Infrared irradiation assisted both the synthesis of ( Z)-(aminomethyl)(aryl)phenylhydrazones via the Mannich coupling reaction and their application to the palladium-catalyzed Heck reaction

Abstract

The Mannich coupling reaction between arylhydrazones, formaldehyde and a secondary amine to generate the ( Z)-(aminomethyl)(aryl)phenylhydrazones 1a–h assisted by infrared irradiation (IR) under solvent-free conditions is herein reported, and the catalytic potential of compounds 1a–h in the palladium-catalyzed and IR-assisted Heck coupling reaction is also evaluated. Coupling products are obtained in high yields and short reaction times. We show the advantages of this new alternative to promote both Mannich and Heck coupling reactions.

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Introduction

Since its early application, the Mannich reaction has become a powerful tool for the synthesis of various β-amino ketones and β-amino esters, which are versatile synthetic building blocks for the preparation of compounds containing nitrogen, and privileged structures useful in synthetic and medicinal chemistry. ¹ In this context, the Mannich reaction using hydrazones has only shown moderate to good yields using formaldehyde. ² This methodology was extended and allows efficient coupling reactions between hydrazones, another aldehydes and secondary amines. ^{2 b} The hydrazones and their derivatives are a versatile class of compound mainly useful in heterocycle synthesis, ³ as organocatalysts, ⁴ and as ligands in metallic complexes. ⁵ Aryl hydrazones are applied as efficient ligands in the palladium-catalyzed Heck reaction, ⁶ the coupling reaction of Suzuki, ⁷ the reaction of Hiyama, ⁸ and the coupling reaction of allyl acetate with boric acid. ⁹

The Heck reaction is one of the most general and useful method for the formation of C–C bonds. ¹⁰ This coupling reaction has a wide variety of applications including total synthesis of natural products, ¹¹ fine chemicals syntheses, ¹² bioorganic chemistry, ¹³ material science ¹⁴ and industrial applications, ¹⁵ among others.

This reaction involves an appropriated chemical source of palladium, in combination with phosphine ligands, and a base under inert conditions. ¹⁰ Nevertheless, the high cost of phosphines and their sensitivity to air and moisture conditions have favored the development more robust new catalytic systems based on different ligands and/or phosphine-free catalytic systems. Among ligands with different donor groups, we can find extensive examples that include N-heterocyclic, ¹⁶ carbocyclic, ¹⁷ and anionic carbocyclic carbenes, ¹⁸ Schiff bases, ¹⁹ pyridines, ²⁰ imidazoles, ²¹ pyrazoles, ²² oxazolines, ²³ hydrazones, ²⁴ selenides, ²⁵ ureas, ²⁶ thioureas, ²⁷ among others. Extensive studies have shown the efficiency and robustness of palladacycles, ²⁸ pincer-type complexes, ²⁹ palladium nanoparticles, ^30,31 Pd( II) species supported in mesoporous materials, ³² etc. in performing this coupling reaction.

On the other hand, new experimental methodologies based on non-conventional energy sources for the activation of chemical reactions different to conventional heating, such as microwaves, ³³ ultrasound, ³⁴ mechanochemistry ³⁵ and infrared, ^36–39 have gained growing attention in recent years, as an important section of what is nowadays known as Green Chemistry. ⁴⁰ In particular, microwave irradiation under controlled conditions is an invaluable technology that has enormous applications in different areas, including academic ^{41 a} and industrial ^{41 b} researches. However, the successful use of this methodology is limited to the access of specific and expensive equipment. ⁴² Infrared irradiation is an energy source hardly explored in comparison to other energy sources. ^36–39

Due to the high value of IR as an energy source for the activation of chemical reactions, and few precedent in the literature regarding to the use of infrared irradiation in both Mannich and Heck coupling reactions, recently we report to use of the IR in the Heck coupling reaction with very good results. ⁴³ To continue with the use of IR as energy source for the activation of chemical reactions, we herein report a practical and efficient method for the synthesis of type ( Z)-(aminomethyl)(aryl)phenylhydrazones via Mannich coupling and their application to the palladium-catalyzed Heck coupling reaction assisted by IR.

Results and discussion

The ( Z)-(aminomethyl)(aryl)phenylhydrazones 1a–h were prepared according to a procedure described in the literature ^{2 c, d} via the Mannich reaction between formaldehyde ( 2), a phenylhydrazone 3a–d, either piperidine or diethylamine as base, under solventless conditions and using infrared irradiation (IR) as the energy source. This method is clean and rapid and affords the corresponding ( Z)-(aminomethyl)(aryl)phenylhydrazones 1a–h with very good yields.

