O- and N-Selective Electrophilic Activation of Allylic Alcohols and Amines in Pd-Catalyzed Direct Alkylation

Abstract

Catalytic control of chemoselectivity is crucial in the synthesis of highly functionalized compounds. Although there are reports of efficient chemoselective reactions of alcohols and amines as nucleophiles, there are no reports of the chemoselective activation of alcohols and amines as electrophiles. In this study, highly O- and N-selective electrophilic activation of allylic alcohols and amines was achieved in Pd-catalyzed direct allylic alkylation. Allylamines were inherently more reactive than allylic alcohols (N-selectivity). On the other hand, the addition of catalytic amounts of 9-phenanthreneboronic acid preferentially activated allylic alcohols over allylamines (O-selectivity). Density functional theory (DFT) calculations suggested that the N-selectivity is due to the selective activation of allylic amines with ammonium cations, and boronate formation accelerates the activation of allylic alcohols.

Introduction

Chemoselectivity is the preferential reactivity of a functional group over others in a molecule.^1–4) The ability to control chemoselectivity is crucial in synthesizing highly functionalized compounds such as natural products and pharmaceuticals. Because chemoselectivity depends on the inherent reactivity of the functional groups in the molecules, reversing chemoselectivity is difficult but can usually be achieved by using protecting groups or equimolar amounts of reagents. The development of catalyst-controlled chemoselective reactions allows for more straightforward synthesis of functionalized compounds without unnecessary transformations such as protection-deprotection steps, thereby contributing to both atom and step economy. In this context, catalytic chemoselective reactions of alcohols and amines as nucleophiles are well studied in different reactions such as cross-coupling,^5–8) acylation,^9–12) and 1,4-addition reactions^13–15) (Chart 1. a). The chemoselectivity of electrophiles, however, is less well explored.^16–28) To the best of our knowledge, the chemoselective activation of allylic alcohols and amines as electrophiles has not been reported (Chart 1. b), although direct catalytic reactions of both allylic alcohols^29–39) and allylic amines^40–42) as the electrophiles have been independently reported. Herein we disclose Pd-catalyzed chemoselective allylic alkylation of allylic alcohols and amines through chemoselective electrophilic activation of allylic alcohols and amines, respectively.

Chart 1. Catalyst-Controlled Chemoselective Reactions Using Alcohols and Amines as Nucleophiles or Nucleophiles

Results and Discussion

In our previous work, we successfully developed a Pt-catalyzed direct substitution of unmodified allylic alcohols with amines, in which water is produced as the sole coproduct. Use of the large bite-angle ligands Xantphos and DPEPhos enables the selective synthesis of monoallylamines, including several bioactive compounds^43–46) (Chart 2. eq. a). In this Pt-catalyzed reaction, Pt(cod)Cl₂ was a better precursor rather than the Pt(0) species. Pt(II) is first reduced to Pt(0) by β-H elimination of the allyl alcohol in the presence of amine. The resulting ammonium salt R²NH₃⁺Cl⁻ efficiently increases the leaving ability of the hydroxy group to form a π-allylplatinum complex through the elimination of water.⁴⁴⁾ The shortest total synthesis of (–)-α-kainic acid was also achieved using this platinum catalysis, in which it was used twice in a six-step synthesis.⁴⁷⁾ In the course of these studies, we observed rapid retro-reaction of allylamine products to the π-allylplatinum intermediate,⁴⁴⁾ suggesting that allylamines can be good substrates for platinum catalysis. For an efficient synthesis of allylamines, however, this retro-reaction must be suppressed and requires the development of allylic alcohol-selective activation conditions even in the presence of allylamines. To facilitate analysis of the chemoselectivity, we used a carbon nucleophile because, based on our previous studies, carbon nucleophiles quickly react with the π-allylplatinum complex and do not undergo the retro reaction from the allylated product (eq. b).⁴⁶⁾ Thus, the chemoselectivity of allylic alcohol and amine can be estimated from the ratio of the products (4/5) in the direct allylic alkylation with allylic alcohols 1 and amines 2 (eq. c).

