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Article

tert-Butyl(2-oxo-2H-pyran-5-yl)carbamate as the First Chameleon Diene Bearing an Electron-Donating Substituent

by
Yasser M. Omar
1,2,
Giulia Santucci
2 and
Kamyar Afarinkia
1,3,*
1
Institute of Cancer Therapeutics, University of Bradford, Bradford BD7 1DP, UK
2
Department Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt
3
School of Biomedical Sciences, University of West London, London W5 5RF, UK
*
Author to whom correspondence should be addressed.
Molecules 2022, 27(17), 5666; https://doi.org/10.3390/molecules27175666
Submission received: 18 July 2022 / Revised: 10 August 2022 / Accepted: 29 August 2022 / Published: 2 September 2022
(This article belongs to the Section Organic Chemistry)
Browse Figures
Versions Notes

Abstract

:
The 2(H)-pyran-2-one bearing electron-donating tert-butylcarbamate (BocNH-) group at the 5- position is a “chameleon” diene and undergoes efficient Diels–Alder cycloadditions with alkene dienophiles with both electron-rich and electron-deficient substituents. Cycloadditions afford the 5-substituted bicyclic lactone cycloadducts regardless of the electronic nature of the dienophile. However, cycloadditions with electronically matched electron-deficient dienophiles proceed faster than those with electronically mismatched electron-rich dienophiles.

1. Introduction

The Diels–Alder (DA) cycloaddition of 2(H)pyran-2-ones [1,2,3,4,5], e.g., 1, is a powerful and versatile methodology in synthetic organic chemistry and is widely used in the preparation of complex molecules [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39]. In particular, cycloadditions of 2(H)pyran-2-one dienes to alkene dienophiles affords bridged bicyclic lactones, e.g., 2 which can then be transformed in few steps to highly substituted, six-membered rings, e.g., 3 (Scheme 1) [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39]. Under more forcing conditions, typically at higher temperatures, cycloadditions to alkyne dienophiles and subsequent aromatization via loss of bridging CO2 leads to substituted benzenes, e.g., 4 [40,41,42,43,44,45,46,47].
We have previously reported on the cycloadditions of a number of 5-substituted 2(H)pyran-2-ones such as 5-aryl-2(H)pyran-2-ones [48], 5, 5-halo-2(H)pyran-2-ones [49,50,51,52,53], 6, and 5-carboethoxy-2(H)pyran-2-one (ethyl coumalate), 7 [6] (Scheme 2). Previously, we [6,7,8,9,10,11], as well as other researchers [9,10,11,12,54,55,56,57,58,59,60], have reported on the application of the cycloadditions of these dienes in synthesis. A unique and highly unprecedented feature of dienes 5 and 6 is that they are electronically unbiased. In other words, they undergo facile and efficient thermal DA cycloadditions with alkene dienophiles bearing electron-withdrawing, electron-donating, and electron-neutral substituents to mostly afford the 5-endo cycloadducts. In addition to our extensive reports on dienophiles of different electron demands that undergo cycloadditions to 5 and 6, we have also provided a computational rationale for the observed ambident nature of the 2(H)pyran-2-one dienes [50,51].
It is so far unclear if the ambident nature of 5-substituted 2(H)pyran-2-one dienes is limited to any specific substituents. It could be argued that for 5 and 6, the electronic bias of either the aryl or halogen substituents at the 5 position of 2(H)pyran-2-one is mild. So, for both 5 and 6, the 5-substituents do not significantly influence the electronic demand of the 2(H)pyran-2-one diene. A more strongly electron donating or withdrawing substituent at that position may cancel the ambident nature of these dienes. To test this hypothesis, we set out to investigate the outcome of the cycloadditions of 2(H)pyran-2-ones with an unequivocally electron donating 5-substituent.
Here, we report on the preparation and Diels–Alder cycloadditions of 5-(BocNH)-2(H)pyran-2-one, 8, an example of a 2(H)pyran-2-one with an electron-donating substituent at its 5- position. We also demonstrate that this pyrone is an ambident diene that undergoes cycloaddition with electron-rich, electron-deficient, and electron-neutral alkene dienophiles.