According with the results showed in Table 1, the use of IR allows the reduction of the reaction time compared with conventional heating, particularly, when electron-withdrawing groups are included in phenylhydrazone ( 3) ( Table 1, entries 3, 4, and 8).

Table 1 Synthesis of ( Z)-(aminomethyl)(aryl)phenylhydrazones 1a–h using IR as energy source

Entry	R 1	R 2	Product	Time (min)	Yield [%]
a Under infrared irradiation using an Osram lamp (bulb model Thera-Therm, 250 W, 125 V). For controlling the temperature, a Digi-Sense variable-time power controller was used. b Under conventional heating.
1	–(CH 2) 5–	H	1a	120 ^a (180) ^b	92 ^a (90) ^b
2	–(CH 2) 5–	OCH 3	1b	120 ^a (180) ^b	80 ^a (80) ^b
3	–(CH 2) 5–	Cl	1c	45 ^a (120) ^b	90 ^a (87) ^b
4	–(CH 2) 5–	NO 2	1d	15 ^a (45) ^b	99 ^a (97) ^b
5	C 2H 5	H	1e	120 ^a (180) ^b	70 ^a (65) ^b
6	C 2H 5	OCH 3	1f	120 ^a (180) ^b	85 ^a (80) ^b
7	C 2H 5	Cl	1g	60 ^a (120) ^b	80 ^a (80) ^b
8	C 2H 5	NO 2	1h	30 ^a (60) ^b	85 ^a (80) ^b

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The compounds 1a–h were fully characterized by conventional spectroscopic methods, FT-IR, ¹H-NMR, ¹³C-NMR and mass spectra.

Once efficiently prepared the compounds 1a–h, we explored as catalytic precursors in the Heck cross-coupling reaction ( Table 2). The effect of concentration of the catalytic system on the Heck reaction between methyl acrylate ( 5) and p-iodotoluene ( 4) under IR heating condition was evaluate. We chose the hydrazone 1a and Pd(AcO) ₂ as model precatalysts. The coupling reaction was stirred under reflux of DMF (5 mL), using different concentrations of the [Pd(AcO) ₂/ 1a] system. Good yields were obtained within 30 minutes, when 0.01 and 0.05% mol of [Pd(AcO) ₂/ 1a] was used ( Table 2, entries 1 and 2). The base influence was also evaluated and employed different salts as K ₃PO ₄, Na ₂CO ₃, Na ₃PO ₄, K ₂CO ₃ and AcOK. We afforded 6b with a good yield ( Table 2, entry 2).

Table 2 Optimization of the conditions of the Heck coupling reaction between p-iodotoluene ( 4b) and methyl acrylate ( 5), using hydrazones 1a–h ^a

Entry	Hydrazone (% mol)	Source of palladium	Time ^b (min)	Base	Yield ^c (%)	TON	TOF
a All reactions were performed with p-iodotoluene ( 4b) (2 mmol), methyl acrylate ( 5) (3.3 mmol), DMF (5 mL), base (2.5 mmol). T = 140 °C under infrared irradiation using an Osram lamp (bulb model Thera-Therm, 250 W, 125 V). For controlling the temperature, a Digi-Sense variable-time power controller was used. b Time reaction based on total consumption of p-iodotoluene determined by TLC. c Isolated yields after extraction with hexane. d Preparing separately the [Pd(AcO) 2/ 1a] catalyst system. e Employing heating blanket.
1	1a (0.05)	Pd(OAc) 2	30	K 3PO 4	96	1920	3840
2	1a (0.01)	Pd(OAc) 2	30	K 3 PO 4	98	9800	19 600
3	1a (0.01)	Pd(OAc) 2	270	Li 3PO 4	50	5000	1111
4	1a (0.01)	Pd(OAc) 2	150	Na 3PO 4	60	6000	2400
5	1a (0.01)	Pd(OAc) 2	90	K 2CO 3	30	3000	2000
6	1a (0.01)	Pd(OAc) 2	60	AcOK	95	9500	9500
7	1a (0.01)	PdCl 2	30	K 3PO 4	86	8600	17 200
8	1a (0.01)	Pd(PhCN) 2Cl 2	30	K 3PO 4	84	8400	16 800
9	1a (0.01)	Pd(PPh 3) 2Cl 2	30	K 3PO 4	85	8500	17 000
10	1b (0.01)	Pd(OAc) 2	30	K 3PO 4	85	8500	17 000
11	1c (0.01)	Pd(OAc) 2	150	K 3PO 4	70	7000	2800
12	1d (0.01)	Pd(OAc) 2	150	K 3PO 4	76	7600	3040
13	1e (0.01)	Pd(OAc) 2	30	K 3PO 4	82	8200	16 400
14	1f (0.01)	Pd(OAc) 2	30	K 3PO 4	75	7500	15 000
15	1g (0.01)	Pd(OAc) 2	30	K 3PO 4	85	8500	1700
16	1h (0.01)	Pd(OAc) 2	120	K 3PO 4	74	7400	3700
17	None	Pd(OAc) 2	60	K 3PO 4	5	500	500
18	1a (0.01)	None	30	K 3PO 4	0	0	0
19 ^d	1a (0.01)	Pd(OAc) 2	30	K 3PO 4	98	9800	19 600
20 ^e	1a (0.01)	Pd(OAc) 2	300	K 3PO 4	90	9000	1800

