Intramolecular oxidative cyclization of alkenes by rhodium/cobalt porphyrins in water

Abstract

Intramolecular oxidative cyclization of alkenes provides a unique pathway to obtain unsaturated heterocyclic compounds. The rhodium(III)/cobalt(III) tetra(p-sulfonatophenyl)porphyrin ((TSPP)M^III) in water was observed to mediate the intramolecular oxidative functionalization of alkenes to a series of unsaturated oxygen heterocyclic compounds.

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The activation of alkenes by coordination to metal centers and subsequent functionalization is one of the most widely exploited synthetic methodologies in the functionalization of organic molecules.^1–3 Intramolecular oxidative cyclization of alkenes provides a unique pathway to obtain unsaturated heterocyclic compounds. Transition metal complex mediated intramolecular Wacker-type oxidative alkoxylation provides a straightforward access to oxygen heterocycles.⁴ The retained C=C double bonds allow further functionalization of the resulting heterocycles. However, this process is far less developed compared with intramolecular hydrofunctionalization of alkenes^5–7 and most oxidative cyclization/functionalization studies focused on palladium catalysis.^1,8 Additionally, the importance of alkene transformations and objectives of green chemistry justify the continuing search for new classes of catalyst materials and new pathways leading to novel oxidative functionalization in water.

Rhodium porphyrin complexes demonstrate a wide range of important substrate reactions.^9,10 Groves demonstrated intramolecular anti-Markovnikov hydrofunctionalization of olefins mediated by the tetraphenyl porphyrin rhodium hydride complex (Scheme 1A).¹⁰ Previous work from our group has accomplished stoichiometric aerobic oxidation of olefins in water mediated by a water soluble rhodium porphyrin complex (TSPP)Rh^III.¹¹ Rhodium porphyrin β-hydroxyalkyl complexes were observed and isolated as intermediates, which underwent β-hydrogen elimination (BHE) to give methyl ketones as the oxidation products (Scheme 1B). Based on these studies, we extended our interest towards the intramolecular oxidative cyclization of alkenes to form unsaturated heterocycles (Scheme 1C) through a four-step cycle involving: (1) alkene coordination to (TSPP)Rh^III; (2) intramolecular nucleophilic attack by the –OH group towards activated alkenes; (3) hydrogen elimination to give unsaturated cyclization products and (4) the reduced metal complex (TSPP)Rh^I was aerobically oxidized to (TSPP)Rh^III.

Scheme 1 The rhodium porphyrin complex mediated transformation of alkenes.

Intramolecular nucleophilic activation of alkenes

Allylphenol was selected as the model substrate which showed good reactivity as previously reported.^8,12 Addition of 2-allylphenol to a borate buffered (pH = 8.0) D₂O solution of (TSPP)Rh^III at room temperature resulted in an immediate color change from sanguine to orange-red. The ¹H NMR experiment revealed complete conversion of (TSPP)Rh^III to the alkyl rhodium complex 1 which was conveniently identified by the appearance of a set of high field resonances attributed to the (2,3-dihydrobenzofuran-2-yl)methyl group bonded to the rhodium center. The ¹H NMR resonances centered at −5.67 and −5.81 ppm were associated with the diastereotopic α-CH₂ in the complex 1, indicating that the rhodium carbon bond was formed regioselectively at the terminal primary CH₂ unit (Fig. 1). No intermolecular addition product was formed as the β-hydroxyl proton observed for the reaction of allylbenzene was not found in the spectrum of the complex 1 (Scheme 2B).¹³ The independently synthesized rhodium alkyl complex by the reaction of (TSPP)Rh^I with 2-(iodomethyl)-2,3-dihydrobenzofuran resulted in the same ¹H NMR spectrum as that of the complex 1. ESI-MS results (C53H33N4O13RhS4, m/z = 291.99903, calcd 291.99900; Fig. 1) also confirmed the structure of 1. The intramolecular –OH attack reaction of (TSPP)Rh^III with 2-allylphenol to form 1 occurred through coordination of an alkene towards the rhodium center, followed by intramolecular nucleophilic attack of the phenoxyl group.¹¹

Fig. 1 ¹H NMR spectrum of the complex 1 in CD₃OD.

