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Synlett 2024; 35(20): 2403-2408
DOI: 10.1055/a-2377-0230
letter
Special Issue to Celebrate the 75th Birthday of Prof. B. C. Ranu

Cobalt(II)-Catalyzed Proficient Synthesis of Enaminones from Aryl Alkenes and Amines

Subham Sau‡
,
Krishna Mohan Das‡
,
Swapnamoy Ghosh
,
Arunabha Thakur∗

S.S. and K.M.D. thank CSIR and UGC, respectively, for JRF and SRF fellowships.
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Dedicated to Professor B. C. Ranu on his 75th birthday.

Abstract

A simple, cost-effective, and modular strategy has been developed to synthesize synthetically and pharmaceutically active enaminones by oxidative amination of aryl alkenes with amines and CHCl3, using tert-butyl hydroperoxide as an oxidant. We describe the synthesis of enaminones from vinyl arenes and sterically hindered N,N-diisopropylethylamine (DIPEA) by employing an Earth-abundant cobalt salt as a catalyst within a very short reaction period for the first time. Furthermore, nitrogen- and oxygen-containing heterocyclic compounds have been synthesized from these highly functionalized enaminones. Moreover, various control experiments, such as radical trapping reaction, along with a Hammett analysis with various types of substituents on the styrene ring unraveled the detailed mechanism of this reaction pathway.


#

Key words

enaminones - vinylarenes - cobalt catalysis - Hammet analysis - Oxidative amination
Zoom Image
Scheme 1 Selected examples of syntheses of enaminones

β-Enaminones have versatile synthetic applications in organic chemistry, as well as in the pharmaceutical field,[1] due to the presence of an O=C–C=C–N fragment that provides three electrophilic and two nucleophilic points.[2] Such compounds act as important precursors for the preparation of heterocycles[3] and naturally occurring alkaloids.[4] Some classical approaches are known for the synthesis of β-enaminones such as the condensation of amines with 1,3-dicarbonyl compounds[5] or the addition of metal enolates to unsaturated C=N bonds.[5] Additionally, many advanced methods have been reported for the synthesis of enaminones in which inorganic acids or microwave[6] and ultrasound irradiation[7] were used. Most of these had many drawbacks, such as tedious workup procedures, unavailable starting materials, low yields, or sensitive or harsh reaction conditions. Recently, to circumvent these problems, Kuwano’s group proposed a novel methodology for preparing β-enaminone through a nickel-catalyzed oxidative amination of ketones with morpholine; however, high temperatures and additives were required for this transformation.[8] Newhouse’s group then developed a similar procedure for the regioselective synthesis of enaminones by using a ketone as starting material in the presence of aminomethylene electrophile (Gold’s reagents); however, the substrate scope was very limited (Scheme [1a]).[9] Another convenient strategy for the synthesis of β-enaminone has been established through condensation of propiolaldehydes and amines in EtOH.[10] Dai and co-workers[11] reported an efficient approach to the synthesis of enaminones through amination of propargyl alcohols in the presence of an expensive silver catalyst (Scheme [1b]), and then the Jang group[12] developed a Brønsted acid-catalyzed stereoselective β-enaminone synthesis from a propargyl aldehyde and morpholine as coupling partners through a Meyer–Schuster rearrangement at high a temperature with a very long reaction time (Scheme [1c]). The starting material used in both cases needed to be presynthesized and purified before performing the reaction. Inspired by Zhang’s work[13] on the synthesis of α-peroxy-β,β-dichloropropylbenzene, Liu et al. reported an efficient method for the synthesis of β-enaminones by using styrene and CHCl3 as model substrates in the presence of NEt3 as a radical initiator.[14] However, this methodology is not suitable for sterically hindered tertiary amines such as N,N-diisopropylethylamine (DIPEA) and, importantly, affords products in low yields even with longer reaction times.