Chart 2. Platinum-Catalyzed Direct Substitution of Amines (a) and Carbon Nucleophiles (b), and Design of Chemoselective Electrophilic Activation of Allylic Alcohols and Amines (c)

We first optimized the reaction conditions using 4-methylcinnamyl alcohol (1b), cinnamylamine (2a), and 2-ethylmalononitrile (3)⁴⁸⁾ as model substrates (Table 1). In a control reaction, the absence of a transition metal catalyst led to no reaction (entry 1). Although the catalyst derived from Pt(cod)Cl₂ and DPEphos efficiently promoted direct allylic alkylation at 60–80 °C,^43,44) the reaction did not proceed at 30 °C (entry 2). On the other hand, the use of palladium complexes as the catalyst afforded the allylated products even at 30 °C, and amine 2a reacted surprisingly faster than alcohol 1b (entries 3 and 4). These results suggested that allylamines 2 are inherently more reactive than allylic alcohols 1 in Pd-catalyzed allylic alkylations. Using MeOH as the solvent further improved the reactivity, while maintaining the high N-selectivity (entry 5, 91% of N-product 5a, O/N = 15/85, Condition N). To reverse this inherent N-selectivity over O-selectivity, we considered using boronic acid as a hydroxyl group activator^29–39) based on our recent studies on the activation of hydroxyl groups.^49,50) Adding 25 mol % of phenylboronic acid (B1) promoted the reaction of alcohol 1b rather than amine 2a and showed high O-selectivity (entry 6, O/N = 83/17). Pinacol boronate B2 did not act as an activator of alcohol but rather inhibited the reaction, suggesting that activation of allylic alcohol occurs via boronate formation of the allylic alcohol (entry 7). Further optimization of the reaction conditions revealed that 9-phenanthreneboronic acid (B3) was a better hydroxy group activator, affording O-product 4b in 84% yield with O/N = 86/14 selectivity (entry 8, Condition O). The presence of an amine is critical in O-allylation under Condition O; in the absence of the amine, the akylation of allyl alcohol was slow, yielding only 17% of 4b after 6 h (entry 9). The hydrochloride salt of the amine may contribute to the acceleration of Pd(0) formation, π-allylplatinum complex formation, or deprotonation of the malononitrile nucleophile. The addition of Et₃N in place of the primary amine 2a, also accelerated the reaction (entry 10).

Table 1. Optimization of Reaction Conditions^a)

Entry	Catalyst	Solvent	Additive	Time (h)	4b (%)	5a (%)	4b/5a (O/N)
1	None	Toluene	—	5	<1	<1	n.d.
2	Pt(cod)Cl2	Toluene	—	5	<1	<1	n.d.
3	Pd(cod)Cl2	Toluene	—	5	10	64	14/86
4	[Pd(allyl)Cl]2	Toluene	—	5	7	52	12/88
5	[Pd(allyl)Cl]2	MeOH	—	2	17	93	15/85
6	[Pd(allyl)Cl]2	Tolueneb)	B1	2	59	12	83/17
7	[Pd(allyl)Cl]2	Tolueneb)	B2	2	4	8	33/67
8	[Pd(allyl)Cl]2	Tolueneb)	B3	2.5	84	12	86/14
9c)	[Pd(allyl)Cl]2	Tolueneb)	B3	6	17	—	—
10d)	[Pd(allyl)Cl]2	Tolueneb)	B3	6	52	—	—

a) Reaction was performed at 0.50 mmol scale in solvent (5.0 M) with 1b/2a/3 = 1 : 1 : 2.1, and yield of 4b and 5a and the ratio of 4b/5a were determined by ¹H-NMR analysis of the crude mixture. b) 1.0 M. DPEphos = bis[2-(diphenylphosphino)phenyl] ether. c) Reaction was performed in the absence of 2a. d) Et₃N was used instead of 2a.

Having determined the optimized reaction conditions for both O- and N-selective electrophilic activation, we next examined the substrate scope of aryl-substituted allylic alcohols 1 (Table 2). Under Condition O, using boronic acid B3 as the O-activator, the desired alkylated products 4 derived from various allylic alcohols 1 were obtained selectively over 5a (O/N = up to 87/13). In contrast, under Condition N, using methanol as the solvent, the desired N-product 5a was obtained selectively over 4 (O/N = up to 8/92). The present catalysis can be run on a 1.0 mmol scale (entry 1). Electron-donating methoxy groups at the 4 and 3 positions on the aryl ring of 1 were tolerated, giving the desired O- and N-products in good yields with high O- and N-selectivities (entries 2 and 3). Allylic alcohols bearing a base-sensitive phenolic TBS ether group also gave the products with slightly higher O-and N-selectivities (entry 4). Electron-withdrawing 4-fluoro, -chloro, and -bromo substituents were also tolerant without any side reactions and gave products 4f–h and 5a while maintaining good to high N/O-selectivity, suggesting that the electronic nature of the allylic alcohols is not crucial for the observed chemoselectivity (entries 5–7). Allylic alcohols with 2-thienyl and naphthyl groups gave the products in good yields with good selectivities (entries 8 and 9).

