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Aerobic Oxidative Cross-Coupling of Substituted Acrylamides with Alkenes Catalyzed by an Electron-Deficient CpRh(III) Complex Ryo Yoshimura, Yu Shibata, and Ken Tanaka J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01733 • Publication Date (Web): 16 Aug 2019 Downloaded from pubs.acs.org on August 18, 2019

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The Journal of Organic Chemistry

Aerobic Oxidative Cross-Coupling of Substituted Acrylamides with Alkenes Catalyzed by an Electron-Deficient CpRh(III) Complex Ryo Yoshimura, Yu Shibata,* and Ken Tanaka* Department of Chemical Science and Engineering, Tokyo Institute of Technology, O-okayama, Meguro-ku, Tokyo 1528550, Japan E-mail: [email protected], [email protected] Supporting Information Placeholder

ABSTRACT: It has been established that an electron-deficient CpRh(III) complex, bearing two ester moieties on the Cp ring, [CpERh(III)] catalyzes the aerobic oxidative cross-coupling of substituted acrylamides with both activated and unactivated alkenes, leading to (2Z,4E)-dienamides, at relatively low temperature (80 °C). Importantly, tertiary, secondary, and primary amide directing groups could equally be used in this catalysis. The mechanistic studies revealed that the electron-deficient nature of the CpERh(III) complex facilitates the turnover-limiting vinylic C–H bond cleavage of the acrylamides.

A 1,3-butadiene scaffold is a useful building block for organic synthesis, and often present in natural products and bioactive molecules.1 As one of the most atom- and step-economical synthesis of 1,3-butadienes, large numbers of transition-metal-catalyzed C–H/C–H coupling reactions between two alkenes have been developed.2–4 For example, the oxidative cross-coupling of acrylamides with alkenes via directed vinylic C–H bond cleavage of the acrylamides selectively produces (2Z,4E)-dienamides (Scheme 1a).5–11 Glorius first reported this transformation by using a cationic Cp*Rh(III) catalyst.5 Subsequently, a Ru(II)-catalyzed variant of this transformation6 and expansion of the substrate scope [coupling partner: aliphatic alkene (2-allylisoindoline-1,3-dione),7 di-

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recting groups: Weinreb amides8] were reported. However, these reactions required high reaction temperature (120–140 °C) and a stoichiometric amount of a Cu(II) oxidant. With respect to the reaction temperature, low-temperature (50–60 °C) reactions were accomplished by using a cationic Ru(II) hydride complex9 as a catalyst or an N-methoxycarbamoyl group as a directing group.10 However, these reactions still required stoichiometric amounts of external or internal oxidants (excess alkenes9 or the Nmethoxycarbamoyl group10), and the available directing groups were strictly limited to secondary amides (NHMe9 or NHOMe10). We have been demonstrating that readily available functionalized CpRh(III) complexes such as a CpERh(III) complex bearing two ester moieties12 and CpARh(III) complexes 1 bearing a pendant amide moiety13 (Scheme 1b) exhibit high catalytic activities in various C–H bond functionalizations.14 For example, we recently reported that moderately electron-deficient CpARh(III) complex 1b bearing one ester moiety catalyzes the oxidative cross-coupling reactions of benzamides with activated and unactivated alkenes including disubstituted ones by using air as a terminal oxidant at relatively low temperature (60–80 °C, Scheme 1c).13c,15 Herein, we have established that substituted acrylamides, possessing tertiary, secondary, and primary amide directing groups, can be used instead of substituted benzamides in the above transformation by using the CpERh(III) complex instead of the CpARh(III) complex 1b as the catalyst (Scheme 1d). Scheme 1. Oxidative Cross-Coupling of Acrylamides with Alkenes


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First, we screened the CpRh(III) catalysts in the reaction of pyrrolidine-derived methacrylamide 2a with styrene (3a) using AgSbF6 and Cu(OAc)2•H2O cocatalysts, and 1,2-dichloroethane solvent at 80 °C under air (Table 1, entries 1–5). The use of the CpARh(III) (1a and 1b) and CpERh(III) catalysts gave the desired product 4aa as a single diastereomer in higher yields than that using the Cp*Rh(III) catalyst (entries 1–4 vs. entry 5). Particularly, the use of the highly electron-deficient CpERh(III) chloride catalyst afforded 4aa in the highest yield (entry 3). This result is contrary to the aerobic oxidative cross-coupling of benzamides with styrenes, in which the use of the moderately electron-deficient CpARh(III) catalyst 1b afforded 4aa in higher yield than the use of the CpERh(III) catalyst due to the formation of a bis-olefinated byproduct.13c We next screened silver salts (entries 3, 6, and 7), which revealed that AgSbF6 was the best one (entry 3). The use of Cu(OAc)2 and CuCO3•Cu(OH)2•H2O as an oxidant failed to im-


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prove the yield of 4aa (entries 8 and 9). The reactions in the absence of the Cu(II) oxidant (entry 10) or under argon atmosphere (entry 11) significantly decreased the yield of 4aa, which revealed that both Cu(II) co-oxidant and molecular oxygen in the air are important for this reaction. Although the reaction was completed, the reaction under O2 decreased the yield of 4aa presumably due to the product decomposition (entry 12). Screening of solvents was also conducted, but the yields were not improved (entries 13 and 14). With regard to the ratios of two alkenes, the use of excess 2a (2a/3a = 1.5:1.0) decreased the yield of 4aa to 52% (entry 15). In contrast, the use of excess 3a (2a/3a = 1.0:3.0) increased the yield of 4aa to 71% (entry 16). Under the optimized reaction conditions (entry 16), CpARh(III) (1b) and Cp*Rh(III) catalysts showed significantly lower catalytic activities than the CpERh(III) catalyst (entries 17 and 18). Table 1. Optimization of Reaction Conditionsa

entry

[CpXRhX2]2

silver salt

oxidant

solvent

atmosphere

yield (%)b

1

1a

AgSbF6

Cu(OAc)2•H2O

(CH2Cl)2

air

31

2

1b

AgSbF6

Cu(OAc)2•H2O

(CH2Cl)2

air

33

3

[CpERhCl2]2

AgSbF6

Cu(OAc)2•H2O

(CH2Cl)2

air

61

4

[CpERhI2]2

AgSbF6

Cu(OAc)2•H2O

(CH2Cl)2

air

55

5

[Cp*RhCl2]2

AgSbF6

Cu(OAc)2•H2O

(CH2Cl)2

air

10

6

[CpERhCl2]2

AgNTf2

Cu(OAc)2•H2O

(CH2Cl)2

air

52

7

[CpERhCl2]2

AgOTf

Cu(OAc)2•H2O

(CH2Cl)2

air

9

8

[CpERhCl2]2

AgSbF6

Cu(OAc)2

(CH2Cl)2

air

57

9

[CpERhCl2]2

AgSbF6

CuCO3•Cu(OH)2• H2O

(CH2Cl)2

air

25

10

[CpERhCl2]2

AgSbF6

none

(CH2Cl)2

air

6

11

[CpERhCl2]2

AgSbF6

Cu(OAc)2•H2O

(CH2Cl)2

Ar

15

12

[CpERhCl2]2

AgSbF6

Cu(OAc)2•H2O

(CH2Cl)2

O2

29

13

[CpERhCl2]2

AgSbF6

Cu(OAc)2•H2O

1,4-dioxane

air

58

14

[CpERhCl2]2

AgSbF6

Cu(OAc)2•H2O

t-AmOH

air

29

15c

[CpERhCl2]2

AgSbF6

Cu(OAc)2•H2O

(CH2Cl)2

air

52

16d

[CpERhCl2]2

AgSbF6

Cu(OAc)2•H2O

(CH2Cl)2

air

71


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a

17d

1b

AgSbF6

Cu(OAc)2•H2O

(CH2Cl)2

air

39

18d

[Cp*RhCl2]2

AgSbF6

Cu(OAc)2•H2O

(CH2Cl)2

air

11

[CpXRhCl2]2 (0.0050 mmol), AgX (0.020 mmol), Cu(OAc)2•H2O (0.020 mmol), 2a (0.100 mmol), 3a (0.150 mmol), and (CH2Cl)2 (0.50

mL) were used.

b

Determined by 1H NMR spectroscopy using dimethyl terephthalate as an internal standard. c 2a (0.150 mmol) and 3a

(0.100 mmol) were used. d 3a (0.300 mmol) was used.