In continuation of our ongoing research interest in the development of cobalt-catalyzed organic transformations,[15] we examined a cobalt-salt-catalyzed difunctionalization of alkenes for the installation of two functional groups on a C=C bond in one step (Scheme [1d]). This methodology involves an inexpensive starting material and Earth-abundant CoCl2·6H2O as a catalyst under an aerobic atmosphere and avoids the need for additive or metal–ligand complex. Among the benefits of this methodology are the formation of enaminones from sterically hindered amines in excellent yields and the formation of various heterocyclic compounds after several postmodifications. Additionally, the reaction proceeds at a relatively low temperature (60 °C) with a short reaction time (3 h) for a wide range of substrates. A number of control reactions have been carried out in conjunction with a radical-scavenger experiment to elucidate the mechanistic pathway, and a Hammett analysis was performed to ascertain the electronic factors involved in the subsequent transformation. An Earth-abundant Co(II) salt catalyzed rapid transformation of aryl alkenes and amines to give industrially relevant enaminones in excellent yields; these products can subsequently be successfully converted into various heterocyclic compounds, making this methodology more desirable, affordable, and in great demand.

Table 1 Optimization of the Reaction Conditionsa,b

Entry

Catalyst (mol%)

Solvent

2a/3a (equiv)

Temp (℃)

Time (h)

Yield (%)b

 1c

CoCl2·6H2O (10)

CHCl3

-

80

12

65

 2

CoCl2·6H2O (10)

CH3CN

3:3

80

12

60

 3

CoCl2·6H2O (10)

PhCl

3:3

80

12

70

 4

CoCl2·6H2O (10)

toluene

3:3

80

12

90

 5

CoCl2·6H2O (10)

benzene

3:3

80

12

75

 6

CoCl2·6H2O (10)

toluene

2:2

80

12

40

 7

CoCl2·6H2O (10)

toluene

4:4

80

12

70

 8

CoCl2·6H2O (10)

toluene

5:5

80

12

75

 9

CoCl2·6H2O (10)

toluene

3:3

60

 3

90

10

CoCl2·6H2O (5)

toluene

4:4

60

 3

30

11

Co(OAc)2·4H2O (10)

toluene

4:4

60

 3

NDd

12e

CoCl2·6H2O (10)

toluene

4:4

60

 3

ND

13

CoCl2·6H2O (10)

toluene

–

60

 3

ND

14

–

toluene

–

60

 3

ND

a Reaction conditions: 1a (1 equiv), 2a, 3a, 70% aq TBHP (4 equiv), catalyst (10 mol%).

b Isolated yield after column chromatography.

c 2a (1.0 mL), 3a (1.0 mL).

d ND = not detected.

e No oxidant.

Inspired by a radical difunctionalization of alkenes,[16] we conducted our initial experiment using styrene (1a) and DIPEA (3a) as model substrates with tert-butyl hydroperoxide (TBHP) as an oxidant and CHCl3 (2a) as the solvent at 80 °C in the presence of CoCl2·6H2O as a catalyst. Pleasingly, the enaminone product 4a was isolated in 65% yield (Table [1], entry 1), which implied that CHCl3 acted as a substrate and DIPEA acted as an atom-transfer agent in this transformation. After this initial success, we attempted to improve the product yield by optimizing the reaction conditions. First, we examined the effect of various solvents [entries 2–5, and Supporting Information (SI); Table S1, entries 2–8]. We found that the maximum amount of product was obtained in the presence of toluene as the solvent (entry 4). Additionally, we screened the reaction in the presence of THF, DMF, and xylene as solvents, and found that no product was obtained with THF or DMF (SI; Table S1, entries 4–6). We then performed the reaction employing various ratios of 2a and 3a (entries 6–8), and the best result was obtained by using three equivalents each of 2a and 3a with respect to styrene (entry 9). We also screened the effect of various oxidants and, interestingly, when di-tert-butyl peroxide (DTBP) or benzoyl peroxide (BzO)2 was used as the oxidant, the product yield diminished to 5% (SI; Table S1, entries 12–14); no product was obtained in the presence of H2O2 (SI; Table S1, entry 15), and only the starting material remained in the reaction mixture. The same result was obtained when the reaction was performed by using O2 as an oxidant instead of an organic oxidant (SI; Table S1, entry 16). These experiments showed that only TBHP is an effective oxidant for this methodology (SI; Table S1, entry 17), possibly due to its higher reduction potential (1.48 V)[16] compared with the reduction potential of CoIII/CoII [0.74 V in the case of Co(OAc)2·4H2O]. On reducing the time and the temperature, the product yield remained unaltered (entry 9; for details, see the SI). Finally, we investigated the reaction using various metal salts, such as cobalt, copper, iron, or nickel salts (entry 11 and SI; Table S1, entries 25–30), as well as a cobalt complex[17] (SI; Table S1, entry 24) that we synthesized previously; these experiments showed that only CuCl2 as a metal salt furnished the desired product with 70% yield (SI; Table S1, entries 27–28).