Scheme 2 Reaction of (TSPP)Rh^III with 2-allylphenol to form the complex 1.

Following the same reactivity pattern, a series of phenyl substituted 2-allylphenol substrates (Table 1, entries 1–5) and a variety of alkenes with different nucleophiles (Table 1, entries 6–12) were observed to react rapidly and quantitatively with (TSPP)Rh^III in water and methanol. Changing from the benzene ring to the cyclohexane ring, 2-allylcyclohexanol reacted with (TSPP)Rh^III rapidly to form the cyclization product 6, indicating that the less nucleophilic alcoholic hydroxyl group could also perform intramolecular oxidative alkoxylation reaction (Table 1, entry 6). 2-Methylhex-5-en-2-ol also experienced a 5-exo-trig ring closure reaction with (TSPP)Rh^III in water with formation of the complex 7 (Table 1, entry 7). The primary alcoholic hydroxyl group could also act as the nucleophile to form the intramolecular cyclization product 8 (Table 1, entry 8). A γ-lactone containing the rhodium alkyl complex 9 was obtained from a reaction of the 3-phenyl-4-pentenoic acid substrate with a carboxylic hydroxyl nucleophile (Table 1, entry 9). It is worth noting that 2-allylaniline also reacted with (TSPP)Rh^III in an intramolecular way with the anilino group as the nucleophile (Table 1, entry 10).

Table 1 Substrate scope towards intramolecular nucleophilic activation of alkenes by (TSPP)Rh(III)^a and (TSPP)Co(III)^b

Entry	Substrate	Product	Yield^c
a Reaction conditions: (TSPP)Rh^III (1.0 mmol L^−1), alkene (10 equiv.), D2O (300 μL, pH 8.0 borate buffer), room temperature, <5 min. b Reaction conditions: (TSPP)Co^III (1.0 mmol L^−1), alkene (10 equiv.), D2O (300 μL, pH 9.0 borate buffer), room temperature, <5 min. c Determined by ^1H NMR. d 0.1 mL CD3OD was added to increase the solubility of the substrate. e Reactions were performed in CD3OD.
1			1: >95%
			14: >95%
2			2: >95%
			15: 73%
3			3: >95%
			16: 82%
4			4: >95%
			17: 88%
5			>95%
6			>95%
7			7: >95%
			18: >95%
8			>95%
9			9: 86%
			19: 57%
10			79%
11			>95%
12			>95%
13			>95%

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Previously, we reported the reactivity of pent-4-en-1-ol in water with rhodium porphyrins, and the reaction generated an exclusively intermolecular nucleophilic attack product 13.¹¹ Comparison of entries 7 and 8 where the substrates share similar skeleton to pent-4-en-1-ol revealed the “pre-organizing” function of both phenyl and di-methyl groups which resulted in immediate intramolecular nucleophilic cyclization reaction. Although no cyclization was observed for pent-4-en-1-ol in water, reaction with (TSPP)Rh^III in the methanol solvent rapidly produced the intramolecular alkoxylation rhodium alkyl complex 11 without observation of the 6-endo-trig product (Table 1, entry 11). Similar reactivity was also observed for hex-5-en-1-ol which underwent 6-exo-trig cyclization to form 12 with high regioselectivity (Table 1, entry 12). The difference between the intermolecular reactivity in water lies in the nucleophilicity increase of the alcoholic hydroxyl groups in methanol where the solvation effect is lower, and that the hydrophobic porphyrin ligand was away from the hydroxyl group on the alkyl chain.

The produced metal alkyl complexes of Table 1 were generally proposed as the key intermediates in Wacker-type oxidation and hydrofunctionalization of alkenes, although only a few studies reported direct observation of the intermediate.¹⁴ Formation of a new C–O bond in these reactions was thought to occur exclusively by attack of an oxygen nucleophile onto a metal-coordinated olefin.^1–3 Recently, migratory insertion of a C=C bond into an M–O bond was proposed as an alternative pathway.¹⁵ However, the four membered transition state of migration insertion would require unsaturation of the metal center with a vacant cis coordination site, which was not conveniently accessible for alkyl rhodium porphyrin complexes.^11,16 Combined with previous studies on intermolecular (TSPP)Rh^III mediated aerobic oxidation of alkenes, formation of alkyl rhodium species in Table 1 was proposed to occur via the intramolecular nucleophilic attack towards coordinated alkenes.