Table 2. Catalytic Chemoselective Direct Alkylation Using Aryl-Substituted Allylic Alcohols and Amine^a)

Entry	Allylic alcohol 1Ar =	Condition O		Condition N
		4 (%)	4/5a (O/N)	5a (%)	4/5a (O/N)
1b)	4-Me-C6H4- (1b)	78c)	85/15	76c)	11/89
2	4-MeO-C6H4- (1c)	64	82/18	63d)	10/90
3	3-MeO-C6H4- (1d)	52	85/15	68d)	17/83
4	4-TBSO-C6H4- (1e)	82	87/13	61d)	8/92
5	4-F-C6H4- (1f)	60	81/19	>99d)	9/91
6	4-Cl-C6H4- (1g)	61	84/16	81e)	16/84
7	4-Br-C6H4- (1h)	64e)	76/24	56e)	11/89
8	2-Thienyl- (1i)	91c)	83/17	91c)	11/89
9	2-naphthyl- (1j)	75	75/25	85	25/75

a) Reaction was performed at 0.50 mmol scale with 1/2a/3 = 1 : 1 : 2.1, and yield of 4 and 5a and the ratio of 4/5a were determined by ¹H-NMR analysis of the crude mixture. b) At 1.0 mmol scale. c) Isolated yield (as a mixture of 4 and 5a). d) Isolated yield. e) [Pd(allyl)Cl]₂ (2 mol%) and DPEphos (8 mol%) were used. TBS = tert-butyldimethylsilyl.

Direct amination of alkyl-substituted allyl alcohols and allylamines is more challenging because of the slow formation of the π-allylpalladium complex and the concomitant β-hydrogen desorption reaction.⁴⁴⁾ Therefore, we next examined chemoselective electrophilic activation using alkyl-substituted allylamine 2b (Table 3). Combining 2b with reactive aryl-substituted allylic alcohol 1a led to high O-selectivity under Condition O (O/N = up to 95/5), and the desired O-product 4a was isolated in 71% yield. Although this is a challenging combination for an N-selective reaction, selective activation of alkyl-substituted 2b over aryl-substituted 1a was achieved under Condition N, resulting in a moderate yield of 5b and good N-selectivity (entry 1). The reactions with alkyl-substituted allylic alcohol 1k and alkyl-substituted allylamine 2b under Conditions O and N gave the desired products in high yields with moderate O-selectivity and good N-selectivity (entry 2).

Table 3. Catalytic Chemoselective Direct Alkylation Using Alkyl-Substituted Amine^a)

Entry	Allylic alcohol 1R1 =	Condition O		Condition N
		4 (%)	4/5b (O/N)	5b (%)	4/5b (O/N)
1	Ph- (1a)	71b)	95/5	52	29/71
2	n-Pr- (1k)	90	65/35	83	26/74

a) Reaction was performed at 0.20 mmol scale with 1/2b/3 = 1 : 1 : 2.1, and yield of 4 and 5b and the ratio of 4/5b were determined by ¹H-NMR analysis of the crude mixture. b) Isolated yield.

To gain insight into the origin of the O- and N-selectivity, we performed a series of computational studies under Conditions O and N⁵¹⁾ (Table 4). Our previous mechanistic studies on Pt-catalyzed direct allylic amination of allylic alcohols revealed that ammonium salts generated in situ from platinum(II) complexes with amine nucleophiles act as efficient activators of the hydroxyl group to accelerate the elimination of hydroxide through hydrogen bonding. Therefore, we considered the presence of cinnamylammonium cations as a co-catalyst.⁴⁴⁾ First, DFT calculations were performed to evaluate the relative transition state energies for the electrophilic activation of cinnamyl alcohol under Conditions O. The transition state energy of cinnamyl boronates was lower than that with cinnamyl alcohol (entries 1–3), consistent with the proposed mechanism in which the formation of allyl boronates accelerates the C–O bond activation under Conditions O.⁵²⁾ On the other hand, C–N bond activation of cinnamylamine is energetically more favorable than C–O bond activation of cinnamyl alcohol in methanol (entries 4 and 5), consistent with the observed N-selectivity under Conditions N. The presumed key to the N-selectivity is the selective activation of allylic amines with acidic ammonium species.⁵³⁾