Several control experiments confirmed that the catalyst, base (3a), and oxidant are all essential components for this transformation (Table [1], entries 12–14). By analyzing the various parameters, we found that the use of styrene 1a (1 equiv), CHCl3 (3 equiv), amine 3a (3 equiv), TBHP (3 equiv), and CoCl2·6H2O (10 mol%) in toluene (2 mL) at 60 ℃ for three hours provided the optimal conditions, giving the desired enaminone 4a in 90% yield (Table [1], entry 9).

After determining the optimal reaction conditions, we examined the reactions of various aryl arenes (1a–q) and amines (3a and 3b) to afford seventeen enaminones 4a–q (Scheme [2]),[18] four of which are new compounds (4d, 4g, 4o, and 4q).[19]

Zoom Image
Scheme 2 Substrate scope of various styrenes and amines. Reagents and conditions: 1 (1 equiv), 2a (3 equiv), 3a (3 equiv), TBHP (3 equiv), CoCl2·6H2O (10 mol%), 60 °C, 3 h. The isolated yields after column chromatography are reported.

Substrates having either an electron-donating or an electron-withdrawing group at the para- or meta-position of the aromatic ring were investigated, and all were well tolerated for producing the desired products. In the presence of an electron-donating group, the corresponding products were formed in higher yields (85–90%) compared with those with electron-withdrawing groups (75–80%) (4a–f). When a nonactivated aliphatic alkene was subjected to the reaction under identical conditions, the corresponding product 4g was formed in a moderate yield. Unfortunately, ortho-substituted vinyl arenes failed to give the desired products, possibly for steric reasons, which implied that, in this conversion, both electronic and steric factors have a major role in product formation. On changing the amine from DIPEA (3a) to triethylamine (3b), the reaction proceeded smoothly with excellent yields (4h–p); however, when DIPEA acted as a coupling partner, it produced a lower yield of the corresponding product compared with NEt3; this was attributed to a steric factor of the amine, as N,N-dimethylaniline was not a suitable coupling partner for this transformation.[14]

To further evaluate the substituent effect, a Hammett analysis was carried out through a series of competitive experiments to ascertain the rate of product formation of styrene and substituted styrene derivatives by using 1H NMR spectroscopy. A straight line was obtained with a negative ρ value of –0.32 (R 2 = 0.906) when the rate constants (log k X/k H) were plotted against the substituent constant (σ) (Figure [1]). The negative ρ value indicates the accumulation of positive charges in the transition state during the transformation for both electron-withdrawing and electron-donating substituents.[20]

Zoom Image
Figure 1 Hammett analysis

Having identified the optimal reaction conditions, we investigated the synthetic utility of the developed methodology in gram-scale reactions. The gram-scale reaction of styrene (1a) with CHCl3 (2a) and DIPEA (3a) or triethylamine (3b) proceeded smoothly to produce the corresponding enaminone products 4a and 4h in yields of 80 and 85%, respectively (Scheme [3a]). Our protocol gives highly functionalized enaminone compounds that provide opportunities for various further modifications. Compound 4h was treated with BrCF2CO2Et in CH3CN solvent in the presence of Na2CO3 at 140 °C to provide the biologically active difluorodihydrofuran derivative 6 in 90% yield (Scheme [3b]).[21] Furthermore, compound 4h gave the quinolin-3-yl ketone derivative 7 in 80% yield on reaction with p-toluidine and p-toluenesulfonic acid (PTSA) in DMSO at 110 °C.[22]

