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Synthesis 2022; 54(23): 5215-5225
DOI: 10.1055/a-1891-0976
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Monitoring of Catalyst-Free Microwave-Assisted MCR-Type Synthesis of 2-Amino-3-cyano-4H-chromene Derivatives Using Raman Spectrometry

Olivier Hebert
a   Université de Rouen-Normandie (UNIROUEN), INSA Rouen, CNRS, COBRA UMR 6014, 76000 Rouen, France
,
Carole Dubouilh-Benard
a   Université de Rouen-Normandie (UNIROUEN), INSA Rouen, CNRS, COBRA UMR 6014, 76000 Rouen, France
,
Joana F. Campos 
b   Institut de Chimie Organique et Analytique (ICOA), Université d’Orléans UMR-CNRS 7311, BP 6759, rue de Chartres, 45067 Orléans cedex 2, France
,
Sabine Berteina-Raboin 
b   Institut de Chimie Organique et Analytique (ICOA), Université d’Orléans UMR-CNRS 7311, BP 6759, rue de Chartres, 45067 Orléans cedex 2, France
,
Corinne Fruit 
a   Université de Rouen-Normandie (UNIROUEN), INSA Rouen, CNRS, COBRA UMR 6014, 76000 Rouen, France
,
Thierry Besson  ∗
a   Université de Rouen-Normandie (UNIROUEN), INSA Rouen, CNRS, COBRA UMR 6014, 76000 Rouen, France
› Author Affiliations

This work was partially supported by University of Rouen Normandy, INSA Rouen Normandy, the Centre National de la Recherche Scientifique (CNRS), European Regional Development Fund (ERDF), Labex SynOrg (ANR-11-LABX-0029), Carnot Institute I2C, the graduate school for research Xl-Chem (ANR-18-EURE-0020 XL CHEM), and by Region Normandie.
› Further Information
 
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Abstract

In order to prepare an array of β-cyanoenamine derivatives as potential precursors of heterocyclic systems with pharmaceutical interest, the synthesis of fifteen polyfunctionalized 4H-chromenes was realized via a microwave-assisted and catalyst-free three-component reaction. Microwave-heated reactions were monitored by Raman spectroscopy, enabling a fast and efficient setting of the process parameters. This study confirms that this monitoring tool may have some limitations linked to homogeneity of reaction medium. This work also investigates the use of some bio-sourced and sustainable solvents currently studied in many works. Ethanol remains the most suitable for this synthesis.


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Key words

microwave - Raman spectroscopy - real-time monitoring - multicomponent reaction - catalyst free - 2-amino-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitriles

1 Introduction

As part of our work aimed at synthesizing heterocyclic systems of high therapeutic value from β-cyanoenamine derivatives,[1] [2] [3] [4] we focused on the convenient access to an array of 2-amino-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile derivatives. These molecules have not only their own biological activity but may also serve as key intermediates for the synthesis of more complex and potentially bioactive heterocyclic systems[5–12] (Figure [1]).

Zoom Image
Figure 1 Heterocyclic β-cyanoenamine derivatives previously studied in our group and the project presented for a catalyst-free MCR reaction under microwaves and monitored by Raman spectroscopy

The synthesis of such bicyclic compounds has been widely described using multicomponent methods in which all the starting reactants (e.g., a benzaldehyde derivative, 1,3-dione, and malonitrile) were incorporated simultaneously into the reaction vessel.[5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] To increase the efficiency of the processes a large variety of basic catalysts were reported, in both homogeneous and heterogeneous conditions.[13–23] In an overall context of sustainable chemistry studies, some authors exposed the reaction media to microwaves in order to improve the heating efficiency and the general conditions of the reaction (e.g., time and yields).[8,23] A synthetic route was also described in the absence of catalysts, using 2,2,2-trifluoroethanol as a reusable solvent.[24] A recent process performed at room temperature, in a H2O/PEG400 mixture, can also be cited. It required the addition of ethanol and heating to allow purification of the products.[25]

This paper describes the achievement of an innovative microwave-assisted procedure of the targeted products via a catalyst-free multicomponent reaction (MCR) in ethanol as a bio-based and reusable solvent. Our previous studies on the use of microwaves for the synthesis of heterocyclic systems frequently demonstrated that controlling and optimizing the conditions of such organic reactions performed in sealed tubes may be trickier than with systems operating at atmospheric pressure.[26] [27] [28] It often requires a large number of trials in which irradiation has to be stopped and glassware cooled before opening vials and taking aliquots. To overcome these drawbacks, we envisioned the use Raman spectrometry to live-monitor the reaction outcome in the sealed tube. As part of our recent work on the search for sustainable chemistry methods,[29–31] the use of some green solvents was also investigated, the results of which are presented here.


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2 Results

2.1 Setup of the Experimental Conditions

2.1.1 Defining the Conditions of Use of Raman Spectroscopy

It is now well established that Raman spectroscopy can be useful to analyze the contents of a closed vessel without having to introduce a dedicated probe into the reaction medium and interact with the samples. After a pioneering paper by Myrick in 1995 that applied Raman spectroscopy to monitor polymer formation under microwave irradiation,[32] Pivonka and Empfield (2004) described the real-time monitoring of the synthesis of a C3-substituted coumarin via microwave-assisted Knoevenagel condensation, in a closed vessel.[33] These studies probably inspired Leadbeater and his co-workers who published, between 2006 and 2013, a series of relevant papers clearly demonstrating the interest of combining microwave technology and Raman spectroscopy to monitor in situ the progress of various organic reactions mainly performed in sealed tubes or in continuous-flow systems.[34] [35] [36] [37] [38] [39] [40] [41] [42] It should be noted that these investigations determined the limitations and drawbacks of this non-intrusive technology based on light scattering. Concurrently, Calvino-Castilla used Raman monitoring of Michael addition for the synthesis of 1-substituted imidazoles.[43] Two years later, Radoiu and Vanden Eynde described the possibility of monitoring the Hantzsch synthesis of 1,4-dihydropyridines using Raman spectroscopy. Initially designed in batch reactors, the synthesis was then scaled up in a continuous flow system, again using Raman monitoring.[44] Surprisingly, since this report almost nothing has been published in the literature on Raman spectroscopy in situ monitoring of organic reactions, although this technique is still used widely in the analytical domain, in particular to control the quality of drugs or materials.[45] [46]

Preliminary experiments were carried out in a new system combining a microwave synthesis reactor and Raman spectroscopy system (details are given in the experimental part).