2. Results

(BocNH)-2(H)pyran-2-one, 8, was prepared as a white stable solid by a modification of a reported procedure through a Curtius reaction of coumalic acid, 9 (Scheme 2) [61]. We then set out to investigate the thermal Diels–Alder cycloadditions of 8 with two dienophiles, methyl acrylate as an example of an electron-deficient dienophile, and butyl vinyl ether as an example of an electron-rich dienophile to afford cycloadducts 10 and 11 (Scheme 3, R = -CO2Me or -OBu, all possible cycloadducts are shown for completeness).
Cycloadditions with methyl acrylate were performed by heating a solution of 8 in excess dienophile at 100 °C and proceeded smoothly to afford cycloadducts 10. Analysis of the crude reaction mixtures at time intervals by lcms and NMR revealed these to comprise only the unreacted starting material and cycloadduct products. Therefore, we were able to easily follow the course of the reactions. At the end of the reaction, cycloadduct products were isolated and purified by column chromatography. The yield and ratio of isolated cycloadducts are given below (Table 1). The reaction afforded only two of the four possible cycloadducts, those with 5-endo and 5-exo configuration, in a 9:1 ratio (negligible presence of other cyloadducts was also confirmed from analysis of crude NMR). The configurations of the cycloadducts, both in isolated samples and in the crude reaction mixture, can be clearly and unequivocally assigned from the analysis of their NMR spectra according to the well-precedented criteria set out earlier by Posner [1] and us [49,51] (see Supplementary Materials). The criteria are highly reliable and are based on the NMR analysis of well over 50 isolated and fully characterized cycloadducts, the configuration of a number which are unequivocally corroborated by X-ray crystallography [51].
Cycloadditions with electron-rich butyl vinyl ether were similarly performed by heating a solution of 8 at 100 °C in excess dienophile to afford cycloadducts 11 (Scheme 3, Table 1). Analysis of the crude reaction mixtures at time intervals by lcms and NMR again revealed that the reactions proceeded cleanly, affording only two cycloadducts. At the end of the reaction, the cycloadduct products were isolated and purified by column chromatography. The yield and ratio of isolated cycloadducts are given below (Table 1). The reaction affords only two of the four possible cycloadducts, with a 5-endo and 5-exo configuration, in an 8:2 ratio (the absence of other cycloadducts was also confirmed from the analysis of crude NMR).
The formation of the endo cycloadduct as the major product is entirely expected and consistent with a secondary orbital interaction to stabilize its transition state (see later). The formation of the 5-substituted cycloadduct in the reaction with methyl acrylate is also expected, assuming the directing effects of an electron-donating BocNH- group at the 5 position of 2(H)pyran-2-one diene. However, the formation of the 5-substituted cycloadduct in the reaction with butyl vinyl ether is wholly expected.
In fact, the only difference between the two reactions appeared to be their rate. Whilst cycloaddition with methyl acrylate was facile and quick, cycloaddition with butyl vinyl ether was sluggish and slow, although it afforded a good yield eventually.
To better understand the difference between the two reactions, we decided to measure and compare the rates of cycloadditions. Since, for both cycloadditions, the dienophile is used in very large excess, reactions become de facto first order in 5-(BocNH)-2(H)pyran-2-one, 8.
We determined the rate of formation of cycloadduct 10, from the reaction between 8 and methyl acrylate and the rate of formation of cycloadduct 11, from the reaction between 8 and butyl vinyl ether (Figure 1). The results confirmed our observation that the cycloaddition of 8 with methyl acrylate (initial rate = 24 mmol/h, t½ = 5 h, pseudo-first-order rate constant = 38.5 × 10−6 s−1) was considerably faster than the cycloaddition to butyl vinyl ether (initial rate = 7.3 mmol/h, t½ = 16.5 h, pseudo-first-order rate constant = 11.7 × 10−6 s−1) when reactions are carried out with the same initial concentrations and reaction temperature. As a side note, the ratio of the cycloadducts remained roughly unchanged throughout the reactions (see Supplementary Materials), confirming that the reactions are under kinetic control.
The faster rate of cycloaddition of 8 to methyl acrylate than to butyl vinyl ether, would be consistent with 5-(BocNH)-2(H)pyran-2-one acting as the diene partner in a normal electron demand cycloaddition with methyl acrylate.
Finally, to investigate the scope of the cycloaddition, we carried out the reaction of 5-(BocNH)-2(H)pyran-2-one, 8, with a range of other dienophiles including methyl metacrylate, acrylonitrile, and styrene. All reactions proceeded smoothly to cleanly afford the cycloadducts 12-16, respectively (Table 1). The only exception was in the cycloaddition to vinyl acetate.