The substrate scope of this cross-coupling reaction is shown in Scheme 2. With regard to directing groups of the acrylamides, not only tertiary (2a–c) but also secondary (2d) and primary (2e) amides could be used to give the corresponding dienamides 4aa– 4ea in moderate to good yields.16 With regard to substituents on the C=C bond of the acrylamides, both 1,1- and 1,2-disubstituted acrylamides 2a–f were applicable to give the corresponding dienamides 4aa–4ga as a single diastereomer. Furthermore, acyclic and cyclic 1,1,2-trisubstituted acrylamides 2h and 2i could be used to give dienamides 4ha and 4ia. The use of pyrrolidine-derived nonsubstituted acrylamide 2j resulted in low product yield.17 Regard to coupling partners, the substituent effect on the benzene ring of the styrene appeared to be small. Substituted styrenes 3b–f with varied electronic and steric nature reacted with 2a to give the corresponding dienamides 4ab–af in good yields. Activated alkene (acrylate) 3g reacted with 2a to give 4ag in the highest yield of 84%,16 although a trace amount of a diastereomer (2E,4Z-isomer) was generated. Fortunately, aliphatic alkene 3h (3,3-dimethyl-1butene) was also able to react with 2a to give the corresponding dienamide 4ah in moderate yield as a mixture of diastereomers.18,19 Scheme 2. Scope of Substratesa


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The Journal of Organic Chemistry a

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[CpERhCl2]2 (0.010 mmol), AgSbF6 (0.040 mmol), Cu(OAc)2•H2O (0.040 mmol), 2 (0.200 mmol), 3 (0.600 mmol), and (CH2Cl)2

(1.0 mL) were used. Cited yields were of the isolated products. The unprecedented reactions of the acrylamide with disubstituted styrenes were also examined (Scheme 3).13c Under the same conditions shown in Scheme 2, α-methylstyrene (3i) and β-methylstyrene (3j) reacted with 2a to give the corresponding crosscoupling products, while these products were isolated as isomeric mixtures of dienamides (4ai/4ai’ and 4aj/4aj’) and their yields were low (35% and 15%, respectively).20 In our previous report on the reactions of benzamides with disubstituted alkenes, the CpARh(III) complex (1b) exhibited higher catalytic activity than the CpERh(III) complex.13c Thus, we applied the catalyst 1b to these oxidative cross-coupling reactions. Pleasingly, the yields of 4ai/4ai’ and 4aj/4aj’ were improved to 39% and 31%, respectively. Scheme 3. Olefination with disubstituted styrenes

The synthetic utility of the oxidative cross-coupling reaction is shown in Scheme 4. The preparative scale reaction of 2a and 3a using a reduced amount of the CpERh(III) complex (2 mol % Rh) was conducted. Fortunately, the desired product 4aa was obtained in almost the same yield as the small scale with the high catalyst loading (Scheme 4a). Besides, the reduction of the thus obtained dienamide 4aa using LiAlH4 could produce dienylamine 5aa in good yield (Scheme 4b). Scheme 4. Synthetic Utilities


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A plausible reaction mechanism, which is analogous to our previously reported CpERh(III) complex-catalyzed C-H bond functionalization,12 is shown in Scheme 5a. In the first step, [CpERhCl2]2 reacts with AgSbF6 and AcO– from Cu(OAc)2 to generate catalytically active rhodium(III) acetate A, which reacts with 2 to give five-membered rhodacycle B through the electrophilic concerted metalation-deprotonation mechanism. Coordination of alkene 3 to B gives intermediate C, and subsequent alkene insertion affords seven-membered rhodacycle D. β-Hydride elimination followed by oxidation with Cu(OAc)2 generate rhodium(III) acetate E bearing diene 4. Finally, dissociation of the diene 4 reproduces A. As in the previously reported CpERh(III) complex-catalyzed C-H bond functionalization reactions, the CpERh(III) complex would accelerate the turnover-limiting C-H bond cleavage compared to the electron-rich Cp*Rh(III) complex.12 In order to confirm the ligand effect, the deuterium kinetic isotope effects (DKIEs) of the cross-coupling of 2g with 3a were determined by the parallel reactions (Scheme 5b) and the intermolecular competition reactions (Scheme 5c) employing the Cp*Rh(III) and CpERh(III) complexes. In the Cp*Rh(III) complex-catalyzed reactions, no significant DKIE difference (5.7 vs. 6.6) was observed between the two measurements, and no significant H/D exchange with H2O was observed in the recovered 2g-d6 of the parallel reactions. These results indicate that the turnover-limiting step involves the irreversible C-H bond cleavage.21 In the CpERh(III) complex-catalyzed reactions, no significant H/D exchange with H2O was observed in the recovered 2g-d6 of the parallel reactions as with the Cp*Rh(III) complex-catalyzed reactions, but significant DKIE difference (1.1 vs. 3.6) was observed between the two measurements. Thus, the use of the CpERh(III) complex in place of the Cp*Rh(III) complex accelerates the C-H bond cleavage step in the catalytic cycle. Scheme 5. Mechanistic Studies


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a) plausible reaction mechanism

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

R

R1 N 2

CpERhCl2 + 2AgSbF6 + AcO–

O

R5

R3

–2AgCl

R2

R1 N

4

R

accelerated by

R5 R4

AcOH

A

[RhIII] OAc

R3

R4

2

AcO [RhIII] O

H

R3

R4

R1 N 2

O

CpE

R2

R1 N

O [RhIII]

R3 R4

E

B R1 N

O

[RhIII]

R2 2 Cu(OAc) 2 Cu(OAc)2 AcOH

R5

R

R3

1/2 O2 AcOH

O

R5

[RhIII]

3

R3

R4

R4

D H 2O

R1 N 2

R5

C [RhIII] = CpERh+

b) DKIEs in parallel reactions N H

O H/D

+

Ph

(CH2Cl)2, 80 °C, 2 h under air

H5/D5 2g or 2g-d6

5 mol % [CpXRhCl2]2 20 mol % AgSbF6 20 mol % Cu(OAc)2•H2O

3a (3 equiv)

N

O

H Ph

H H H5/D5

4ga/4ga-d5 KIE = 5.7 (13% / 2%, Cp*) KIE = 1.1 (23% / 21%, CpE)

c) DKIEs in intermolecular competition reactions

2g 2g-d6 3a + + (0.5 equiv) (0.5 equiv) (3 equiv)

5 mol % [CpXRhCl2]2 20 mol % AgSbF6 20 mol % Cu(OAc)2•H2O

4ga + 4ga-d5 (CH2Cl)2, 80 °C, 2 h under air 4ga/4ga-d5 = 6.6 (11%, Cp*) 4ga/4ga-d5 = 3.6 (21%, CpE)

In conclusion, we have established that an electron-deficient cyclopentadienyl-rhodium(III) complex, bearing two ester moieties on the Cp ring, [CpERh(III)] is able to catalyze the oxidative cross-coupling of acrylamides with both activated and unactivated alkenes, leading to (2Z,4E)-dienamides, using air as a terminal oxidant at relatively low temperature (80 °C). It is worthy of note that tertiary, secondary, and primary amide directing groups could equally be employed for the present catalysis, and the preparative scale reaction with a low catalyst loading afforded the desired product in almost the same yield as the small scale with the high catalyst loading. The mechanistic studies [the deuterium kinetic isotope effect (DKIE) measurements] revealed that the electrondeficient nature of the CpERh(III) complex facilitates the turnover-limiting vinylic C–H bond cleavage of the acrylamides.