Zoom Image
Scheme 3 Gram-scale reaction and postmodifications

To understand the reaction mechanism in detail, various control reactions were carried out under the optimized reaction conditions. Initially, to ascertain the role of the catalyst, the reaction was performed without the catalyst (Scheme [4a]); this failed to give the desired product 4h, indicating that the metal catalyst (CoCl2·6H2O) acts as an initiator of the subsequent conversion. Furthermore, when the reaction was carried out in the absence of the oxidant, the desired product 4h was not obtained (Scheme [4b]). Interestingly, when the reaction was carried out in the absence of the base 3b, an intermediate product 4a′ was obtained instead of the desired product 4h (Scheme [4c]); this was confirmed by 1H NMR spectroscopy (SI; Figure S36). Therefore, we can conclude that not only the metal catalyst, but also the oxidant and base, play pivotal roles in the overall transformation. Furthermore, to confirm the involvement of radical intermediates, the reaction was performed in the presence of the radical scavenger 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO). As expected, the reaction of styrene (1a) with CHCl3 (2a) was quenched, producing the radical adduct 5a (Scheme [4d]). The formation of the radical adduct 5a with TEMPO was detected by HRMS analysis, indicating that the reaction proceeds through a radical intermediate (SI; Figure S42).

Zoom Image
Scheme 4 Control experiments

On the basis of the control reactions and a report in the literature,[23] we propose the plausible reaction mechanism shown in Scheme [5]. Initially the Co(II) salt induces the generation of a tert-butyloxy radical (t-BuO∙) and a hydroxy radical (HO∙) from t-BuOOH, and the cobalt is oxidized to Co(III); simultaneously, Co(III) is reduced to Co(II) through the formulation of a tert-butylperoxy radical (t-BuOO∙) from t-BuOOH to complete the catalytic cycle.[24] Then, the generated hydroxy radical abstracts a chlorine (HAT) from the CHCl3 to form a dichloromethane radical 2a ∙. This combines with styrene (1a) to generate a transitory radical A that combines with the previously generated t-BuOO∙ radical to form intermediate B (4a′). In the presence of a base, intermediate B undergoes a Kornblum–DeLaMare rearrangement to form another intermediate C.[25] Intermediate C then undergoes an elimination reaction followed by conjugate addition to furnish intermediates D and E sequentially. Finally, the target product 4a is formed with liberation of HCl from the intermediate F, which is formed by the elimination of the ethyl group from E with the help of Cl–.

Zoom Image
Scheme 5 Plausible reaction mechanism

In summary, we have developed a facile protocol for generating functionalized enaminones from aryl alkene derivatives in the presence of an Earth-abundant Co(II) salt as a catalyst, where several bond-breaking and bond-formation events take place within a single step. This stable synthetic approach can be scaled up to a gram scale and the products can be further modified to give various heterocyclic compounds. The precise effects and necessities for the catalyst, oxidant, and base involved in the catalytic cycle were elucidated by various control experiments. These types of multicomponent one-pot reactions have attracted considerable attention in the field of molecular synthesis due to their special qualities with regard to cost, atom and step economy, and synthetic divergence. Considering the medical significance of enaminones, this developed methodology might be beneficial and more economical for the pharmaceutical sector.


#

Conflict of Interest

The authors declare no conflict of interest.

Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/a-2377-0230.
  • Supporting Information