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It is important to remark that all the compounds ( 1a–h) evaluated are effective for the Heck reaction (entries 10–16), where hydrazone 1a provides better yields in comparison to other compounds, with turn over numbers (TON) around ∼10 ³. Other sources of palladium were evaluated including PdCl ₂, Pd(PhCN) ₂Cl ₂ and Pd(PPh ₃) ₂Cl ₂ ( Table 2, entries 7–9) but these salts obtained moderated yields in comparison with Pd(OAc) ₂ ( Table 2, entry 2).

With these results, we found the following optimized conditions: [Pd(AcO) ₂/ 1a] system 0.01% mol, in DMF with K ₃PO ₄ at 140 °C for 30 minutes using infrared irradiation (IR) as an energy source.

In order to know the molecular structure of the formed complex by the reaction between the hydrazone 1a and Pd(OAc) ₂, we have conducted some experiments in different reaction conditions, observing in all cases the total consumption of the ligand, however, it was not possible to isolate the reaction product in neither case. In our experience, we believe that hydrazone behaves as [ N, N] ligand, as in other structurally similar hydrazone ligands we have detected. ^43,44 Thus, we conducted three additional experiments, the first one in absence of ligand, other one in absence of Pd(OAc) ₂ and, as expected, only in the case of Pd(OAc) ₂, we observe the formation of the coupling product but in low yield ( Table 2, entries 17 and 18). In the last experiment, we carried out the preformation of the catalytic system and we observe a change of color and total consumption of the ligand. After that, we added the substrates and base and the reaction was put in reflux under infrared irradiation. In this reaction condition, we obtained a similar yield of the coupling product (entry 19, Table 2), showing that the preformation of the palladium complex does not affect the C–C coupling reaction.

For to compare the energy sources, we made an experiment under the same reaction conditions described in Table 2, using conventional heating (entry 20), and this results showed a dramatic decreased time of reaction with the use of IR.

To evaluate the scope of [Pd(AcO) ₂/ 1a] as a catalytic system in the Heck coupling reaction, a variety of activated and deactivated aryl iodides and methyl acrylate was examined using this catalytic system with the optimized condition reactions ( Table 3). The results show that the [Pd(AcO) ₂/ 1a] system is an active and efficient catalyst in the Heck coupling reaction producing good and moderate yields of the corresponding coupling product 6a–g.

Table 3 Scope of the Heck cross-coupling using aril iodides and the [Pd(AcO) ₂/ 1a] system ^a

Entry	R	Time ^b (min)	Product	Yield ^c (%)	TON	TOF
a All reactions were performed with aryl iodides 4a–g (2 mmol), methyl acrylate ( 5) (3.3 mmol), DMF (5 mL), K 3PO 4 (2.5 mmol), [Pd(AcO) 2/ 1a] = 0.01% mol. T = 140 °C under infrared irradiation using an Osram lamp (bulb model Thera-Therm, 250 W, 125 V). For controlling the temperature, a Digi-Sense variable-time power controller was used. b Time reaction based on total consumption of aryl iodide determined by TLC. c Isolated yields after extraction with hexane and SiO 2 column chromatography.
1	H	60	4a	95	9500	9500
2	CH 3	30	4b	98	9800	19 600
3	OCH 3	60	4c	97	9700	9700
4	Br	90	4d	70	7000	4666
5	COCH 3	180	4e	50	5000	1666
6	OCOCH 3	120	4f	70	7000	3500
7	NO 2	120	4g	70	7000	3500

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Under similar conditions, the cross-coupling reaction was carried out with p-bromotoluene 7b and methyl acrylate ( 5), which provided methyl trans-cinnamate 6b, unfortunately the reaction did not proceed ( Table 4, entry 1). Consequently, we attempted to re-optimize the conditions for the coupling of p-bromotoluene ( 7b) and methyl acrylate ( 5) ( Table 4).

