Formation of macrocyclic lactones in the Paternò–Büchi dimerization reaction

Abstract

Furan-2-ylmethyl 2-oxoacetates 1a,b, in which the furan ring and the carbonyl moiety were embedded intramolecularly, were synthesized from commercially available furan-2-ylmethanol and their photochemical reaction (hν > 290 nm) was investigated. Twelve-membered macrocyclic lactones 2a,b with C_i symmetry including two oxetane-rings, which are the Paternò–Büchi dimerization products, were isolated in ca. 20% yield. The intramolecular cyclization products, such as 3-alkoxyoxetane and 2,7-dioxabicyclo[2.2.1]hept-5-ene derivatives, were not detected in the photolysate.

Findings

Photochemical [2 + 2] cycloaddition reaction of alkenes with carbonyls, so-called Paternò–Büchi reaction [1–13], is one of the most efficient methods for preparing synthetically useful four-membered heterocyclic compounds, i.e., oxetanes. The Paternò–Büchi reaction of furan with a triplet carbonyl, such as n,π* triplet benzophenone, produces regioselectively 2-alkoxyoxetanes 2OX (Scheme 1). The regioselective formation is rationalized by the relative stability of the intermediary triplet biradicals, BR versus BR’, and also by the relative nucleophilicity of the furan-ring carbons, i.e., C1 versus C2 (Scheme 1) [14–18].

Scheme 1.

Reaction of furan with triplet excited carbonyls, regioselectivity.

Biradical BR, in principle, possess two resonance forms, i.e., 1,4-biradical form and 1,6-biradical form. The 1,4-biradical form affords oxetane 2OX after the intersystem crossing (ISC). Alternatively, 2,7-dioxabicyclo[2.2.1]hept-5-ene OBH would be formed from the 1,6-biradical form. The regioisomeric oxetane 3OX should be formed via the regioisomeric biradical BR’. Biradical BR is energetically more stable than BR’, because BR can undergo radical delocalization. The electrophilic oxygen of the excited carbonyl should preferably interact with more nucleophilic C1 carbon to give selectively the biradical BR. Thus, only the 2-alkoxyoxetane 2OX has been observed in the Paternò–Büchi reactions reported so far [19–27]. Thus, in this study, furan-2-ylmethyl 2-oxoacetates 1a,b and 2-(furan-2-yl)ethyl 2-oxo-2-phenylacetate 1c [28] were synthesized, in which the furan ring and the carbonyl moiety are connected intramolecularly, and their photochemical reactions were investigated to see whether the reaction proceeds intramolecularly to produce the 3-alkoxyoxetane derivative A and/or the dioxabicyclo[2.2.1]hept-5-ene derivative B, or intermolecularly to give the 2-alkoxyoxetane derivative C (Scheme 2).

Scheme 2.

Possible pathways for the photochemical reaction of furan derivatives 1a–c.

Compounds 1a–c [28] were synthesized from furan-2-ylmethanol or furan-2-ylethanol [29] (Scheme 3). Compound 1a (R = Ph) was irradiated in degassed benzene with a high-pressure Hg lamp with a Pyrex filter (Scheme 3). Interestingly, the Paternò–Büchi dimer product 2a (R = Ph), which possesses C_i symmetry, was obtained as the major product and contains the biologically important macrocyclic lactone structure [30–33]. The structure of 2a was unequivocally determined by the X-ray crystallographic analysis (Figure 1). The one-step preparation of the highly functionalized twelve-membered macrocyclic lactone is synthetically attractive. Intramolecular products, such as compounds A and B, were not detected in the photolysate, although intramolecular cyclization products are known to be products in the photoreaction of 3-substituted furan derivatives [11,21]. Furan-2-carbaldehyde (3) was the only assignable product during the photochemical reaction, which was monitored by ¹H NMR spectroscopy (Figure 2). The intermolecular Paternò–Büchi reaction product, i.e., C in Scheme 2, was also not observed in the photolysate. This result suggests that the intramolecular Paternò–Büchi reaction of C is faster than the first intermolecular Paternò–Büchi reaction of 1a. The photoreaction of 1b (R = Me) gave 2b and 3 in 25% and 18%, respectively (Scheme 3). The dimerization product 2c was not observed in the reaction of 1c. Only polymeric products were present in the photolysate. Although the dimerization is sensitive to the chain-length, the Paternò–Büchi dimerization reaction could in future be applicable to the synthesis of a variety of macrocyclic lactones.

Scheme 3.

Synthesis and the photochemical reaction of furan-2-ylmethyl 2-oxoacetates 1a,b.

Figure 1.

X-ray crystal structure of the macrocyclic lactone 2a.

Figure 2.

¹H NMR spectra (500 MHz) for (a) the photolysate of 1a after 4 h irradiation in degassed and dried C₆D₆ solution, (b) for isolated macrocyclic lactone 2a, and (c) for furan-2-carbaldehyde (3).