Table 4. Calculated Relative Transition State Energies for the Activation of Cinnamyl Alcohol and Cinnamylamine by [(Dpephos)Pd⁰(cinnamylOH)] Complex^a)

a) DFT calculations were performed at the level of M06/def2-TZVP/SMD(toluene)//B3LYP-D3/def2-SVP for Condition O and M06/def2-TZVP/SMD(MeOH)//B3LYP-D3/def2-SVP for Condition N, and corrected energies at 1 M and 298.15 K were reported. b) Relative to the transition state energy for cinnamyl alcohol (∆∆G^‡ = ∆G_X^‡−∆G_OH^‡) under Condition O or N, respectively.

In summary, we report Pd-catalyzed O- and N-selective electrophilic activation of allylic alcohols and allylamines. Allylamines were inherently more reactive than allylic alcohols in Pd-catalyzed allylic alkylation, and the use of MeOH as the solvent efficiently accelerated the reaction (O/N = up to 8/92). The addition of a catalytic amount of boronic acid as an activator of allylic alcohols reversed the chemoselectivity, where O-products derived from allylic alcohols were obtained in good yield with high O-selectivity (O/N = up to 95/5). To our knowledge, this is the first example of highly O-selective and N-selective electrophilic activation of allylic alcohols and amines. Further extension of this concept to other reactions is ongoing in our laboratory.

Experimental

General

Reagents and solvents were obtained from commercial sources and used as received unless otherwise stated. Air- and moisture-sensitive liquids were transferred via a syringe and a stainless-steel needle. Reactions were performed under an argon atmosphere and monitored by thin layer chromatography using Merck Silica Gel 60 F254 plates. All work-up and purification procedures were carried out with reagent-grade solvents under an ambient atmosphere. Flash silica gel column chromatography was conducted with Kanto Chemical Silica gel 60N (spherical neutral, particle size 40–50 µm).

NMR spectra were acquired on a 500 MHz Bruker Avance III spectrometer. ¹H- and ¹³C-NMR chemical shifts are reported in ppm and referenced to tetramethylsilane or residual solvent peaks as internal standards (for CDCl₃, tetramethylsilane 0 ppm for ¹H and CDCl₃ 77.16 ppm for ¹³C; for DMSO-d₆, 2.50 ppm for ¹H and 39.52 ppm for ¹³C). NMR data are reported as follows: chemical shifts, multiplicity (s, singlet; d, doublet; dd, doublet of doublet; t, triplet; td, triplet of doublet; q, quartet; m, multiplet; br, broad signal), coupling constants (Hz), and integration. IR spectra were recorded with Shimadzu FTIR-8400. High-resolution mass spectroscopy (HRMS) was obtained with Waters ACQUITY UPLC^®–LCT-Premier™ XE system. Melting points were determined by using a Yanaco micro melting point apparatus and were uncorrected.

General Procedure for O-Selective Allylic Alkylation (Condition O)

To a 4 mL vial with a magnetic stir bar were added allylic alcohol 1 (0.50 mmol), [Pd(allyl)Cl]₂ (0.0050 mmol, 1.0 mol% for Pd), DPEphos (0.020 mmol, 4.0 mol%), 9-phenenthreneboronic acid (B3) (0.125 mmol, 25 mol%), and toluene (0.50 mL, 1.0 M) under an argon atmosphere. To the mixture were added allylic amine 2a (0.50 mmol, 1.0 equivalent (equiv.)) and malononitrile 3 (1.05 mmol, 2.1 equiv.), and the mixture was stirred at 30 °C on a hot plate for indicated time. The O/N-selectivity was determined by ¹H-NMR analysis of the crude mixture. The crude mixture was directly purified by flash silica gel column chromatography to give product 4.

General Procedure for N-Selective Allylic Alkylation (Condition N)

To a 4 mL vial with a magnetic stir bar were added allylic alcohol 1 (0.50 mmol), [Pd(allyl)Cl]₂ (0.0050 mmol, 1.0 mol% for Pd), DPEphos (0.020 mmol, 4.0 mol%), and MeOH (0.10 mL, 5.0 M) under an argon atmosphere. To the mixture were added allylic amine 2a (0.50 mmol, 1.0 equiv) and malononitrile 3 (1.05 mmol, 2.1 equiv), and the mixture was stirred at 30 °C on a hot plate for indicated time. The O/N-selectivity was determined by ¹H-NMR analysis of the crude mixture. The crude mixture was directly purified by flash silica gel column chromatography to give product 5a.