Zoom Image
Scheme 1 Schematic representation of the multi-component reaction (MCR) of 1a, 2a, and 3, in situ monitored by Raman spectroscopy

Before starting experiments, Raman spectra of each reactant and solvent were recorded in order to identify and assign peaks to reactants with characteristic functional groups [e.g., carbonyl groups in the starting aldehyde 1 and the 1,3-dione 2 or the carbonitrile function of malonitrile (3)] (Figure [2]).

Zoom Image
Figure 2 (a) Recorded Raman spectra (intensities (arbitrary units [a.u.]) of peaks in relation to the Raman shift) for benzaldehyde (1a), 5,5-dimethylcyclohexa-1,3-dione (2a) and malonitrile (3). The laser excitation wavelength was 785 nm with a laser power of 450 mW. A background spectrum was also performed and used for baseline correction; (b) Part A is the overlapping of the three reagents’ spectra measured under the same conditions (concentration and solvent) and for a similar relative intensity; part B is the Raman spectrum of the mixture of the three reagents measured at t = 0 min for the synthesis of 4a.

The Raman spectrum of malonitrile (3) can be identified by the strong stretching-band attributed to the carbonitrile function at 2200 cm–1, while benzaldehyde (1a) and 5,5-dimethylcyclohexa-1,3-dione (2a) do not show any Raman activity in this area. In the recorded spectrum of benzaldehyde (1a), two characteristic peaks at 1600 cm–1 and 1700 cm–1 were also detected. The starting 1,3-cyclohexadione (2a) also shows bands in this area, but the intensity of the peaks is quite low as can be observed by comparing the data of the three reagents (reported on the same scale of relative intensity) on the right side of Figure [2] (part A). In part B, the early-stage pattern of the reaction mixture spectrum is different from the one obtained by simple overlapping of the reactant spectra initially collected. The Raman profile of the homogeneous starting mixture shows two intense peaks arising in the 1600–1800 cm–1 area, probably resulting from the different stretching modes of the carbonyl functions present in the reaction medium. After analyzing these data, it was decided to monitor the progress of the reaction by only checking the behavior (signal strength and peak displacement) of the characteristic band of malonitrile (3) arising at 2270 cm–1 (see more details in the Supporting Information section).

In a first experiment, an equimolar mixture of benzaldehyde (1a; 0.5 g), 5,5-dimethylcyclohexa-1,3-dione (2a) and malonitrile (3) was solubilized in ethanol (10 mL) and the sealed tube was heated at 150 °C. A ramp of 1 minute was programmed to reach the set temperature (Scheme [1]).

Starting with the microwave irradiation, a Raman measurement was performed every 10 seconds. Baseline-corrected (background and ethanol) spectra were recorded during the heating phase and the evolution of characteristic peaks was analyzed.

Figure [3a] depicts the Raman spectra measured at time (t) = 0, 2, 3, and 5 minutes. As expected, changes were observed in the spectrum with a shift and decrease or loss of some peaks accompanied by the emergence and growth of new signals, making it more difficult to follow the evolution of the peaks in the 1600–1800 cm–1 range. In contrast, the peak at 2270 cm–1 decreased significantly until disappearing at the end of the reaction. Concurrently, a new signal emerged at 2200 cm–1 and its height increased until reaching a maximum after about 5 minutes of irradiation. This was confirmed when relative intensities of the signals at 2200 cm–1 and 2270 cm–1 were compared versus time, as described in Figure [3b]. Results demonstrate that peak intensity at 2200 is reached after 6 minutes (1 min ramp + 5 min of reaction) and that it does not evolve afterwards (blue curve).

Zoom Image
Figure 3 (a) Overlapping of the Raman spectra measured for the same reaction mixture at time (t) = 0 min (grey), 2 min (blue), 3 min (green) and 5 min (orange); (b) Relative intensities (arbitrary units [a.u.]) of the signals at 2200 cm–1 and 2270 cm–1 vs time.

At the end of the process, the homogeneous reaction mixture was allowed to cool slowly. The crystallized product was filtered off, washed with ethanol and dried to give the expected 2-amino-7,7-dimethyl-5-oxo-4-phenyl-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (4a) in 86% yield. Its recorded Raman spectrum (blue) showed a slight difference compared to that of the final reaction mixture (grey). The significant peak occurring at 2200 cm–1 was assigned to the carbonitrile function of the product (Figure [4]).

Zoom Image
Figure 4 (a) Raman spectra measured at the end of the process after 6 min (1 min ramp and 5 min reaction); (b) Raman spectra of the purified 2-amino-7,7-dimethyl-5-oxo-4-phenyl-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (4a): relative intensities of the signals are given in arbitrary units [a.u.].

# 2.1.2

Setting the Reaction Temperature

The operating conditions for the MCR reaction were extended to other target temperatures (80, 100, and 125 °C) and monitored as described above. The reaction time was set to 5 minutes and results are presented in Table [1].

