Unusual tandem sequence of oxa Diels–Alder reaction, retro Diels–Alder reaction, and oxa 6π-electrocyclic ring opening in the reaction of 6-amino-4-(4-methoxyphenyl)-2H-pyran-2-ones with benzaldehydes

Abstract

The oxa Diels–Alder reaction of 6-amino-4-(4-methoxyphenyl)-2H-pyran-2-ones with benzaldehydes took an unusual path whereby a tandem sequence of the oxa Diels–Alder reaction, retro Diels–Alder reaction, and 6π-electrocyclic ring opening of the pyran yielded 3-(4-methoxyphenyl)-5-phenyl-1-(piperidin-1-yl/pyrrolidin-1-yl)penta-2,4-dien-1-ones. The reaction took place in boiling toluene with a series of substituted benzaldehydes. An electron-donating group on benzaldehyde retarded the reaction, while an electron-withdrawing group favoured it, thus indicating the normal electron demand pathway.

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2-Pyrones function as dienes in the Diels–Alder reaction. The first Diels–Alder reaction of 2-pyrone was reported in 1931 by Otto Diels and Kurt Alder, only three years after the discovery of the Diels–Alder reaction.¹ Subsequently, the reaction has been applied to synthesize various natural and synthetic products.^2,3 Applications in the synthesis and utility of 2-pyrones have been described in reviews.^4,5 The reaction is interesting, as the intermediate bicyclic adduct undergoes rapid expulsion of carbon dioxide through a retro Diels–Alder reaction to form the carbocyclic product. There are a few reports in which the unstable bicyclic adduct has been isolated.^6–8 An electron-donating group on the 2-pyrones ring favours a normal electron demand Diels–Alder reaction. The Diels–Alder reaction of 3-hydroxy-2-pyrones is accelerated in the presence of a base due to the formation of better electron-donating oxide anions.^9,10 3,5-Dibromo-2-pyrone reacts with electron-deficient as well as electron-rich dienophiles and gives normal and inverse electron demand Diels–Alder reactions, thus showing an ambident diene characteristic.⁸ An electron-donating group such as methyl or methoxyl groups at the 6-position of the 2-pyrones ring is highly favorable, and the corresponding Diels–Alder reaction has been used to construct diverse skeletons.^11,12

The Diels–Alder reactions of 2-pyrones reported thus far are mostly carbocyclic. There are only a few reports of normal electron demand hetero Diels–Alder reactions of 2-pyrones (1) with the nitrile group of toluene sulfonyl cyanide¹³ (2a) or benzonitrile (2b)¹⁴ as the heterodienophile to afford pyridine derivatives (3a–b). Interestingly, in an attempt to carry out the Diels–Alder reaction of 3-hydroxy-2-pyrone (4) with the carbonyl group of aromatic aldehydes (5), a vinylogous aldol reaction took place and 6-arylhydroxymethyl-3-hydroxy-2-pyrone (6) was formed instead of the hetero Diels–Alder adduct (7) (Scheme 1).¹⁵

Scheme 1 Previous attempts of hetero Diels–Alder reaction 2-pyrones.

The normal electron demand Diels–Alder reaction of 2-pyrones is favored by an electron-donating group in the 2-pyrones ring, particularly at the 4- and 6-positions, and the use of an electron-deficient dienophile. The carbonyl group of benzaldehydes is known to function as a dienophile in the hetero Diels–Alder reaction.^16,17 Hence, we thought that if a 2-pyrone is activated by an amino group at the 6-position, the pyrone would undergo a normal electron demand¹⁸ oxa Diels–Alder reaction with the carbonyl group of an aryl aldehyde; the reaction would provide 2-aminopyrans. With this objective, we attempted the Diels–Alder reaction of 6-amino-4-(4-methoxyphenyl)-2H-pyran-2-ones (11) with benzaldehydes (12). Unexpectedly, the Diels–Alder reaction gave 3,5-diaryl-1-aminopenta-2,4-dien-1-ones (15 and 16), through the expected Diels–Alder reaction followed by an oxa 6π-electrocyclic ring opening of the initial adduct. This unusual reaction is described herein.

Acetone dicarboxylic acid was prepared by treating citric acid with concentrated sulfuric acid and reacting it with anisole in situ to obtain 3-(4-methoxyphenyl)pent-2-enedioic acid (8).¹⁹ The conversion of 3-arylpent-2-enedioic acid directly to 6-chloro-4-aryl-2-pyrone is known to occur using PCl₅ in chlorobenzene.²⁰ We used a similar condition for the conversion of 8 to 9, but found that isolation of 9 from chlorobenzene solution was difficult, and hence we replaced chlorobenzene with DCM. We recorded the m.p. of 9 as 110–112 °C. Synthesis of 9 by another procedure is known, and interestingly, the m.p. reported earlier is 216–217 °C.²¹ Upon reaction with piperidine (10a) and pyrrolidine (10b), 9 gave 6-amino-4-(4-methoxyphenyl)-2-pyrones 11a and 11b, respectively (Scheme 2).

Scheme 2 Synthesis of 6-amino-2-pyrones 11a and 11b.

