Catalyst-free reactions of anilines with β-chloroenones: synthesis of α-chloroenaminones and 1,4-benzodiazepines

Abstract

The Michael addition of anilines to β-chloroenones gives enaminones by the elimination of hydrochloric acid (HCl). These enaminones are transformed into α-chloroenaminones via in situ sp² C–H functionalization. Anilines that are attached to an electron-donating group react more readily with β-chloroenone to give the corresponding products in excellent yields. A highly atom-economical method has been developed using dimethyl sulfoxide (DMSO) as a green oxidant and solvent. The desired α-functionalized enaminones are formed in good yields with excellent Z-selectivity. We have established the generality of this reaction with many substrates, and scaled-up reactions have been performed to showcase the practical applications. A catalyst-free double annulation of β-chloroenones with o-phenylenediamine has also been demonstrated for the synthesis of 1,4-benzodiazepine derivatives in moderate yields under mild reaction conditions.

---

Introduction

Enaminones with many reactive sites exhibit a wide range of reactivities such as functionalization of the sp² C–H bond, reactions of the amino group, and 1,2- and 1,4-addition reactions.¹ Reactions of the sp² C–H bond have been largely studied for C–C, C–O, C–N, C–X, and C–S bond formation in the recent past.¹ Recently, a highly regioselective method was reported for the site-selective acyoxylation of either the α- or β-site of enaminones by changing the solvent system.² In 2016, an elegant metal-free reaction of enaminone with thiophenols was developed for the synthesis of polyfunctionalized aminothioalkenes in the presence of KIO₃.³ Over the past few years, several other methods have been established for the production of SCN-containing enaminones.⁴ Enaminones have been previously utilized for sp² C–H halogenation using either a transition metal catalyst or metal-free reaction conditions (Scheme 1a).⁵ The C–H functionalization of enaminone has gained considerable research attention and is widely used to produce a variety of functionalized enaminone derivatives.⁶

Scheme 1 Synthesis of enaminones and benzodiazepines.

Some reactions involving N,N-dimethylenaminones have been outlined in which the N,N-dimethyl group acts as a leaving group.⁷ Due to the presence of both nucleophilic and electrophilic sites, the enaminones are an important starting material for producing molecular diversity and complexity. In addition, enaminone derivatives have been utilized as key intermediates to construct heterocyclic compounds.⁸ Moreover, they are also found in many bioactive compounds and exhibit antitumor, anti-inflammatory, antibiotic, and antidepressant activities.⁹

Synthetic methods have been documented to readily access enaminones because of their wide range of applications in interdisciplinary fields.¹⁰ Relatively few methods have been reported in the literature that did not use the corresponding enaminones as the starting materials for the synthesis of α-functionalized enaminones. For example, Murakami and co-workers described a transition metal-catalyzed reaction of N-sulfonyl-1,2,3-triazoles with formamides that directly gave α-functionalized enaminones.¹¹

Recently, a metal-free strategy was reported for the one-pot synthesis of α-bromoenaminones by reacting 3-bromopropenals with anilines in the presence of a catalytic amount of TsOH·H₂O (Scheme 1b).¹² One-pot methods involving the direct synthesis of α-functionalized compounds are quite rare, and therefore, the development of such methods can be highly useful to readily access enaminone intermediates for applications in synthetic chemistry.

Benzodiazepines are ubiquitous and an important structural unit found in many marketed drugs and natural products (Fig. 1).¹³ The synthesis of benzodiazepines has been accomplished via condensation of o-phenylenediamines with an α,β-unsaturated carbonyl compound under acidic conditions (Scheme 1c).¹⁴ The synthesis of bioactive benzodiazepine derivatives can also be achieved using a carbonyl compound as a coupling partner with o-phenylenediamines.¹⁵ There are no methods in the literature that utilize β-chloroenones as a reaction partner in the synthesis of benzodiazepine derivatives. Herein, we disclose a catalyst-free divergent method for the synthesis of α-chloroenaminones and 1,4-benzodiazepines using DMSO as a green solvent and reagent (Scheme 1d).

Fig. 1 Representative examples of bioactive enaminones and benzodiazepines.

Results and discussion

An atom-economical synthesis of α-functionalized enaminones was anticipated from the reaction of anilines with halopropenones in DMSO. Synthesis of β-bromoenone was previously reported by reacting phenylpropynone with aluminium chloride (AlCl₃) and sodium bromide (NaBr).¹⁶ We decided to prepare β-bromoenone using this strategy for application in the one-pot synthesis of α-functionalized enaminone derivatives. Later, reactions were performed, and the results are presented in Table 1.

Table 1 Optimization of reaction conditions^a

Entry	Solvent	Temp. (°C)	Time (h)	Yield	Yield
				3aa ^b (%)	4aa ^b (%)
a All reactions were carried out using 1a (0.3 mmol, 50 mg), 2a (0.25 mmol, 23 mg), and solvent (2 mL). b The yields were determined by ^1H NMR analyses of the crude reaction mixtures using CH2Br2 as the internal standard. c Isolated yield. DMF = dimethylformamide; DCE = 1,2-dichloroethane.
1	DMSO	rt	12	—	64 (58)^c
2	DMSO	50	4	28	41
3	DMSO	70	4	75	6
4	DMSO	70	6	84	5
5	DMSO	90	4	97 (92)^c	Trace
6	DMF	90	4	—	56
7	Toluene	90	4	—	51
8	CH3CN	90	4	—	49
9	1,4-Dioxane	90	4	—	31
10	DCE	90	4	—	82

---

First, a reaction was carried out at room temperature, and enaminone 4aa was obtained in 58% isolated yield (entry 1). When the reaction was carried out at 50 °C, the desired α-functionalized enaminone 3aa was formed in 28% yield along with 4aa in 41% yield (entry 2). The single crystal analysis of 3aa revealed that the product is a (Z)-α-chloroenaminone and not the expected bromoenaminone (see the ESI†). This outcome suggests that the starting material 1a used here should be a β-chloroenone.

The reaction temperature was further increased to 70 °C, resulting in the formation of product 3aa in 75% and 84% yields (entries 3 and 4), respectively. However, the reaction at 90 °C gave the (Z)-α-chloroenaminone 3aa in excellent yield of 92% (entry 5). The solvent screening revealed that DMSO can act as an oxidant, and is crucial for the in situ chlorination of enaminone 4aa (entries 6–10). Thus, atom-economical synthesis was accomplished using DMSO as a solvent system in which DMSO can also act as a green oxidizing agent.

We performed reactions using different β-chloroenones and anilines to establish the generality of this method (Table 2). The reactions were carried out under the conditions that afforded the product (Z)-3aa in 92% yield. We found that ortho-toluidine reacted with 2a and gave the corresponding enaminone 3ab in 68% yield, suggesting that the steric hindrance of the ortho-methyl group decreased the rate of this reaction to some extent. The reactions using meta- and para-toluidines as reaction partners resulted in the formation of the desired α-functionalized products (3ac and 3ad) in good yields. These observations further indicated that the steric effect of a substituent attached at the ortho-position can influence the rate of this reaction.

Table 2 Atom-economical synthesis of α-chloroenaminones^a,b,c

a Reactions were performed using 1 (0.3 mmol, 1.2 equiv.) and 2 (0.25 mmol) in DMSO (2 mL) at 90 °C. b Product 4 was formed in trace amounts. c The minor product was formed in 10–15% yield.

---

A smooth reaction was observed of 4-ethylaniline 2e with 1a under the reaction conditions to give α-chloroenaminone 3ae in 80% yield. The product 3af was obtained in an excellent yield of 87% when para-isopropylaniline 2f was used as a reaction partner with 1a. In the case of 2,6-dimethylaniline, the corresponding enaminone 3ag was isolated in only 65% yield. The analysis of the crude reaction mixture revealed that a minor product 4ag, which was not isolated in a pure form, was formed in 15% yield. Due to the presence of two ortho-methyl groups, the reactivity of aniline derivative 2g was decreased by a considerable amount. Nevertheless, the reaction of 2,4-dimethylaniline with 1a resulted in the formation of product 3ah in an 80% yield.

Anilines bearing an electron-donating group reacted more efficiently and afforded the corresponding products 3ai and 3aj in 90% and 94% yields, respectively. This reaction was found to be sluggish when ortho-nitroaniline was reacted with 1a, and the desired product 3ak was isolated in only 40% yield after 8 h. Combined steric and electron-withdrawing effects of the ortho-nitro group greatly retarded this reaction. However, the product 3al was formed in 79% yield using meta-nitroaniline as a reaction partner with 1a.

The nitro group at the meta-position can withdraw electrons only by an inductive effect. The result obtained from the reaction of para-nitroaniline with 1a suggested that both inductive and mesomeric effects are operating in this case. It was established from the above observations that the efficiency of this reaction is diminished when an aniline bearing a sterically hindered and electron-withdrawing group was used for the synthesis of enaminones.

To increase our understanding, we then used halo-substituted aniline derivatives. Using ortho-chloroaniline, the enaminone product 3an was obtained in a 51% isolated yield. The reactions of meta- and para-chloroaniline offered the corresponding products 3ao and 3ap in 63% and 82% yields, respectively. The impact of the electronic effect on the outcomes of these reactions was further established from these results. When para-bromoaniline was reacted with 1a, the desired product was formed in 85% yield.

Next, we employed benzylamine as a coupling partner and observed the formation of product 3ar in 50% yield. Furthermore, we also observed that the enaminone product 3as can be formed with only a 36% yield under the reaction conditions and using phenylethylamine 2s as a reaction partner. With these observations, we determined that amines with the aliphatic unit are not a good reaction partner. Reactions were also performed to produce α-functionalized enaminones containing an indole moiety using 5-amino-N-benzylindole as a Michael donor. Nevertheless, a mixture of inseparable products was only formed in small quantities.

We then studied the effect of substituents that are attached to the aromatic ring of β-chloroenones. The β-chloroenones containing either an electron-donating or an electron-withdrawing group were subjected to reactions under optimized reaction conditions. The reactions were initially carried out using β-chloroenone 1b and anilines with an electron-donating group. As observed earlier, anilines that contain an electron-donating group reacted more efficiently than anilines with an electron-withdrawing group. A similar trend of reactivity was observed using β-chloroenone 1c with a para-methoxy group as a Michael acceptor in this atom-economical synthesis.