EXPERIMENTAL SECTION General: Anhydrous (CH2Cl)2 (No. 28,450-5) was obtained from Aldrich used as received. Solvents for the synthesis of substrates were dried over Molecular Sieves 4A (Wako) prior to use. Rh(III) complexes [CpERhCl2]2,12a 1a,13a and 1b,13c benzamides 2a,22 2b,23 2e,24 2f,24 2g,25 2h,25 and 2i,26 and alkene 3c27 were already reported. All other reagents were obtained from commercial sources and used as received. 1H and 13C{1H} NMR data were collected on a Bruker AVANCE III HD 400 (400 MHz) at ambient


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temperature. HRMS data were obtained on a Bruker microTOF Focus II. All reactions were carried out in oven-dried glassware with magnetic stirring. An oil bath was used for the reactions that require heating (80 °C). Synthesis of [CpERhI2]2: To a solution of [CpERhCl2]2 (42.5 mg, 0.0500 mmol) in acetone (1.0 mL) was added NaI (74.9 mg, 0.500 mmol) and acetone (1.0 mL) and the mixture was stirred at 40 °C for 16 hours. The resulting mixture was concentrated under reduced pressure, and dissolved in CH2Cl2 (5 mL). The resulting solution was filtered, and the filtrate was poured into n-hexane (30 mL). The resulting precipitates were collected, washed with Et2O (10 mL) and dried under vacuum to give [CpERhI2]2 (31.0 mg, 0.510 mmol, 51% yield) as a black soild. Mp 252 °C (dec.); 1H NMR (CDCl3, 400 MHz) δ 4.41–4.34 (m, 8H), 2.78 (s, 6H), 2.40 (s, 12H), 1.38 (t, J = 7.1, 12H); 13C{1H} NMR (CDCl3, 100 MHz) δ 163.6, 103.9 (d, J = 5.9), 82.0 (d, J = 7.5), 77.7, 62.3, 14.9, 14.3, 13.1; HRMS (ESI) calcd for C28H38O8I3Rh2 [M−I]+ 1088.7805, found 1088.7797; calcd for C14H19O4I2RhNa [M+Na]+ 630.8320, found 630.8283. Representative procedure for the rhodium-catalyzed oxidative olefination (Scheme 2): To a Schlenk flask was added AgSbF6 (13.6 mg, 0.0400 mmol), [CpERhCl2]2 (8.5 mg, 0.0100 mmol), Cu(OAc)2•H2O (8.0 mg, 0.0400 mmol), 2a (27.8 mg, 0.200 mmol), 3a (62.4 mg, 0.300 mmol), and (CH2Cl)2 (1.0 mL) in this order. The mixture stirred at 80 °C using an oil bath under air for 16 hours. The resulting mixture was diluted with diethyl ether, filtered through a silica gel pad, and washed with EtOAc. The eluent was concentrated under reduced pressure, and the residue was purified by a preparative thin layer chromatography (TLC, toluene/acetone = 1:1) to give 4aa (33.9 mg, 0.140 mmol, 70% yield) as a colorless oil. Procedure for the preparative scale reaction (Scheme 4): To a Schlenk flask was added AgSbF6 (13.6 mg, 0.0400 mmol), [CpERhCl2]2 (8.5 mg, 0.0100 mmol), Cu(OAc)2•H2O (8.0 mg, 0.0400 mmol), 2a (139 mg, 1.00 mmol), 3a (312 mg, 3.00 mmol), and (CH2Cl)2 (5.0 mL) in this order. The mixture was stirred at 80 °C using an oil bath under air for 16 hours. The resulting mixture was diluted with diethyl ether, filtered through a silica gel pad, and washed with EtOAc. The eluent was concentrated under reduced pressure, and the residue was purified by a preparative TLC (toluene/acetone = 1:1) to give 4aa (165 mg, 0.682 mmol, 68% yield) as a colorless oil. (2Z,4E)-2-Methyl-5-phenyl-1-(pyrrolidin-1-yl)penta-2,4-dien-1-one (4aa) The stereochemistry of the title compound was determined by the NOESY experiment and the coupling constant of vinyl protons. 1H NMR (CDCl3, 400 MHz) δ 7.37–7.29 (m, 4H), 7.24–7.20 (m, 1H), 6.67 (dd, J = 15.5, 10.8 Hz, 1H), 6.55 (d, J = 15.6 Hz, 1H), 6.13 (dq, J = 10.8, 1.3 Hz, 1H), 3.60 (t, J = 6.8 Hz, 2H), 3.35 (t, J = 6.5 Hz, 2H), 2.02 (d, J = 1.3 Hz, 3H), 1.97–1.85 (m, 4H); 13

C{1H} NMR (CDCl3, 100 MHz) δ 170.1, 137.1, 135.5, 133.4, 128.6, 128.2, 127.8, 126.5, 124.9, 47.4, 45.2, 26.0, 24.6, 20.3;

HRMS (ESI) calcd for C16H19NNaO [M+Na]+ 264.1359, found 264.1357. (2Z,4E)-N,N-Dibenzyl-2-methyl-5-phenylpenta-2,4-dienamide (4ba) The stereochemistry of the title compound was determined by comparing the 1H NMR spectra of 4ba and 4aa. Colorless solid; 35.0 mg, 0.0952 mmol, 48% isolated yield; Mp 86.4–87.2 °C; 1H NMR (CDCl3, 400 MHz) δ 7.39–7.14 (m, 15H), 6.64 (dd, J =


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15.5, 11.1 Hz, 1H), 6.49 (d, J = 15.6 Hz, 1H), 6.17 (dq, J = 11.0, 1.4 Hz, 1H), 4.63 (br, 2H), 4.46 (br, 2H), 2.07 (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz) δ 172.1, 137.3, 136.9, 136.4, 133.6, 129.1, 128.94, 128.88, 128.6, 127.81, 127.76, 127.67, 127.4, 126.5, 124.4, 50.8, 46.3, 21.2; HRMS (ESI) calcd for C26H25NNaO [M+Na]+ 390.1828, found 390.1822. (2Z,4E)-N-Benzyl-2-methyl-N,5-diphenylpenta-2,4-dienamide (4ca) The stereochemistry of the title compound was determined by comparing the 1H NMR spectra of 4ca and 4aa. Colorless solid; 26.0 mg, 0.0736 mmol, 37% isolated yield; Mp 140.3–141.1 °C; 1H NMR (CDCl3, 400 MHz) δ 7.34–7.20 (m, 13H), 6.96 (br, 2H), 6.86 (dd, J = 15.5, 11.2 Hz, 1H), 6.35 (d, J = 15.7 Hz, 1H), 5.86 (d, J = 10.5, 1H), 5.01 (s, 2H), 1.80 (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz) δ 171.3, 142.0, 137.8, 137.1, 134.8, 132.9, 129.9, 129.0, 128.9, 128.604, 128.598, 127.69, 127.66, 127.5, 126.5, 125.3, 52.9, 21.0; HRMS (ESI) calcd for C25H23NNaO [M+Na]+ 376.1672, found 376.1681. (2Z,4E)-N,2-Dimethyl-5-phenylpenta-2,4-dienamide (4da) The stereochemistry of the title compound was determined by comparing the 1H NMR spectra of 4da and 4ea. Colorless amorphos; 17.0 mg, 0.0845 mmol, 42% isolated yield; 1H NMR (CDCl3, 400 MHz) δ 7.45–7.38 (m, 3H), 7.33–7.29 (m, 2H), 7.26–7.22 (m, 1H), 6.59 (d, J = 15.6 Hz, 1H), 6.31 (d, J = 11.1 Hz, 1H), 5.68 (br, 1H), 2.94 (d, J = 4.9 Hz, 3H), 2.03 (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz) δ 169.9, 137.0, 135.4, 133.8, 131.9, 128.6, 128.0, 126.8, 125.3, 26.3, 21.2; HRMS (ESI) calcd for C13H15NnaO [M+Na]+ 224.1046, found 224.1035. (2Z,4E)-2-Methyl-5-phenylpenta-2,4-dienamide (4ea)5 Colorless solid; 16.2 mg, 0.0865 mmol, 43% isolated yield; Mp 145.9–146.2 °C; 1H NMR (CDCl3, 400 MHz) δ 7.53 (dd, J = 15.6, 11.2 Hz, 1H), 7.44–7.43 (m, 2H), 7.33–7.30 (m, 2H), 7.26–7.22 (m, 1H), 6.63 (d, J = 15.6 Hz, 1H), 6.39 (d, J = 11.2 Hz, 1H), 5.81–5.64 (br, 2H), 2.06 (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz) δ 171.0, 136.9, 136.3, 135.3, 130.3, 128.6, 128.2, 126.9, 125.3, 21.2. (2Z,4E)-3-Methyl-5-phenyl-1-(pyrrolidin-1-yl)penta-2,4-dien-1-one (4fa) The stereochemistry of the title compound was determined by comparing the 1H NMR spectra of 4fa and (2Z,4E)-N,N-diethyl3-methyl-5-phenylpenta-2,4-dienamide.5 Colorless oil; 23.8 mg, 0.0986 mmol, 49% isolated yield; 1H NMR (CDCl3, 400 MHz) δ 8.22 (d, J = 16.4 Hz, 1H), 7.53–7.51 (m, 2H), 7.33–7.29 (m, 2H), 7.26–7.22 (m, 1H), 6.81 (d, J = 16.4 Hz, 1H), 5.92 (s, 1H), 3.56 (t, J = 6.8 Hz, 2H), 3.49 (t, J = 6.7 Hz, 2H), 2.11 (d, J = 1.2 Hz, 3H), 1.99–1.85 (m, 4H); 13C{1H} NMR (CDCl3, 100 MHz) δ 165.8, 144.7, 137.1, 133.4, 128.6, 127.2, 126.9, 120.6, 47.1, 45.6, 26.3, 24.4, 20.8; HRMS (ESI) calcd for C16H19NNaO [M+Na]+ 264.1359, found 264.1367. (2E,4E)-3,5-Diphenyl-1-(pyrrolidin-1-yl)penta-2,4-dien-1-one (4ga) The stereochemistry of the title compound was determined by comparing the 1H NMR spectra of 4ga and (2E,4E)-N,N-diethyl3,5-diphenylpenta-2,4-dienamide.5 Colorless oil; 28.3 mg, 0.0932 mmol, 47% isolated yield; 1H NMR (CDCl3, 400 MHz) δ 8.43 (dd, J = 16.3, 0.8 Hz, 1H), 7.47–7.36 (m, 7H), 7.31–7.27 (m, 2H), 7.25–7.21 (m, 1H), 6.52 (d, J = 16.3 Hz, 1H), 5.96 (s, 1H), 3.61