Table 1 Optimization of the Temperature Conditions of the MCR Reaction from 1a, 2a, and 3 a

Entry

Temp (°C)

Time (min)

Yield (%)b

1

 80

 5

37

2

100

 5

52

3

125

 5

57

4

150

 5

86

5

150

 2

54

6

150

15

80

a Reagents were all introduced in equimolar amounts and the volume of EtOH was kept constant.

b Purified products.

It can be observed that the best yield (86%, Table [1], entry 4) was obtained at 150 °C for 5 minutes. A lower temperature (80 °C) led to incomplete solubilization of the three reagents and was not suitable for measuring the Raman­ spectrum.

At 100 and 125 °C (Table [1], entries 2 and 3), the results were identical but remained moderate. They are similar to the results obtained when the reaction at 150 °C was stopped after 2 min (entry 5). This result confirmed the preliminary study described above [Figure [2] part (b)]. A longer reaction time (15 min, entry 6) was also tested. The yield obtained was close to the highest, demonstrating that since the reaction remains homogeneous, it is possible to follow the process by Raman spectroscopy. In the case studied, it was also shown that the product remains stable under these conditions.

Zoom Image
Figure 5 Alternative solvents used in this study

Table 2 Screening of Various Solvents

Entry

Solvent

Temp (°C)

Yield (%)a of 4a

 1

EtOH

150

86

 2

i-PrOH

150

67

 3

t-BuOH

150

76

 4

EtOAc

150

50

 5

2-MeTHF

150

38

 6

limonene

150

35

 7

CPME

150

43

 8

p-cymene

150

58

 9

p-cymene

200

39

10

eucalyptol

150

51

11

eucalyptol

200

67

12

ethylene glycol

150

73

13

ethylene glycol

200

23

a Purified product.


# 2.1.3

Solvent

Even if ethanol is one of the most abundant bio-based solvents in nature and is used in many chemical processes, we next focused on screening various sustainable and/or bio-based solvents for the development of an eco-friendly MCR reaction.

Some bio-based solvents (solvents of renewable origin) such as ethyl acetate (EtOAc) limonene, p-cymene, and eucalyptol (1,8-cineole) depicted in Figure [5] were tested. Cyclopentyl methyl ether (CPME) and 2-methyltetrahydrofuran (2-MeTHF) are described in numerous papers[47] [48] and were also chosen as alternative solvents as well as ethylene glycol considered as toxic but showing interesting dielectric properties in microwave-assisted heated processes. Ethyl acetate and two alcohols, isopropyl alcohol, tert-butyl alcohol, possessing boiling point values close to ethanol, were also investigated (Figure [5]).

Table [2] reports the results of experiments carried out in the optimized conditions described above (1 min ramp + 5 min MW heating at 150 °C or at 200 °C for high boiling point solvents).

It demonstrates that polar protic solvents (alcohols) produced the best yields and that ethanol has the best physicochemical properties in the conditions studied: it allowed homogeneous mixtures and can be heated at 150 °C under microwaves (tan δ = 0.943). It may be mentioned that ethylene glycol led to the desired compound in 73% yield (Table [2], entry 12), and that higher heating (200 °C) was required with eucalyptol as solvent to provide a good yield of 67% after purification of the product (entry 11). The low solubility of the products formed sometimes generated complicated spectra.


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# 2.2

Scope of the Reaction

With the optimized conditions in hand, an array of 2-amino-7,7-dimethyl-5-oxo-4-(het)aryl-5,6,7,8-tetrahydro-4H-chromene-3-carbonitriles were obtained in good yields, except from the pyridine-3-carbaldehyde (35%) and the 1H-imidazole-5-carbaldehyde (no reaction) (Scheme [2]). These results can be attributed to the low solubility of these aldehydes in the reaction medium. All reactions were monitored by Raman spectroscopy; details are given in the Supporting Information section.

Zoom Image
Scheme 2 Scope of the reaction of 5,5-dimethylcyclohexane-1,3-dione (2a) with various (het)aromatic aldehydes 1a–j

As eucalyptol has recently been highlighted as a relevant sustainable solvent for organic transformations and heterocyclic chemistry,[49] [50] [51] a case study was carried out on a range of five aldehydes at 200 °C for 5 minutes (Scheme [3]).

Zoom Image
Scheme 3 Case study with eucalyptol as solvent. Yields of purified product.

Unfortunately, the promising result described in Table [2] (entry 11) was not successfully reproduced and it is clear that this solvent is not suitable for this reaction.

The catalyst-free operating conditions in ethanol were applied to cyclohexa-1,3-dione (2b) with various aldehydes to yield a small series of 5-oxo-4-(het)aryl-5,6,7,8-tetrahydro-4H-chromene-3-carbonitriles 5a–f (Scheme [4]).

Zoom Image
Scheme 4 Scope of the reaction of cyclohexane-1,3-dione with (het)aromatic aldehydes 1a–d, 1g, and 1h

# 2.3

Comparing Thermal and Microwave Heating

Based on our results, we considered transferring the experimental procedure to a microwave reactor operating at atmospheric pressure. In this case, the pressure generated by the overheating of ethanol will not affect the process. The initial concentrations of the reactants were maintained and were identical to those described above. Because there was no integrated Raman system in the reactor used, monitoring of the reactions was not performed by Raman spectroscopy but by thin layer chromatography. The results are described in Table [3].