Subsequently, reactions of β-chloroenone 1d with anilines were studied to evaluate a chloro-substituent effect on the outcomes of reactions. The desired products (3da, 3dj, and 3dp) were obtained in moderate to good yields. However, enaminone product 3dl was obtained with only a 47% yield from the reaction of 1d with meta-nitroaniline 2l under the reaction conditions. Finally, we used β-chloroenone bearing a bromo group at the para-position to understand the effect of this group on this reaction. The corresponding α-chloroenaminones (3ea, 3ej, 3el, and 3ep) were obtained in good yields when the corresponding anilines were reacted with 1e under catalyst-free conditions.

To demonstrate the practical applications of this strategy, scaled-up reactions were examined under optimal reaction conditions (Scheme 2). A reaction of β-chloroenone 1a with aniline 2a was carried out on a 3.5 mmol scale, and the desired product 3aa was obtained in 85% yield. We also tested the efficiency of this strategy using aniline derivative 2d as a coupling partner with 1a. In this case, the corresponding product 3ad was isolated in 87% yield when the reaction was carried out at 90 °C for 8 h.

Scheme 2 Scaled-up reactions.

When o-phenylenediamine 5a was used as an amine partner at 90 °C, this reaction did not give fruitful results. However, we observed the formation of 1,4-benzodiazepine 6aa in 40% yield under ambient conditions (see the ESI†). A similar result was also obtained when 5b was reacted with 1a (Table 3). The desired products (6ba, 6bb, 6ca, and 6cb) were isolated in moderate yields using β-chloroenones attached to an electron-donating group. Moreover, the efficiency of this reaction decreased to a considerable extent when 1d was employed with a chloro substituent attached at the para-position.

Table 3 Synthesis of 1,4-benzodiazepines^a,b,c

a Reactions were performed using 1 (0.5 mmol) and 5 (0.5 mmol) in DMSO (3 mL) at room temperature. b Product 7 was formed in trace amounts. c Isolated yield based on 1.

---

In these cases, the expected 1,4-benzodiazepine derivatives 6da and 6db were only formed in 10–15% yields. The reactions of o-phenylenediamines 5a and 5b with 1e offered the corresponding 1,4-benzodiazepine derivatives 6ea and 6eb in 20% and 27% yields, respectively. Subsequently, reactions of 1a with 4,5-dichloro-o-phenylenediamine 5c were investigated, and it was found that this reaction was sluggish when this substrate was used. This result revealed that o-phenylenediamines bearing electron-withdrawing groups are not a suitable coupling partner.

The reaction between β-chloroenone 1a and aniline 2a delivered enaminone 4aa as the product in DMF at 90 °C (Scheme 3). Moreover, the intermediate 4aa formed only as the product in reactions that were carried out using other solvent systems (Table 1, entries 6–10). Hence, we established that DMSO as a solvent system is required for the generation of α-chlorinated enaminone derivatives.

Scheme 3 Control experiment.

To explain the formation of α-chloroenaminone in an atom-economical manner, a suitable reaction mechanism is proposed in Scheme 4. The 1,4-addition of aniline 2a to 1a gives enaminone 4aa with the elimination of hydrochloric acid (HCl). The in situ oxidation of HCl produces chlorine molecules (Cl₂). Reaction of 4aa with Cl₂ can give imine intermediate A, which then undergoes isomerization to give a thermodynamically more stable product (Z)-3aa under the reaction conditions. Similarly, o-phenylenediamine 5a reacts with two molecules of 1a to give dienaminone B as an intermediate. Next, this intermediate is transformed into another intermediate Cvia an intramolecular cyclization. The more stable product 6aa is finally formed under ambient reaction conditions.

Scheme 4 Proposed reaction mechanism.

Conclusions

A catalyst-free method was developed for the synthesis of a variety of (Z)-α-chloroenaminones. The corresponding enaminone products were obtained in excellent yields when anilines bearing an electron-donating group were employed as a reaction partner. The reactions were accomplished with high atom economy (>99%) using DMSO as the solvent system. We also found that anilines attached to an electron-withdrawing group required a longer reaction time.

The reactions using o-phenylenediamine as an amine partner gave benzodiazepine derivatives in moderate yields under catalyst-free conditions. Therefore, molecular diversity was readily achieved by using these methods. Because enaminones have been widely used as reactive intermediates, this method could find significant applications in synthetic chemistry.

Experimental section

General information

All of the reagents and solvents were purchased from commercial suppliers and were directly used without any further purification. DMSO that was obtained from a commercial supplier was used in this study. Prior to use, 10 mL round bottom flasks were dried in an oven and cooled to room temperature. All reactions were carried out under a nitrogen atmosphere.

Flash column chromatography was performed on 63–200 mesh silica gel using hexane and ethyl acetate as eluents. ¹H and ¹³C NMR spectra were recorded on a Bruker Ascend spectrometer at 400 and 100 MHz, respectively. Chemical shifts are reported in parts per million (ppm) on the δ scale using CDCl₃ as an internal standard. Multiplicities are indicated using abbreviations: s = singlet; d = doublet; t = triplet; q = quartet; dd = doublet of doublets; m = multiplet, br = broad signal. Coupling constants are expressed in Hertz (Hz). High-resolution mass spectrometry (HRMS) was performed, and spectra were recorded in electrospray ionization-time-of-flight (ESI-TOF) mode. The melting points (mp) were obtained using an Electro-Thermal FARGO MP-2D capillary melting point apparatus.

General procedure for the synthesis of β-chloroenones 1

To an oven-dried 50 mL reaction flask cooled under a N₂ atmosphere was added the corresponding propargyl ketone (3 mmol), CH₃CN (20 mL), tert-butanol (2 mL), AlCl₃ (4.5 mmol, 599 mg), and NaBr (6 mmol, 617 mg). The reaction mixture was heated at 80 °C for 16 h, and was subsequently cooled to room temperature and quenched by the addition of water (5–10 mL). Then, the reaction mixture was extracted with ethyl acetate (30 mL), and the aqueous layer was again extracted using ethyl acetate (20 mL). The combined organic layer was washed with brine solution and dried over MgSO₄. The organic layer was evaporated under reduced pressure, and the crude product was purified by silica gel column chromatography using an ethyl acetate/hexane (1 : 99) mixture as the eluent.

3-Chloro-1-phenylprop-2-en-1-one (1a). The crude product was purified by column chromatography on silica gel using hexane/ethyl acetate = 99 : 1 (v/v) as the eluent. Yield 85% (424 mg); colorless liquid. ¹H NMR (400 MHz, CDCl₃) δ 7.95–7.92 (m, 2.1H), 7.70 (d, J = 12.0 Hz, 0.08H), 7.62–7.58 (m, 1.1H), 7.52–7.45 (m, 3.1H), 7.32 (d, J = 12.0 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 187.8, 138.2, 136.8, 133.4, 128.8, 128.6, 128.5; HRMS (EI) m/z calcd for C₉H₇ClO [M]⁺ 166.0185, found 166.0181.

3-Chloro-1-(p-tolyl)prop-2-en-1-one (1b). The crude product was purified by column chromatography on silica gel using hexane/ethyl acetate = 99 : 1 (v/v) as the eluent. Yield 82% (443 mg); colorless liquid. ¹H NMR (400 MHz, CDCl₃) δ 7.85–7.82 (m, 2.5H), 7.67 (d, J = 12.0 Hz, 0.17H), 7.57 (d, J = 16.0 Hz, 0.17H), 7.45 (d, J = 12.0 Hz, 1H), 7.33–7.28 (m, 3.6H), 2.43 (s, 3.6H); ¹³C NMR (100 MHz, CDCl₃) δ 187.3, 144.5, 137.7, 134.3, 129.5, 128.8, 128.7, 128.5, 21.7; HRMS (EI) m/z calcd for C₁₀H₉ClO [M]⁺ 180.0342, found 180.0338.

3-Chloro-1-(4-methoxyphenyl)prop-2-en-1-one (1c). The crude product was purified by column chromatography on silica gel using hexane/ethyl acetate = 99 : 1 (v/v) as the eluent. Yield 75% (441 mg); white solid, 53.5–55 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.95–7.91 (m, 2.3H), 7.66 (d, J = 12.0 Hz, 0.14H), 7.57 (d, J = 16.0 Hz, 0.14 Hz), 7.43 (d, J = 16.0 Hz, 1H), 7.31 (d, J = 16.0 Hz, 1H), 6.98–6.94 (m, 2.3H), 3.88 (s, 3.4H); ¹³C NMR (100 MHz, CDCl₃) δ 186.1, 163.9, 137.3, 132.5, 131.0, 130.9, 129.7, 128.3, 114.0, 55.5; HRMS (EI) m/z calcd for C₁₀H₉ClO₂ [M]⁺ 196.0291, found 196.0284.

3-Chloro-1-(4-chlorophenyl)prop-2-en-1-one (1d). The crude product was purified by column chromatography on silica gel using hexane/ethyl acetate = 99 : 1 (v/v) as the eluent. Yield 52% (312 mg); white solid, melting point: 37.5–39 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.91–7.88 (m, 2.2H), 7.74 (d, J = 16.0 Hz, 0.19H), 7.56 (d, J = 16.0 Hz, 0.19H), 7.52–7.47 (m, 3H), 7.29 (d, J = 12.0 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 186.5, 186.4, 140.0, 138.8, 135.1, 134.8, 132.2, 130.0, 129.9, 128.2, 128.0; HRMS (ESI) m/z calcd for C₉H₇Cl₂O [M + H]⁺ 200.9874, found 200.9874.

1-(4-Bromophenyl)-3-chloroprop-2-en-1-one (1e). The crude product was purified by column chromatography on silica gel using hexane/ethyl acetate = 99 : 1 (v/v) as the eluent. Yield 64% (469 mg); white solid, melting point: 41–42 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.83–7.80 (m, 2.2H), 7.75 (d, J = 12.0 Hz, 0.04H), 7.67–7.64 (m, 2.2H), 7.55 (d, J = 16.0 Hz, 0.06H), 7.50 (d, J = 12.0 Hz, 1H), 7.29 (d, J = 16.0 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 186.6, 138.8, 135.6, 132.2, 130.1, 130.0, 128.7, 128.0; HRMS (EI) m/z calcd for C₉H₆ClBrO [M]⁺ 243.9291, found 243.9287.