(E)-2-Ethyl-2-(3-(4-methylphenyl)allyl)malononitrile (4b)

Mp. 67–68 °C. ¹H-NMR (500 MHz, CDCl₃) δ: 7.30 (d, J = 8.0 Hz, 2H, Ar–H), 7.15 (d, J = 8.0 Hz, 2H, Ar–H), 6.64 (d, J = 15.0 Hz, 1H, CH = CHCH₂), 6.16 (dt, J = 15.0, 7.5 Hz, 1H, CH = CHCH₂), 2.83 (d, J = 7.5 Hz, 2H, CH = CHCH₂), 2.35 (s, 3H, ArCH₃), 2.03 (q, J = 7.5 Hz, 2H, CH₂CH₃), 1.30 (t, J = 7.5 Hz, 3H, CH₂CH₃). ¹³C-NMR (125 MHz, CDCl₃) δ: 138.6, 137.7, 133.1, 129.5, 126.7, 118.2, 115.4, 40.9, 39.0, 31.0, 21.4, 10.0. IR (neat) 2985, 2920, 2358, 2339, 1512, 1462, 1444, 975, 806 cm⁻¹. HRMS (electrospray ionization-time-of-flight (ESI-TOF)) m/z: Calcd for C₁₅H₁₆N₂Na [M + Na]⁺ 247.1206. Found 247.1202.

(E)-2-Ethyl-2-(3-(4-methoxyphenyl)allyl)malononitrile (4c)

Mp. 77–78 °C. ¹H-NMR (500 MHz, CDCl₃) δ: 7.34 (d, J = 8.5 Hz, 2H, Ar–H), 6.87 (d, J = 8.5 Hz, 2H, Ar–H), 6.62 (d, J = 16.0 Hz, 1H, CH = CHCH₂), 6.07 (dt, J = 16.0, 7.0 Hz, 1H, CH = CHCH₂), 3.82 (s, 3H, CH₃O), 2.82 (d, J = 7.0 Hz, 2H, CH = CHCH₂), 2.03 (q, J = 7.5 Hz, 2H, CH₂CH₃), 1.26 (t, J = 7.5 Hz, 3H, CH₂CH₃). ¹³C-NMR (125 MHz, CDCl₃) δ: 160.0, 137.2, 128.6, 128.1, 116.9, 115.5, 114.2, 55.5, 40.9, 39.1, 31.0, 10.0. IR (neat) 2964, 2358, 2339, 1604, 1508, 1465, 1440, 1247, 1176, 1029, 972, 812 cm⁻¹. HRMS (ESI-TOF) m/z: Calcd for C₁₅H₁₆N₂ONa [M + Na]⁺ 263.1155, Found 263.1155.

(E)-2-Ethyl-2-(3-(3-methoxyphenyl)allyl)malononitrile (4d)

¹H-NMR (500 MHz, CDCl₃) δ: 7.28 (dd, J = 8.0, 8.0 Hz, 1H, Ar–H), 7.00 (d, J = 8.0 Hz, 1H, Ar–H), 6.93 (s, 1H, Ar–H), 6.85 (d, J = 8.0 Hz, 1H, Ar–H), 6.65 (d, J = 15.5 Hz, 1H, CH = CHCH₂), 6.21 (dt, J = 15.5, 7.5 Hz, 1H, CH = CHCH₂), 3.83 (s, 3H, CH₃O), 2.84 (d, J = 7.5 Hz, 2H, CH = CHCH₂), 2.04 (q, J = 7.5 Hz, 2H, CH₂CH₃), 1.31 (t, J = 7.5 Hz, 3H, CH₂CH₃). ¹³C-NMR (125 MHz, CDCl₃) δ: 160.0, 137.7, 137.2, 129.9, 119.6, 119.5, 115.4, 114.2, 112.2, 55.4, 40.8, 39.0, 31.0, 10.0. IR (neat) 2976, 2939, 2361, 2341, 1597, 1579, 1489, 1458, 1433, 1290, 1261, 1157, 1041, 968, 867, 777, 692, 669 cm⁻¹. HRMS (ESI-TOF) m/z: Calcd for C₁₅H₁₆N₂ONa [M + Na]⁺ 263.1155. Found 263.1155.