  • References and Notes

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  • 18 Enaminones 4a–q; General Procedure An oven-dried round-bottomed flask equipped with a stirrer bar was charged with CoCl2·6H2O (0.1 equiv, 0.1 mmol, 23.8 mg), DIPEA (3 equiv, 3 mmol, 0.52 mL), TBHP (3 equiv, 3 mmol, 0.29 mL), and toluene (1 mL). CHCl3 (3 equiv, 3 mmol, 0.24 mL) was added to the mixture, followed by the appropriate styrene derivative 1 (1.0 equiv, 1.0 mmol). The mixture was stirred for 3 h in a preheated oil bath at 60 °C, then cooled to r.t. H2O was added, and the mixture and extracted with CH2Cl2 (3 × 10 mL) and H2O. The organic phase was washed with brine, dried (Na2SO4), and concentrated under reduced pressure. The crude product was purified by column chromatography [silica gel (100–200 mesh), EtOAc–PE (3:7 to 4:6)].
  • 19 3-[(2E)-3-(Diisopropylamino)prop-2-enoyl]benzonitrile (4d) Purified by column chromatography (silica gel, 30% EtOAc–PE) to give a yellow oil; yield: 204.92 mg (0.80 mmol, 80%). 1H NMR (300 MHz, CDCl3): δ = 8.14–8.11 (m, 2 H), 7.98 (d, J = 12 Hz, 1 H), 7.72 (d, J = 9 Hz, 1 H), 7.52 (t, J = 7.5 Hz, 1 H), 5.70 (d, J = 12 Hz, 1 H), 3.33 (q, J = 7 Hz, 2 H), 1.32–1.27 (m, 12 H). 13C{1H} NMR (75 MHz, CDCl3): δ = 185.9, 151.7, 144.8, 141.8, 133.9, 131.8, 131.3, 129.5, 129.2, 112.4, 90.9, 57.7, 52.5, 41.6, 22.1, 12.7. Anal. Calcd for C16H20N2O: C, 74.97; H, 7.86; N, 10.93. Found: C, 74.71; H, 7.60; N, 11.06. (1E)-1-(Diisopropylamino)hept-1-en-3-one (4g) Purified by column chromatography (silica gel, 20% EtOAc–PE) to give a yellow oil; yield: 133.44 mg (0.65 mmol, 65%). 1H NMR (300 MHz, CDCl3): δ = 7.50 (d, J = 9 Hz, 1 H), 4.62 (d, J = 9 Hz, 1 H), 2.29 (t, J = 6 Hz, 2 H), 1.44–1.17 (m, 21 H). 13C{1H} NMR (75 MHz, CDCl3): δ = 170.3, 146.8, 84.9, 71.4, 68.9, 51.0, 37.3, 28.8, 27.6, 22.7, 14.1. Anal. Calcd for C13H25NO: C, 73.88; H, 11.92; N, 6.63. Found: C, 73.55; H, 11.65; N, 6.44. 3-[(2E)-3-(Diethylamino)prop-2-enoyl]benzonitrile (4o) Purified by column chromatography (silica gel, 40% EtOAc–PE) to give a yellow liquid; yield: 159.80 mg (0.70 mmol, 70%). 1H NMR (300 MHz, CDCl3): δ = 8.15–8.11 (m, 2 H), 7.90 (d, J = 12 Hz, 1 H), 7.73–7.70 (m, 1 H), 7.53 (t, J = 7.5 Hz, 1 H), 5.70 (d, J = 12 Hz, 1 H), 3.43–3.31 (m, 4 H), 1.28 (s, 6 H). 13C {1H} NMR (75 MHz, CDCl3): δ = 185.9, 153.5, 141.8, 133.9, 131.8, 131.3, 129.2, 118.9, 112.4, 90.9, 51.0, 43.2, 14.9, 14.2. HRMS (ESI): m/z [M + H]+ calcd for C14H17N2O; 229.1341; found: 229.1340. (2E)-3-(Diethylamino)-1-(3-nitrophenyl)prop-2-en-1-one (4q) Purified by column chromatography (silica gel, 30% EtOAc–PE) to give a yellow liquid; yield: 176.28 mg (0.71 mmol, 71%). 1H NMR (300 MHz, CDCl3): δ = 8.67 (t, J = 3 Hz, 1 H), 8.31–8.23 (m, 2 H), 7.90 (d, J = 15 Hz, 1 H), 7.59 (t, J = 9 Hz, 1 H), 5.76 (d, J = 12 Hz, 1 H), 3.41–3.35 (m, 4 H), 1.28 (t, J = 6 Hz, 6 H). 13C {1H} NMR (75 MHz, CDCl3): δ = 185.6, 153.6, 148.3, 142.4, 133.6, 129.4, 125.4, 122.4, 90.8, 50.9, 43.2, 14.9, 11.8. Anal. Calcd for C13H16N2O3: C, 62.89; H, 6.50; N, 11.28. Found: C, 62.60; H, 6.22; N, 11.01.
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Corresponding Author

