New Palladacycle-Derived Acylhydrazones as Pre-catalysts in Mirozoki-Heck Coupling and Oxyarylations

ABSTRACT

New acylhydrazone-based palladacycles are prepared and evaluated as pre-catalysts in Mirozoki-Heck and oxyarylation reactions.

Key words:
acylhydrazone; palladacycle; Mirozoki-Heck reaction; oxyarylation

INTRODUCTION

Palladacycles were discovered in the mid-1960s as intermediates in palladium- mediated transformations and have been employed as active intermediates in cascade transformations leading to complex molecular architectures (Beletskaya and Cheprakov 2004, Dupont et al. 2005).

Since the preparation of the cyclopalladate tri-o-tolyl-phosphine complex reported by Herman (Hermann et al. 1995, 1999) and its use as a pre-catalyst for palladium-catalyzed Mirozoki-Heck and other cross-coupling reactions, the use of palladacycles has experienced tremendous growth (Beletskaya and Cheprakov 2004, Dupont et al. 2005).

Their high thermal stability in the solid state, easy preparation and ready modulation of both steric and electronic properties make them affordable tools in organic synthesis. In fact, a large number of new palladacycles have been prepared and used as pre-catalysts (Alonso et al. 2000, Nájera 2016).

Despite some suggestion of a mechanism involving Pd(II) and Pd(IV) species (Shaw et al. 1998a, Shaw 1998), they are considered as a source of in situ formed Pd(0) nanoparticles, which have been successfully used in several coupling reactions in low catalytic loading. In addition, palladacycles can be prepared in water and do not require the presence of ligands, making their use very attractive (Beletskaya and Cheprakov 2004, Dupont et al. 2005).

Although some hydrazone-based palladacycles are known in the literature and promote Suzyki-Miyaura and Mirozoki-Heck coupling reactions (Cardenas and Echavarren 1995, Nagy et al. 2005), herein we describe the first synthesis and application of acyl-hydrazone-based paladacycles as pre-catalysts in Mirozoki-Heck and oxyarylation reactions.

DISCUSSION AND RESULTS

Acylhydrazones (1a-c) are easily prepared by the reaction of acylhydrazines with aromatic aldehydes and have been extensively used as a platform to construct interesting biologically active compounds (Fraga and Barreiro 2006).

The new palladacycles 2a-c were prepared by electrophilic C-H activation of acylhydrazones 1a-c with Li₂PdCl₄ in methanol in the presence of NaOAc as the base at room temperature (Figure 1) (Alonso et al. 2002). Compounds 2a-c precipitated from the reaction medium and were obtained as yellowish stable solids after filtration.

Figure 1
Preparation of the palladacycles 2a-c.

Once ¹H NMR spectra are complex to analyze the structures of 2a-c were determined by indirect way. Palladacycles 2a and 2c were reduced with NaCNBD₃ in THF/MeOH (Figure 2) (Alonso et al. 2002) leading to the respective deuterated acylhydrazones 3a and 3c, which were characterized by GC/MS and ¹H NMR. Also, the palladacycle 2b was reduced under the same conditions, yielding the acylhydrazone 3b (GC/MS).

Figure 2
Reduction of the palladacycles 2a-c.

A fragment of the oxonium ion at m/z = 105 was the base peak in all three cases (Figure 3). Since this fragment does not present deuterium in its structure, the Pd-C bond in palladacycles 2a-c must be located at the B ring. Deuterated acylhydrazones 3a and 3c led to a deuterated fragment at m/z = 224, while for 3b a fragment was observed at m/z = 147, by releasing a deuterated phenyl group. These analyses clearly indicate that the deuterium is located in the B-ring, in accordance with the proposed structures of 2a-c.

Figure 3
Proposed mechanism for the fragmentation of 3a-c.