General procedure for the synthesis of α-chloroenaminones 3

Aniline (0.25 mmol), β-chloroenone (0.3 mmol), and DMSO (2 mL) were added to a 10 mL reaction flask that was dried in an oven and cooled to room temperature under a N₂ atmosphere. The reaction mixture was heated at 90 °C using an oil bath for 4–8 h. The reaction mixture was then cooled to room temperature and transferred to a separatory funnel using ethyl acetate (30 mL). Water (30 mL) was added, and the organic layer was separated. The aqueous layer was extracted again with ethyl acetate (20 mL). The combined organic layer was washed with brine solution and dried over MgSO₄. The solvent was evaporated under reduced pressure using a rotary evaporator. The crude product was purified by silica gel column chromatography using an ethyl acetate/hexane mixture as the eluent.

(Z)-2-Chloro-1-phenyl-3-(phenylamino)prop-2-en-1-one (3aa). The crude product was purified by column chromatography on silica gel using hexane/ethyl acetate = 85 : 15 (v/v) as the eluent. Yield 92% (59 mg); yellow solid, melting point: 144–145 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.84 (d, J = 12 Hz, 1H), 7.63–7.60 (m, 2H), 7.55–7.50 (m, 1H), 7.48–7.44 (m, 2H), 7.33–7.29 (m, 2H), 7.24 (d, J = 12 Hz, 1H), 7.10–7.06 (m, 1H), 6.93–6.90 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 188.1, 141.2, 139.2, 138.8, 131.1, 130.0, 128.5, 128.4, 128.1, 124.1, 116.4, 109.8; HRMS (ESI) m/z calcd for C₁₅H₁₃NOCl [M + H]⁺ 258.0686, found 258.0691.

(Z)-1-Phenyl-3-(phenylamino)prop-2-en-1-one (4aa). This product was obtained from a room-temperature reaction (Table 1, entry 1). The crude product was purified by column chromatography on silica gel using hexane/ethyl acetate = 85 : 15 (v/v) as the eluent. Yield 58% (32 mg); yellow solid, melting point: 138–139 °C. ¹H NMR (400 MHz, CDCl₃) δ 12.18 (d, J = 12 Hz, 1H), 7.98–7.96 (m, 2H), 7.57–7.45 (m, 4H), 7.39–7.34 (m, 2H), 7.14–7.08 (m, 3H), 6.06 (d, J = 8.0 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 191.0, 144.9, 140.2, 139.2, 131.6, 129.7, 128.5, 127.3, 123.7, 116.3, 93.7; HRMS (ESI) m/z calcd for C₁₅H₁₄NO [M + H]⁺ 224.1075, found 224.1081.

(Z)-2-Chloro-1-phenyl-3-(o-tolylamino)prop-2-en-1-one (3ab). The crude product was purified by column chromatography on silica gel using hexane/ethyl acetate = 90 : 10 (v/v) as the eluent. Yield 68% (46 mg); yellow solid, melting point: 128–130 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.83 (d, J = 12.0 Hz, 1H), 7.63–7.61 (m, 2H), 7.54–7.50 (m, 1H), 7.47–7.44 (m, 2H), 7.20–7.14 (m, 2H), 7.07 (d, J = 12.0 Hz, 1H), 7.01 (t, J = 8.0 Hz, 1H), 6.84 (d, J = 8.0 Hz, 1H), 2.34 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 187.9, 141.8, 138.8, 137.5, 131.4, 131.0, 128.5, 128.4, 127.5, 126.2, 124.2, 115.2, 110.1, 17.2; HRMS (EI) m/z calcd for C₁₆H₁₄ClNO [M]⁺ 271.0764, found 271.0758.

(Z)-2-Chloro-1-phenyl-3-(m-tolylamino)prop-2-en-1-one (3ac). The crude product was purified by column chromatography on silica gel using hexane/ethyl acetate = 85 : 15 (v/v) as the eluent. Yield 84% (57 mg); yellow solid, melting point: 104–105.5 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.83 (d, J = 12.0 Hz, 1H), 7.62–7.61 (d, J = 8.0 Hz, 2H), 7.54–7.51 (m, 1H), 7.46 (t, J = 8.0 Hz, 2H), 7.20–7.16 (m, 2H), 6.89 (d, J = 8.0 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 188.1, 141.3, 140.1, 139.1, 138.8, 131.0, 129.7, 128.5, 128.4, 125.0, 117.2, 113.3, 109.5, 21.4; HRMS (EI) m/z calcd for C₁₆H₁₄ClNO [M]⁺ 271.0764, found 271.0780.

(Z)-2-Chloro-1-phenyl-3-(p-tolylamino)prop-2-en-1-one (3ad). The crude product was purified by column chromatography on silica gel using hexane/ethyl acetate = 85 : 15 (v/v) as the eluent. Yield 93% (63 mg); yellow solid, melting point: 161–163 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.81 (d, J = 12.0 Hz, 1H), 7.62–7.59 (m, 2H), 7.53–7.49 (m, 1H), 7.46–7.42 (m, 2H), 7.17 (d, J = 16.0 Hz, 1H), 7.10 (d, J = 8.0 Hz, 2H), 6.83–6.80 (m, 2H), 2.29 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 188.0, 141.7, 138.9, 136.8, 133.9, 130.9, 130.4, 128.5, 128.4, 116.5, 109.3, 20.7; HRMS (EI) m/z calcd for C₁₆H₁₄ClNO [M]⁺ 271.0764, found 271.0755.

(Z)-2-Chloro-3-((4-ethylphenyl)amino)-1-phenylprop-2-en-1-one (3ae). The crude product was purified by column chromatography on silica gel using hexane/ethyl acetate = 85 : 15 (v/v) as the eluent. Yield 80% (57 mg); yellow solid, melting point: 146–147 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.84 (d, J = 12.0 Hz, 1H), 7.65–7.62 (m, 2H), 7.56–7.52 (m, 1H), 7.49–7.45 (m, 2H), 7.20–7.15 (m, 3H), 6.88–6.85 (m, 2H), 2.63 (q, J = 8.0 Hz, 2H), 1.23 (t, J = 8.0 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 188.0, 141.7, 140.4, 138.9, 136.9, 130.9, 129.2, 128.5, 128.4, 116.5, 109.3, 28.1, 15.6; HRMS (EI) m/z calcd for C₁₇H₁₆ClNO [M]⁺ 285.0920, found 285.0913.

(Z)-2-Chloro-3-((4-isopropylphenyl)amino)-1-phenylprop-2-en-1-one (3af). The crude product was purified by column chromatography on silica gel using hexane/ethyl acetate = 90 : 10 (v/v) as the eluent. Yield 87% (65 mg); yellow solid, melting point: 160–161 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.82 (d, J = 12.0 Hz, 1H), 7.62–7.59 (m, 2H), 7.54–7.49 (m, 1H), 7.47–7.42 (m, 2H), 7.19–7.13 (m, 3H), 6.87–6.84 (m, 2H), 2.86 (sep, J = 8.0 Hz, 1H), 1.21 (d, J = 8.0 Hz, 6H); ¹³C NMR (100 MHz, CDCl₃) δ 188.0, 145.1, 141.8, 138.9, 137.0, 130.9, 128.5, 128.4, 127.8, 116.5, 109.3, 33.4, 23.9; HRMS (EI) m/z calcd for C₁₈H₁₈ClNO [M]⁺ 299.1077, found 299.1074.

(Z)-2-Chloro-3-((2,6-dimethylphenyl)amino)-1-phenylprop-2-en-1-one (3ag). The crude product was purified by column chromatography on silica gel using hexane/ethyl acetate = 90 : 10 (v/v) as the eluent. Yield 65% (46 mg); yellow solid, melting point: 153–154 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.56–7.53 (m, 2H), 7.47–7.42 (m, 1H), 7.40–7.36 (m, 2H), 7.31 (d, J = 12.0 Hz, 1H), 7.07 (s, 3H), 6.66 (d, J = 12.0 Hz, 1H), 2.27 (s, 6H); ¹³C NMR (100 MHz, CDCl₃) δ 187.9, 148.2, 139.0, 137.0, 132.7, 130.7, 129.1, 128.3, 126.9, 107.9, 18.5; HRMS (EI) m/z calcd for C₁₇H₁₆ClNO [M]⁺ 285.0920, found 285.0910.

(Z)-2-Chloro-3-((2,4-dimethylphenyl)amino)-1-phenylprop-2-en-1-one (3ah). The crude product was purified by column chromatography on silica gel using hexane/ethyl acetate = 90 : 10 (v/v) as the eluent. Yield 80% (57 mg); yellow solid, melting point: 149–150 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.81 (d, J = 12.0 Hz, 1H), 7.65–7.62 (m, 2H), 7.56–7.51 (m, 1H), 7.49–7.45 (m, 2H), 7.09–6.97 (m, 3H), 6.77 (d, J = 8.0 Hz, 1H), 2.33 (s, 3H), 2.30 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 187.9, 142.4, 138.9, 135.2, 134.1, 132.0, 130.9, 128.5, 128.4, 127.9, 126.4, 115.7, 109.6, 20.6, 17.1; HRMS (EI) m/z calcd for C₁₇H₁₆ClNO [M]⁺ 285.0920, found 285.0910.

(Z)-2-Chloro-3-((2-methoxyphenyl)amino)-1-phenylprop-2-en-1-one (3ai). The crude product was purified by column chromatography on silica gel using hexane/ethyl acetate = 80 : 20 (v/v) as the eluent. Yield 90% (65 mg); yellow solid, melting point: 103–104 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.87 (d, J = 12.0 Hz, 1H), 7.73 (d, J = 12.0 Hz, 1H), 7.62–7.60 (m, 2H), 7.54–7.50 (m, 1H), 7.48–7.44 (m, 2H), 7.04–7.00 (m, 1H), 6.92–6.86 (m, 2H), 6.80 (dd, J = 1.2, 8.0 Hz, 1H), 3.92 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 188.1, 148.1, 140.4, 138.9, 130.9, 128.6, 128.5, 128.4, 123.7, 121.2, 113.4, 111.1, 110.1, 55.9; HRMS (ESI) m/z calcd for C₁₆H₁₅NO₂Cl [M + H]⁺ 288.0791, found 288.0803.