Table 4 Optimization of the reaction conditions on the Heck reaction of p-bromotoluene ( 7b) with 5 ^a

Entry	[Pd(AcO) 2/ 1a] (% mol)	TBAB	Time ^b (min)	Yield ^c (%)
a All reactions were performed with p-bromotoluene 7b (2 mmol), methyl acrylate ( 5) (3.3 mmol), DMF (5 mL), K 3PO 4 (2.5 mmol). T = 140 °C under infrared irradiation using an Osram lamp (bulb model Thera-Therm, 250 W, 125 V). For controlling the temperature, a Digi-Sense variable-time power controller was used. b Time reaction based on total consumption of p-bromotoluene 7b determined by TLC. c Isolated yields after extraction with hexane.
1	0.01	0	420	N.R
2	0.05	20	180	N.R
3	0.1	20	150	Traces
4	0.1	40	180	10
5	0.1	50	270	33
6	0.5	50	150	50
7	1	50	60	90

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When 0.1% mol of the [Pd(AcO) ₂/ 1a] system and 40% mol of TBAB were used, a small amount of the Heck reaction product was obtained ( Table 4, entry 4). After increasing the concentration of the [Pd(AcO) ₂/ 1a] system to 1% mol and adding 50% mol TBAB, the reaction produced good yields of 6b in 1 h. ( Table 4, entry 7).

Finally, we studied the effect of several aryl bromides 7a–f in the Heck reaction using methyl acrylate ( 5) ( Table 5). Using p-substituted aryl bromides 7a–c with electron-donor groups, we obtained good yields of 6a–c ( Table 5, entries 2 and 3). However, moderate yields were obtained using p-substituted aryl bromides 6d–f with electron-withdrawing groups ( Table 5, entries 4–7).

Table 5 Scope of Heck cross-coupling using aryl bromides 7a–f and the [Pd(AcO) ₂/ 1a] system ^a

Entry	R	Time ^b (min)	Product	Yield ^c (%)	TON	TOF
a All reactions were performed with p-iodotoluene 7a–f (2 mmol), methyl acrylate ( 5) (3.3 mmol), DMF (5 mL), K 3PO 4 (2.5 mmol), [Pd(AcO) 2/ 1a] = 1% mol, 50% mol TBAB. T = 140 °C under infrared irradiation using an Osram lamp (bulb model Thera-Therm, 250 W, 125 V). For controlling the temperature, a Digi-Sense variable-time power controller was used. b Time reaction based on total consumption of aryl bromide 7a–f determined by TLC. c Isolated yields after purification by column chromatography with SiO 2 eluted with hexane.
1	H	90	6a	70	7000	4666
2	CH 3	60	6b	85	8500	8500
3	OCH 3	180	6c	90	9000	3000
4	Cl	45	6d	80	8000	10 666
5	COCH 3	60	6e	50	5000	5000
6	NO 2	30	6f	50	5000	10 000

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In attempt to extend this methodology to aryl chlorides, we also conducted some experiments using p-chlorotoluene and p-nitrochlorobenzene in the optimized conditions for aryl bromides, but unfortunately, the corresponding coupling products were not detected.

Experimental

General

All operations were carried out in open atmosphere. Column chromatographies were performed using 70–230 mesh silica gel. All reagents and solvents were obtained from commercial suppliers and used without further purification. All compounds were characterized by IR spectra, recorded on a Perkin-Elmer 283B or 1420 spectrophotometer, by means of film and KBr techniques, and all data are expressed in wave numbers (cm ⁻¹). Melting points were obtained on a Melt-Temp II apparatus and are uncorrected. NMR spectra were measured with a VARIAN+ 300 MHz, using CDCl ₃ as solvent. Chemical shifts are in ppm ( δ), relative to TMS. The MS-EI spectra were obtained on a JEOL SX 102A, the values of the signals are expressed in mass/charge units ( m/ z), followed by the relative intensity with reference to a 100% base peak.

IR equipment

The equipment used for irradiation with IR energy was created by employing an empty cylindrical metal vessel in which an Osram lamp (bulb model Thera-Therm, 250 W, 125 V) was inserted. ⁴³ This lamp is special short-wave IR lamp (IR-A) for use in body care and wellness applications, with a maximum radiation at a wavelength of 1100 nm. The lamp instantly emits a full thermal output as soon as it is switched on. For controlling the temperature, a Digi-Sense variable-time power controller was used. This time controller turned the output load on and off and then repeated the cycle. Although all the reactions were performed in open atmosphere, this arrangement also allows the use of inert conditions.