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(t, J = 6.8 Hz, 2H), 3.52 (t, J = 6.7 Hz, 2H), 2.01–1.87 (m, 4H); 13C{1H} NMR (CDCl3, 100 MHz) δ 165.4, 151.0, 140.8, 137.7, 137.0, 129.1, 128.5, 128.3, 128.2, 128.1, 127.4, 126.6, 120.7, 47.2, 45.8, 26.3, 24.4; HRMS (ESI) calcd for C21H21NNaO [M+Na]+ 326.1515, found 326.1525. (2Z,4E)-2,3-Dimethyl-5-phenyl-1-(pyrrolidin-1-yl)penta-2,4-dien-1-one (4ha) The stereochemistry of the title compound was determined by comparing the 1H NMR spectra of 4ha and (2Z,4E)-N,N-diethyl2,3-dimethyl-5-phenylpenta-2,4-dienamide.5 Colorless oil; 24.0 mg, 0.0940 mmol, 47% isolated yield; 1H NMR (CDCl3, 400 MHz) δ 7.37–7.35 (m, 2H), 7.32–7.28 (m, 2H), 7.23–7.19 (m, 1H), 6.84 (d, J = 15.9 Hz, 1H), 6.59 (d, J = 16.0 Hz, 1H), 3.60 (t, J = 6.8 Hz, 2H), 3.28 (t, J = 6.5 Hz, 2H), 2.00 (s, 3H), 1.96–1.83 (m, 4H), 1.92 (d, J = 0.9 Hz, 3H); 13C{1H} NMR (CDCl3, 100 MHz) δ 171.5, 137.5, 132.9, 128.9, 128.6, 128.0, 127.5, 126.5, 47.3, 45.1, 25.9, 24.6, 16.3, 13.2; HRMS (ESI) calcd for C17H21NNaO [M+Na]+ 278.1515, found 278.1521. (E)-Pyrrolidin-1-yl(2-styrylcyclohex-1-en-1-yl)methanone (4ia) Colorless oil; 35.8 mg, 0.127 mmol, 64% isolated yield; 1H NMR (CDCl3, 400 MHz) δ 7.37–7.35 (m, 2H), 7.31–7.28 (m, 2H), 7.23–7.19 (m, 1H), 6.80 (d, J = 16.0 Hz, 1H), 6.58 (d, J = 16.0 Hz, 1H), 3.60 (t, J = 6.8 Hz, 2H), 3.31 (t, J = 6.5 Hz, 2H), 2.34 (br, 4H), 1.96–1.83 (m, 4H), 1.74–1.73 (m, 4H); 13C{1H} NMR (CDCl3, 100 MHz) δ 171.1, 137.6, 135.8, 131.0, 128.6, 128.0, 127.4, 127.2, 126.5, 47.4, 45.1, 27.2, 25.9, 24.6, 24.4, 22.2, 22.1; HRMS (ESI) calcd for C19H23NNaO [M+Na]+ 304.1672, found 304.1668. (2Z,4E)-5-Phenyl-1-(pyrrolidin-1-yl)penta-2,4-dien-1-one (4ja) The stereochemistry of the title compound was determined by the coupling constants of vinyl protons. Colorless oil; 10.3 mg, 0.0453 mmol, 23% isolated yield; 1H NMR (CDCl3, 400 MHz) δ 8.18 (ddd, J = 15.8, 11.2, 0.9 Hz, 1H), 7.52–7.50 (m, 2H), 7.33– 7.29 (m, 2H), 7.27–7.23 (m, 1H), 6.74 (d, J = 15.8 Hz, 1H), 6.59 (t, J = 11.3 Hz, 1H), 5.95 (d, J = 11.3 Hz, 1H), 3.57 (t, J = 6.8 Hz, 2H), 3.51 (t, J = 6.7 Hz, 2H), 2.01–1.88 (m, 4H); 13C{1H } NMR (CDCl3, 100 MHz) δ 165.5, 140.6, 139.3, 136.8, 128.6, 128.5, 127.4, 125.8, 119.4, 47.0, 45.6, 26.3, 24.4; HRMS (ESI) calcd for C15H17NNaO [M+Na]+ 250.1202, found 250.1191. (2Z,4E)-2-Methyl-1-(pyrrolidin-1-yl)-5-(p-tolyl)penta-2,4-dien-1-one (4ab) The stereochemistry of the title compound was determined by comparing the 1H NMR spectra of 4ab and 4aa. Colorless oil; 31.8 mg, 0.125 mmol, 62% isolated yield; 1H NMR (CDCl3, 400 MHz) δ 7.26–7.24 (m, 2H), 7.11 (d, J = 8.0 Hz, 2H), 6.62 (dd, J = 15.5, 10.7 Hz, 1H), 6.52 (d, J = 15.6 Hz, 1H), 6.11 (dq, J = 10.7, 1.5 Hz, 1H), 3.60 (t, J = 6.8 Hz, 2H), 3.35 (d, J = 6.5 Hz, 2H), 2.23 (s, 3H), 2.01 (d, J = 1.2 Hz, 3H), 1.97–1.88 (m, 4H); 13C{1H} NMR (CDCl3, 100 MHz) δ 170.2, 137.7, 134.8, 134.3, 133.4, 129.4, 128.4, 126.4, 124.0, 47.4, 45.2, 26.0, 24.6, 21.2, 20.3; HRMS (ESI) calcd for C17H21NNaO [M+Na]+ 278.1515, found 278.1506. (2Z,4E)-2-Methyl-1-(pyrrolidin-1-yl)-5-[4-(trifluoromethyl)phenyl]penta-2,4-dien-1-one (4ac) The stereochemistry of the title compound was determined by comparing the 1H NMR spectra of 4ac and 4aa. Colorless solid; 38.7 mg, 0.125 mmol, 63% isolated yield; Mp 94.8–96.2 °C; 1H NMR (CDCl3, 400 MHz) δ 7.54 (d, J = 8.2 Hz, 2H), 7.44 (d, J =