(Z)-2-Chloro-3-((4-methoxyphenyl)amino)-1-phenylprop-2-en-1-one (3aj). The crude product was purified by column chromatography on silica gel using hexane/ethyl acetate = 80 : 20 (v/v) as the eluent. Yield 94% (68 mg); yellow solid, melting point: 147–148 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.77 (d, J = 12.0 Hz, 1H), 7.63–7.61 (m, 2H), 7.55–7.45 (m, 3H), 7.19 (d, J = 12.0 Hz, 1H), 6.92–6.87 (m, 4H), 3.80 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 187.9, 156.6, 142.4, 138.9, 132.7, 130.9, 128.4, 128.4, 118.2, 115.1, 108.8, 55.6; HRMS (ESI) m/z calcd for C₁₆H₁₅NO₂Cl [M + H]⁺ 288.0791, found 288.0790.

(Z)-2-Chloro-3-((2-nitrophenyl)amino)-1-phenylprop-2-en-1-one (3ak). The crude product was purified by column chromatography on silica gel using hexane/ethyl acetate = 80 : 20 (v/v) as the eluent. Yield 40% (30 mg); yellow solid, melting point: 137–138 °C. ¹H NMR (400 MHz, CDCl₃) δ 10.56 (d, J = 12.0 Hz, 1H), 8.29 (dd, J = 8.0, 1.2 Hz, 1H), 7.98 (d, J = 12.0 Hz, 1H), 7.72–7.69 (m, 2H), 7.63–7.57 (m, 2H), 7.53–7.49 (m, 2H), 7.16–7.12 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 188.4, 138.1, 137.4, 136.5, 136.3, 135.7, 131.7, 128.7, 128.5, 127.1, 122.2, 115.7, 114.3; HRMS (EI) m/z calcd for C₁₅H₁₂N₂O₃Cl [M + H]⁺ 303.0536, found 303.0542.

(Z)-2-Chloro-3-((3-nitrophenyl)amino)-1-phenylprop-2-en-1-one (3al). The crude product was purified by column chromatography on silica gel using hexane/ethyl acetate = 80 : 20 (v/v) as the eluent. Yield 79% (60 mg); yellow solid, melting point: 188–189 °C. ¹H NMR (400 MHz, CDCl₃) δ 9.90 (d, J = 12.0 Hz, 1H), 8.13–8.12 (m, 1H), 7.95 (d, J = 12.0 Hz, 1H), 7.87–7.83 (m, 1H), 7.68–7.65 (m, 2H), 7.61–7.50 (m, 5H); ¹³C NMR (100 MHz, CDCl₃) δ 187.8, 148.9, 142.9, 142.2, 139.1, 131.6, 131.2, 129.0, 128.9, 123.0, 117.8, 112.4, 109.3; HRMS (EI) m/z calcd for C₁₅H₁₂N₂O₃Cl [M + H]⁺ 303.0536, found 303.0539.

(Z)-2-Chloro-3-((4-nitrophenyl)amino)-1-phenylprop-2-en-1-one (3am). The crude product was purified by column chromatography on silica gel using hexane/ethyl acetate = 80 : 20 (v/v) as the eluent. Yield 62% (47 mg); yellow solid, melting point: 255–256 °C. ¹H NMR (400 MHz, CDCl₃) δ 10.04 (brs, 1H), 8.20–8.16 (m, 2H), 7.96 (brs, 1H), 7.69–7.66 (m, 2H), 7.63–7.59 (m, 1H), 7.54–7.51 (m, 2H), 7.41–7.38 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 188.0, 146.9, 142.5, 141.8, 138.8, 131.8, 129.0, 129.0, 126.0, 117.1, 1108; HRMS (EI) m/z calcd for C₁₅H₁₂N₂O₃Cl [M + H]⁺ 303.0536, found 303.0541.

(Z)-2-Chloro-3-((2-chlorophenyl)amino)-1-phenylprop-2-en-1-one (3an). The crude product was purified by column chromatography on silica gel using hexane/ethyl acetate = 85 : 15 (v/v) as the eluent. Yield 51% (37 mg); yellow solid, melting point: 128–129 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.86 (d, J = 12.0 Hz, 1H), 7.71–7.65 (m, 3H), 7.59–7.54 (m, 1H), 7.51–7.47 (m, 2H), 7.42 (dd, J = 8.0, 1.2 Hz, 1H), 7.26–7.21 (m, 1H), 7.02 (dd, J = 8.0 1.2 Hz, 1H), 6.92 (dd, J = 8.0, 1.2 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 188.1, 139.5, 138.5, 135.8, 131.3, 130.2, 128.6, 128.5, 128.3, 124.0, 122.5, 114.8, 111.5; HRMS (EI) m/z calcd for C₁₅H₁₂NOCl₂ [M + H]⁺ 292.0296, found 292.0284.

(Z)-2-Chloro-3-((3-chlorophenyl)amino)-1-phenylprop-2-en-1-one (3ao). The crude product was purified by column chromatography on silica gel using hexane/ethyl acetate = 85 : 15 (v/v) as the eluent. Yield 63% (46 mg); yellow solid, melting point: 123–124 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.72 (d, J = 12.0 Hz, 1H), 7.57–7.55 (m, 2H), 7.50–7.46 (m, 1H), 7.43–7.38 (m, 2H), 7.15 (d, J = 8.0 Hz, 1H), 7.06 (d, J = 12.0 Hz, 1H), 6.99–6.96 (m, 1H), 6.85 (t, J = 2.0 Hz, 1H), 6.74–6.71 (m, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 188.1, 140.4, 140.1, 138.4, 135.7, 131.3, 130.9, 128.56, 128.53, 124.0, 116.4, 114.3, 110.7; HRMS (EI) m/z calcd for C₁₅H₁₂NOCl₂ [M + H]⁺ 292.0296, found 292.0305.

(Z)-2-Chloro-3-((4-chlorophenyl)amino)-1-phenylprop-2-en-1-one (3ap). The crude product was purified by column chromatography on silica gel using hexane/ethyl acetate = 85 : 15 (v/v) as the eluent. Yield 82% (60 mg); yellow solid, melting point: 179–180 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.79 (d, J = 12.0 Hz, 1H), 7.65–7.62 (m, 2H), 7.58–7.54 (m, 1H), 7.50–7.46 (m, 2H), 7.30–7.24 (m, 3H), 6.90–6.87 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 188.1, 140.7, 138.6, 137.9, 131.2, 129.9, 129.2, 128.53, 128.50, 117.5, 110.2; HRMS (EI) m/z calcd for C₁₅H₁₂NOCl₂ [M + H]⁺ 292.0296, found 292.0299.

(Z)-3-((4-Bromophenyl)amino)-2-chloro-1-phenylprop-2-en-1-one (3aq). The crude product was purified by column chromatography on silica gel using hexane/ethyl acetate = 85 : 15 (v/v) as the eluent. Yield 85% (71 mg); yellow solid, melting point: 192–193 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.79 (d, J = 12.0 Hz, 1H), 7.65–7.62 (m, 2H), 7.58–7.54 (m, 1H), 7.50–7.47 (m, 2H), 7.45–7.41 (m, 2H), 7.21 (d, J = 12.0 Hz, 1H), 6.85–6.81 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 188.1, 140.5, 138.5, 138.3, 132.9, 131.2, 128.54, 128.50, 117.8, 116.6, 110.3; HRMS (EI) m/z calcd for C₁₅H₁₂NOClBr [M + H]⁺ 335.9791, found 335.9792.

(Z)-3-(Benzylamino)-2-chloro-1-phenylprop-2-en-1-one (3ar). The crude product was purified by column chromatography on silica gel using hexane/ethyl acetate = 90 : 10 (v/v) as the eluent. Yield 50% (34 mg); yellow solid, melting point: 133–134 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.53–7.50 (m, 2H), 7.49–7.45 (m, 1H), 7.42–7.33 (m, 6H), 7.26–7.23 (m, 2H), 5.71 (t, J = 4.0 Hz, 1H), 4.44 (d, J = 4.0 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 187.6, 149.6, 139.2, 136.9, 130.4, 129.1, 128.3, 128.29, 128.26, 127.3, 106.5, 51.9; HRMS (EI) m/z calcd for C₁₆H₁₅NOCl [M + H]⁺ 272.0842, found 272.0849.

(Z)-2-Chloro-3-(phenethylamino)-1-phenylprop-2-en-1-one (3as). The crude product was purified by column chromatography on silica gel using hexane/ethyl acetate = 90 : 10 (v/v) as the eluent. Yield 36% (26 mg); yellow solid, melting point: 169–170 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.42 (t, J = 8.0 Hz, 1H), 7.35–7.25 (m, 6H), 7.14 (d, J = 8.0 Hz, 2H), 7.01 (d, J = 16.0 Hz, 1H), 5.45 (t, J = 8.0 Hz, 1H), 3.50 (q, J = 8.0 Hz, 2H), 2.84 (t, J = 8.0 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 187.4, 150.1, 139.2, 137.4, 130.2, 128.99, 128.95, 128.26, 128.19, 127.0, 105.9, 49.8, 37.6; HRMS (EI) m/z calcd for C₁₇H₁₆NOCl [M]⁺ 285.0920, found 285.0912.

(Z)-2-Chloro-3-(phenylamino)-1-(p-tolyl)prop-2-en-1-one (3ba). The crude product was purified by column chromatography on silica gel using hexane/ethyl acetate = 85 : 15 (v/v) as the eluent. Yield 75% (51 mg); yellow solid, melting point: 142–143 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.87 (d, J = 12.0 Hz, 1H), 7.54–7.52 (m, 2H), 7.33–7.31 (m, 2H), 7.29–7.25 (m, 2H), 7.18 (d, J = 12.0 Hz, 1H), 7.10–7.05 (m, 1H), 6.94–6.91 (m, 2H), 2.43 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 188.0, 141.6, 140.8, 139.3, 135.9, 129.9, 129.1, 128.7, 123.9, 116.3, 109.8, 21.5; HRMS (EI) m/z calcd for C₁₆H₁₅NOCl [M + H]⁺ 272.0842, found 272.0833.