Production of unsaturated heterocyclic compounds

In the absence of air, the complex 1 was spontaneously transformed to (TSPP)Rh^I and 2-methylbenzofuran over 30 min at 333 K in water (Scheme 3). The resulting product was extracted with CDCl₃ and identified by GC-MS and ¹H NMR. The product was proposed to be formed by β-hydrogen elimination of the complex 1. The stoichiometric reactivity of a series of phenyl substituted 2-allylphenol substrates was examined (Scheme 3). Reactions with (TSPP)Rh^III in pH 8.0 buffer solution were rapid and quantitative. The formed β-phenoxyalkyl rhodium porphyrins 2–5 underwent β-hydrogen elimination at 333 K under a nitrogen atmosphere to produce 2-methylbenzofurans quantitatively within 1 hour. The reaction exhibited good tolerance for a decent range of substituents including alkyl, alkoxyl, acyl, and formyl groups.

Scheme 3 Formation of heterocyclic unsaturated compounds. See Table S1 in ESI† for detailed experimental conditions and results.

(TSPP)Co^III mediated oxidative alkoxylation of alkenes

(TSPP)Rh^III showed an unusual pathway for oxidative alkoxylation/cyclization of alkenes in water. The cheap metal complex (TSPP)Co^III was a much more attractive catalyst if this complex could react in the same reactivity pattern as that of (TSPP)Rh^III. However, (TSPP)Co^III did not react with alkenes through the intermolecular pathway to form β-hydroxyl alkyl cobalt porphyrins. Fortunately, the intramolecular reaction occurred rapidly. Addition of 2-allylphenol to a pH 8.0 buffer solution of (TSPP)Co^III immediately led to formation of the cyclization product β-phenoxyalkyl cobalt complex 14 (Table 1, entry 1). Methyl, formyl, and acyl substituted allylphenols also showed similar reactivities (Table 1, entries 2–4). Rapid formation of alkyl cobalt species 18 and 19 was also observed by a reaction of 2-methylhex-5-en-2-ol and 3-phenyl-4-pentenoic with (TSPP)Co^III (Table 1, entries 7 and 9). These reactions provide rare examples of Co(III) mediated oxidation of alkenes,¹⁷ since both the interaction of Co(III) with alkenes and the Co(III)–C bonding are weak, which explained the unfavorable intermolecular formation of Co^III–CR₂–CR₂OH. The efficient formation of complexes 14–19 through the intramolecular nucleophilic addition pathway was ascribed to the entropy-driven effect. Upon heating to 333 K, complexes 14–17 gave an oxidative cyclization product 2-methylbenzofuran as observed for 1 (Scheme 3).

The (TSPP)Rh-H species formed in elimination reactions in Scheme 3 occurs in a rapid dissociation equilibrium with (TSPP)Rh^I and H⁺. Rapid air oxidation of (TSPP)Rh^I to (TSPP)Rh^III completes the Wacker-type oxidation cycle which provides the potential for aerobic catalytic intramolecular cyclization of olefins with exclusive regioselectivity (eqn (1)).¹⁸

(TSPP)Rh^I + 1/2O₂ + H₂O ⇌ (TSPP)Rh^III + 2OH⁻ (1)

Conclusions

In summary, we have described an unusual pathway for intramolecular oxidative cyclization of substituted 2-allylphenols by (TSPP)Rh^III and (TSPP)Co^III to form 2-methylbenzofuran derivatives in water. Key intermediates β-phenoxyalkyl rhodium/cobalt porphyrin complexes were observed and characterized. A series of substrates including unsaturated alcohols, carboxylic acid, and aniline also reacted with (TSPP)Rh^III to form thermally stable β-hetero-functionalized alkyl rhodium porphyrins with exclusive regioselectivity. These complexes provide valuable insights into mechanistic studies of transition metal catalyzed Wacker-type oxidation of alkenes and a novel construction protocol for heterocycle synthesis. Developing new methods for further cleavage of the Rh–C bond and Co–C bond and catalytic intramolecular oxidative cyclization of alkenes is ongoing.

Acknowledgements

This work was supported by the National Science Foundation of China (21171012).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c4qi00066h

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