Arunabha Thakur
Department of Chemistry, Jadavpur University
Kolkata 700032, West Bengal
India   

Publication History

Received: 18 June 2024

Accepted after revision: 31 July 2024

Accepted Manuscript online:
31 July 2024

Article published online:
22 August 2024

© 2024. Thieme. All rights reserved

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  • References and Notes

  • 2 Abdulla R F, Morgan LA. Synth. Commun. 1982; 12: 351
    CrossrefSearch in Google Scholar
  • 6 Braibante HT. S, Braibante ME. F, Rosso GB, Oriques DA. J. Braz. Chem. Soc. 2003; 14: 994
    CrossrefSearch in Google Scholar
  • 7 Brandt CA, da Silva AC. M. P, Pancote CG, Brito CL, da Silveira MA. B. Synthesis 2004; 1557
    Thieme Connect
  • 8 Ueno S, Shimizu R, Kuwano R. Angew. Chem. Int. Ed. 2009; 48: 4543
    CrossrefPubMedSearch in Google Scholar
  • 9 Schuppe AW, Cabrera JM, McGeoch CL. B, Newhouse TR. Tetrahedron 2017; 73: 3643
    CrossrefPubMedSearch in Google Scholar
  • 10 Shi W, Sun S, Wu M, Catano B, Li W, Wang J, Guo H, Xing Y. Tetrahedron Lett. 2015; 56: 468
    CrossrefSearch in Google Scholar
  • 11 Li M, Fang D, Geng F, Dai X. Tetrahedron Lett. 2017; 58: 4747
    CrossrefSearch in Google Scholar
  • 12 Kang Y.-W, Cho YJ, Han SJ, Jang H.-Y. Org. Lett. 2016; 18: 272
    CrossrefPubMedSearch in Google Scholar
  • 13 Neff RK, Su Y.-L, Liu S, Rosado M, Zhang X, Doyle MP. J. Am. Chem. Soc. 2019; 141: 16643
    CrossrefPubMedSearch in Google Scholar
  • 14 Zhang J, Zhou P, Yin A, Zhang S, Liu W. J. Org. Chem. 2021; 86: 8980
    CrossrefPubMedSearch in Google Scholar
  • 17 Pal A, Thakur A. Org. Biomol. Chem. 2022; 20: 8977
    CrossrefPubMedSearch in Google Scholar
  • 18 Enaminones 4a–q; General Procedure An oven-dried round-bottomed flask equipped with a stirrer bar was charged with CoCl2·6H2O (0.1 equiv, 0.1 mmol, 23.8 mg), DIPEA (3 equiv, 3 mmol, 0.52 mL), TBHP (3 equiv, 3 mmol, 0.29 mL), and toluene (1 mL). CHCl3 (3 equiv, 3 mmol, 0.24 mL) was added to the mixture, followed by the appropriate styrene derivative 1 (1.0 equiv, 1.0 mmol). The mixture was stirred for 3 h in a preheated oil bath at 60 °C, then cooled to r.t. H2O was added, and the mixture and extracted with CH2Cl2 (3 × 10 mL) and H2O. The organic phase was washed with brine, dried (Na2SO4), and concentrated under reduced pressure. The crude product was purified by column chromatography [silica gel (100–200 mesh), EtOAc–PE (3:7 to 4:6)].