(Z)-2-Chloro-3-((4-methoxyphenyl)amino)-1-(p-tolyl)prop-2-en-1-one (3bj). The crude product was purified by column chromatography on silica gel using hexane/ethyl acetate = 85 : 15 (v/v) as the eluent. Yield 70% (53 mg); yellow solid, melting point: 160–161 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.77 (d, J = 12.0 Hz, 1H), 7.52–7.50 (m, 2H), 7.26–7.24 (m, 2H), 7.12 (d, J = 12.0 Hz, 1H), 6.91–6.84 (m, 4H), 3.78 (s, 3H), 2.42 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 187.8, 156.5, 142.0, 141.3, 136.1, 132.8, 129.0, 128.6, 118.1, 115.1, 108.9, 55.6, 21.5; HRMS (EI) m/z calcd for C₁₇H₁₇NO₂Cl [M + H]⁺ 302.0948, found 302.0947.

(Z)-2-Chloro-3-((3-nitrophenyl)amino)-1-(p-tolyl)prop-2-en-1-one (3bl). The crude product was purified by column chromatography on silica gel using hexane/ethyl acetate = 85 : 15 (v/v) as the eluent. Yield 60% (47 mg); yellow solid, melting point: 223–224 °C. ¹H NMR (400 MHz, CDCl₃) δ 9.84 (d, J = 12.0 Hz, 1H), 815–8.14 (m, 1H), 7.97 (d, J = 12.0 Hz, 1H), 7.85 (dt, J = 8.0, 4.0 Hz, 1H), 7.61–7.56 (m, 4H), 7.32 (d, J = 8.0 Hz, 2H), 2.40 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 187.6, 148.9, 142.4, 142.3, 141.6, 136.3, 131.3, 129.4, 129.2, 122.9, 117.7, 112.4, 109.4, 21.5; HRMS (EI) m/z calcd for C₁₆H₁₄N₂O₃Cl [M + H]⁺ 317.0693, found 317.0696.

(Z)-2-Chloro-3-((4-chlorophenyl)amino)-1-(p-tolyl)prop-2-en-1-one (3bp). The crude product was purified by column chromatography on silica gel using hexane/ethyl acetate = 85 : 15 (v/v) as the eluent. Yield 63% (48 mg); yellow solid, melting point: 189–190 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.89 (d, J = 16.0 Hz, 1H), 7.55–7.52 (m, 2H), 7.28–7.25 (m, 4H), 7.17 (d, J = 12.0 Hz, 1H), 6.89–6.86 (m, 2H), 2.43 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 188.0, 141.8, 140.2, 138.0, 135.7, 129.9, 129.1, 129.0, 128.7, 117.4, 110.3, 21.5; HRMS (EI) m/z calcd for C₁₆H₁₄NOCl₂ [M + H]⁺ 306.0452, found 306.0450.

(Z)-2-Chloro-1-(4-methoxyphenyl)-3-(phenylamino)prop-2-en-1-one (3ca). The crude product was purified by column chromatography on silica gel using hexane/ethyl acetate = 80 : 20 (v/v) as the eluent. Yield 78% (56 mg); yellow solid, melting point: 125–127 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.87 (d, J = 12.0 Hz, 1H), 7.66–7.62 (m, 2H), 7.34–7.29 (m, 2H), 7.14 (d, J = 12.0 Hz, 1H), 7.09–7.05 (m, 1H), 6.98–6.92 (m, 4H), 3.88 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 187.3, 162.1, 140.4, 139.3, 131.0, 130.7, 129.9, 123.9, 116.2, 113.7, 109.6, 55.4; HRMS (EI) m/z calcd for C₁₆H₁₅NO₂Cl [M + H]⁺ 288.0791, found 288.0800.

(Z)-2-Chloro-1-(4-methoxyphenyl)-3-((4-methoxyphenyl)amino)prop-2-en-1-one (3cj). The crude product was purified by column chromatography on silica gel using hexane/ethyl acetate = 75 : 25 (v/v) as the eluent. Yield 72% (57 mg); yellow solid, melting point: 162–163 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.80 (d, J = 12.0 Hz, 1H), 7.66–7.62 (m, 2H), 7.10 (d, J = 12.0 Hz, 1H), 6.99–6.95 (m, 2H), 6.94–6.89 (m, 4H), 3.89 (s, 3H), 3.80 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 187.1, 161.9, 156.5, 141.5, 132.9, 131.3, 130.6, 118.1, 115.1, 113.7, 108.7, 55.6, 55.4; HRMS (EI) m/z calcd for C₁₇H₁₆NO₃Cl [M]⁺ 317.0819, found 317.0812.

(Z)-2-Chloro-1-(4-methoxyphenyl)-3-((3-nitrophenyl)amino)prop-2-en-1-one (3cl). The crude product was purified by column chromatography on silica gel using hexane/ethyl acetate = 80 : 20 (v/v) as the eluent. Yield 55% (46 mg); yellow solid, melting point: 169–170 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.94–7.88 (m, 2H), 7.82 (t. J = 4.0 Hz, 1H), 7.73–7.69 (m, 2H), 7.52 (t, J = 8.0 Hz, 1H), 7.34–7.27 (m, 2H), 7.03–6.99 (m, 2H), 3.91 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 187.3, 162.6, 149.4, 140.8, 138.2, 130.9, 130.8, 130.4, 121.5, 117.9, 113.9, 111.5, 110.7, 55.5; HRMS (EI) m/z calcd for C₁₆H₁₄N₂O₄Cl [M + H]⁺ 333.0642, found 333.0645.

(Z)-2-Chloro-3-((4-chlorophenyl)amino)-1-(4-methoxyphenyl)prop-2-en-1-one (3cp). The crude product was purified by column chromatography on silica gel using hexane/ethyl acetate = 80 : 20 (v/v) as the eluent. Yield 65% (52 mg); yellow solid, melting point: 174–175 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.81 (d, J = 12.0 Hz, 1H), 7.68–7.65 (m, 2H), 7.32–7.28 (m, 2H), 7.12 (d, J = 16.0 Hz, 1H), 7.00–6.96 (m, 2H), 6.92–6.88 (m, 2H), 3.90 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 187.2, 162.3, 139.5, 138.1, 130.8, 130.7, 129.9, 128.9, 117.3, 113.7, 110.1, 55.4; HRMS (EI) m/z calcd for C₁₆H₁₃NO₂Cl₂ [M]⁺ 321.0323, found 321.0318.

(Z)-2-Chloro-1-(4-chlorophenyl)-3-(phenylamino)prop-2-en-1-one (3da). The crude product was purified by column chromatography on silica gel using hexane/ethyl acetate = 85 : 15 (v/v) as the eluent. Yield 80% (58 mg); yellow solid, melting point: 170–171 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.85 (d, J = 12.0 Hz, 1H), 7.61–7.57 (m, 2H), 7.48–7.44 (m, 2H), 7.37–7.30 (m, 3H), 7.15–7.11 (m, 1H), 6.98–6.95 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 186.8, 141.1, 139.0, 137.3, 137.1, 129.99, 129.97, 128.7, 124.3, 116.4, 109.3; HRMS (EI) m/z calcd for C₁₅H₁₂NOCl₂ [M + H]⁺ 292.0296, found 292.0301.

(Z)-2-Chloro-1-(4-chlorophenyl)-3-((4-methoxyphenyl)amino)prop-2-en-1-one (3dj). The crude product was purified by column chromatography on silica gel using hexane/ethyl acetate = 85 : 15 (v/v) as the eluent. Yield 75% (60 mg); yellow solid, melting point: 173–174 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.74 (d, J = 16.0 Hz, 1H), 7.59–7.57 (m, 2H), 7.46–7.43 (m, 2H), 7.17 (d, J = 12.0 Hz, 1H), 6.93–6.88 (m, 4H), 3.81 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 186.6, 156.8, 142.3, 137.3, 137.1, 132.5, 129.9, 128.7, 118.3, 115.2, 108.5, 55.6; HRMS (EI) m/z calcd for C₁₆H₁₄NO₂Cl₂ [M + H]⁺ 322.0402, found 322.0405.

(Z)-2-Chloro-1-(4-chlorophenyl)-3-((3-nitrophenyl)amino)prop-2-en-1-one (3dl). The crude product was purified by column chromatography on silica gel using hexane/ethyl acetate = 85 : 15 (v/v) as the eluent. Yield 47% (39 mg); yellow solid, melting point: 200–201 °C. ¹H NMR (400 MHz, CDCl₃) δ 9.90 (d, J = 12.0 Hz, 1H), 8.19 (t, J = 4.0 Hz, 1H), 7.88–7.85 (m, 1H), 7.71–7.65 (m, 3H), 7.60–7.55 (m, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 186.6, 148.9, 143.2, 142.1, 137.9, 136.3, 131.2, 130.9, 128.9, 123.2, 117.9, 112.7, 109.1; HRMS (EI) m/z calcd for C₁₅H₁₁N₂O₃Cl₂ [M + H]⁺ 337.0147, found 337.0147.

(Z)-2-Chloro-1-(4-chlorophenyl)-3-((4-chlorophenyl)amino)prop-2-en-1-one (3dp). The crude product was purified by column chromatography on silica gel using hexane/ethyl acetate = 85 : 15 (v/v) as the eluent. Yield 69% (56 mg); yellow solid, melting point: 199–200.5 °C. ¹H NMR (400 MHz, CDCl₃) δ 9.69 (d, J = 12.0 Hz, 1H), 7.84 (d, J = 12.0 Hz, 1H), 7.66–7.63 (m, 2H), 7.56–7.53 (m, 2H), 7.38–7.34 (m, 2H), 7.28–7.24 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 186.3, 143.8, 139.8, 138.1, 136.0, 130.8, 129.7, 128.9, 127.8, 119.4, 108.1; HRMS (EI) m/z calcd for C₁₅H₁₁NOCl₃ [M + H]⁺ 325.9906, found 325.9912.

(Z)-1-(4-Bromophenyl)-2-chloro-3-(phenylamino)prop-2-en-1-one (3ea). The crude product was purified by column chromatography on silica gel using hexane/ethyl acetate = 85 : 15 (v/v) as the eluent. Yield 91% (76 mg); yellow solid, melting point: 179–180 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.82 (d, J = 12.0 Hz, 1H), 7.62–7.59 (m, 2H), 7.52–7.48 (m, 2H), 7.36–7.32 (m, 2H), 7.23 (d, J = 12.0 Hz, 1H), 6.95–6.93 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 186.9, 141.1, 138.9, 137.5, 131.7, 130.1, 125.7, 124.4, 116.4, 109.4; HRMS (EI) m/z calcd for C₁₅H₁₁NOClBr [M]⁺ 334.9713, found 334.9703.