General procedure for the synthesis of ( Z)-(aminomethyl)(aryl)phenylhydrazones 1a–h

A mixture of 1 equivalent of phenylhydrazone ( 3), 2 equivalent of formaldehyde (in a 37% aqueous solution), and 2 equivalent of secondary amine (piperidine or diethylamine) was irradiated using an Osram lamp (bulb model Thera-Therm, 250 W, 125 V) at reflux and stirred for the time stated in Table 1.

The reaction mixture was poured into water (15 mL) and extracted with ether (3 × 15 mL). The combined organic layers were washed with water (3 × 15 mL) and dried over anhydrous sodium sulfate. The crude product was finally purified by flash column chromatography on silica gel using hexane as an eluent to give the corresponding isolated products.

The starting phenylhydrazones ( 1) were prepared from phenylhydrazine with various commercially available benzaldehydes in methanol. ⁴⁵

( Z)-1-(2-Phenyl-2-(phenylhydrazono)ethyl)piperidine 1a . This compound was obtained in a pure way in 92% yield as a yellow solid. Mp: 90–91 °C. MS-IE + m/ z (rel. intensity%): 293 [M ⁺] (55), 201 [C ₁₃H ₁₇N ₂] ⁺ (60), 98 [C ₆H ₁₂N] ⁺ (100). Select IR ν _max/cm ⁻¹ (KBr): 1597 (C=N), 1515 (C _Ar=C _Ar). δ _H (300 MHz; CDCl ₃; Me ₄Si) 1.50–1.64 (m, 6H, H-b, H-b′ and H-c), 2.5 (m, 4H, H-a, H-a′), 3.69 (s, 2H, H-d), 6.84 (d, 1H, H-n, J _HnHm = 6.9 Hz), 7.15 (d, 2H, H-l, H-l′ J _HlHm = 7.5 Hz), 7.25 (dd, 1H, H-m, J _HmHn = 6.9 Hz, J _HmHl = 7.5 Hz), 7.30–7.37 (m, 4H, H-h, H-h′ and H-i), 7.77 (d, 2H, H-g, H-g′) and 11.45 (s, 1H, H-j). δ _C (75 MHz; CDCl ₃; Me ₄Si) 24.0 (C-c), 26.3 (C-b, C-b′), 53.7 (C-a, C-a′), 53.7 (C-d), 112.7 (C-l, C-l′), 119.5 (C-n), 125.5 (C-g, C-g′), 127.4 (C-i), 128.2 (C-h, C-h′), 129.1 (C-m, C-m′), 139.0 (C-f), 139.5 (C-k), 145.7 (C-e).

( Z)-1-(2-( p-Methoxyphenyl)-2-(phenylhydrazono)ethyl)piperidine 1b . Yellow solid in 80%. Yield. Mp: 68–70 °C. MS-IE + m/ z (rel. intensity%): 323 [M] ⁺ (28), 231 [C ₁₄H ₁₉N ₂O] ⁺ (27), 133 [C ₈H ₉N ₂] ⁺ (60), 98 [C ₆H ₁₂N] ⁺ (100). Select IR ν _max/cm ⁻¹ (KBr): 1601.25 (C=N), 1504.57 (C _Ar=C _Ar). δ _H (300 MHz; CDCl ₃; Me ₄Si) 1.57–1.61 (m, 6H, H-b, H-b′ and H-c), 2.46 (m, 4H, H-a, H-a′), 3.62 (s, 2H, H-d), 3.79 (s, 3H, OCH ₃), 6.87 and 7.69 (2d, 4H, H-g, H-g′ and H-h, H-h′, J _HgHh = 9 Hz), 7.10–7.12 (m, 3H, H-l, H-l′ and H-n), 7.22–7.27 (m, 2H, H-m, H-m′), 11.27 (s, 1H, H-j). δ _C (75 MHz; CDCl ₃; Me ₄Si) 24.0 (C-c), 26.2 (C-b, C-b′), 53.7 (C-a, C-a′), 55.2 (C–OCH ₃), 57.2 (C-d), 112.6 (C-l, C-l′), 113.6 (C-g, C-g′), 119.2 (C-n), 126.8 (C-h, C-h′), 129.0 (C-m, C-m′), 131.9 (C-f), 139.6 (C-k), 145.9 (C-e), 159.2 (C-i).