To demonstrate the efficiency of these new acylhydrazone-based palladacycles, they were evaluated in the Mirozoki-Heck reaction between iodobenzene (4) and methyl acrylate (5). The yield of methyl cinnamate (6) and the major reaction conditions studied are shown in Figure 4 and Table I. Triethylamine was used as the base and after 10 h at 110 ^oC in the presence of 0.1 mol% Pd source, 6 was obtained in excellent yield, regardless of the pre-catalyst used (entries 1-3, Table I). Similar yields were obtained in the presence of 0.001 mol% of 2a-c, but using a more prolonged reaction time (entries 3-6, Table I). Similar results were obtained when DIPEA was used as the base (entries 7 and 8, Table I) but yields decreased in the presence of Na₂CO₃ (entries 9-11, Table I). The yields were still good when MeCN or NMP were employed as solvents (entries 12-16, Table I). However, no reaction was observed when the reaction was conducted in the mixture DIPEA-water (data not shown).

TABLE I
Yields and main conditions for reactions shown in Figure 4.

entry	Solvent	Base	Pd(mol%)	T( o C)	Time (h)	Yield (%)
1	DMF	TEA	0.1(2a)	110	10	96
2	DMF	TEA	0.1(2b)	110	10	98
3	DMF	TEA	0.1(2c)	110	10	98
4	DMF	TEA	0.001(2a)	110	24	80
5	DMF	TEA	0.001(2b)	110	24	95
6	DMF	TEA	0.001(1c)	110	24	95
7	DMF	DIPEA	0.001(2a)	110	24	85
8	DMF	DIPEA	0.001(2b)	110	24	80
9	DMF	Na2CO3	0.001(2a)	110	24	65
10	DMF	Na2CO3	0.001(2b)	110	24	72
11	DMF	Na2CO3	0.001(2c)	110	24	70
12	MeCN	TEA	0.001(2a)	80	24	90
13	MeCN	TEA	0.001(2b)	80	24	92
14	MeCN	TEA	0.001(2c)	80	24	92
15	NMP	TEA	0.001(2b)	110	24	80
16	NMP	TEA	0.001(1c)	110	24	75

Figure 4
Mirozoki-Heck reaction of 4 and 5 in palladacycles 2a-c as pre-catalysts.

Next, we studied the Mirozoki-Heck reaction between 4 and styrene (7), shown in Figure 5 and Table II. Stilbene (8) was obtained in reasonable yield when 0.1 mol% 2b or 2c were used as pre-catalyst (entries 1 and 2, Table II) but the yield decreased when 0.001 mol% of pre-catalyst was employed (entries 3 and 4, Table II).

TABLE II
Yields and main conditions for the reaction shown in Figure 5.

entry	Solvent	Base	Pd (mol%)	T ( o C)	Time (h)	Yield (%)
1	DMF	TEA	0.1(2b)	110	24	67
2	DMF	TEA	0.1(2c)	110	24	60
3	DMF	TEA	0.001(2b)	110	24	50
4	DMF	TEA	0.001(2c)	110	24	45

Figure 5
Mirozoki-Heck reaction of 4 and 7 in palladacycles 2a,b.

Finally, we turned our attention to a more challenging transformation, the oxyarylation reaction. The first catalytic version of the oxyarylation reaction was reported (Larock 1998) under conditions that favored the neutral pathway. Kiss et al. (2003) reported the use of silver carbonate as base, conditions where the cationic mechanism is favored.

The scope of this reaction in the presence of Ag₂CO₃ was studied by our group and a cationic palladacycle formed in the migratory insertion step could be intercepted by ESI-MS and characterized by ESI-MS/MS (Buarque et al. 2010). As the carbopalladation step occurs with the attachment of the aryl group and the palladium atom in the same face of the olefin, the cis-stereoselectivity observed in oxyarylation reaction can be understood by the retention of configuration in the course of the formation of O-C bond in the reductive elimination step (Buarque et al. 2010).

The Najera’s palladacycle also catalyzed these reactions, but the mechanism was not studied under these conditions (Leão et al. 2011). The use of PEG-400 as solvent and additive was also reported (de Moraes et al. 2015).