(Z)-1-(4-Bromophenyl)-2-chloro-3-((4-methoxyphenyl)amino)prop-2-en-1-one (3ej). The crude product was purified by column chromatography on silica gel using hexane/ethyl acetate = 80 : 20 (v/v) as the eluent. Yield 87% (79 mg); yellow solid, melting point: 188–189 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.72 (d, J = 12.0 Hz, 1H), 7.60–7.57 (m, 2H), 7.50–7.46 (m, 2H), 7.18 (d, J = 12.0 Hz, 1H), 6.91–6.85 (m, 4H), 3.78 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 186.7, 156.8, 142.3, 137.7, 132.5, 131.6, 130.1, 125.5, 118.3, 115.2, 108.5, 55.6; HRMS (EI) m/z calcd for C₁₆H₁₃NO₂ClBr [M]⁺ 364.9818, found 364.9812.

(Z)-1-(4-Bromophenyl)-2-chloro-3-((3-nitrophenyl)amino)prop-2-en-1-one (3el). The crude product was purified by column chromatography on silica gel using hexane/ethyl acetate = 80 : 20 (v/v) as the eluent. Yield 72% (68 mg); yellow solid, melting point: 197–198 °C. ¹H NMR (400 MHz, CDCl₃) δ 9.91 (s, 1H), 8.20 (t, J = 2.0 Hz, 1H), 7.99 (s, 1H), 7.88–7.85 (m, 1H), 7.72–7.56 (m, 6H); ¹³C NMR (100 MHz, CDCl₃) δ 186.7, 148.9, 143.2, 142.1, 138.2, 131.9, 131.2, 131.1, 125.2, 123.2, 117.9, 112.7, 109.0; HRMS (EI) m/z calcd for C₁₅H₁₀N₂O₃ClBr [M]⁺ 379.9563, found 379.9554.

(Z)-1-(4-Bromophenyl)-2-chloro-3-((4-chlorophenyl)amino)prop-2-en-1-one (3ep). The crude product was purified by column chromatography on silica gel using hexane/ethyl acetate = 85 : 15 (v/v) as the eluent. Yield 76% (70 mg); yellow solid, melting point: 209–210 °C. ¹H NMR (400 MHz, CDCl₃) δ 9.69 (d, J = 12.0 Hz, 1H), 7.84 (d, J = 16.0 Hz, 1H), 7.70–7.67 (m, 2H), 7.59–7.56 (m, 2H), 7.38–7.34 (m, 2H), 7.28–7.24 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 186.4, 143.7, 139.8, 138.5, 131.9, 130.9, 129.7, 127.8, 124.9, 119.4, 108.1; HRMS (EI) m/z calcd for C₁₅H₁₁NOCl₂Br [M + H]⁺ 369.9401, found 369.9404.

General procedure for the scaled-up synthesis of 3aa and 3ad

Aniline 2a or 2d (3.5 mmol), β-chloroenone 1a (4.2 mmol, 0.697 g), and DMSO (20 mL) were added to a 100 mL reaction flask that was dried in an oven and cooled to room temperature under an N₂ atmosphere. The reaction mixture was heated at 90 °C using an oil bath for 8 h. Then, the reaction mixture was cooled to room temperature and transferred to a separatory funnel using ethyl acetate (60 mL). Water (50 mL) was added, and the organic layer was separated. The aqueous layer was extracted again with ethyl acetate (30 mL). The combined organic layer was washed with brine solution and dried over MgSO₄. The solvent was evaporated under reduced pressure using a rotary evaporator. The crude product was purified by silica gel column chromatography using an ethyl acetate/hexane mixture as the eluent.

General procedure for the synthesis of 1,4-benzodiazepine derivatives

o-Phenylenediamine (0.5 mmol), β-chloroenone (0.5 mmol), and DMSO (3 mL) were added to an oven-dried 10 mL reaction flask cooled under a N₂ atmosphere. The reaction mixture was stirred for 12 h at room temperature. Then, the reaction mixture was transferred to a separatory funnel using ethyl acetate (30 mL). Water (30 mL) was added, and the organic layer was separated. The aqueous layer was extracted again with ethyl acetate (20 mL). The combined organic layer was washed with brine solution and dried over MgSO₄. The solvent was evaporated under reduced pressure using a rotary evaporator. The crude product was purified by silica gel column chromatography using an ethyl acetate/hexane mixture as the eluent.

2-(3-Benzoyl-2,5-dihydro-1H-benzo[b][1,4]diazepin-2-yl)-1-phenylethan-1-one 6aa. The crude product was purified by column chromatography on silica gel using hexane/ethyl acetate = 80 : 20 (v/v) as the eluent. Yield 40% (37 mg); yellow solid, melting point: 102–103 °C. ¹H NMR (400 MHz, DMSO-d₆) δ 9.45 (d, J = 8.0 Hz, 1H), 7.94–7.91 (m, 2H), 7.60 (t, J = 8.0 Hz, 1H), 7.50–7.39 (m, 7H), 7.01 (d, J = 8.0 Hz, 1H), 6.89–6.85 (m, 2H), 6.78–6.72 (m, 2H), 6.69–6.66 (m, 2H), 5.72 (d, J = 4.0 Hz, 1H), 5.11–5.06 (m, 1H), 3.11–2.98 (m, 2H); ¹³C NMR (100 MHz, DMSO-d₆) δ 199.2, 192.4, 146.7, 141.0, 137.7, 137.0, 133.6, 131.4, 129.9, 129.0, 128.5, 128.4, 123.8, 122.1, 121.0, 120.3, 116.0, 51.5, 45.6; HRMS (EI) m/z calcd for C₂₄H₂₀N₂O₂ [M]⁺ 368.1525, found 368.1537.

2-(3-Benzoyl-7,8-dimethyl-2,5-dihydro-1H-benzo[b][1,4]diazepin-2-yl)-1-phenylethan-1-one 6ab. The crude product was purified by column chromatography on silica gel using hexane/ethyl acetate = 80 : 20 (v/v) as the eluent. Yield 42% (44 mg); yellow solid, melting point: 113–114 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.85 (d, J = 4.0 Hz, 2H), 7.50 (t, J = 8.0 Hz, 1H), 7.46–7.34 (m, 6H), 7.30–7.26 (m, 2H), 7.05 (d, J = 8.0 Hz, 1H), 6.45 (s, 1H), 6.37 (s, 1H), 5.17 (dd, J = 8.0, 4.0 Hz, 1H), 4.98 (brs, 1H), 3.32 (dd, J = 16.0, 4.0 Hz, 1H), 2.87 (dd, J = 12.0, 16.0 Hz, 1H), 2.00 (s, 3H), 1.96 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 200.0, 193.9, 146.9, 140.3, 136.8, 134.0, 133.1, 132.9, 130.0, 129.7, 128.5, 128.4, 128.3, 128.0, 123.4, 121.1, 115.7, 52.2, 43.8, 18.8, 18.7; HRMS (EI) m/z calcd for C₂₆H₂₄N₂O₂ [M]⁺ 396.1838, found 396.1834.

2-(3-(4-Methylbenzoyl)-2,5-dihydro-1H-benzo[b][1,4]diazepin-2-yl)-1-(p-tolyl)ethan-1-one 6ba. The crude product was purified by column chromatography on silica gel using hexane/ethyl acetate = 80 : 20 (v/v) as the eluent. Yield 39% (39 mg); yellow solid, melting point: 67–68 °C. ¹H NMR (400 MHz, DMSO-d₆) δ 9.38 (d, J = 8.0 Hz, 1H), 7.81 (d, J = 8.0 Hz, 2H), 7.32–7.23 (m, 6H), 7.02 (d, J = 8.0 Hz, 1H), 6.87–6.85 (m, 2H), 6.76–6.70 (m, 2H), 6.66–6.63 (m, 1H), 5.67 (d, J = 4.0 Hz, 1H), 5.05 (quint, J = 4.0 Hz, 1H), 3.06–2.95 (m, 2H), 2.35 (s, 3H), 2.34 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ 198.7, 192.4, 146.4, 143.9, 139.6, 138.2, 137.7, 134.6, 131.5, 129.6, 128.9, 128.6, 123.7, 122.1, 120.9, 120.2, 116.1, 51.5, 45.4, 21.6, 21.4; HRMS (EI) m/z calcd for C₂₆H₂₄N₂O₂ [M]⁺ 396.1838, found 396.1850.

2-(7,8-Dimethyl-3-(4-methylbenzoyl)-2,5-dihydro-1H-benzo[b] [1,4]diazepin-2-yl)-1-(p-tolyl)ethan-1-one 6bb. The crude product was purified by column chromatography on silica gel using hexane/ethyl acetate = 80 : 20 (v/v) as the eluent. Yield 37% (39 mg); yellow solid, melting point: 108–109 °C. ¹H NMR (400 MHz, DMSO-d₆) δ 9.23 (d, J = 8.0 Hz, 1H), 7.83–7.80 (m, 2H), 7.28–7.22 (m, 6H), 6.97 (d, J = 8.0 Hz, 1H), 6.61 (s, 1H), 6.41 (s, 1H), 5.41 (brs, 1H), 5.1–4.96 (m, 1H), 3.05–2.90 (m, 2H), 2.36 (s, 6H), 2.05 (s, 3H), 1.97 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ 198.9, 192.2, 146.4, 143.8, 139.4, 138.4, 135.2, 134.7, 131.5, 130.1, 129.5, 128.9, 128.6, 128.5, 128.4, 123.1, 121.2, 115.7, 51.6, 45.4, 21.6, 21.4, 19.0, 18.8; HRMS (EI) m/z calcd for C₂₈H₂₈N₂O₂ [M]⁺ 424.2151, found 424.2136.