(E)-2-(3-(4-((tert-Butyldimethylsilyl)oxy)phenyl)allyl)-2-ethylmalononitrile (4e)

Mp. 47–48 °C. ¹H-NMR (500 MHz, CDCl₃) δ: 7.28 (d, J = 8.5 Hz, 2H, Ar–H), 6.80 (d, J = 8.5 Hz, 2H, Ar–H), 6.60 (d, J = 15.5 Hz, 1H, CH = CHCH₂), 6.06 (dt, J = 15.5, 7.5 Hz, 1H, CH = CHCH₂), 2.81 (d, J = 7.5 Hz, 2H, CH = CHCH₂), 2.02 (q, J = 7.5 Hz, 2H, CH₂CH₃), 1.29 (t, J = 7.5 Hz, 3H, CH₂CH₃), 0.98 (s, 9H, CCH₃), 0.20 (s, 6H, SiCH₃). ¹³C-NMR (125 MHz, CDCl₃) δ: 156.2, 137.3, 129.2, 128.0, 120.4, 117.1, 115.4, 40.8, 39.1, 30.9, 25.8, 18.3, 10.0, –4.3. IR (neat) 2955, 2930, 2859, 2359, 2342, 1603, 1508, 1472, 1462, 1254, 1169, 968, 908, 837, 810, 797, 779, 737, 702, 669 cm⁻¹. HRMS (ESI-TOF) m/z: Calcd for C₂₀H₂₈N₂ONa [M + Na]⁺ 363.1864. Found 263.1863.

(E)-2-Ethyl-2-(3-(4-fluorophenyl)allyl)malononitrile (4f)

¹H-NMR (500 MHz, CDCl₃) δ: 7.38 (dd, J = 8.5, 8.5 Hz, 2H, Ar–H), 7.03 (dd, J = 8.5, 8.5 Hz, 2H, Ar–H), 6.65 (d, J = 16.0 Hz, 1H, CH = CHCH₂), 6.14 (dt, J = 16.0, 7.5 Hz, 1H, CH = CHCH₂), 2.83 (d, J = 7.5 Hz, 2H, CH = CHCH₂), 2.04 (q, J = 7.5 Hz, 2H, CH₂CH₃), 1.31 (t, J = 7.5 Hz, 3H, CH₂CH₃). ¹³C-NMR (125 MHz, CDCl₃) δ: 162.9 (d, J_C–F = 246.6 Hz), 136.6, 132.0 (d, J_C–F = 3.4 Hz), 128.4 (d, J_C–F = 8.1 Hz), 119.1 (d, J_C–F = 1.8 Hz), 115.8 (d, J_C–F = 21.5 Hz), 115.3, 40.7, 39.1, 31.1, 10.0. ¹⁹F-NMR (470 MHz, CDCl₃) δ –112.9. IR (neat) 2974, 2941, 2358, 2341, 1598, 1508, 1456, 1436, 1390, 1311, 1232, 1161, 1147, 1097, 983, 968, 935, 860, 840, 827, 810, 785, 769, 667 cm⁻¹. HRMS (ESI-TOF) m/z: Calcd for C₁₄H₁₃N₂FNa [M + Na]⁺ 251.0955. Found 251.0955.

(E)-2-(3-(4-Chlorophenyl)allyl)-2-ethylmalononitrile (4g)

Mp. 71–72 °C. ¹H-NMR (500 MHz, CDCl₃) δ: 7.35–7.30 (m, 4H, Ar–H), 6.64 (d, J = 16.0 Hz, 1H, CH = CHCH₂), 6.20 (dt, J = 16.0, 7.5 Hz, 1H, CH = CHCH₂), 2.84 (d, J = 7.5 Hz, 2H, CH = CHCH₂), 2.04 (q, J = 7.5 Hz, 2H, CH₂CH₃), 1.32 (t, J = 7.5 Hz, 3H, CH₂CH₃). ¹³C-NMR (125 MHz, CDCl₃) δ: 136.6, 134.4, 134.3, 129.1, 128.0, 120.1, 115.3, 40.8, 39.0, 31.2, 10.0. IR (neat) 2361, 2340, 1489, 1456, 1404, 1090, 1011, 964, 943, 858, 810 cm⁻¹. HRMS (ESI-TOF) m/z: Calcd for C₁₄H₁₃N₂³⁵ClNa [M + Na]⁺ 267.0659. Found 267.0659.