Table 3 Reaction of 5,5-Dimethylcyclohexane-1,3-dione with Various (Het)aromatic Aldehydes Assisted by Microwaves at Atmospheric Pressure

Entry

(Het)ArCHO

Time (min)

Product

Yield (%)a

 1

1a

 15

4a

70

 2

1a

 60b

4a

70

 3

1b

 15

4b

79

 4

1b

 60b

4b

73

 5

1b

 15

4b

87

 6

1c

 15

4c

80

 7

1d

 15

4d

88

 8

1e

 15

4e

83

 9

1f

 15

4f

78

10

1g

 15

4g

43

11

1h

 15

4h

50

12

1i

 15

4i

70

a Purified product.

b Conventional thermal heating.

The data in Table [3] show that a longer microwave heating (15 min) at atmospheric pressure provides similar yields to those obtained in a pressurized environment (sealed tubes). In the case of aldehydes 1a and 1b, a traditional thermal heating was also applied, and similar yields were obtained after 1 h (Table [3], entries 2 and 4).

The results described in Table [3] also show that pressure plays an important role in the efficiency of the reaction. When the reaction was carried out in a sealed tube heated at 150 °C by a conventional method, the yield was as good as under microwaves and at the same time (entry 5).

Therefore, this catalyst-free MCR-type synthesis can be scaled up in microwave or conventional heating systems operating at atmospheric pressure although it will require a longer reaction time than in a pressurized system.


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# 3

Conclusion

The initial objective of our work was to create an array of β-cyanoenamine derivatives, which are potential precursors of heterocyclic systems with pharmaceutical interest. On that point we succeeded in synthesizing 4H-chromenes via a microwave-assisted and catalyst-free three-component reaction, in ethanol, a biosourced and recyclable solvent.

In order to avoid too many experimental setups, the microwave-heated reactions were followed by Raman spectroscopy. In the case studied, a major point is that there are visible differences between the spectra of the reactants and those of the products which show clearly identifiable peaks. This enabled a fast and efficient setting of the process parameters and allowed the reaction to be monitored under convenient conditions.

Throughout our investigations the syntheses of compounds 4a–i and 5a–f were all monitored by Raman Spectrometry and spectra of the various processes are described in the Supporting Information section.

As reported in previous work, this monitoring tool may have some limitations. We observed spectra that were not easy to read when (a) products began to crystallize in the sealed tube before the reaction appeared to be complete; and (b) products crystallized when the reaction temperature was not sufficient to maintain a homogenous reaction medium.

This work was also the opportunity to investigate the use of some bio-sourced or sustainable solvents currently studied and described in many studies. We tried to replace ethanol by emerging solvents such as CPME, 2-MeTHF, p-cymene, limonene, or eucalyptol. Unfortunately, none of the alternative solvents proved as efficient as ethanol, which remains the most suitable for this synthesis. This solvent also has the advantage of being bio-compatible under certain conditions.


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All reagents were purchased from commercial suppliers and were used without further purification except for DMF, which was stored under argon and activated molecular sieves. All reactions were monitored by TLC with silica gel 60 F254 (Merck KGaA, Darmstadt, Germany) precoated aluminum plates (0.25 mm). Visualization was performed with UV light at a wavelength of 254 nm. Purifications were conducted with a flash column chromatography system (Puriflash) equipped with a dual UV/Vis spectrophotometer (200–600 nm), a fraction collector (176 tubes), and a dual piston pump (1 to 200 mL/min, Pmax = 15 bar), which allowed quaternary gradients and an additional inlet for air purge (Interchim, Montluçon, France). Melting points of solid compounds were measured with an SMP3 Melting Point instrument (STUART, Bibby Scientific Ltd, Roissy, France) with a precision of 1.5 °C. IR spectra were recorded with a Spectrum 100 Series FTIR spectrometer (PerkinElmer, Villebon S/Yvette, France). Liquids and solids were investigated with a single-reflection attenuated total reflectance (ATR) accessory; the absorption bands are given in cm–1. NMR spectra (1H and 13C) were acquired at 295 K using an AVANCE 300 MHz spectrometer (Bruker, Wissembourg, France) at 300 and 75.4 MHz, using TMS as an internal standard. Coupling constants J are in Hz, and chemical shifts are given in ppm. Mass spectrometry was performed by the Mass Spectrometry Laboratory of the University of Rouen. The mass spectra (ESI, EI, and field desorption FD) were recorded with an LCP 1er XR spectrometer (WATERS, Guyancourt, France). Microwave-assisted reactions were carried out in 10 mL sealed tubes with a Monowave 400R system coupled with a CORA 5001 Fiber Raman spectrometer (Anton Paar France S.A.S., les Ulis, France), and temperatures were measured by an IR-sensor. Microwave experiments at atmospheric pressure were performed in 50 mL tube with a flexiWAVETM reactor (Milestone S.r.l. Italy) with a microwave power delivery system able to reach 1900 W. In all these experiments, the same setup parameters were used. Starting materials were weighed directly into the reaction vessel and dissolved with the appropriate solvent. An agitator was inserted in the vessel. For optimum results, the stirring speed was set in accordance to the filling volume. In the two systems used, temperatures of the reactions were mainly monitored via contact-less infrared pyrometer which was calibrated by the supplier in control experiments with a fiber-optic contact thermometer directly in the reaction mixtures. The time indicated in the various protocols is the time measured when the mixtures were at the programmed temperature (a ramp of 1 min was programmed to reach the set temperature). The pressure measured in the sealed tubes at the end of the reactions performed never exceeded 5 to 6 bars.

Compounds 4a–i and 5a–f were randomly described in the academic studies cited in this paper. To complete data that were sometimes incomplete, all the compounds 4a–i and 5a–f were fully characterized. The Raman in situ monitoring data of each reaction is described in the Supporting Information section (S1–S18). General information and procedure for their synthesis are described below.