  • 19 3-[(2E)-3-(Diisopropylamino)prop-2-enoyl]benzonitrile (4d) Purified by column chromatography (silica gel, 30% EtOAc–PE) to give a yellow oil; yield: 204.92 mg (0.80 mmol, 80%). 1H NMR (300 MHz, CDCl3): δ = 8.14–8.11 (m, 2 H), 7.98 (d, J = 12 Hz, 1 H), 7.72 (d, J = 9 Hz, 1 H), 7.52 (t, J = 7.5 Hz, 1 H), 5.70 (d, J = 12 Hz, 1 H), 3.33 (q, J = 7 Hz, 2 H), 1.32–1.27 (m, 12 H). 13C{1H} NMR (75 MHz, CDCl3): δ = 185.9, 151.7, 144.8, 141.8, 133.9, 131.8, 131.3, 129.5, 129.2, 112.4, 90.9, 57.7, 52.5, 41.6, 22.1, 12.7. Anal. Calcd for C16H20N2O: C, 74.97; H, 7.86; N, 10.93. Found: C, 74.71; H, 7.60; N, 11.06. (1E)-1-(Diisopropylamino)hept-1-en-3-one (4g) Purified by column chromatography (silica gel, 20% EtOAc–PE) to give a yellow oil; yield: 133.44 mg (0.65 mmol, 65%). 1H NMR (300 MHz, CDCl3): δ = 7.50 (d, J = 9 Hz, 1 H), 4.62 (d, J = 9 Hz, 1 H), 2.29 (t, J = 6 Hz, 2 H), 1.44–1.17 (m, 21 H). 13C{1H} NMR (75 MHz, CDCl3): δ = 170.3, 146.8, 84.9, 71.4, 68.9, 51.0, 37.3, 28.8, 27.6, 22.7, 14.1. Anal. Calcd for C13H25NO: C, 73.88; H, 11.92; N, 6.63. Found: C, 73.55; H, 11.65; N, 6.44. 3-[(2E)-3-(Diethylamino)prop-2-enoyl]benzonitrile (4o) Purified by column chromatography (silica gel, 40% EtOAc–PE) to give a yellow liquid; yield: 159.80 mg (0.70 mmol, 70%). 1H NMR (300 MHz, CDCl3): δ = 8.15–8.11 (m, 2 H), 7.90 (d, J = 12 Hz, 1 H), 7.73–7.70 (m, 1 H), 7.53 (t, J = 7.5 Hz, 1 H), 5.70 (d, J = 12 Hz, 1 H), 3.43–3.31 (m, 4 H), 1.28 (s, 6 H). 13C {1H} NMR (75 MHz, CDCl3): δ = 185.9, 153.5, 141.8, 133.9, 131.8, 131.3, 129.2, 118.9, 112.4, 90.9, 51.0, 43.2, 14.9, 14.2. HRMS (ESI): m/z [M + H]+ calcd for C14H17N2O; 229.1341; found: 229.1340. (2E)-3-(Diethylamino)-1-(3-nitrophenyl)prop-2-en-1-one (4q) Purified by column chromatography (silica gel, 30% EtOAc–PE) to give a yellow liquid; yield: 176.28 mg (0.71 mmol, 71%). 1H NMR (300 MHz, CDCl3): δ = 8.67 (t, J = 3 Hz, 1 H), 8.31–8.23 (m, 2 H), 7.90 (d, J = 15 Hz, 1 H), 7.59 (t, J = 9 Hz, 1 H), 5.76 (d, J = 12 Hz, 1 H), 3.41–3.35 (m, 4 H), 1.28 (t, J = 6 Hz, 6 H). 13C {1H} NMR (75 MHz, CDCl3): δ = 185.6, 153.6, 148.3, 142.4, 133.6, 129.4, 125.4, 122.4, 90.8, 50.9, 43.2, 14.9, 11.8. Anal. Calcd for C13H16N2O3: C, 62.89; H, 6.50; N, 11.28. Found: C, 62.60; H, 6.22; N, 11.01.
  • 21 Ying J, Liu T, Liu Y, Wang J.-P. Org. Lett. 2022; 24: 2404
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Scheme 1 Selected examples of syntheses of enaminones
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Scheme 2 Substrate scope of various styrenes and amines. Reagents and conditions: 1 (1 equiv), 2a (3 equiv), 3a (3 equiv), TBHP (3 equiv), CoCl2·6H2O (10 mol%), 60 °C, 3 h. The isolated yields after column chromatography are reported.
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Figure 1 Hammett analysis
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Scheme 3 Gram-scale reaction and postmodifications
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Scheme 4 Control experiments
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Scheme 5 Plausible reaction mechanism