( Z)-1-(2-( p-Chlorophenyl)-2-(phenylhydrazono)ethyl)piperidine 1c . This compound was obtained in a pure way in 90% yield as a yellow solid. Mp: 72–74. MS-IE + m/ z (rel. intensity%): 327 [M] ⁺ (10), 235 [C ₁₃H ₁₆N ₂Cl] ⁺ (20), 98 [C ₆H ₁₂N] ⁺ (100), 84 [C ₅H ₁₀N] ⁺ (32). Select IR ν _max/cm ⁻¹ (KBr): 1600 (C=N), 1491 (C _Ar=C _Ar). δ _H (300 MHz; CDCl ₃; Me ₄Si) 1.53–1.63 (m, 5H, H-b, H-b′ and H-c), 2.63 (m, 4H, H-a, H-a′), 3.65 (s, 2H, H-d), 6.85 (d, 1H, H-n), 7.14 and 7.69 (2d, 4H, H-g, H-g′, H-h, H-h′, J _HgHh = 8.7 Hz), 7.25–7.32 (m, 4H, H-l, H-l′, H-m, H-m′), 11.43 (s, 1H, H-j). δ _C (75 MHz; CDCl ₃; Me ₄Si) 23.9 (C-c), 25.8 (C-b, C-b′), 53.7 (C-a, C-a′), 57.1 (C-d), 112.8 (C-l, C-l′), 119.7 (C-n), 126.6 (C-h, C-h′), 128.3 (C-g, C-g′), 129.1 (C-m, C-m′), 133.2 (C-k), 137.5 (C-i), 138.1 (C-f), 145.4 (C-e).

( Z)-1-(2-( p-Nitrophenyl)-2-(phenylhydrazono)ethyl)piperidine 1d . This compound was obtained in a pure way in 99% yield as an orange solid. Mp: 140–141 °C. MS-IE + m/ z (rel. intensity%): 338 [M] ⁺ (47), 246 [C ₁₃H ₁₆N ₃O ₂] ⁺ (38), 105 [C ₆H ₅N ₂] ⁺ (30), 98 [C ₆H ₁₂N] ⁺ (100), 84 [C ₆H ₁₀N] ⁺ (58), 77 [C ₆H ₅] ⁺ (56). Select IR ν _max/cm ⁻¹ (KBr): 1595 (C=N), 1514 (C _Ar=C _Ar), 1542, 1337 (N=O). δ _H (300 MHz; CDCl ₃; Me ₄Si) 1.48–1.52 (m, 5H, H-b, H-b′ and H-c), 2.46 (m, 4H, H-a, H-a′), 3.67 (s, 2H, H-d), 6.87 (d, 1H, H-n, J _HnHm = 4.5 Hz), 7.13 (dd, 2H, H-m, H-m′, J _HmHn = 4.5 Hz, J _HmHl = 5.1 Hz), 7.27 (d, 2H, H-l, H-l′, J _HlHm = 5.1 Hz), 7.85 and 8.14 (2d, 4H, H-g, H-g′, H-h, H-h′ J _HgHh = 7.2 Hz), 11.75 (s, 1H, H-j). δ _C (75 MHz; CDCl ₃; Me ₄Si) 23.9 (C-c), 25.8 (C-b, C-b′), 53.0 (C-a, C-a′), 56.8 (C-d), 113.1 (C-l, C-l′), 120.7 (C-n), 123.6 (C-h, C-h′), 125.4 (C-g, C-g′), 129.2 (C-m, C-m′), 136.1 (C-k), 144.7 (C-e), 145.0 (C-f), 146.4 (C-i).

( Z)- N, N-Diethyl-2-phenyl-2-(2-phenylhydrazono)ethanamine 1e . Yellow oil in 70% yield. MS-IE + m/ z (rel. intensity%): 281 [M] ⁺ (60), 209 [C ₁₄H ₁₃N ₂] ⁺ (20), 189 [C ₁₂H ₁₇N ₂] ⁺ (60), 86 [C ₅H ₁₂N] ⁺ (100). Select IR ν _max/cm ⁻¹ (KBr): 2817, 2932, 2968 (H–Csp ³), 3023, 3056 (H–Csp ²), 1599 (C=N), 1556, 1491 (C _Ar=C _Ar), 1443 (CH ₂), 1384 (CH ₃). δ _H (300 MHz; CDCl ₃; Me ₄Si) 1.11 (t, 6H, H-a, H-a′, J _HaHb = 6.9 Hz), 2.6 (q, 4H, H-b, H-b′, J _HbHa = 6.9 Hz), 3.77 (s, 2H, H-c), 6.83 (d, 1H, H-m, J = 7.8 Hz), 7.14 (d, 2H, H-k, H-k′, J = 8.1 Hz), 7.24–7.37 (m, 5H, H-l, H-l′, H-g, H-g′, H-h), 7.77 (d 2H, H-f, H-f′, J = 8.1 Hz). δ _C (75 MHz; CDCl ₃; Me ₄Si) 12.0 (C-a, C-a′), 46.9 (C-b, C-b′), 52.5 (C-c), 112.7 (C-k, C-k′), 119.4 (C-m), 125.4 (C-f, C-f′), 127.4 (C-h), 128.2 (C-l, C-l′), 129.1 (C-g, C-g′), 139.0 (C-d), 140.0 (C-j), 145.6 (C-e).