The oxyarylation reaction of dihydronaphthalene 10 with ortho-iodophenols 9a-c was used in order to evaluate the efficiency of the palladacycles 2a-c. (Figure 6 and Table III). Interestingly, these reactions did not proceed when performed in DMF. However, compounds 11a-c were obtained in reasonable yields using the mixture MeCN-H₂O (MeCN-H₂O =1/3), irrespective of the pre-catalyst used (entries 1-5, Table III). Yields for 11a are higher than that obtained with Najera’s palladacycle (35% under thermal conditions, data not shown) (Leão et al. 2011). In contrast, for reactions using silver carbonate as base (de Moraes et al. 2015) the yields did not depend on the pattern of substitution in 9.

TABLE III
Yields and main conditions for the reaction shown in Figure 6.

entry	ArI	Pd (1mol%)	Product	T (o C)	Time (h)	Yield (%)
1	9a	2a	11a	120	12	50
2	9a	2b	11a	120	12	55
3	9a	2c	11a	120	12	56
4	9b	2c	10b	120	12	52
5	9c	2c	10c	120	12	53

Figure 6
Oxyarylation reaction of 10 with 9 in the presence of palladacycles 2a-c.

CONCLUSIONS

In summary, we describe the synthesis of new acylhydrazone-based palladacycles and their application as efficient pre-catalysts in Mirozoki-Heck and oxyarylation reactions in reasonable to good yield using low catalytic load.

EXPERIMENTAL SECTION

GENERAL

All the reagents and solvents were purchased from Aldrich Chem. Co. and used without purification. Melting points were determined with a Thomas-Hoover apparatus. Column chromatography was performed on flash silica 0.035-0.070 mm (Acros). IR spectra were obtained in an IR Prestige-21 Shimadzu. NMR spectra were recorded on a Varian 400 (400 MHz) spectrometer. Low-resolution mass spectra were obtained from a GCMS-QP 5000 Plus Shimadzu.

SYNTHESIS OF ACYLHYDRAZONES 1a-c

To a solution of benzohydrazide (0.3 g; 2.20 mmol) in absolute ethanol (5 mL) containing three drops of 37% hydrochloric acid, was added 2.31 mmol of the appropriated aromatic carbonyl. The mixture was stirred at 70 ^oC for 8 hours when an extensive precipitation occurs. The mixture was poured into cold water, neutralized with 10% aqueous sodium bicarbonate solution and the precipitate was filtered off and washed several times with petroleum ether.

Acylhydrazone1a: 55%; Mp 205-206 ^oC. ¹H RMN (400 MHz, DMSO-d₆), d(ppm): d11.85 (s, 1H), 8.48 (s, 1H), 7.93 (d, J= 7.35 Hz, 2H), 7.74 (d, J= 6.31 Hz, 2H), 7.62-7.46 (m, 6H).

Acylhydrazone 1b: 30%; Mp 150-151 ^oC. ¹H NMR (400 MHz, DMSO-d₆), d(ppm): δ 10.75 (s, 1H), 7.86 (s, 4H), 7.64 - 7.35 (m, 6H), 2.35 (s, 3H). MS (70 eV): m/z= 238 (7), 223 (23), 105 (100).

Acylhydrazone 1c: 67%; Mp 113-114 ^oC. ¹H NMR (400 MHz, CDCl₃) δ 7.48 - 7.46 (m, 3H), 7.42 - 7.36 (m, 4H), 7.34 - 7.26 (m, 9H). MS (70 eV): m/z= 300 (30), 223 (9), 195 (7), 165 (10), 105 (100).

SYNTHESIS OF PALLADACYCLES 2a-c

To a solution of Li₂PdCl₄ (0.99 mmol) in methanol (2 mL) was added a methanolic solution (3 mL) of the appropriated acylhydrazone 1a-c (0.99 mmol) and sodium acetate (0.081 g, 0.99 mmol). The solution was stirred for 3 days at room temperature. After this time, water (10 mL) was added and the corresponding cyclopalladated complexes precipitated were filtered off. The compounds 2a-c were obtained with yields between 73-79%.