Under similar conditions to the one used for other dienophiles, the reaction between 5-(BocNH)-2(H)pyran-2-one, 8, and vinyl acetate proceeds very slowly and affords the expected cycloadduct 15 only as a minor product. The chromatographic isolation of the major product in this reaction afforded a white amorphous solid which was not amenable to X-ray crystal structure determination. However, based on its spectroscopic data, the byproduct is proposed to be a [4+2] cycloadduct 17, a dimer of 8 (Scheme 4). The ready formation of a dimer during the cycloadditions of pyrones is precedented. Unsubstituted 2(H)pyran-2-one is reported to undergo dimerization under photochemical and high-pressure conditions [62,63,64]. To the best of our knowledge, however, this is the first example of the dimerization of pyrones under thermal conditions. Spectroscopic data support the structure of the dimer to be 17 (see Supplementary Materials), mainly due to the presence of two coupled olefinic protons at 6.02 and 6.47 ppm, indicative of a CH=CH-C=O system.
Before we could analyze the cycloaddition of 8 with vinyl acetate, we had to find a means of limiting the dimerization and formation of 10 and maximizing the formation of the cycloadducts.
We first established that the formation of 17 is irreversible. When a sample of 17 was heated at 100 °C in a large excess of methyl acrylate as a dienophiles trap, we detected no cycloadduct 10, or any 8, in the crude reaction mixture by NMR and lcms. We concluded that 17 does not break down to 8, so its formation must be irreversible under these reaction conditions.
We then compared the rates of the formation of cycloadduct 15, a product of the reaction of 8 with vinyl acetate and dimer 17. We prepared two solutions of equal concentration (50 mg/mL or 0.24 M). One contained 8 in vinyl acetate and the other contained 8 in ethyl acetate. Ethyl acetate was chosen as its physiochemical properties (bp, polarity, etc.) are roughly similar to those of vinyl acetate. The solutions were transferred to two sealed tubes and heated at 100 °C under identical conditions. We used NMR and lcms on small aliquots withdrawn from each reaction to quantify the formation of products over a period of time and used that data to compare the rates of reactions and found them to be similar.
Since the cycloaddition was carried out in large excess of vinyl acetate, the reaction becomes a de facto unimolecular reaction and the rate of cycloaddition is directly proportionate to the concentration of 5-(BocNH)-2(H)pyran-2-one, 8. In contrast, the dimerization of 8 is bimolecular. To confirm this, we doubled the concentration of 8 in the above rate experiments (100 mg/mL or 0.48 M). We observed that whilst the initial rate of cycloaddition doubled, in line with a de facto unimolecular reaction, the initial rate for dimerization quadrupled, confirming the reaction is bimolecular.
Based on these observations, we concluded that carrying out the reactions under more dilute conditions would reduce the formation of dimer 17, whilst proportionally increasing the amount of cycloadduct, 15. Hence, by carrying out cycloadditions of 8 and vinyl acrylate in concentrations around 0.10 M, we were thus able to effectively reduce the yield of 17 at the end of the reaction to negligible.
As was the case in the cycloadditions of methyl acrylate, cycloadduct products were isolated at the end of the reaction and purified by column chromatography. A similar analysis of the crude reaction mixtures and purified cycloadducts by NMR allowed us to determine the regio- and stereoselectivity of the cycloadditions. Surprisingly, the cycloaddition between 8 and vinyl acetate afforded three cycloadducts which have the 5-endo, 5-exo, and 6-endo configuration in a 25 : 63 : 12 ratio. In other words, whilst the cycloaddition is still regioselective and favors the 5-substituted cycloadduct, the stereoselectivity is reversed and instead of the endo isomer, the exo isomer is favored. We have previously shown that exo isomers are more thermodynamically stable than endo isomers, although the latter are favored on kinetic grounds [1]. However, the shift from endo to exo isomer being major in this cycloaddition is not due to thermodynamic factors, since the ratio of the isomers does not change upon prolonged heating of the reaction mixture. This suggests that the preference for the exo isomer is not a result of the cycloaddition being reversible. However, the exact reason why the exo isomer is the favored cycloadduct in the cycloadditions of vinyl acetate remains unclear. We should, however, note that in the cycloadditions of 5-Br-2(H)pyran-2-one, 6, we observed poor stereoselectivity for some dienophiles which could not be rationalized even with computational models [50,51].
We also measured the rate of cycloaddition as described above. This confirmed that the cycloaddition with vinyl acetate is slower (initial rate = 3.4 mmol/h, t½ = 36 h, pseudo-first-order rate constant = 5.35 × 10−6 s−1) than both the cycloadditions to methyl acrylate and butyl vinyl ether (Figure 1). The slow rate of reaction between 8 and vinyl acetate can explain why the dimerization of 8 becomes a major byproduct in that cycloaddition. Presumably, the slow rate of cycloaddition allows the normally slow dimerization to compete with the cycloaddition, whereas in the other cycloadditions, the rates for dimerization are negligible.
Finally, to confirm that the cycloaddition to vinyl acetate proceeds more slowly than that to butyl vinyl ether, we carried out a competition experiment. 5-(BocNH)-2(H)pyran-2-one was heated with a large excess of a 1:1 v/v mixture of vinyl acetate and butyl vinyl ether. The reaction mixture was analyzed after 24, 48, and 72 h by NMR for the relative ratio of the cycloadducts from the two dienophiles. At all-time points, cycloadducts to butyl vinyl ether were predominant, confirming that the cycloaddition to butyl vinyl ether is faster than that to vinyl acetate.