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8.3 Hz, 2H), 6.75 (dd, J = 15.6, 11.0 Hz, 1H), 6.56 (d, J = 15.6 Hz, 1H), 6.14 (dq, J = 11.0, 1.1 Hz, 1H), 3.61 (t, J = 6.8 Hz, 2H), 3.35 (d, J = 6.5 Hz, 2H), 2.05 (d, J = 1.0 Hz, 3H), 1.99–1.87 (m, 4H); 13C{1H} NMR (CDCl3, 100 MHz) δ 169.8, 140.5 (q, J = 1.5 Hz), 137.5, 131.7 (q, J = 0.6 Hz), 129.4 (q, J = 32.4 Hz), 127.7, 127.3, 126.6, 125.6 (q, J = 3.9 Hz), 124.2 (q, J = 271.8 Hz), 47.4, 45.2, 26.0, 24.5, 20.4; HRMS (ESI) calcd for C17H18F3NNaO [M+Na]+ 332.1233, found 332.1261. Methyl 3-[(1E,3Z)-4-methyl-5-oxo-5-(pyrrolidin-1-yl)penta-1,3-dien-1-yl]benzoate (4ad) The stereochemistry of the title compound was determined by comparing the 1H NMR spectra of 4ad and 4aa. Colorless oil; 30.2 mg, 0.101 mmol, 50% isolated yield; 1H NMR (CDCl3, 400 MHz) δ 8.00 (s, 1H), 7.89 (d, J = 7.7 Hz, 1H), 7.54 (d, J = 7.8 Hz, 1H), 7.37 (t, J = 7.7 Hz, 1H), 6.73 (dd, J = 15.5, 10.9, 1H), 6.57 (d, J = 15.6 Hz, 1H), 6.14 (dq, J = 10.9, 1.2 Hz, 1H), 3.92 (s, 3H), 3.62 (t, J = 6.7 Hz, 2H), 3.36 (t, J = 6.5 Hz, 2H), 2.04 (d, J = 0.8 Hz, 3H), 1.99–1.87 (m, 4H); 13C{1H} NMR (CDCl3, 100 MHz) δ 169.9, 166.9, 137.4, 136.5, 132.3, 130.63, 130.56, 128.7, 127.9, 127.7, 126.0, 52.2, 47.4, 45.2, 26.0, 24.6, 20.4; HRMS (ESI) calcd for C18H21NNaO3 [M+Na]+ 322.1414, found 322.1408. (2Z,4E)-5-(2-Methoxyphenyl)-2-methyl-1-(pyrrolidin-1-yl)penta-2,4-dien-1-one (4ae) The stereochemistry of the title compound was determined by comparing the 1H NMR spectra of 4ae and 4aa. Colorless oil; 25.3 mg, 0.0932 mmol, 47% isolated yield; 1H NMR (CDCl3, 400 MHz) δ 7.40 (dd, J = 7.6, 1.5 Hz, 1H), 7.23–7.18 (m, 1H), 6.92– 6.84 (m, 3H), 6.70 (dd, J = 15.7, 11.0 Hz, 1H), 6.16 (dd, J = 11.0, 1.0 Hz, 1H), 3.84 (s, 3H), 3.59 (t, J = 6.8 Hz, 2H), 3.36 (t, J = 6.5 Hz, 2H), 2.01 (s, 3H), 1.96–1.84 (m, 4H); 13C{1H} NMR (CDCl3, 100 MHz) δ 170.3, 156.9, 134.7, 129.0, 128.8, 128.3, 126.7, 126.1, 125.6, 120.7, 110.9, 55.5, 47.4, 45.2, 26.0, 24.6, 20.3; HRMS (ESI) calcd for C17H21NNaO2 [M+Na]+ 294.1465, found 294.1478. (2Z,4E)-5-(2-Chlorophenyl)-2-methyl-1-(pyrrolidin-1-yl)penta-2,4-dien-1-one (4af) The stereochemistry of the title compound was determined by comparing the 1H NMR spectra of 4af and 4aa. Colorless oil; 34.5 mg, 0.125 mmol, 63% isolated yield; 1H NMR (CDCl3, 400 MHz) δ 7.50 (dd, J = 7.6, 1.8 Hz, 1H), 7.34 (dd, J = 7.7, 1.6 Hz, 1H), 7.22–7.18 (m, 2H), 6.94 (d, J = 15.5 Hz, 1H), 6.66 (dd, J = 15.5, 11.1 Hz, 1H), 6.20 (dq, J = 11.1, 0.9 Hz, 1H), 3.59 (t, J = 6.7 Hz, 2H), 3.36 (t, J = 6.4 Hz, 2H), 2.04 (s, 3H), 1.97–1.86 (m, 4H); 13C{1H} NMR (CDCl3, 100 MHz) δ 170.0, 136.8, 135.1, 133.3, 129.8, 129.2, 128.6, 128.2, 127.3, 126.9, 126.6, 47.4, 45.2, 26.0, 24.5, 20.3; HRMS (ESI) calcd for C16H18NNaOCl [M+Na]+ 298.0969, found 298.0972. Butyl (2E,4Z and 2Z,4E)-5-methyl-6-oxo-6-(pyrrolidin-1-yl)hexa-2,4-dienoate (4ag) The title compounds were isolated as a mixture of (2E,4Z)-4ag and (2Z,4E)-4ag [(2E,4Z)-4ag/(2Z,4E)-4ag = 93:7]. The stereochemistries of (2E,4Z)-4ag was determined by comparing the 1H NMR spectra of (2E,4Z)-4ag and butyl (2E,4Z)-6-(diethylamino)5-methyl-6-oxohexa-2,4-dienoate.6 The stereochemistries of (2Z,4E)-4ag was determined by comparing the 1H NMR spectra of (2Z,4E)-4ag and dibutyl and (2E,4Z)-2-methylhexa-2,4-dienedioate.5 Yellow oil; 44.8 mg, 0.169 mmol, 84% isolated yield; 1H NMR (CDCl3, 400 MHz) of (2E,4Z)-4ag: δ 7.18 (dd, J = 15.2, 11.7 Hz, 1H), 6.09 (dq, J = 11.7, 0.8 Hz, 1H), 5.88 (d, J = 15.3 Hz,


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1H), 4.13 (q, J = 6.6 Hz, 2H), 3.57 (t, J = 6.7 Hz, 2H), 3.29 (t, J = 6.4 Hz, 2H), 2.05 (s, 3H), 1.98–1.88 (m, 4H), 1.67–1.60 (m, 2H), 1.47–1.34 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H); 1H NMR (CDCl3, 400 MHz) of (2Z,4E)-4ag: δ 7.32 (d, J = 11.9 Hz, 1H), 6.52 (t, J = 11.7 Hz, 1H), 5.66 (d, J = 11.5 Hz, 1H), 4.13 (q, J = 6.6 Hz, 2H), 3.59–3.54 (m, 2H), 3.31–3.27 (m, 2H), 2.06 (s, 3H), 1.98–1.88 (m, 4H), 1.67–1.60 (m, 2H), 1.47–1.34 (m, 2H), 0.95 (t, J = 7.3 Hz, 3H); 13C{1H} NMR (CDCl3, 100 MHz) δ 168.8, 166.7, 143.8, 139.9, 139.7, 125.5, 123.5, 122.4, 118.5, 64.3, 64.0, 47.5, 47.4, 45.23, 45.2, 30.7, 25.9, 24.4, 20.7, 20.6, 19.2, 13.7; HRMS (ESI) calcd for C15H23NnaO3 [M+Na]+ 288.1570, found 288.1559. (2Z,4E and 2Z,4Z)-2,6,6-Trimethyl-1-(pyrrolidin-1-yl)hepta-2,4-dien-1-one (4ah) The title compounds were isolated as a mixture of (2Z,4E)-4ah and (2Z,4Z)-4ah [(2Z,4E)-4ah/(2Z,4Z)-4ah = 90:10]. The stereochemistries of the title compounds were determined by the NOESY experiment and the coupling constants of vinyl protons. Colorless oil; 19.6 mg, 0.0886 mmol, 44% isolated yield; 1H NMR (CDCl3, 400 MHz) of (2Z,4E)-4ah: δ 5.93–5.82 (m, 2H), 5.73 (d, J = 14.7 Hz, 1H), 3.55 (t, J = 6.7 Hz, 2H), 3.32 (t, J = 6.6 Hz, 2H), 1.93 (d, J = 1.1 Hz, 3H), 1.91–1.87 (m, 4H), 1.00 (s, 9H); 1H NMR (CDCl3, 400 MHz) of (2Z,4Z)-4ah: δ 6.43 (d, J = 12.0 Hz, 1H), 5.70 (t, J = 12.0 Hz, 1H), 5.39 (d, J = 12.0 Hz, 1H), 3.57–3.51 (m, 4H), 1.97 (t, J = 1.5 Hz, 3H), 1.91–1.87 (m, 4H), 1.16 (s, 9H); 13C{1H} NMR (CDCl3, 100 MHz) δ 170.5, 147.1, 132.5, 128.5, 123.7, 121.3, 47.2, 47.0, 45.1, 33.2, 31.5, 29.5, 26.0, 24.6, 20.0; HRMS (ESI) calcd for C14H23NNaO [M+Na]+ 244.1672, found 244.1668. (2Z,4E and