2-(3-(4-Methoxybenzoyl)-2,5-dihydro-1H-benzo[b][1,4]diazepin-2-yl)-1-(4-methoxyphenyl)ethan-1-one 6ca. The crude product was purified by column chromatography on silica gel using hexane/ethyl acetate = 60 : 40 (v/v) as the eluent. Yield 41% (44 mg); yellow solid, melting point: 110–111 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.85–7.83 (m, 2H), 7.65–7.52 (m, 1H), 7.45–7.43 (m, 2H), 7.13 (d, J = 8.0 Hz, 1H), 6.84–6.81 (m, 4H), 6.76–6.69 (m, 3H), 6.62–6.61 (m, 1H), 5.16 (dd, J = 1.7, 12.0 Hz, 1H), 4.98 (brs, 1H), 3.80 (s, 6H), 3.33 (d, J = 12.0 Hz, 1H), 2.82 (dd, J = 12.0, 16.0 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 198.3, 193.4, 163.5, 161.2, 146.0, 136.4, 132.4, 131.2, 130.6, 130.3, 129.8, 124.1, 122.4, 121.7, 119.9, 116.0, 113.6, 113.4, 55.4, 55.3, 52.5, 43.7; HRMS (EI) m/z calcd for C₂₆H₂₄N₂O₄ [M]⁺ 428.1736, found 428.1731.

2-(3-(4-Methoxybenzoyl)-7,8-dimethyl-2,5-dihydro-1H-benzo[b] [1,4]diazepin-2-yl)-1-(4-methoxyphenyl)ethan-1-one 6cb. The crude product was purified by column chromatography on silica gel using hexane/ethyl acetate = 60 : 40 (v/v) as the eluent. Yield 38% (44 mg); yellow solid, melting point: 115–116 °C. ¹H NMR (400 MHz, DMSO-d₆) δ 9.23 (d, J = 8.0 Hz, 1H), 7.93–7.89 (m, 2H), 7.42–7.38 (m, 2H), 7.03 (d, J = 8.0 Hz, 1H), 7.00–6.96 (m, 4H), 6.63 (s, 1H), 6.41 (s, 1H), 5.42 (brs, 1H), 4.97 (d, J = 8.0 Hz, 1H), 3.82 (s, 3H), 3.81 (s, 3H), 3.03 (dd, J = 4.0, 16.0 Hz, 1H), 2.89 (dd, J = 12.0, 16.0 Hz), 2.05 (s, 3H), 1.97 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ 197.7, 191.6, 163.5, 160.8, 145.9, 135.1, 133.3, 131.3, 130.8, 130.5, 130.1, 129.0, 128.4, 123.1, 121.1, 115.6, 114.2, 113.7, 55.9, 55.7, 45.1, 19.0, 18.8; HRMS (EI) m/z calcd for C₂₈H₂₈N₂O₄ [M]⁺ 456.2049, found 456.2033.

2-(3-(4-Chlorobenzoyl)-2,5-dihydro-1H-benzo[b][1,4]diazepin-2-yl)-1-(4-chlorophenyl)ethan-1-one 6da. The crude product was purified by column chromatography on silica gel using hexane/ethyl acetate = 80 : 20 (v/v) as the eluent. Yield 10% (11 mg); yellow solid, melting point: 151–152 °C. ¹H NMR (400 MHz, DMSO-d₆) δ 9.51 (d, J = 8.0 Hz, 1H), 7.94–7.91 (m, 2H), 7.56–7.52 (m, 2H), 7.51–7.49 (m, 2H), 7.43–7.40 (m, 2H), 6.97 (d, J = 8.0 Hz, 1H), 6.90–6.86 (m, 1H), 6.78–6.74 (m, 2H), 6.70–6.64 (m, 1H), 5.77 (brs, 1H), 5.02 (t, J = 8.0 Hz, 1H), 3.06–2.98 (m, 2H); ¹³C NMR (100 MHz, DMSO-d₆) δ 198.1, 190.9, 146.8, 139.7, 138.5, 137.8, 135.7, 134.6, 131.2, 130.4, 130.3, 129.1, 128.5, 123.9, 122.1, 121.0, 120.5, 115.8, 51.5, 45.9; HRMS (EI) m/z calcd for C₂₄H₁₈N₂O₂Cl₂ [M]⁺ 436.0745, found 436.0736.

2-(3-(4-Chlorobenzoyl)-7,8-dimethyl-2,5-dihydro-1H-benzo[b] [1,4]diazepin-2-yl)-1-(4-chlorophenyl)ethan-1-one 6db. The crude product was purified by column chromatography on silica gel using hexane/ethyl acetate = 80 : 20 (v/v) as the eluent. Yield 15% (18 mg); yellow solid, melting point: 141–142 °C. ¹H NMR (400 MHz, DMSO-d₆) δ 9.37 (d, J = 8.0 Hz, 1H), 7.94–7.91 (m, 2H), 7.56–7.52 (m, 2H), 7.51–7.48 (m, 2H), 7.40–7.37 (m, 2H), 6.93 (d, J = 8.0 Hz, 1H), 6.64 (s, 1H), 6.43 (s, 1H), 5.57 (s, 1H), 4.99 (t, J = 8.0 Hz, 1H), 3.05–2.95 (m, 2H), 2.06 (s, 3H), 1.98 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ 198.3, 190.8, 146.8, 139.9, 138.4, 135.8, 135.2, 134.5, 131.8, 130.4, 130.2, 129.1, 128.8, 128.6, 128.5, 123.2, 121.4, 115.5, 51.7, 45.8, 19.0, 18.8; HRMS (EI) m/z calcd for C₂₆H₂₂N₂O₂Cl₂ [M]⁺ 464.1058, found 464.1051.

2-(3-(4-Bromobenzoyl)-2,5-dihydro-1H-benzo[b][1,4]diazepin-2-yl)-1-(4-bromophenyl)ethan-1-one 6ea. The crude product was purified by column chromatography on silica gel using hexane/ethyl acetate = 85 : 15 (v/v) as the eluent. Yield 20% (26 mg); yellow solid, melting point: 203–204 °C. ¹H NMR (400 MHz, DMSO-d₆) δ 9.48 (d, J = 8.0 Hz, 1H), 7.86–7.83 (m, 2H), 7.70–7.66 (m, 2H), 7.65–7.62 (m, 2H), 7.36–7.32 (m, 2H), 6.96 (d, J = 8.0 Hz, 1H), 6.89–6.86 (m, 1H), 6.77–6.73 (m, 2H), 6.69–6.65 (m, 1H), 5.76 (d, J = 4.0 Hz, 1H), 5.05–5.00 (m, 1H), 3.06–2.96 (m, 2H); ¹³C NMR (100 MHz, DMSO-d₆) δ 198.3, 191.0, 146.8, 140.1, 137.8, 136.1, 132.1, 131.4, 131.2, 130.5, 127.7, 124.0, 123.3, 122.1, 121.0, 120.5, 115.8, 51.5, 45.8; HRMS (EI) m/z calcd for C₂₄H₁₈N₂O₂Br₂ [M]⁺ 523.9735, found 523.9738.

2-(3-(4-Bromobenzoyl)-7,8-dimethyl-2,5-dihydro-1H-benzo[b] [1,4]diazepin-2-yl)-1-(4-bromophenyl)ethan-1-one 6eb. The crude product was purified by column chromatography on silica gel using hexane/ethyl acetate = 85 : 15 (v/v) as the eluent. Yield 27% (37 mg); yellow solid, melting point: 167–169 °C. ¹H NMR (400 MHz, DMSO-d₆) δ 9.35 (d, J = 8.0 Hz, 1H), 7.85–7.82 (m, 2H), 7.68–7.66 (m, 2H), 7.64–7.61 (m, 2H), 7.33–7.30 (m, 2H), 6.93 (d, J = 8.0 Hz, 1H), 6.63 (s, 1H), 6.42 (s, 1H), 5.52 (d, J = 8.0 Hz, 1H), 5.05–4.96 (m, 1H), 3.05–2.95 (m, 2H), 2.05 (s, 3H), 1.98 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ 198.5, 190.8, 146.9, 140.2, 136.1, 135.4, 132.0, 131.8, 131.4, 130.5, 130.4, 128.7, 128.5, 127.6, 123.2, 123.1, 121.4, 115.5, 51.6, 45.8, 19.1, 18.8; HRMS (EI) m/z calcd for C₂₆H₂₂N₂O₂Br₂ [M + 2]⁺ 554.0028, found 554.0021.

3-((2-Aminophenyl)amino)-1-phenylprop-2-en-1-one 7aa. The crude product was purified by column chromatography on silica gel using hexane/ethyl acetate = 85 : 15 (v/v) as the eluent. Yield 28% (33 mg); the product was obtained as a mixture of stereoisomers in a 1 : 0.7 ratio. Yellow solid, melting point: 145–147 °C. ¹H NMR (400 MHz, CDCl₃) δ 12.20 (d, J = 12.0 Hz, 0.7H), 12.11 (d, J = 12.0 Hz, 1H), 7.95–7.93 (m, 3.3H), 7.49–7.38 (m, 7H), 7.17–6.96 (m, 3.5H), 6.85–6.79 (m, 2H), 6.12 (d, J = 8.0 Hz, 0.7H), 6.05 (d, J = 8.0 Hz, 1H), 3.56 (brs, 2.7H); ¹³C NMR (100 MHz, CDCl₃) δ 191.3, 190.9, 147.3, 146.4, 139.3, 139.2, 137.2, 132.2, 131.5, 131.4, 128.6, 128.5, 128.3, 127.5, 127.3, 125.3, 125.2, 119.9, 119.0, 117.8, 117.3, 95.5, 93.8; HRMS (EI) m/z calcd for C₁₅H₁₄N₂O [M]⁺ 238.1106, found 238.1102.

Data availability

The data supporting this article have been included as part of the ESI.†

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

The Ministry of Science and Technology ROC (MOST 111-2133-M-003-016) is gratefully acknowledged for its financial support. The authors are grateful to the instrumentation center at National Taiwan Normal University for providing the analytical NMR (Ms Chiu-Hui He) and HRMS (Ms Hsiu-Min Huan) data presented in this paper.