Compound 2a: 78%; Mp 180-182 ^oC. ¹H NMR (400 MHz, DMSO-d6) δ 7.97 (d, J = 7.2 Hz, 6H), 7.63-7.58 (m, 5H), 7.54 - 7.50 (m, 7H), 7.08 (sl, 5H).

Compound 2b: 73%; Mp 215-216 ^oC. ¹H NMR (400 MHz, DMSO-d6) δ 11.84 (s, 1H), 8.53 - 8.24 (m, 22H), 8.20-8.00 (m, 3H), 7.83 (dd, J = 72.3, 7.0 Hz, 37H), 7.68 - 7.46 (m, 9H), 7.22 - 6.95 (m, 3H), 3.33 (s, 6H).

Compound 2c: 79%; Mp 206-209 ^oC. ¹H NMR (400 MHz, DMSO-d6) δ 11.25 (sl, 2H), 7.85 (dd, J = 14.4, 6.8 Hz, 1H), 7.74 (d, J = 6.7 Hz, 6H), 7.60 - 7.34 (m, 16H), 7.05 (d, J = 28.9 Hz, 3H), 6.78 (s, 2H).

REDUCTION OF COMPLEXES 2a-c WITH SODIUM CYANOBORODEUTERIDE

To a mixture of the appropriated complex 2a-c (0.125 mmol) in THF (2.5 mL) and MeOH (1.25 mL), was added portionwise sodium cyanoborodeuteride (0.016 g, 0.250 mmol) at 0 ^oC and the mixture was stirred for 1 hour and allowed to reach room temperature. The black precipitate was filtered off, the solvents were evaporated and the residue hydrolyzed with water, extracted with ethyl acetate, the organic layer dried with Na₂SO₄, and evaporated. The deuterated acylhydrazones (3a, 3b and 3c) were obtained in 78, 73 and 63% yields, respectively.

Deuterated acylhydrazone of benzaldehyde 3a: 78%; Mp 138-140 ^oC. ¹H NMR (400 MHz, DMSO-d6) δ 11.85 (s, 1H), 8.48 (s, 1H), 7.93 (d, J = 7.4 Hz, 2H), 7.74 (d, J = 6.3 Hz, 2H), 7.54 (ddd, J = 30.9, 19.0, 7.0 Hz, 7H). MS (70 eV): m/z= 225 (2%), 224 (4%), 121 (20%), 105 (100), 77 (26).

Deuterated acylhydrazone of acetophenone3b: 73%; Mp 200-201 ^oC. ¹H NMR (400 MHz, DMSO-d6) δ 10.77 (s, 1H), 7.88 (sl, 2H), 7.62 - 7.55 (m, 1H), 7.52 (t, J = 7.3 Hz, 2H), 7.43 (s, 3H), 2.37 (s, 3H). MS (70 eV): m/z= 239 (4), 224 (19), 105 (100), 77 (46).

Deuterated acylhydrazone of benzophenone 3c: 63%; Mp 100-102 ^oC. ¹H NMR (500 MHz, CDCl₃) δ 9.07 (s, 1H), 7.71 (d, J = 5.2 Hz, 1H), 7.62 - 7.56 (m, 5H), 7.48 (dd, J = 12.7, 7.4 Hz, 2H), 7.39 - 7.33 (m, 6H). MS (70 eV): m/z= 301 (10), 300 (10), 223 (5), 165 (6), 105 (100), 77 (42).

CONCLUSIONS

In summary, we describe the synthesis of new acylhydrazone-based palladacycles and their application as efficient pre-catalysts in Mirozoki-Heck and oxyarylation reactions in reasonable to good yield using low catalytic load.

ACKNOWLEDGMENTS

The authors thank Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Coordenação de Aperfeiçoamento de Pessoal de Ensino Superior (CAPES), Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ) and Financiadora de Estudos e Projetos (FINEP) for financial support and fellowships.

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Publication Dates

• Publication in this collection
  14 May 2018
• Date of issue
  2018

History

• Received
  25 Oct 2017
• Accepted
  12 Jan 2018