PPh mol3)4%), 2eq), 3 Ratio 3 )4 (10 4 Two 3 (30 mol %),equivalents NaOAc (3 heteroarylboronic eq), Ag3PO eq), (0.05 M), microwave (10 mol %), CuI mol %), PPh Isolated yield or combined yield of4 (1.1 isolated Eand irradiation, 150 (5 °C, 10 min; of heteroarylboronic acid were used. between isolated Eand Z-isomers; ◦ C, the 2%), 3 Ratio 4 Two Next, we investigated the of derivatization of propiolamide 1Z-isomers; (Table 10). When CuI (5 %), mol %), PPh (30%), mol NaOAc (3 eq), Ag eq), (0.05 M), DMF microwave irradiation, 150 Isolated yield or combined yield of isolated Eand Z-isomers; irradiation, 150 °C, min; equivalents of heteroarylboronic acid were used. between isolated Eand Z-isomers; 3 possibility (30 mol %), NaOAc eq), Ag 3DMF PO 4 (1.1 eq), (0.05 M), microwave (10 mol CuI (5 mol PPh 310 3 PO(3 4 (1.1 3 When 4 Two Next, we2isolated investigated the2 possibility of derivatization ofofpropiolamide 1 (Table 10).Z-isomers; 3 isolated Isolated yield or combined yield Eand Z-isomers; Ratio the irradiation, 150 °C, 10 min; equivalents ofZ-isomers; heteroarylboronic acid were used. between Eand Z-isomers; 10 min; Isolated yield or combined yield of isolated Eand Ratio between isolated Eand 4 2 3 N-substituent of was changed tocombined a H orofaheteroarylboronic Bn group, the reactions showed good yieldthe and Next, weisolated investigated the 1possibility of derivatization ofofpropiolamide 1 Z-isomers; (Table When Two equivalents acid were used.10). between E- 10 andmin; Z-isomers; Isolated yield or yield isolated Eand Ratio irradiation, 150propiolamide °C, 4 Two equivalents 4 Two heteroarylboronic acid were used. Next, weisolated the possibility of of propiolamide 1showed (Table 10). When the N-substituent ofinvestigated propiolamide 1 was changed toderivatization a H or aofBn group, the reactions yield and equivalents heteroarylboronic acid were used.good between E-ofand Z-isomers; 4 Two Next, we the possibility of propiolamide 1showed (Table 10). When the6c moderate stereoselectivity (entries 1changed and 2).of Under conditions, oneacid carbon-extended substrate N-substituent ofinvestigated propiolamide 1 was toderivatization a Hstandard or aofBn group, the reactions yield and equivalents heteroarylboronic were used.good between isolated E- and Z-isomers;

Next,stereoselectivity weofinvestigated the possibility oftoderivatization of propiolamide 1showed (Table good 10).substrate When the N-substituent propiolamide 1 was changed a standard H or a Bnconditions, group, the one reactions yield and moderate (entries 1 and 2). Under carbon-extended 6c Next,stereoselectivity weofyield investigated the1 was possibility oftoincreased derivatization of at propiolamide 1showed (Table 10).substrate When the N-substituent propiolamide changed a standard H or a Bn group, the reactions good yield and moderate 1 and 2). Under one carbon-extended 6c showed low (35%,(entries entry 3). The yield toconditions, 45% higher reaction temperature (180 °C) Next, we the possibility of derivatization of propiolamide 1showed (Table 10). When the N-substituent ofinvestigated propiolamide 13). was changed to aderivatization H or atoBn group, the one reactions good yield and moderate stereoselectivity (entries 1possibility and 2). Under standard conditions, carbon-extended substrate 6c showed low yield (35%, entry The yield increased 45% atof higher reaction temperature (180 °C) Next, we investigated the of propiolamide 1 (Table 10). When the weyield the13). possibility ofincreased ofatpropiolamide 1showed (Table 10). When the N-substituent ofinvestigated propiolamide was changed toderivatization a(1.1:1 H or E/Z atoBn group, the one reactions good yield moderate stereoselectivity (entries 1The and 2). Under standard conditions, carbon-extended substrate 6c butNext, almost no stereoselectivity was observed ratio, entry 4).reaction Propiolate ester 6d turned out showed low (35%, entry yield 45% higher temperature (180 and °C) 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 lownoyield (35%, entry 3). The yield increased toaratio, 45% at higher reaction temperature (180 °C) but almost stereoselectivity was observed (1.1:1 E/Z entry 4). Propiolate ester 6d turned out N-substituent of propiolamide 1 1was changed to aH or Bn group, the reactions showed good yield and N-substituent of propiolamide changed togiving a standard H or atoBn group, the reactions showed yield and moderate stereoselectivity (entries and 2). Under one carbon-extended 6c showed (35%,for entry 3). The yield increased 45% at higher reaction temperature (180 °C) to almost be a low poor substrate our1domino MCRs, both aconditions, low yield and poor stereoselectivity (entry 5). but noyield stereoselectivity was observed (1.1:1 E/Z ratio, entry 4). Propiolate estergood 6dsubstrate turned out moderate stereoselectivity (entries 1The and 2). Under standard conditions, one carbon-extended 6c showed low yield (35%, entry 3). yield increased toaratio, 