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2-Amino-3-cyano-4H-chromene Derivatives; General Procedure

In a 10 mL sealed microwave-vial, a mixture of (het)aryl aldehyde 1a–i (0.5 g, 1 equiv.), cyclohexa-1,3-dione 2a,b (1 equiv) and malonitrile (3; 1 equiv) in EtOH (3 mL) was heated at 150 °C for 5 min (a ramp of 1 min was programmed to reach the set temperature). At the end of the reaction, EtOH was added to the reaction mixture and the resulting solution was allowed to cool slowly. The crystallized product was filtered off, washed with EtOH and dried to give the expected 2-amino-5-oxo-4-(het)aryl-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile 4a–i and 5a–f.


#

2-Amino-7,7-dimethyl-5-oxo-4-phenyl-5,6,7,8-tetrahydro-4H-3-carbonitrile (4a)

Prepared from 1a (0.5 g, 4.71 mmol); yield: 1.198 g (86%); white solid; mp 234–235 °C.

1H NMR (300 MHz, DMSO-d 6): δ = 7.29 (t, J = 7.3 Hz, 2 H, CHar), 7.22–7.10 (m, 3 H, CHar), 6.99 (s, 2 H, NH2), 4.17 (s, 1 H), 2.51 (s, 2 H, CH2), 2.18 (dd, J = 46.2, 16.1 Hz, 2 H, CH2), 1.04 (s, 3 H, CH3), 0.96 (s, 3 H, CH3).

13C NMR (75 MHz, DMSO-d 6): δ = 196.11 (Cq), 162.96 (Cq), 158.97 (Cq), 145.23 (Cq), 128.80 (CH), 127.63 (CH), 127.04 (CH), 120.20 (Cq), 113.22 (Cq), 58.79 (Cq), 50.46 (CH2), 40.16 (CH2), 36.06 (CH), 32.28 (Cq), 28.88 (CH3), 27.28 (CH3).

HRMS (EI-MS): m/z calcd for C16H16N2O3: 295.1368 [M – H]+; found: 295.1289.


#

2-Amino-4-(4-chlorophenyl)-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (4b)

Prepared from 1b (0.5 g, 3.56 mmol); yield; 0.702 g (67%); white solid; mp 213–214 °C.

1H NMR (300 MHz, DMSO-d 6): δ = 7.34 (d, J = 8.4 Hz, 2 H, CHar), 7.17 (d, J = 8.4 Hz, 2 H, CHar), 7.05 (s, 2 H, NH2), 4.20 (s, 1 H, CH), 2.51 (s, 2 H, CH2), 2.17 (dd, J = 44.7, 16.1 Hz, 2 H, CH2), 1.03 (s, 3 H, CH3), 0.95 (s, 3 H, CH3)

13C NMR (75 MHz, DMSO-d 6): δ = 195.69 (Cq), 162.64 (Cq), 158.51 (Cq), 143.76 (Cq), 131.13 (Cq), 129.13 (CHar), 128.30 (CHar), 119.57 (Cq), 112.35 (Cq), 57.80 (Cq), 49.96 (CH2), 39.68(CH2), 35.13 (CH), 31.81 (Cq), 28.32 (CH3), 26.87 (CH3)

HRMS (EI-MS): m/z calcd for C18H18ClN2O2: 327.0901 [M – H]+; found: 327.0895.


#

2-Amino-4-(4-bromophenyl)-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (4c)

Prepared from 1c (0.5 g, 2.70 mmol); yield: 0.742 g (74%); white solid; mp 203–204 °C.

1H NMR (300 MHz, DMSO-d 6): δ = 7.48 (d, J = 8.4 Hz, 2 H, CHar), 7.11 (d, J = 8.4 Hz, 2 H, CHar), 7.06 (s, 2 H, NH2), 4.18 (s, 1 H), 2.51 (s, 2 H, CH2), 2.17 (dd, J = 44.9, 16.1 Hz, 2 H, CH2), 1.03 (s, 3 H, CH3), 0.95 (s, 3 H, CH3).

13C NMR (75 MHz, DMSO-d 6): δ = 195.70 (Cq), 162.65 (Cq), 158.50 (Cq), 144.19 (Cq), 131.22 (CHar), 129.53 (CHar), 119.62 (Cq), 119.56 (Cq), 112.28 (Cq), 56.04 (Cq), 49.95 (CH2), 39.68 (CH2), 35.21 (CH), 31.81 (Cq), 28.32 (CH3), 26.88 (CH3).

HRMS (EI-MS): m/z calcd for C18H18BrN2O2: 372.473 [M – H]+; found: 372.0466.


#

2-Amino-7,7-dimethyl-4-(4-nitrophenyl)-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (4d)

Prepared from 1d (0.5 g, 3.31 mmol); yield: 0.774 g (69%); yellow solid; mp 176–177 °C.

1H NMR (300 MHz, DMSO-d 6): δ = 8.17 (d, J = 8.7 Hz, 2 H, CHar), 7.44 (d, J = 8.7 Hz, 2 H, CHar), 7.17 (s, 2 H, NH2), 4.37 (s, 1 H), 2.54 (s, 2 H, CH2), 2.19 (dd, J = 46.4, 16.0 Hz, 2 H, CH2), 1.04 (s, 3 H), 0.96 (s, 3 H).

13C NMR (75 MHz, DMSO-d 6): δ = 195.68 (Cq), 163.09 (Cq), 158.58 (Cq), 152.28 (Cq), 146.26 (Cq), 128.62 (CH), 123.67 (CH), 119.31 (Cq), 111.72 (Cq), 56.97 (Cq), 49.85 (CH2), 39.67 (CH2), 35.64 (CH), 31.82 (Cq), 28.25 (CH3), 26.93 (CH3).