2Z,4Z)-2-Methyl-5-phenyl-1-(pyrrolidin-1-yl)hexa-2,4-dien-1-one

(4ai)

and

(Z)-2-methyl-5-phenyl-1-

(pyrrolidin-1-yl)hexa-2,5-dien-1-one (4ai’) The title compounds were isolated as a mixture of (2Z,4E)-4ai, (2Z,4Z)-4ai, and (2Z)-4ai’ [(2Z,4E)-4ai/(2Z,4Z)-4ai/(2Z)-4ai’ = 64:19:17]. The stereochemistry of (2Z,4E)-4ai was determined by comparing the 1H NMR spectra of (2Z,4E)-4ai and methyl (2E,4E)-2-methyl-5-phenylhexa-2,4-dienoate.4 The stereochemistries of (2Z,4Z)-4ai and (2Z)-4ai’ were determined by the NOESY experiments. Colorless oil; 16.0 mg, 0.0627 mmol, 31% isolated yield; 1H NMR (CDCl3, 400 MHz) of (2Z,4E)-4ai: δ 7.42–7.21 (m, 5H), 6.38–6.31 (m, 2H), 3.56 (t, J = 6.9 Hz, 2H), 3.35 (t, J = 6.7 Hz, 2H), 2.17 (s, 3H), 2.05 (s, 3H), 1.95–1.85 (m, 4H); (2Z,4Z)4ai: δ 7.42–7.21 (m, 5H), 6.04–5.95 (m, 2H), 3.60–3.50 (m, 2H), 3.40–3.28 (m, 2H), 2.10 (s, 3H), 1.95–1.85 (m, 7H); (2Z)-4ai’: δ 7.42–7.21 (m, 5H), 5.48–5.44 (m, 1H), 5.33 (d, J = 1.0 Hz, 1H), 5.08 (q, J = 1.4 Hz, 1H), 3.60–3.50 (m, 2H), 3.40–3.28 (m, 2H), 3.20 (d, J = 7.4 Hz, 2H), 1.95–1.85 (m, 7H); 13C{1H} NMR (CDCl3, 100 MHz) δ 170.4, 143.1, 140.1, 137.3, 135.3, 133.7, 128.34, 128.30, 128.1, 127.6, 127.2, 127.1, 126.0, 125.8, 125.6, 125.1, 124.4, 122.9, 122.7, 112.8, 71.7, 47.3, 47.0, 45.1, 45.0, 35.0, 26.0, 25.9, 25.7, 24.6, 24.5, 24.5, 21.3, 20.6, 20.1, 19.9, 16.0; HRMS (ESI) calcd for C17H21NNaO [M+Na]+ 278.1515, found 278.1527. (2Z,4E and 2Z,4Z)-2,4-Dimethyl-5-phenyl-1-(pyrrolidin-1-yl)penta-2,4-dien-1-one (4aj) The title compounds were isolated as a mixture of (2Z,4E)-4aj and (2Z,4Z)-4aj [(2Z,4E)-4aj/(2Z,4Z)-4aj = 85:15]. The stereochemistries of the title compounds was determined by the NOESY experiments. Colorless oil; 7.6 mg, 0.030 mmol, 15% isolated yield; 1H NMR (CDCl3, 400 MHz) of (2Z,4E)-4aj: δ 7.35–7.30 (m, 2H), 7.25–7.19 (m, 3H), 6.52 (s, 1H), 6.02 (s, 1H), 3.49 (t, J = 6.9 Hz, 2H), 3.37 (t, J = 6.7 Hz, 2H), 2.02 (d, J = 1.4 Hz, 3H), 1.94 (d, J = 1.3 Hz, 3H), 1.94–1.87 (m, 4H); (2Z,4Z)-4aj: δ 7.35–


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7.19 (m, 5H), 6.40 (s, 1H), 6.32 (s, 1H), 3.54–3.48 (m, 2H), 3.43–3.35 (m, 2H), 2.00 (d, J = 1.5 Hz, 3H), 1.97 (d, J = 1.4 Hz, 3H), 1.94–1.87 (m, 4H); 13C{1H} NMR (CDCl3, 100 MHz) δ 171.0, 137.6, 137.5, 134.4, 134.2, 133.5, 132.4, 132.1, 131.5, 130.7, 129.6, 129.3, 129.2, 128.3, 128.1, 126.81, 126.75, 126.68, 47.2, 47.1, 45.3, 45.1, 25.95, 25.90, 24.53, 24.47, 22.02, 21.98, 21.92, 15.6; HRMS (ESI) calcd for C17H21NNaO [M+Na]+ 278.1515, found 278.1525. DKIE measured by two parallel reactions using [Cp*RhCl2]2 (Scheme 5b). Reaction using 4ga: The reaction was carried out following the general procedure using AgSbF6 (6.8 mg, 0.020 mmol), [Cp*RhCl2]2 (3.1 mg, 0.0050 mmol), Cu(OAc)2•H2O (4.0 mg, 0.020 mmol), 2g (20.1 mg, 0.100 mmol), 3a (31.2 mg, 0.300 mmol), and (CH2Cl)2 (0.5 mL) at 80 °C for 2 hours, which furnished 4ga (3.9 mg, 0.013 mmol, 13% yield). Reaction using 4ga-d5: The reaction was carried out following the general procedure using AgSbF6 (6.8 mg, 0.020 mmol), [Cp*RhCl2]2 (3.1 mg, 0.0050 mmol), Cu(OAc)2•H2O (4.0 mg, 0.020 mmol), 2g-d6 (20.7 mg, 0.100 mmol), 3a (31.2 mg, 0.300 mmol), and (CH2Cl)2 (0.5 mL) at 80 °C for 2 hours, which furnished 4ga-d5 (0.6 mg, 0.002 mmol, 2% yield). No significant deuterium incorporation was observed in the recovered 2g-d6 (19.3 mg, 0.0918 mmol, 92% recovery). DKIE measured by two parallel reactions using [CpERhCl2]2 (Scheme 5b). Reaction using 4ga: The reaction was carried out following the general procedure using AgSbF6 (6.8 mg, 0.020 mmol), [CpERhCl2]2 (4.3 mg, 0.0050 mmol), Cu(OAc)2•H2O (4.0 mg, 0.020 mmol), 2g (20.1 mg, 0.100 mmol), 3a (31.2 mg, 0.300 mmol), and (CH2Cl)2 (0.5 mL) at 80 °C for 2 hours, which furnished 4ga (7.0 mg, 0.023 mmol, 23% yield). Reaction using 4ga-d5: The reaction was carried out following the general procedure using AgSbF6 (6.8 mg, 0.020 mmol), [CpERhCl2]2 (4.3 mg, 0.0050 mmol), Cu(OAc)2•H2O (4.0 mg, 0.020 mmol), 2g-d6 (20.7 mg, 0.100 mmol), 3a (31.2 mg, 0.300 mmol), and (CH2Cl)2 (0.5 mL) at 80 °C for 2 hours, which furnished 4ga-d5 (6.51 mg, 0.0211 mmol, 21% yield). No significant deuterium incorporation was observed in the recovered 2g-d6 (14.9 mg, 0.0721 mmol, 72% recovery). DKIE measured by intermolecular competition reaction using [Cp*RhCl2]2 (Scheme 5c): The reaction was carried out following the general procedure using AgSbF6 (6.8 mg, 0.020 mmol), complex [Cp*RhCl2]2 (3.1 mg, 0.0050 mmol), Cu(OAc)2•H2O (4.0 mg, 0.020 mmol), 2g (10.1 mg, 0.0500 mmol), 2g-d6 (10.4 mg, 0.0500 mmol), 3a (31.2 mg, 0.300 mmol), and (CH2Cl)2 (0.5 mL) at 80 °C for 2 hours, which furnished a mixture of 4ga and 4ga-d5 (3.4 mg, 0.011 mmol, 11% yield, 4ga/4ga-d5 = 87:13). DKIE measured by intermolecular competition reaction using [CpERhCl2]2 (Scheme 5c): The reaction was carried out following the general procedure using AgSbF6 (6.8 mg, 0.020 mmol), complex [CpERhCl2]2 (4.3 mg, 0.0050 mmol), Cu(OAc)2•H2O (4.0 mg, 0.020 mmol), 2g (10.1 mg, 0.0500 mmol), 2g-d6 (10.4 mg, 0.0500 mmol), 3a (31.2 mg, 0.300 mmol), and (CH2Cl)2 (0.5 mL) at 80 °C for 2 hours, which furnished a mixture of 4ga and 4ga-d5 (6.5 mg, 0.021 mmol, 21% yield, 4ga/4ga-d5 = 78:22). Reduction of 4aa (Scheme 6): To a solution of LiAlH4 (15.2 mg, 0.400 mmol) in THF (1.0 mL) was added 4aa (48.3 mg, 0.200 mmol) and THF (1.0 mL), and the mixture was stirred at 60 °C using an oil bath for 4 hours. The reaction was quenched with H2O and 2N NaOH, and extracted with CH2Cl2. The combined organic layer was dried over Na2SO4 and concentrated. The residue was purified by a preparative TLC (CHCl3/MeOH = 10:1) to give 5aa (38.6 mg, 0.170 mmol, 85% yield) as a colorless oil. 1-[(2Z,4E and 2E,4E)-2-methyl-5-phenylpenta-2,4-dien-1-yl]pyrrolidine (5aa)