45% at higher reaction temperature (180 °C) but no stereoselectivity was observed (1.1:1 E/Z entry 4). Propiolate ester 6dsubstrate turned out to bealmost a poor substrate for our domino MCRs, giving both low yield and poor stereoselectivity (entry 5). moderate stereoselectivity (entries 1 and 2). Under standard conditions, one carbon-extended substrate 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 stereoselectivity was observed (1.1:1both E/Z aratio, entry 4). MCRs Propiolate ester 6d turned out All implied that applying our microwave-assisted domino to the synthesis of other to bealmost aresults poorno substrate for our domino MCRs, giving low yield and poor stereoselectivity (entry 5). ◦ C) showed lowno yield (35%, entry 3). The yield increased toaratio, 45% at higher reaction temperature (180 °C) but almost stereoselectivity was observed (1.1:1 E/Z entry 4). Propiolate ester 6d turned out to beresults a poor substrate for our domino MCRs, giving both low yield poor stereoselectivity (entry 5). All implied that applying our microwave-assisted domino MCRs to the synthesis of other 6c showed low yield (35%, entry 3). The yield increased to 45% at and higher reaction temperature (180 showed lowno yield (35%, entry 3). The yield increased to 45% at higher reaction temperature (180 °C) but almost stereoselectivity was observed (1.1:1 E/Z entry 4). Propiolate ester 6d turned out toheterocycles beresults a poor substrate for our domino MCRs, giving both aratio, lowdomino yield and poor stereoselectivity (entry 5). is possible, but needs further study for optimization ofMCRs each reaction. All implied that applying our microwave-assisted to the synthesis of other but almost no stereoselectivity was observed (1.1:1 E/Z ratio, entry 4). Propiolate ester 6d turned out tobut beresults aalmost poorimplied substrate for but our domino MCRs, giving both a lowdomino yieldof and poor stereoselectivity (entry 5). All that applying our microwave-assisted MCRs to the synthesis of other heterocycles isnopossible, needs further study for optimization each reaction. stereoselectivity was observed (1.1:1 E/Z ratio, entry 4). Propiolate ester 6d turned but was observed (1.1:1 E/Z entry 4). Propiolate 6d turned out to a In poor substrate for but our domino MCRs, giving both aratio, low yield and poor stereoselectivity (entry 5). Allbealmost results implied that applying our microwave-assisted MCRs to theester synthesis of other allno of the above results, the stereoselectivity of thedomino domino MCRs varied depending on the heterocycles isstereoselectivity possible, needs further study for optimization of each reaction. to beresults atopoor substrate for results, our domino MCRs, giving both low yield and poor stereoselectivity (entry 5). All implied that applying microwave-assisted MCRs to thepoor synthesis ofon other heterocycles is possible, but needs further study for optimization of each reaction. In all of the above theour stereoselectivity of athe domino MCRs varied depending the out be a poor substrate for our domino MCRs, giving both a low yield and stereoselectivity 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 to the ofon other heterocycles isthe possible, but needs further study for optimization of MCRs each3reaction. substrate. One ofabove the reasons forthe this could be the isomerization of product under thesynthesis reaction conditions. In all of results, stereoselectivity of the domino varied depending the All results implied that applying our microwave-assisted to the reaction synthesis ofon other heterocycles isthe but needs further for optimization of MCRs each reaction. In all of above results, thecould stereoselectivity of the domino varied depending theof substrate. One ofpossible, the reasons for this bestudy the isomerization of product 3 under (entry 5). All results implied that applying our microwave-assisted domino to theconditions. synthesis All results implied that applying our microwave-assisted to MCRs the reaction synthesis ofBoth other heterocycles isthe but needs further optimization of MCRs each reaction. In all of above results, the stereoselectivity of standard the domino varied depending on the Thus, weOne exposed pure (Z)and (E)-isomers of isomerization 3efor to the reaction conditions (Table 11). (Z)substrate. ofpossible, the reasons for this could bestudy the of product 3 under conditions. heterocycles butand needs further study of MCRs each reaction. Inweall of isthe above results, thecould stereoselectivity of the varied depending on (Z)the substrate. One ofpossible, the reasons for this befurther the of product 3conditions under thereaction. reaction conditions. Thus, exposed pure (Z)(E)-isomers of 3eisomerization tofor theoptimization standard reaction (Table 11). Both other heterocycles is possible, but needs study for domino optimization of each 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. and (E)-3e showed very low isomerization rates (