3. Discussions and Conclusions

Ring substituents play a critical role in the cycloadditions of 2(H)pyran-2-ones. Generally speaking, the unsubstituted ring 2(H)pyran-2-one, 18 (Figure 2), undergoes cycloadditions only under harsh conditions and with alkynes to afford benzenes following the tandem loss of CO2 [1,2,3,4,5,40,41,42,43,44,45,46,47]. Examples of cycloadditions of 2(H)pyran-2-one, 18, with alkenes to afford bridged bicyclic lactones do exist, but are rare [65,66,67,68,69,70]. The introduction of substituents to the ring does allow the cycloaddition to proceed under relatively mild thermal conditions. Prior to our work, the function of substituents was considered to be that of altering the electronic demand of the 2(H)pyran-2-one and matching it with that of the dienophile. This matching results in lowering the activation energy for the reactions by reducing the HOMO-LUMO energy gaps, as we have shown before [50,51]. This will, in turn, result in increasing the rate of cycloadditions between electronically matched 2(H)pyran-2-ones and dienophiles. Furthermore, the presence of substituents on 2(H)pyran-2-one is also associated with the regioselectivity of the cycloadditions by matching electron density at the reaction centers (Figure 2). This is best exemplified by the work of Posner who demonstrated that 3-phenylsulfenyl-2(H)pyran-2-one, 19, reacts with electron-deficient dienes [71] whereas 3-phenylsulfonyl-2(H)pyran-2-one, 20, reacts with electron-rich dienes (Figure 2) [40,41,72]. In both of these examples, substituents favor the formation of the 5-substituted cycloadducts which is consistent with the electronic features of a normal electron demand for 19 and an inverse electron demand for 20 (Figure 2).
The results outlined here suggest that the cycloaddition of 5-substituted 2(H)pyran-2-ones does not follow a similar pattern. It is expected that the presence of the electron-donating BocNH- at the 5- position lowers the HOMO-LUMO energy gap with methyl acrylate, which in turn reduces the activation energy for the cycloaddition, resulting in a fast reaction. Indeed, the rate of the reaction of 8 with its electronically matched dienophile, methyl acrylate, is quite fast (t½ = 5 h), compared with the rate of reaction with its electronically mismatched dienophile, butyl vinyl ether (t½ = 16.5 h). However, the observation that the cycloaddition to vinyl acetate is slower (t½ = 36 h) than that to both methyl acrylate and butyl vinyl ether, strongly hints that the reactivity of this diene does not directly correlate to the electron density of the dienophile.
The other unexpected feature of these cycloadditions is that they always afford the 5-substituted cycloadduct as the major regioisomer, regardless of the substituent on the dienophile. The observation that the electron-donating BocNH- favors the formation of the 5-substituted cycloadducts with methyl acrylate is consistent with the electronic features of 8. However, the observation that it also favors the formation of the 5-substituted cycloadducts with butyl vinyl ether is wholly inconsistent with the expected electronic features of 8.
Considering the fact that 2(H)pyran-2-ones with less electronically discerning 5-substituents such as aryl and halogens are also chameleon dienes [48,49,50,51,52,53], our observations point to the possibility that 2(H)pyran-2-ones with any substituent at its 5- position may be capable of exhibiting chameleon properties. To demonstrate this, we plan to carry out a detailed study of the role of electron-withdrawing substituents at the 5- position of 2(H)pyran-2-ones, and whether these are also chameleon dienes, and will report our findings in due course. Other groups have sporadically reported (and our preliminary observations also confirm) that coumalates such as 7 undergo thermal cycloadditions with dienophiles bearing electron-donating [73,74,75], electron-neutral [76,77], and electron-withdrawing [78,79,80] dienophiles. However, a systematic study of their aptitude towards both electron-rich and electron-deficient dienes has not yet been carried out.
Clearly, understanding the highly unprecedented chameleon-like properties of 5-substituted 2(H)pyran-2-ones would be quite useful in understanding the role of electron demand in Diels–Alder cycloadditions. More importantly, however, identification of the range of substituted 2(H)pyran-2-one dienes that lack electron demand would be useful in extending the applicability of the pyrone cycloaddition methodology in target synthesis, particularly in diversity-oriented synthesis.