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The Journal of Organic Chemistry The title compounds were isolated as a mixture of (2Z,4Z)-5aa and (2E,4E)-5aa [(2Z,4E)-5aa/(2E,4E)-5aa = 80:20]. The stere-

ochemistries of the title compounds were determined by the NOESY experiment and the coupling constants of vinyl protons; 1H NMR (CDCl3, 400 MHz) of (2Z,4E)-5aa: δ 7.41–7.38 (m, 2H), 7.33–7.28 (m, 2H), 7.21–7.14 (m, 2H), 6.45 (d, J = 15.5 Hz, 1H), 6.11 (d, J = 11.0 Hz, 1H), 3.26 (s, 2H), 2.50–2.45 (m, 4H), 1.93 (s, 3H), 1.82–1.76 (m, 4H); 1H NMR (CDCl3, 400 MHz) of (2E,4E)-5aa: δ 7.41–7.38 (m, 2H), 7.33–7.28 (m, 2H), 7.21–7.14 (m, 1H), 7.03 (dd, J = 15.5, 11.0 Hz, 1H), 6.50 (d, J = 15.7 Hz, 1H), 6.16 (d, J = 11.1 Hz, 1H), 3.07 (s, 2H), 2.50–2.45 (m, 4H), 1.92 (s, 3H), 1.82–1.76 (m, 4H); 13C{1H} NMR (CDCl3, 100 MHz) δ 138.0, 137.94, 137.93, 137.88, 131.2, 130.8, 129.1, 128.6, 128.20, 128.15, 127.15, 127.13, 126.4, 126.2, 125.3, 124.9, 65.1, 57.0, 54.35, 54.27, 23.59, 23.57, 23.55, 16.1; HRMS (ESI) calcd for C16H22N [M+I]+ 228.1747, found 1228.1761.

ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website. 1

H and 13C NMR spectra. (PDF).

AUTHOR INFORMATION Corresponding Authors * E-mail: [email protected] * E-mail: [email protected]

Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT This work was supported partly by a Grant-in-Aid for Scientific Research for Young Scientists (No. 17K14481) from JSPS (Japan). We thank Umicore for generous support in supplying RhCl3·nH2O.

REFERENCES (1) For reviews, see: (a) Negishi, E.-I. Magical Power of Transition Metals: Past, Present, and Future (Nobel Lecture). Angew. Chem. Int. Ed. 2011, 50, 6738–6764. (b) Negishi, E.-I.; Huang, Z.; Wang, G.; Mohan, S.; WANG, C.; Hattori, H. Recent Advances in Efficient and Selective Synthesis of Di-, Tri-, and Tetrasubstituted Alkenes via Pd-Catalyzed Alkenylation-Carbonyl Olefination Synergy. Acc. Chem. Res., 2008, 41, 1474–1485. (c) Cereghetti, D. M.; Carreira, E. M. Amphotericin B: 50 Years of Chemistry and Biochemistry. Synthesis 2006, 914–942. (d) Luh, T.-Y.; Wong, K.-T. Silyl-Substituted Conjugated Dienes: Versatile Building Blocks in Organic Synthesis. Synthesis 1993, 349–370. (2) For reviews, see: (a) Liu, C.; Yuan, J.; Gao, M.; Tang, S.; Li, W.; Shi, R.; Lei, A. Oxidative Coupling between Two Hydrocarbons: An Update of Recent C−H Functionalizations. Chem. Rev. 2015, 115, 12138−12204. (b) Shang, X.; Liu, Z.-Q. Transition Metal-Catalyzed Cvinyl–Cvinyl Bond Formation via Double Cvinyl–H Bond Activation. Chem. Soc. Rev., 2013, 42, 3253-3260.


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(3) For selected examples of the oxidative cross-coupling of two alkenes giving (1Z,3E)-butadienes, initiated by vinylic C-H bond cleavage, see: (a) Mochida, S.; Hirano, K.; Satoh, T.; Miura, M. Rhodium-Catalyzed Regioselective Olefination Directed by a Carboxylic Group. J. Org. Chem. 2011, 76, 3024-3033. (b) Hu, X.-H.; Zhang, J.; Yang, X.-F.; Xu, Y.-H.; Loh, T.-P. Stereo- and Chemoselective Cross-Coupling between Two Electron-Deficient Acrylates: An Efficient Route to (Z,E)-Muconate Derivatives. J. Am. Chem. Soc. 2015, 137, 3169-3172. (4) The oxidative cross-coupling of two alkenes giving (1E,3E)-butadienes, initiated by oxymetallation of alkenes, has also been reported. See: Xu, Y.-H.; Lu, J.; Loh, T.-P. Direct Cross-Coupling Reaction of Simple Alkenes with Acrylates Catalyzed by Palladium Catalyst. J. Am. Chem. Soc. 2009, 131, 1372-1373. (5) Besset, T.; Kuhl, N.; Patureau, F. W.; Glorius, F. RhIII-Catalyzed Oxidative Olefination of Vinylic C–H Bonds: Efficient and Selective Access to Di-unsaturated a-Amino Acid Derivatives and Other Linear 1,3-Butadienes. Chem. - Eur. J. 2011, 17, 7167–7171. (6) Zhang, J.; Loh, T.-P. Ruthenium- and Rhodium-Catalyzed Cross-Coupling Reaction of Acrylamides with Alkenes: Efficient Access to (Z,E)Dienamides. Chem. Commun., 2012, 48, 11232–11234. (7) Xue, X.; Xu, J.; Zhang, L.; Xu, C.; Pan, Y.; Xu, L.; Li, H.; Zhang, W. Rhodium(III)-Catalyzed Direct C-H Olefination of Arenes with Aliphatic Olefins. Adv. Synth. Catal. 2016, 358, 573-583. (8) Li, F.; Yu, C.; Zhang, J.; Zhong, G. Weinreb Amide Directed Cross-Coupling Reaction between Electron-Deficient Alkenes Catalyzed by a Rhodium Catalyst. Org. Biomol. Chem., 2017, 15, 1236–1244. (9) Kwon, K.-H.; Lee, D. W.; Yi, C. S. Scope and Mechanistic Study of the Coupling Reaction of α,β Unsaturated Carbonyl Compounds with Alkenes: Uncovering Electronic Effects on Alkene Insertion vs Oxidative Coupling Pathways. Organometallics 2012, 31, 495−504. (10) Yu, C.; Li, F.; Zhang, J.; Zhong, G. A Direct Cross-Coupling Reaction of Electron-Deficient Alkenes Using an Oxidizing Directing Group. Chem. Commun., 2017, 53, 533−536. (11) A single example of the low-temperature (80 °C) oxidative cross-coupling reaction of a methacrylamide with an acrylate has been reported by using a Weinreb Amide directing group, an excess amount of oxidant (AgOAc), and a cationic Cp*Co(III) catalyst. See: Kawai, K.; Bunno, Y.; Yoshino, T.; Matsunaga, S. Weinreb Amide Directed Versatile C-H Bond Functionalization under (h5-Pentamethylcyclopentadienyl)cobalt(III) Catalysis. Chem.-Eur. J. 2018, 24, 10231-10237. (12) (a) Shibata, Y.; Tanaka, K. Catalytic [2+2+1] Cross-Cyclotrimerization of Silylacetylenes and Two Alkynyl Esters To Produce Substituted Silylfulvenes. Angew. Chem., Int. Ed. 2011, 50, 10917-10921. (b) Hoshino, Y.; Shibata, Y.; Tanaka, K. Oxidative Annulation of Anilides with Internal Alkynes Using an (Electron-Deficient η5-Cyclopentadienyl)Rhodium(III) Catalyst Under Ambient Conditions. Adv. Synth. Catal. 2014, 356, 1577-1585. (c) Fukui, M.; Hoshino, Y.; Satoh, T.; Miura, M.; Tanaka, K. The Oxidative Annulation of Tertiary Benzyl Alcohols with Internal Alkynes Using an (Electron-Deficient η5-Cyclopentadienyl)rhodium(III) Catalyst under Ambient Conditions. Adv. Synth. Catal. 2014, 356, 16381644. (d) Takahama, Y.; Shibata, Y.; Tanaka, K. Oxidative Olefination of Anilides with Unactivated Alkenes Catalyzed by an (Electron-Deficient η5-Cyclopentadienyl)Rhodium(III) Complex Under Ambient Conditions. Chem.-Eur. J. 2015, 21, 9053-9056. (e) Fukui, M.; Shibata, Y.; Hoshino, Y.; Sugiyama, H.; Teraoka, K.; Uekusa, H.; Noguchi, K.; Tanaka, K. Rhodium(III)-Catalyzed Tandem [2+2+2] Annulation-Lactamization of Anilides with Two Alkynoates via Cleavage of Two Adjacent C-H or C-H/C-O bonds. Chem.-Asian J. 2016, 11, 2260-2264. (f) Kudo, E.; Shibata, Y.; Yamazaki, M.; Masutomi, K.; Miyauchi, Y.; Fukui, M.; Sugiyama, H.; Uekusa, H.; Satoh, T.; Miura, M.; Tanaka, K. Oxidative Annulation of Arenecarboxylic and Acrylic Acids with Alkynes Under Ambient Conditions Catalyzed by an Electron-Deficient Rhodium(III) Complex. Chem.Eur. J. 2016, 22, 14190-14194. (g) Takahama, Y.; Shibata, Y.; Tanaka, K. Heteroarene-Directed Oxidative sp2 C-H Bond Allylation with Aliphatic Alkenes Catalyzed by an (Electron-Deficient η5-Cyclopentadienyl)rhodium(III) Complex. Org. Lett. 2016, 18, 2934-2937.