(E)-2-(3-(4-Bromophenyl)allyl)-2-ethylmalononitrile (4h)

Mp. 94–95 °C. ¹H-NMR (500 MHz, CDCl₃) δ: 7.47 (d, J = 7.0 Hz, 2H, Ar–H),7.27 (d, J = 7.0 Hz, 2H, Ar–H), 6.63 (d, J = 16.5 Hz, 1H, CH = CHCH₂), 6.22 (dt, J = 16.5, 7.5 Hz, 1H, CH = CHCH₂), 2.83 (d, J = 7.5 Hz, 2H, CH = CHCH₂), 2.04 (q, J = 7.5 Hz, 2H, CH₂CH₃), 1.32 (t, J = 7.5 Hz, 3H, CH₂CH₃). ¹³C-NMR (125 MHz, CDCl₃) δ: 136.6, 134.7, 132.0, 128.3, 122.6, 120.2, 115.3, 40.8, 39.0, 31.2, 10.0. IR (neat) 2980, 2943, 2360, 2339, 1487, 1456, 1435, 1400, 1338, 1236, 1072, 1006, 964, 943, 858, 806, 669 cm⁻¹. HRMS (ESI-TOF) m/z: Calcd for C₁₄H₁₃N₂⁷⁹BrNa [M + Na]⁺ 311.0154, Found 311.0147.

(E)-2-Ethyl-2-(3-(thiophen-2-yl)allyl)malononitrile (4i)

Mp. 70–71 °C. ¹H-NMR (500 MHz, CDCl₃) δ: 7.22 (d, J = 5.0 Hz, 1H, Ar–H), 7.02 (d, J = 3.5 Hz, 1H, Ar–H), 6.98 (dd, J = 5.0, 3.5 Hz, 1H, Ar–H), 6.80 (d, J = 15.0 Hz, 1H, CH = CHCH₂), 6.03 (dt, J = 15.0, 7.5 Hz, 1H, CH = CHCH₂), 2.82 (d, J = 7.5 Hz, 2H, CH = CHCH₂), 2.03 (q, J = 7.5 Hz, 2H, CH₂CH₃), 1.31 (t, J = 7.5 Hz, 3H, CH₂CH₃). ¹³C-NMR (125 MHz, CDCl₃) δ: 140.6, 130.7, 127.6, 127.1, 125.5, 118.5, 115.3, 40.7, 39.0, 31.0, 10.0. IR (neat) 2984, 2361, 2341, 1651, 1465, 1433, 1394, 1321, 1207, 1087, 985, 954, 854, 804, 702 cm⁻¹. HRMS (ESI-TOF) m/z: Calcd for C₁₂H₁₂N₂SNa [M + Na]⁺ 239.0613. Found 239.0617.

(E)-2-Ethyl-2-(3-(naphthalen-2-yl)allyl)malononitrile (4j)

Mp. 98–99 °C. ¹H-NMR (500 MHz, CDCl₃) δ: 7.82–7.76 (m, 4H, Ar–H), 7.60–7.58 (m, 1H, Ar–H), 7.49–7.45 (m, 2H, Ar–H), 6.83 (d, J = 15.0 Hz, 1H, CH = CHCH₂), 6.33 (dt, J = 15.0, 7.5 Hz, 1H, CH = CHCH₂), 2.86 (d, J = 7.5 Hz, 2H, CH = CHCH₂), 2.05 (q, J = 7.5 Hz, 2H, CH₂CH₃), 1.32 (t, J = 7.5 Hz, 3H, CH₂CH₃). ¹³C-NMR (125 MHz, CDCl₃) δ: 137.9, 133.6, 133.5, 133.3, 128.6, 128.2, 127.8, 127.2, 126.6, 126.5, 123.5, 119.6, 115.4, 40.9, 39.1, 31.1, 10.0. IR (neat) 2986, 2359, 2340, 1462, 1393, 993, 959, 866, 826, 797, 756, 746 cm⁻¹. HRMS (ESI-TOF) m/z: Calcd for C₁₈H₁₆N₂Na [M + Na]⁺ 283.1206. Found 283.1206.