References

1. (a) Y. Han, L. Zhou, C. Wang, S. Feng, R. Ma and J.-P. Wan, Chin. Chem. Lett., 2024, 35, 108977; (b) Z. Wang, B. Zhao, Y. Liu and J.-P. Wan, Adv. Synth. Catal., 2022, 364, 1508; (c) M.-Z. Lu, J. Goh, M. Maraswami, Z. Jia, J.-S. Tian and T.-P. Loh, Chem. Rev., 2022, 122, 17479; (d) I. J. Amaye, R. D. Haywood, E. M. Mandzo, J. J. Wirick and P. L. Jackson-Ayotunde, Tetrahedron, 2021, 83, 131984.
2. F. Wang, W. Sun, Y. Wang, Y. Jiang and T.-P. Loh, Org. Lett., 2018, 20, 1256.
3. J.-P. Wan, S. Zhong, L. Xie, X. Cao, Y. Liu and L. Wei, Org. Lett., 2016, 18, 584.
4. (a) Y. Gao, Y. Liu and J.-P. Wan, J. Org. Chem., 2019, 84, 2243; (b) Z. Yang, L. Hu, T. Cao, L. An, L. Li, T. Yang and C. Zhou, New J. Chem., 2019, 43, 16441; (c) X. Duan, X. Liu, X. Cuan, L. Wang, K. Liu, H. Zhou, X. Chen, H. Li and J. Wang, J. Org. Chem., 2019, 84, 12366.
5. (a) Y. Xie, Z. Zhang, B. Zhang, N. He, M. Peng, S. Song, B. Wang and F. Yu, J. Org. Chem., 2024, 89, 8521; (b) G. S. Sorabad and M. R. Maddani, New J. Chem., 2019, 43, 6563; (c) H. Xu, P. Zhou, R. Hang, J. Zhou, L.-L. Lu, Y. Shen and F.-C. Yu, Tetrahedron Lett., 2016, 57, 4965; (d) N. G. Ramesh, E. H. Heijne, A. J. H. Klunder and B. Zwanenburg, Tetrahedron, 2002, 58, 1361.
6. (a) T. Zhang, W. Yao, J.-P. Wan and Y. Liu, Adv. Synth. Catal., 2021, 363, 4811; (b) B. Zhang, D. Liu, Y. Sun, Y. Zhang, J. Feng and F. Yu, Org. Lett., 2021, 23, 3076; (c) Y. Lin, J. Jin, C. Wang, J.-P. Wan and Y. Liu, J. Org. Chem., 2021, 86, 12378; (d) T. Luo, J.-P. Wan and Y. Liu, Org. Chem. Front., 2020, 7, 1107; (e) Y. Siddaraju and K. R. Prabhu, J. Org. Chem., 2017, 82, 3084; (f) Y. Yuan, W. Hou, D. Zhang-Negrerie, K. Zhao and Y. Du, Org. Lett., 2014, 16, 5410.
7. (a) J.-i. Yamaguchi, Y. Akagi, R. Koike, K. Katou, T. Katakura, T. Hanase and T. Homma, Tetrahedron Lett., 2024, 135, 154876; (b) X. Li, Z. Chen, Y. Liu, N. Luo, W. Chen, C. Liu, F. Yu and J. Huang, J. Org. Chem., 2022, 87, 10349; (c) H. Wu, T. Luo, J.-P. Wan, J. Jiang and Y. Liu, Eur. J. Org. Chem., 2022, e202200552; (d) T. Liu, L. Wei, B. Zhao, Y. Liu and J.-P. Wan, J. Org. Chem., 2021, 86, 9861; (e) Z. Jiang, J. Zhou, H. Zhu, H. Liu and Y. Zhou, Org. Lett., 2021, 23, 4406; (f) J. Chen, P. Guo, J. Zhang, J. Rong, W. Sun, Y. Jiang and T.-P. Loh, Angew. Chem., Int. Ed., 2019, 58, 12674; (g) J. Sun, X. Cheng, J. K. Mansaray, W. Fei, J. Wan and W. Yao, Chem. Commun., 2018, 54, 13953.
8. (a) M. Baidya, D. Maiti, L. Roy and S. D. Sarkar, Angew. Chem., Int. Ed., 2022, 61, e202111679; (b) L. Fu, J.-P. Wan, L. Zhou and Y. Liu, Chem. Commun., 2022, 58, 1808; (c) H. Guo, L. Tian, Y. Liu and J.-P. Wan, Org. Lett., 2022, 24, 228; (d) L. Fu, Y. Liu and J.-P. Wan, Org. Lett., 2021, 23, 4363; (e) S. Mkrtchyan and V. O. Iaroshenko, Chem. Commun., 2020, 56, 2606; (f) S. Zhou, D.-Y. Liu, S. Wang, J.-S. Tian and T.-P. Loh, Chem. Commun., 2020, 56, 15020; (g) M.-N. Zhao, Z.-J. Zhang, Z.-H. Ren, D.-S. Yang and Z.-H. Guan, Org. Lett., 2018, 20, 3088; (h) Y.-X. Jiao, L.-S. Wei, C.-Y. Zhao, K. Wei, D.-L. Mo, C.-X. Pan and G.-F. Su, Adv. Synth. Catal., 2018, 360, 4446; (i) S. Tang, X. Gao and A. Lei, Chem. Commun., 2017, 53, 3354; (j) J. Liu, W. Wei, T. Zhao, X. Liu, J. Wu, W. Yu and J. Chang, J. Org. Chem., 2016, 81, 9326; (k) C.-J. Wu, Q.-Y. Meng, T. Lei, J.-J. Zhong, W.-Q. Liu, L.-M. Zhao, Z.-J. Li, B. Chen, C.-H. Tung and L.-Z. Wu, ACS Catal., 2016, 6, 4635.
9. (a) R. Kumar, N. Saha, P. Purohit, S. K. Garg, K. Seth, V. S. Meena, S. Dubey, K. Dave, R. Goyal, S. S. Sharma, U. C. Banerjee and A. K. Chakraborti, Eur. J. Med. Chem., 2019, 182, 111601; (b) M. M. Ghorab, F. A. Ragab, H. I. Heiba, M. G. Ei-Gazzar and M. G. M. Ei-Gazzar, Bioorg. Med. Chem. Lett., 2018, 28, 1464; (c) M. Cindric, M. Rubcic, T. Hrenar, J. Pisk, D. Cvijanovic, J. Lovric and V. Vrdoljak, J. Mol. Struct., 2018, 1154, 636; (d) P. V. Sowmya, B. Poojary, B. C. Revanasiddappa, M. Vijayakumar, P. Nikil and V. Kumar, Res. Chem. Intermed., 2017, 43, 7399.
10. (a) K. Keskar, C. Zepeda-Velazquez, C. B. Dokuburra, H. A. Jenkins and J. McNulty, Chem. Commun., 2019, 55, 10868; (b) M. J. Gonzalez-Soria and F. Alonso, Adv. Synth. Catal., 2019, 361, 5005; (c) A. Pal and S. R. Hussaini, ACS Omega, 2019, 4, 269; (d) Y.-P. Liu, C.-J. Zhu, C.-C. Yu, A.-E. Wang and P.-Q. Huang, Eur. J. Chem., 2019, 7169; (e) X. Duan, S. Yang, C. Yao, F. Jia, L. Wang, W. Li, Z. Meng, Y. Zhou and X. Li, ChemistrySelect, 2019, 4, 12992; (f) Z. Zheng, Q. Tao, Y. Ao, M. Xu and Y. Li, Org. Lett., 2018, 20, 3907; (g) A. Leggio, A. Comande, E. L. Belsito, M. Greco, L. L. Feudo and A. Liguori, Org. Biomol. Chem., 2018, 16, 5677; (h) Y.-W. Kang, Y. J. Cho, S. J. Han and H.-Y. Jang, Org. Lett., 2016, 18, 272; (i) W. Shi, S. Sun, M. Wu, B. Catano, W. Li, J. Wang, H. Guo and Y. Xing, Tetrahedron Lett., 2015, 56, 468; (j) S. M. Kim, D. Lee and S. H. Hong, Org. Lett., 2014, 16, 6168.
11. T. Miura, Y. Funakoshi, T. Tanaka and M. Murakami, Org. Lett., 2014, 16, 2760.
12. S. Suresh, P. B. Patil, P.-H. Yu, C.-C. Fang, Y.-Z. Weng, V. Kavala and C.-F. Yao, Adv. Synth. Catal., 2021, 363, 4915.
13. (a) S. A. Dhabale, S. Kumar, N. Bhanwala and G. L. Khatik, Curr. Org. Chem., 2023, 27, 1471; (b) J. Schimer, P. Cígler, J. Veselý, K. G. Šašková, M. Lepšík, J. Brynda, P. Řezáčová, M. Kožíšek, I. Císařová, H. Oberwinkler, H.-G. Kraeusslich and J. Konvalinka, J. Med. Chem., 2012, 55, 10130; (c) L.-Z. Wang, X.-Q. Li and Y.-S. An, Org. Biomol. Chem., 2015, 13, 5497.
14. (a) S. Farooq and Z. Ngaini, J. Heterocycl. Chem., 2021, 58, 1914; (b) R. Jamatia, A. Gupta, B. Dam, M. Saha and A. K. Pal, Green Chem., 2017, 19, 1576; (c) M. Kodomari, T. Noguchi and T. Aoyama, Synth. Commun., 2004, 34, 1783.
15. (a) F. K. Sarkar, A. Gupta, R. Jamatia, J. M. H. Anal and A. K. Pal, New J. Chem., 2021, 45, 19553; (b) K. J. Tamuli and M. Bordoloi, ChemistrySelect, 2020, 5, 1353; (c) M. Jeganathan and K. Pitchumani, ACS Sustainable Chem. Eng., 2014, 2, 1169; (d) C.-W. Kuo, C.-C. Wang, V. Kavala and C.-F. Yao, Molecules, 2008, 13, 2313; (e) S. D. Sharma, P. Gogoi and D. Konwar, Green Chem., 2007, 9, 153; (f) R. Kumar, P. Chaudhary, S. Nimesh, A. K. Verma and R. Chandra, Green Chem., 2006, 8, 519.
16. L. Feray, P. Perfetti and M. Bertrand, Tetrahedron, 2009, 65, 8733.

---

Footnotes

† Electronic supplementary information (ESI) available: Spectra copies of all the compounds and mass spectrometric data. CCDC 2334143 (3aa), 2370736 (3af) and 2360356 (6ea). For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d4ob00954a

‡ These authors contributed equally.

---