( Z)- N, N-Diethyl-2-( p-methoxyphenyl)-2-(2-phenylhydrazono)ethanamine 1f . Yellow oil in 80% yield. MS-IE + m/ z (rel. intensity%): 311 [M] ⁺ (80), 281 [C ₁₈H ₂₃N ₃] ⁺ (25), 239 [C ₁₅H ₁₅N ₂O] ⁺ (20), 133 [C ₉H ₉O] ⁺ (100), 86 [C ₅H ₁₂N] ⁺ (90). Select IR ν _max/cm ⁻¹ (KBr): 2835 (H–Csp ³), 2932, 2966 (H–Csp ²), 1599 (C=N), 1503, 1463 (C _Ar=C _Ar), 1440 (CH ₂), 1384 (CH ₃). δ _H (300 MHz; CDCl ₃; Me ₄Si) 1.11 (t, 6H, H-a, H-a′, J _HaHb = 7.2 Hz), 2.59 (q, 4H, H-b, H-b′, J _HbHa = 7.2 Hz), 3.74 (s, 2H, H-c), 6.81 (d, 1H, H-m, J _HmHl = 8.1 Hz), 6.89 (d, 2H, H-k, H-k′, J _HkHl = 8.7 Hz), 7.27 (dd, 2H, H-l, H-l′, J _HlHm = 8.1 Hz, J _HlHk = 8.7 Hz), 7.11 and 7.70 (2d, 4H, H-g, H-g′ and H-f, H-f′ J = 9 Hz), 11.31 (s, 1H, H-i). δ _C (75 MHz; CDCl ₃; Me ₄Si) 12.2 (C-a, C-a′), 47.0 (C-b, C-b′), 52.6 (C-c), 112.7 (C-g, C-g′), 113.8 (C-k, C-k′), 119.3 (C-m), 126.9 (C-f, C-f′), 129.2 (C-l, Cl′), 132.0 (C-d), 140.4 (C-j), 139.0 (C-d), 146.0 (C-e), 159.4 (C-h).

( Z)- N, N-Diethyl-2-( p-chlorophenyl)-2-(2-phenylhydrazono)ethanamine 1g . Yellow oil in 80% yield. MS-IE + m/ z (rel. intensity%): 315 [M] ⁺ (60), 223 [C ₁₂H ₁₆ClN ₂] ⁺ (45), 137 [C ₈H ₆Cl] ⁺ (63), 105 [C ₆H ₅N ₂] ⁺ (65), 86 [C ₅H ₁₂N] ⁺ (100), 77 [C ₆H ₅] (50). Select IR ν _max/cm ⁻¹ (KBr): 2819, 2932, 2968 (H–Csp ³, H–Csp ²), 1599 (C=N), 1574, 1548, 1488 (C _Ar=C _Ar), 1400 (CH ₂), 1384 (CH ₃). δ _H (300 MHz; CDCl ₃; Me ₄Si) 1.07 (t, 6H, H-a, H-a′, J _HaHb = 6.9 Hz), 2.54 (q, 4H, H-b, H-b′, J _HbHa = 6.9 Hz), 3.69 (s, 2H, H-c), 6.80 (d, 1H, H-m, J _HmHl = 8.4 Hz), 7.06 (d, 2H, H-k, J _HkHl = 6.6 Hz), 7.22 (dd, 2H, H-l, J _HlHm = 8.4, J _HlHk = 6.6 Hz), 7.27 and 7.64 (2d, 4H, H-g, H-g′ and H-f, H-f′, J = 9.0 Hz), 11.42 (s, 1H, H-i). δ _C (75 MHz; CDCl ₃; Me ₄Si) 12.0 (C-a, C-a′), 46.9 (C-b, C-b′), 52.3 (C-c), 112.7 (C-k, C-k′), 119.7 (C-m), 126.5 (C-f, C-f′), 128.3 (C-l, C-l′), 129.1 (C-g, C-g′), 133.8 (C-h), 137.4 (C-j), 138.7 (C-d), 145.4 (C-e).