To investigate the effects of concentration, solvent, and temperature on the formation of 2a, the photochemical reaction of 1a was conducted under the variety of conditions (Table 1). The yield of intermolecular product 2a was expected to be improved when the concentration of 1a was increased; however, no concentration effect was observed (entry 2). Under the reaction conditions, the formation of polymeric products increased as evidenced by ¹H NMR analysis of the photolysate. Even with low concentrations of 1a (entry 3), the intramolecular photoproducts A and B were not detected by ¹H NMR (500 MHz). To investigate the medium effect on the formation of 2a, the photochemical reaction of 1a was performed in several solvents (entries 4–6). The yield of 2a decreased with increasing solvent polarity; 16% in toluene (entry 4) and 10% in CH₃CN (entry 6). Temperature had no effect on the yield of 2a (entries 7–9).

Table 1.

Formation of 2a in the photochemical reaction of 1a under the various conditions^a.

entry	solvent	concentration of 1a (mM)	temperature (°C)	yield of 2a (%)b
1	benzene	80	15	18
2	benzene	800	15	8
3	benzene	8	15	17
4	toluene	80	15	16
5	CH2Cl2	80	15	10
6	CH3CN	80	15	10
7	benzene	80	50	5
8	toluene	80	−35	18
9	toluene	80	−75	14

^aThe photochemical reactions of 1a were performed for 4 h with a high-pressure Hg lamp (300 W) with a Pyrex filter under a dry nitrogen atmosphere in dried and degassed solvent. ^bThe yields of 2a were determined on the basis of ¹H NMR (500 MHz) peak areas; error ± 3%. Dimethyl fumarate was used as an internal standard.

In summary, the intramolecular products such as A and B were not observed in the photochemical reaction of furan derivatives 1a,b, but interestingly the Paternò–Büchi dimers 2a,b with the C_i symmetry, i.e., macrocyclic lactones, were isolated in ca. 20% yield. The results indicate that the intramolecular reactions, which produce 3-alkoxyoxetanes and 2,7-dioxabicyclo[2.2.1]hept-5-ene (Scheme 1 and Scheme 2), are slower than the intermolecular reaction which leads to the preferential formation of 2-alkoxyoxetane C which is followed by a second Paternò–Büchi reaction to give the observed macrocyclic lactones 2. This finding should stimulate future experimental and computational studies on the mechanistically and synthetically fascinating formation of macrocyclic lactone derivatives.

Experimental

NMR and MS measurements were made using JEOL JMN-LA500 and Thermo Fisher Scientific LTD Orbitrap XL spectrometers, respectively, at the Natural Science Center for Basic Research and Development (N-BARD), Hiroshima University.

The furan derivatives 1a–c (129 mg, 0.561 mmol) were dissolved in benzene (7.0 ml) and the degassed reaction mixture was irradiated with a high-pressure Hg lamp (300 W, hν > 290 nm) with a Pyrex filter. After 13 h, the solvent was removed in vacuo and dimethyl fumarate added as an internal standard. ¹H NMR (500 MHz, CDCl₃) was measured to determine the ratio of products. After the photoreaction, the residue was purified by repeated column chromatography and PTLC (hexane–EtOAc = 2:1) to give 2a,b as colorless crystals.

2a: ¹H NMR (500 MHz, CDCl₃) δ 7.55–7.51 (m, 4H), 7.40–7.31 (m, 6H), 6.35 (dd, J = 3.1, 1.1 Hz, 2H), 5.28 (dd, J = 12.5, 0.9 Hz, 2H), 4.82 (dt, J = 3.0, 0.9 Hz, 2H), 4.67 (dd, J = 3.0, 1.1 Hz, 2H), 3.71 (d, J = 12.5 Hz, 2H); ¹³C NMR (125 MHz, CDCl₃): δ 171.6 (C), 148.7 (CH), 136.0 (CH), 128.6 (CH), 128.4 (CH), 125.7 (CH), 112.6 (C), 102.1 (CH), 90.7 (C), 61.4 (CH2), 55.2 (CH); HRMS (ESI) m/z calcd for C₂₆H₂₀O₈Na (M + Na)⁺ 483.10504, found 483.10526.

2b: ¹H NMR (500 MHz, CDCl₃): δ 6.66 (dd, J = 3.0, 1.2 Hz, 2H), 5.23 (dt, J = 3.0, 0.8 Hz, 2H), 5.14 (dd, J = 12.5, 0.8 Hz, 2H), 4.27 (dd, J = 3.0, 1.2 Hz, 2H), 3.77 (d, J = 12.5 Hz, 2H), 1.57 (s, 6H); ¹³C NMR (125 MHz, CDCl₃): δ 173.3 (C), 149.8 (CH), 112.7 (C), 101.3 (CH), 88.1 (C), 61.5 (CH₂), 53.1 (CH), 21.2 (CH₃); HRMS (ESI) m/z calcd for C₁₆H₁₆O₈Na (M + Na)⁺ 359.07374, found 359.07391.

Supporting Information

File 1

Experimental section for preparation of compounds 1a–c, the detail of the X-ray structure of compound 2a, and ¹H NMR and ¹³C NMR spectra for compounds 2a,b.

File 2

X-Ray crystallographic data for compound 2a.

This article is part of the Thematic Series "Photocycloadditions and photorearrangements"