The Diels–Alder reaction of 11a with benzaldehyde (12a) was attempted in refluxing toluene. The reaction was very slow; after 50 h, the diene was almost consumed and product 15a was obtained. The expected product of the hetero Diels–Alder reaction of 11a with benzaldehyde (12a) under thermal conditions would be 2-aminopyran (14a), after the expulsion of CO₂ from the initial adduct 13 (Scheme 3). However, product 15a was found to be different than 14a.

Scheme 3 Hetero Diels–Alder reaction of 11a with benzaldehyde.

In the IR spectrum of 15a, there was a strong amide carbonyl peak at 1619 cm⁻¹. The lower frequency was due to conjugated carbonyl groups. In the ¹H NMR spectrum of 15a, the piperidine ring protons were intact along with the aromatic protons of both the phenyl rings – one of the diene and the other of the dienophile. Interestingly, a pair of doublets with trans coupling, J² = 16 Hz, due to olefinic protons was obtained at δ 6.54 and δ 7.69.

A third olefinic proton was observed at δ 6.01 as a singlet. The magnetically non-equivalent protons at δ 3.52(2H) and δ 3.68(2H) as two triplets hinted that there could be a piperidine amide moiety in the product. The structure was further confirmed by ¹H–¹H COSY spectrum, with two trans coupling protons being seen at 6.54 and 7.69 δ.

On the basis of the spectral analysis structure, 14a was ruled out and structure 15a was assigned to the product. Thus, it appeared that the course of the reaction involved the formation of the initial Diels–Alder adduct 13, which underwent decarboxylation to form 6-aminopyran 14a, which in turn underwent a 6π-electrocyclic ring opening to form the product (2E,4E)-3-(4-methoxyphenyl)-5-phenyl-1-(piperidin-1-yl)penta-2,4-dien-1-one (15a).

This is in accord with the fact that the 2H-pyran ring is unstable and undergoes a reversible ring opening to form open chain 1-oxodienes, even at ambient temperature.^22–31 Such 1-oxodienes find many synthetic applications.^32–34

The dienamides 15 and 16 are interesting dienoic acid amides that are otherwise difficult to synthesize, as the respective dienoic acids are not available.

Furthermore, such compounds are present in natural products. For example, piperine (17) and piperyline (18) are pentadienoic acid amides, which are biologically active and are present in black pepper, Piper nigrum.^37–39 Synthesis of these compounds often requires multistep and cumbersome processes.^35,36

11a and 11b were reacted with a series of substituted benzaldehydes (12a–g) in refluxing toluene to obtain a series of dienamides (15a–g and 16a–c) (Table 1).

Table 1 Hetero Diels–Alder reaction of 6-amino-2H-pyrones (11) with benzaldehydes (12)^a

Entry	Pyrone	Benzaldehydes				Product	Time^b (h)	Yield (%)	m.p. (°C)
		12	X	R^1	R^2
a Reaction conditions: 11a/b: 0.5 mmol; 12 : 1 mmol; solvent: toluene (5 mL), reflux.b Complete consumption of 11a/b.c No reaction.
1	11a	12a	C	H	H	15a	50	81	94–96
2	11a	12b	C	H	CN	15b	48	86	124–126
3	11a	12c	C	H	CF3	15c	32	84	112–114
4	11a	12d	N	H	H	15d	60	49	90–92
5	11a	12e	C	NO2	H	15e	38	56	100–102
6	11a	12f	C	CH3	H	15f	80	33	Gum
7	11a	12g	C	H	NO2	15g	40	73	128–130
8	11b	12a	C	H	H	16a	46	61	114–116
9	11b	12b	C	H	CN	16b	42	78	146–148
10	11b	12c	C	H	CF3	16c	42	79	122–124
11^c	11a	Piperonal				—	80	—	—

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An electron-donating group on benzaldehyde retarded the reaction; even a methyl group gave poor yield (10f), and piperonal failed to furnish the product. However, electron-withdrawing groups such as –CN, –CF₃, and –NO₂ gave excellent product yield.

Conclusions

In conclusion, we have discovered, for the first time, an unusual reaction of 6-amino-4-(4-methoxyphenyl)-2H-pyran-2-ones with aromatic aldehydes involving a tandem sequence of a normal electron demand Diels–Alder reaction, elimination of carbon dioxide from the adduct, and oxa 6π-electrocyclic ring opening of the pyran to form 3,5-diaryl-1-alkylamino-penta-2,4-diene-1-ones. The pentadienoic acid amide products are not common and are difficult to prepare, and hence, in addition to the theoretical interest, the reaction has the potential to furnish such unusual compounds.

Acknowledgements

AIK is grateful to CSIR, Delhi (India), for a fellowship. The authors are thankful to the Institute for Intensive Research in Basic Sciences (IIRBS), M. G. University, Kottayam, Kerala (India) and Guru Jambheshwar University of Science and Technology (GJUST), Haryana, (India) for providing the NMR facility.

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures, characterisation data of compounds, and copies of NMR and HRMS spectra. See DOI: 10.1039/c4ra13374a

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