HRMS (EI-MS): m/z calcd for C18H18N3O4: 339.1219 [M – H]+; found: 339.1253.


#

2-Amino-4-(4-methoxyphenyl)-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (4e)

Prepared from 1e (0.5 g, 3.672 mmol); yield: 0.740 g (62%); white solid; mp 199–200 °C.

1H NMR (300 MHz, DMSO-d 6): δ = 7.06 (d, J = 8.7 Hz, 2 H, CHar), 6.98 (s, 2 H, NH2), 6.85 (d, J = 8.7 Hz, 2 H, CHar), 4.12 (s, 1 H, CH), 3.72 (s, 3 H, CH3), 2.50 (s, 2 H, CH2), 2.17 (dd, J = 48.2, 16.1 Hz, 2 H, CH2), 1.04 (s, 3 H, CH3), 0.95 (s, 3 H, CH3).

13C NMR (75 MHz, CDCl3): δ = 195.69 (Cq), 162.16 (Cq), 158.43 (Cq), 157.93 (Cq), 136.87 (Cq), 128.23 (CH), 119.82 (Cq), 113.69 (CH), 113.01 (Cq), 58.58 (Cq), 55.01 (CH), 50.02 (CH), 39.69 (CH2), 34.77 (CH), 31.79 (Cq), 28.42 (CH3), 26.78 (CH3).

HRMS (EI-MS): m/z calcd for C19H20N2O3: 324.1474 [M – H]+; found: 324.1487.


#

2-Amino-7,7-dimethyl-5-oxo-4-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (4f)

Prepared from 1f (0.5 g, 2.548 mmol); yield: 0.833 g (70%); white solid; mp 180–181 °C.

1H NMR (300 MHz, DMSO-d 6): δ = 6.99 (s, 2 H, NH2), 6.38 (s, 2 H, CHar), 4.14 (s, 1 H, CH), 3.72 (s, 6 H, m-OCH3), 3.62 (s, 3 H, p-OCH3), 2.53 (s, 2 H, CH2), 2.21 (dd, J = 44.1, 16.1 Hz, 2 H, CH2), 1.05 (s, 3 H, CH3), 1.02 (s, 2 H, CH3).

13C NMR (75 MHz, CDCl3): δ = 195.75 (Cq), 162.80 (Cq), 158.38 (Cq), 152.77 (Cq), 140.47 (Cq), 136.17 (Cq), 112.37 (Cq), 104.19 (CH), 59.94 (CH), 58.37 (CH), 55.81 (CH), 50.01 (CH2), 39.52 (CH2), 35.62 (CH), 31.75 (Cq), 28.61 (CH), 26.58 (CH).

HRMS (EI-MS): m/z calcd for C21H24N2O5: 384.1685 [M – H]+; found: 384.1684.


#

2-Amino-7,7-dimethyl-5-oxo-4-(thiophen-2-yl)-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (4g)

Prepared from 1g (0.5 g, 4.458 mmol); yield: 0.979 g (74%); yellow solid; mp 224–225 °C.

1H NMR (300 MHz, DMSO-d 6): δ = 7.31 (d, J = 4.3 Hz, 1 H, CHar), 7.11 (s, 2 H, NH2), 6.93–6.88 (t, 1 H, CHar), 6.86 (d, J = 2.7 Hz, 1 H, CHar), 4.54 (s, 1 H, CH), 2.50 (dd, 2 H, CH2), 2.23 (dd, J = 46.4, 16.2 Hz, 2 H, CH2), 1.04 (s, 3 H, CH3), 0.98 (s, 3 H, CH3).

13C NMR (75 MHz, DMSO-d 6): δ = 195.50 (Cq), 162.48 (Cq), 158.91 (Cq), 149.27 (Cq), 126.80 (CH), 124.40 (CH), 123.99, 119.59 (Cq), 112.93 (Cq), 58.07 (Cq), 49.88 (CH2), 39.62 (CH2), 31.73 (CH), 30.41 (Cq), 28.63 (CH3), 26.47 (CH3).

HRMS (EI-MS): m/z calcd for C16H16N2O2S: 340.1219 [M – H]+; found: 340.1143.


#

2-Amino-4-(furan-2-yl)-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (4h)

Prepared from 1h (0.5 g, 5.204 mmol); yield: 0.954 g (65%); black solid; mp 208–209 °C.

1H NMR (300 MHz, DMSO-d 6): δ = 7.48 (dd, J = 1.8, 0.8 Hz, 1 H, CHar), 7.07 (s, 2 H, NH2), 6.32 (dd, J = 3.2, 1.9 Hz, 1 H, CHar), 6.05 (d, J = 3.0 Hz, 1 H, CHar), 4.32 (s, 1 H, CH), 2.50 (s, 2 H, CH2), 2.23 (dd, J = 37.2, 16.1 Hz, 2 H, CH2), 1.04 (s, 3 H, CH3), 0.99 (s, 3 H, CH3).

13C NMR (75 MHz, DMSO-d 6): δ = 195.41 (Cq), 163.25 (Cq), 159.30 (Cq), 155.73 (Cq), 141.75 (CH), 119.55 (Cq), 110.44 (CH), 110.36 (Cq), 105.05 (CH), 55.38 (Cq), 49.89 (CH2), 39.72 (CH2), 31.81 (Cq), 28.98 (CH), 28.42 (CH3), 26.56 (CH3).

HRMS (EI-MS): m/z calcd for C16H16N2O3: 284.1161 [M – H]+; found: 284.1159.