(E)-2-Ethyl-2-(hex-2-enyl)malononitrile (4k)

¹H-NMR (500 MHz, CDCl₃) δ: 5.80 (dt, J = 7.0, 15.0 Hz, 1H, CH₃CH₂CH₂CH), 5.50 (dt, J = 15.0, 7.5 Hz, 1H, CHCH₂C), 2.62 (d, J = 7.5 Hz, 2H, CHCH₂C), 2.08 (td, J = 7.0, 7.0 Hz, 2H, CH₂CH₂CH), 1.98 (q, J = 7.5 Hz, 2H, CCH₂CH₃), 1.44 (qt, J = 7.5, 7.5 Hz, 2H, CH₃CH₂CH₂), 1.28 (t, J = 7.5 Hz, 3H, CCH₂CH₃), 0.92 (q, J = 7.5 Hz, 3H, CH₃CH₂CH₂). ¹³C-NMR (CDCl₃, 125 MHz) δ: 139.7, 120.1, 115.4, 40.4, 39.1, 34.5, 30.8, 22.1, 13.6, 9.8. IR (neat) 2960, 2931, 2873, 2358, 2339, 1460, 1388, 1340, 1159, 972, 785, 739, 669 cm⁻¹. HRMS (ESI-TOF) m/z: Calcd for C₁₁H₁₆N₂Na [M + Na]⁺ 199.1206. Found 199.1204.

(E)-2-Cinnamyl-2-ethylmalononitrile (5a)

¹H-NMR (500 MHz, CDCl₃) δ: 7.42–7.28 (m, 5H, Ar–H), 6.69 (d, J = 16.0 Hz, 1H, CH = CHCH₂), 6.22 (dt, J = 16.0, 7.5 Hz, 1H, CH = CHCH₂), 2.85 (d, J = 7.5 Hz, 2H, CH = CHCH₂), 2.04 (q, J = 7.5 Hz, 2H, CH₂CH₃), 1.31 (t, J = 7.5 Hz, 3H, CH₂CH₃). ¹³C-NMR (125 MHz, CDCl₃) δ: 137.9, 135.9, 128.9, 128.6, 126.8, 119.3, 115.4, 40.8, 39.0, 31.1, 10.0. IR (neat) 2976, 2943, 2361, 2342, 1497, 1456, 1437, 1387, 984, 962, 750, 692, 669 cm⁻¹. HRMS (ESI-TOF) m/z: Calcd for C₁₄H₁₄N₂Na [M + Na]⁺ 233.1049. Found 233.1050.

(E)-2-Ethyl-2-(5-phenylpent-2-enyl)malononitrile (5b)

¹H-NMR (500 MHz, CDCl₃) δ: 7.29 (dd, J = 7.5 Hz, 2H, Ar–H), 7.21–7.17 (m, 3H, Ar–H), 5.80 (dt, J = 15.0, 7.0 Hz, 1H, CH₂CH₂CH), 5.49 (dt, J = 7.5, 15 Hz, 1H, CHCH₂C), 2.74 (t, J = 7.5 Hz, 2H, ArCH₂), 2.59 (d, J = 7.5 Hz, CHCH₂C), 2.44 (td, J = 7.5, 7.5 Hz, 2H, ArCH₂CH₂), 1.85 (q, J = 7.5 Hz, 2H, CCH₂CH₃), 1.24 (t, J = 7.5 Hz, 3H, CCH₂CH₃). ¹³C-NMR (125 MHz, CDCl₃) δ: 141.1, 138.6, 128.5, 128.4, 126.0, 120.8, 115.3, 40.2, 38.8, 35.2, 34.1, 30.6, 9.8. IR (neat) 2978, 2937, 2360, 1508, 1496, 1456, 1236, 1151, 1078, 972, 746, 700, 669 cm⁻¹. HRMS (ESI-TOF) m/z: Calcd for C₁₆H₁₈N₂Na [M + Na]⁺ 261.1362. Found 261.1362.

Acknowledgments

This work was supported by a Grant-in-Aid for Transformative Research Areas (A) Digitalization-driven Transformative Organic Synthesis (Digi-TOS) (MEXT KAKENHI Grant Numbers JP21A204, JP21H05207, and JP21H05208) from MEXT, and Grant-in-Aid for Scientific Research on Innovative Areas (JSPS KAKENHI Grant No. JP15H05846 in Middle Molecular Strategy for T.O.), Grants-in-Aid for Scientific Research (B) (JSPS KAKENHI Grant Numbers JP17H03972 and JP21H02607 to T.O.) and (C) (JSPS KAKENHI Grant Numbers JP18K06581 and JP21K06477 to H.M.) from JSPS, Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS) (AMED Grant Numbers JP21am0101091 and JP22ama121031) from AMED. L.L. thanks Ministry of Education, Culture, Sports, Science and Technology (MEXT) for fellowship. The computation was carried out using the computer resource offered under the category of General Projects by Research Institute for Information Technology, Kyushu University.

Conflict of Interest

The authors declare no conflict of interest.

Supplementary Materials

This article contains supplementary materials.

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