( Z)- N, N-Diethyl-2-( p-nitrophenyl)-2-(2-phenylhydrazono)ethanamine 1f . Orange oil in 85% yield. MS-IE + m/ z (rel. intensity%): 326 [M] ⁺ (35), 281 [C ₁₈H ₂₃N ₃O] ⁺ (50), 234 [C ₁₂H ₁₆N ₃O ₂] ⁺ (30), 105 [C ₆H ₅N ₂] ⁺ (85), 86 [C ₅H ₁₂N] ⁺ (100), 77 [C ₆H ₅] (95). Select IR ν _max/cm ⁻¹ (KBr): 2931, 2968 (H–Csp ³, H–Csp ²), 1593 (C=N), 1544, (C _Ar=C _Ar), 1490, 1331 (N=O), 1407 (CH ₂), 1384 (CH ₃). δ _H (300 MHz; CDCl ₃; Me ₄Si) 1.06 (t, 6H, H-a, H-a′, J _HaHb = 6.9 Hz), 2.53 (q, 4H, H-b, H-b′, J _HbHa = 6.9 Hz), 3.74 (s, 2H, H-c), 6.83 (d, 1H, H-m, J _HmHl = 6.6 Hz), 7.06 (d, 2H, H-k, H-k′, J _HkHl = 8.4 Hz), 7.22 (dd, 2H, H-l, H-l′, J _HlHm = 6.6 Hz, J _HlHk = 8.4 Hz), 7.83 and 8.12 (2d, 4H, H-g, H-g′ and H-f, H-f′, J = 9.3 Hz), 11.79 (s, 1H, H-i). δ _C (75 MHz; CDCl ₃; Me ₄Si) 11.9 (C-a, C-a′), 46.8 (C-b, C-b′), 52.0 (C-c), 1131 (C-k, C-k′), 120.6 (C-m), 123.7 (C-g, C-g′), 125.3 (C-f, C-f′), 129.2 (C-l, C-l′), 136.6 (C-j), 144.6 (C-d), 145.0 (C-e), 146.3 (C-h).

General procedure for Heck coupling reactions

In a 50 mL round-bottomed flask, a mixture of aryl halide (2 mmol), methyl acrylate (3.3 mmol), and the corresponding base (2.5 mmol), was placed in 5 mL of DMF, then the source of palladium and the corresponding hydrazone 1 were added (see Tables 2–5). The reaction mixture was irradiated using an Osram lamp (bulb model Thera-Therm, 250 W, 125 V) for the time stated in Tables 2–5 at 140 °C. The reaction mixture was poured into water (10 mL) and extracted with ether or hexane (3 × 10 mL). The combined organic layers were dried over anhydrous sodium sulfate.

The crude product was finally purified by flash column chromatography on silica-gel to give the isolated products in yields stated in the Tables 2–5. The purified product was identified by means of determination of mp and by ¹H and ¹³C NMR, the data obtained are consistent with literature. ⁴⁶

Note: the entire round flasks used in each coupling reaction were meticulously cleaned with aqua regia to avoid the presence of unseen palladium catalyst.

Conclusions

We describe the synthesis of new ( Z)-(aminomethyl)(aryl)phenylhydrazones ( 1a–h) with good yields via the Mannich coupling reaction using IR as a source energy and solvent-free conditions. These new hydrazones 1a–h are promising for the catalysis of Heck coupling reactions using IR and Pd(AcO) ₂. Particularly, the [Pd(AcO) ₂/ 1a] system showed to be a good catalyst in this reaction, being more active when electron-rich aryl halide are used as substrates.

As we have described, the use of infrared as energy source favors the Mannich and Heck coupling reactions to obtain the corresponding products in an efficient manner. The reaction times decrease in all the cases, in comparison to experiments conducted in conductive heating. Thus, infrared irradiation effectively penetrates the reaction vessel and causes a sudden increase in temperature, which allows to easily reach the activation energy to transform substrates into products.

Therefore, we evidence that infrared irradiation (IR) is an efficient, economical and accessible alternative source of energy to assist both, the synthesis of ( Z)-(aminomethyl)(aryl)phenylhydrazones, and Heck coupling reactions.

Acknowledgements

The authors would like to acknowledge the technical assistance provided by Luis Velasco and Javier Pérez. The authors also thank CONACYT 153059 and Facultad de Estudios Superiores Cuautitlán PIAPIC14 projects.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c5ra12715g

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