#

2-Amino-7,7-dimethyl-5-oxo-4-(pyridin-3-yl)-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (4i)

Prepared from 1i (0.5 g, 4.668 mmol); yield: 0.529 g (35%); white solid; mp 206–207 °C.

1H NMR (300 MHz, DMSO-d 6): δ = 8.40 (m, 2 H, CHar), 7.54 (dd, J = 6.1, 1.8 Hz, 1 H, CHar), 7.32 (dd, J = 7.7, 4.8 Hz, 1 H, CHar), 7.11 (s, 2 H, NH2), 4.25 (s, 1 H, CH), 2.53 (s, 2 H, CH2), 2.19 (dd, J = 41.3, 16.0 Hz, 2 H, CH2), 1.04 (s, 3 H, CH3), 0.95 (s, 3 H, CH3).

13C NMR (75 MHz, CDCl3): δ = 194.76 (Cq), 161.99 (Cq), 157.61 (Cq), 147.70 (CH), 146.87 (CH), 139.06 (Cq), 133.76 (CH), 122.68 (CH), 118.51 (Cq), 110.81 (Cq), 56.34 (Cq), 48.92 (CH2), 38.68 (CH2), 32.41 (CH), 30.84 (Cq), 27.24 (CH3), 25.93 (CH3).

HRMS (EI-MS): m/z calcd for C17H17N3O2: 295.1321 [M – H]+; found: 295.1313.


#

2-Amino-5-oxo-4-phenyl-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (5a)

Prepared from 1a (0.5 g, 4,71 mmol); yield: 0.909 g (72%); yellow solid; mp 239–240 °C.

1H NMR (300 MHz, DMSO-d 6): δ = 7.28 (t, J = 7.5 Hz, 2 H, CHar), 7.17 (dd, J = 11.9, 6.6 Hz, 3 H, CHar), 6.98 (s, 2 H, NH2), 4.18 (s, 1 H, CH), 2.62 (d, J = 4.2 Hz, 2 H, CH2), 2.28 (dt, J = 10.7, 5.4 Hz, 2 H, CH2), 1.95 (ddd, J = 13.5, 5.7 Hz, 2 H, CH2).

13C NMR (75 MHz, DMSO-d 6): δ = 195.84 (Cq), 164.47 (Cq), 158.47 (Cq), 144.79 (Cq), 128.33 (CH), 127.12 (CH), 126.52 (CH), 119.77 (Cq), 113.79 (Cq), 58.21 (Cq), 36.32 (CH2), 35.44 (CH), 26.46 (CH2), 19.80 (CH2).

HRMS (EI-MS): m/z calcd for C16H14N2O2: 266.1055 [M – H]+; found: 266.1054.


#

2-Amino-4-(4-chlorophenyl)-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (5b)

Prepared from 1b (0.5 g, 3.557 mmol); yield: 0.865 g (81%) yellow solid; mp 245–246 °C.

1H NMR (300 MHz, DMSO-d 6): δ = 7.34 (d, J = 8.1 Hz, 2 H, CHar), 7.18 (d, J = 8.0 Hz, 2 H, CHar), 7.04 (s, 2 H, NH2), 4.20 (s, 1 H, CH), 2.61 (s, 2 H, CH2), 2.27 (dt, J = 4.7 Hz, 2 H, CH2), 1.93 (dd, J = 5.1 Hz, 2 H, CH2).

13C NMR (75 MHz, DMSO-d 6): δ = 195.85 (Cq), 164.62 (Cq), 158.47 (Cq), 143.79 (Cq), 131.11 (Cq), 129.10 (CH), 128.27 (CH), 119.61 (Cq), 113.38 (Cq), 57.71 (Cq), 36.29 (CH2), 35.02 (CH), 26.48 (CH2), 19.77 (CH2).

HRMS (EI-MS): m/z calcd for C16H13ClN2O2: 300.0666 [M – H]+; found: 300.0676.


#

2-Amino-4-(4-bromophenyl)-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (5c)

Prepared from 1c (0.5 g, 2.702 mmol); yield: 0.782 g (84%); yellow solid; mp 240–241 °C.

1H NMR (300 MHz, CDCl3): δ = 7.47 (d, J = 8.4 Hz, 2 H, CHar), 7.13 (d, J = 8.4 Hz, 2 H, CHar), 7.05 (s, 2 H, NH2), 4.19 (s, 1 H, CH), 2.60 (t, J = 5.5 Hz, 2 H, CH2), 2.26 (t, J = 5.4 Hz, 2 H, CH2), 1,93 (m, 2 H, CH2).

13C NMR (75 MHz, CDCl3): δ = 195.89 (Cq), 164.66 (Cq), 158.47 (Cq), 144.23 (Cq), 131.20 (CH), 129.51 (CH), 119.61 (Cq), 113.32 (Cq), 57.63 (Cq), 36.30 (CH2), 35.10 (CH), 26.49 (CH2), 19.77 (CH2).

HRMS (EI-MS): m/z calcd for C16H13BrN2O2: 344.0160 [M – H]+; found: 344.0160.


#

2-Amino-4-(4-nitrophenyl)-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (5d)

Prepared from 1d (0.5 g, 3.309 mmol); yield: 0.850 g (78%); yellow solid; mp 235–236 °C.

1H NMR (300 MHz, DMSO-d 6): δ = 8.16 (d, J = 8.8 Hz, 2 H, CHar), 7.46 (d, J = 8.8 Hz, 2 H, CHar), 7.16 (s, 2 H, NH2), 4.36 (s, 1 H, CH), 2.63 (t, J = 6.0 Hz, 2 H, CH2), 2.28 (m, J = 6.0 Hz, 2 H, CH2), 2.01–1.86 (m, 2 H, CH2).