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The Journal of Organic Chemistry (13) (a) Yoshizaki, S.; Shibata, Y.; Tanaka, K. Fulvene Synthesis by Rhodium(I)-Catalyzed [2+2+1] Cycloaddition: Synthesis and Catalytic Ac-

tivity of Tunable Cyclopentadienyl Rhodium(III) Complexes with Pendant Amides. Angew. Chem., Int. Ed. 2017, 56, 3590-3593. (b) Yamada, T.; Shibata, Y.; Kawauchi, S.; Yoshizaki, S.; Tanaka, K. Formal Lossen Rearrangement/[3+2] Annulation Cascade Catalyzed by a Modified Cyclopentadienyl RhIII Complex. Chem.-Eur. J. 2018, 24, 5723-5727. (c) Yoshimura, R.; Shibata, Y.; Yamada, T.; Tanaka, K. Aerobic Oxidative Olefination of Benzamides with Styrenes Catalyzed by a Moderately Electron-Deficient CpRh(III) Complex with a Pendant Amide. J. Org. Chem. 2019, 84, 2501-2511. (14) For recent reviews of modified CpRh(III)-catalyzed C-H functionalization reactions, see: (a) Piou, T.; Rovis, T. Electronic and Steric Tuning of a Prototypical Piano Stool Complex: Rh(III) Catalysis for C–H Functionalization. Acc. Chem. Res. 2018, 51, 170-180. (b) Loginov, D. A.; Konoplev, V. E. Oxidative Coupling of Benzoic Acids with Alkynes: Catalyst Design and Selectivity. J. Organomet. Chem. 2018, 867, 14-24. (15) Recently, the efficient aryl C-H olefination with electron-rich alkenes has been achieved by using electron-deficient CpRh(III) complexes as catalysts. See: Lin, W.; Li, W.; Lu, D.; Su, F.; Wen, T.-B.; Zhang, H.-J. Dual Effects of Cyclopentadienyl Ligands on Rh(III)-Catalyzed Dehydrogenative Arylation of Electron-Rich Alkenes. ACS Catal. 2018, 8, 8070-8076. (16) In the reaction of less polar methacrylamide 2b with 3a, homo-coupling products were isolated in 6% yield as a mixture of diastereomers. In the optimization study (Table 1), increasing the amount of 3a increased the yield of 4aa (entry 16) presumably due to the suppression of the homo-coupling of 2a. On the contrary, more electron-deficient nature of acrylate 3g than acrylamide 2a may suppress the homo-coupling of 2a and accelerate the cross-coupling of 2a with 3g, which accounts for the observed high yield of 4ag.

(17) This low product yield is presumably due to the rapid homo-coupling of 2i. (18) The reaction of 2a with primary aliphatic alkene 3i afforded allylation product 5ai as a major product, and inseparable mixtures of olefination products 4ai and 6ai as minor products.

(19) The formation of diastereomeric mixture may be caused by the E/Z isomerization of the product via addition of rhodium hydride to the diene and β-elimination. See: Arthurs, M.; Sloan, M.; Drew, M. G. B.; Nelson, S. M. Transition Metal-Diene Complexes. II. Isomerization of Rhodium-Complexed Penta-1,4- and cis-Penta-1,3-dienes J. Chem. Soc., Dalton Trans. 1975, 1794-802. (20) The reactions of 2a with α-(trifluoromethyl)styrene (3l) in the presence of CpE and CpARh catalysts were examined; however, the yields of 4al were low.


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(21) Simmons, E. M.; Hartwig, J. F. On the Interpretation of Deuterium Kinetic Isotope Effects in C-H Bond Functionalizations by TransitionMetal Complexes. Angew. Chem., Int. Ed. 2012, 51, 3066-3072. (22) Weber, F.; Brückner, R. Asymmetric Dihydroxylation of Esters and Amides of Methacrylic, Tiglic, andAngelic Acid: No Exception to the Sharpless Mnemonic!. Eur. J. Org. Chem. 2015, 2428-2449. (23) Nishio, T.; Iseki, K.; Araki, N.; Miyazaki, T. Synthesis of Indolones via Radical Cyclization of N-(2-Halogenoalkanoyl)-Substituted Anilines. Helv. Chim. Acta 2005, 88, 35-41. (24) Li, L.-H.; Niu, Z.-J. Lia, Y.-X.; Liang, Y.-M. Transition-Metal-Free Multinitrogenation of Amides by C–C Bond Cleavage: a New Approach to Tetrazoles. Chem. Commun., 2018, 54, 11148-11151. (25) Kim, M.; Sharma, S.; Mishra, N. K.; Han, S.; Park, J.; Kim, M.; Shin, Y.; Kwak, J. H.; Han S. H.; Kim, I. S. Direct Allylation of Aromatic and a,b-Unsaturated Carboxamides under Ruthenium Catalysis. Chem. Commun., 2014, 50, 11303-11306. (26) Svejstrup, T. D.; Zawodny, W.; Douglas, J. J.; Bidgeli, D.; Sheikhc, N. S.; Leonori, D. Visible-Light-mediated generation of nitrile oxides for the photoredox synthesis of isoxazolines and isoxazoles. Chem. Commun., 2016, 52, 12302-12305. (27) Yasu, Y.; Koike, T.; Akita, M. Intermolecular Aminotrifluoromethylation of Alkenes by Visible-Light-Driven Photoredox Catalysis. Org. Lett. 2013, 15, 2136-2139.


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