13C NMR (75 MHz, CDCl3): δ = 195.93 (Cq), 165.17 (Cq), 158.57 (Cq), 152.35 (Cq), 146.27 (Cq), 128.60 (CH), 123.66 (CH), 119.40 (Cq), 112.76 (Cq), 56.94 (Cq), 36.24 (CH2), 35.60 (CH), 26.55 (CH2), 19.76 (CH2).

HRMS (EI-MS): m/z calcd for C16H13N3O4: 311.0906 [M – H]+; found: 311.0913.


#

2-Amino-5-oxo-4-(thiophen-2-yl)-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (5e)

Prepared from 1g (0.5 g, 4.458 mmol); yield: 0.799 g (66%); yellow solid; mp 235–236 °C.

1H NMR (300 MHz, DMSO-d 6): δ = 7.31 (dd, J = 5.0, 1.2 Hz, 1 H, CHar), 7.12 (s, 2 H, NH2), 6.90 (dd, J = 5.0, 3.5 Hz, 1 H, CHar), 6.85 (dd, J = 2.9, 0.5 Hz, 1 H, CHar), 4.53 (s, 1 H, CH), 2.58 (t, 2 H, CH2), 2.32 (t, 2 H, CH2), 1.96 (dt, J = 5.3 Hz, 2 H, CH2).

13C NMR (75 MHz, CDCl3): δ = 195.75 (Cq), 164.32 (Cq), 159.02 (Cq), 149.28 (Cq), 126.86 (CH), 124.40 (CH), 123.98 (CH), 119.67 (Cq), 114.09 (Cq), 57.84 (Cq), 36.25 (CH2), 30.33 (CH), 26.43 (CH2), 19.77 (CH2).

HRMS (EI-MS): m/z calcd for C14H12N2O2S: 272.0619 [M – H]+; found: 272.0620.


#

2-Amino-4-(furan-2-yl)-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (5f)

Prepared from 1h (0.5 g, 5.208 mmol); yield: 0.867 g (65%); black solid; mp 242–243 °C.

1H NMR (300 MHz, DMSO-d 6): δ = 7.48 (m, J = 1.9 Hz, 1 H, CHar), 7.07 (s, 2 H, NH2), 6.31 (dd, J = 3.1, 1.9 Hz, 1 H, CHar), 6.05 (d, J = 3.1 Hz, 1 H, CHar), 4.33 (s, 1 H, CH), 2.58 (t, J = 6.0 Hz, 2 H, CH2), 2.32 (t, J = 6.6 Hz, 2 H, CH2), 1.93 (ddd, J = 20.9, 13.5, 7.2 Hz, 2 H, CH2).

13C NMR (75 MHz, CDCl3): δ = 195.64 (Cq), 165.20 (Cq), 159.33 (Cq), 155.83 (Cq), 141.81 (CH), 119.61 (Cq), 111.48 (Cq), 110.43 (CH), 105.14 (CH), 55.30 (Cq), 36.21 (CH2), 29.00 (CH), 26.50 (CH2), 19.78 (CH2).

HRMS (EI-MS): m/z calcd for C14H12N2O3: 256.0848 [M – H]+; found: 256.0856.


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Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

T.B. and C.F. thank Anton Paar France S.A.S., les Ulis, France for technical assistance.

Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/a-1891-0976.
  • Supporting Information

Corresponding Author

Thierry Besson
Université de Rouen-Normandie (UNIROUEN), INSA Rouen, CNRS, COBRA UMR 6014
76000 Rouen
France   

Publication History

Received: 20 June 2022

Accepted after revision: 04 July 2022

Accepted Manuscript online:
04 July 2022

Article published online:
22 August 2022

© 2022. Thieme. All rights reserved

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Zoom Image
Figure 1 Heterocyclic β-cyanoenamine derivatives previously studied in our group and the project presented for a catalyst-free MCR reaction under microwaves and monitored by Raman spectroscopy
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Scheme 1 Schematic representation of the multi-component reaction (MCR) of 1a, 2a, and 3, in situ monitored by Raman spectroscopy
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Figure 2 (a) Recorded Raman spectra (intensities (arbitrary units [a.u.]) of peaks in relation to the Raman shift) for benzaldehyde (1a), 5,5-dimethylcyclohexa-1,3-dione (2a) and malonitrile (3). The laser excitation wavelength was 785 nm with a laser power of 450 mW. A background spectrum was also performed and used for baseline correction; (b) Part A is the overlapping of the three reagents’ spectra measured under the same conditions (concentration and solvent) and for a similar relative intensity; part B is the Raman spectrum of the mixture of the three reagents measured at t = 0 min for the synthesis of 4a.
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Figure 3 (a) Overlapping of the Raman spectra measured for the same reaction mixture at time (t) = 0 min (grey), 2 min (blue), 3 min (green) and 5 min (orange); (b) Relative intensities (arbitrary units [a.u.]) of the signals at 2200 cm–1 and 2270 cm–1 vs time.
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Figure 4 (a) Raman spectra measured at the end of the process after 6 min (1 min ramp and 5 min reaction); (b) Raman spectra of the purified 2-amino-7,7-dimethyl-5-oxo-4-phenyl-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (4a): relative intensities of the signals are given in arbitrary units [a.u.].
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Figure 5 Alternative solvents used in this study
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Scheme 2 Scope of the reaction of 5,5-dimethylcyclohexane-1,3-dione (2a) with various (het)aromatic aldehydes 1a–j
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Scheme 3 Case study with eucalyptol as solvent. Yields of purified product.
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Scheme 4 Scope of the reaction of cyclohexane-1,3-dione with (het)aromatic aldehydes 1a–d, 1g, and 1h