Supplementary Materials

The following Supplementary Materials can be downloaded at: https://www.mdpi.com/article/10.3390/molecules27175666/s1, Experimental procedures and copies of spectroscopic characterisation of all new compounds.

Author Contributions

Conceptualization, K.A.; Data curation, Y.M.O., G.S. and K.A.; Formal analysis, Y.M.O.; Investigation, Y.M.O. and G.S.; Project administration, K.A.; Supervision, K.A.; Writing—original draft, K.A.; Writing—review & editing, K.A. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the Ministry of Higher Education of the Arab Republic of Egypt; European Union Erasmus Exchange program and the University of Bradford.

Data Availability Statement

Data is contained within the article or Supplementary Material.

Acknowledgments

We thank Victoria Vinader for useful discussions.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Afarinkia, K.; Nelson, T.D.; Vinader, M.V.; Posner, G.H. Diels-Alder cycloadditions of 2-pyrones and 2-pyridones. Tetrahedron 1992, 48, 9111–9171. [Google Scholar] [CrossRef]
  2. Woodward, B.T.; Posner, G.H. Recent Advances in Diels—Alder Cycloadditions of 2-Pyrones. Adv. Cyloaddition 1999, 5, 47–83. [Google Scholar]
  3. Goel, J.; Ram, V.J. Natural and synthetic 2H-pyran-2-ones and their versatility in. Tetrahedron 2009, 65, 7865–7913. [Google Scholar] [CrossRef]
  4. Cai, Q. The [4+ 2] Cycloaddition of 2-Pyrone in Total Synthesis. Chin. J. Chem. 2019, 37, 946–976. [Google Scholar] [CrossRef]
  5. Huang, G.; Kouklovsky, C.; de la Torre, A. Inverse-Electron-Demand Diels–Alder Reactions of 2-Pyrones: Bridged Lactones and Beyond. Chem. Eur. J. 2021, 27, 4760–4788. [Google Scholar] [CrossRef] [PubMed]
  6. Afarinkia, K.; Mahmood, F. A novel and concise synthesis of (±) 2-epi-Validamine. Tetrahedron 1999, 55, 3129–3140. [Google Scholar] [CrossRef]
  7. Vinader, V.; Haji Abdullahi, M.; Patterson, L.H.; Afarinkia, K. Synthesis of a pseudo-disaccharide library and its application to the characterisation of the heparanase catalytic site. PLoS ONE 2013, 8, e82111. [Google Scholar]
  8. Vinader, V.; Afarinkia, K. Carbasugar Probes to Explore the Enzyme Binding Pocket at the Anomeric Position: Application to the Design of Golgi Mannosidase II Inhibitors. Curr. Med. Chem. 2013, 20, 3797–3801. [Google Scholar] [CrossRef]
  9. Afarinkia, K.; Haji Abdullahi, M.; Scowen, I. A new, general method for the synthesis of carbasugar-sugar pseudodisaccharides. J. Org. Lett. 2009, 11, 5182–5184. [Google Scholar] [CrossRef]
  10. Afarinkia, K.; Haji Abdullahi, M.; Scowen, I. Synthesis of Carbasugar−Sugar Pseudodisaccharides via a Cycloaddition− Cycloreversion Reaction of 2 H-Pyran-2-ones. J. Org. Lett. 2010, 12, 5564–5566. [Google Scholar] [CrossRef]
  11. Afarinkia, K.; Ndibwami, A. A general synthesis of phenanthridinone alkaloids. Synlett 2007, 2007, 1940–1944. [Google Scholar] [CrossRef]
  12. Posner, G.H.; Kinter, C.M. Asymmetric total synthesis of an A-ring precursor to hormonally active 1. alpha., 25-dihydroxyvitamin D3. J. Org. Chem. 1990, 55, 3967–3969. [Google Scholar] [CrossRef]
  13. Posner, G.H.; Nelson, T.D. Stereocontrolled synthesis of highly functionalized cyclohexenes. A short synthesis of a chorismic acid precursor. Tetrahedron 1990, 46, 4573–4586. [Google Scholar] [CrossRef]
  14. Whitney, J.G.; Gregory, W.A.; Kauer, J.C.; Roland, J.R.; Snyder, J.A.; Benson, R.E.; Hermann, E.C. Antiviral agents. I. Bicyclo[2.2.2]octan- and -oct-2-enamines. J. Med. Chem. 1970, 13, 254–258. [Google Scholar] [CrossRef] [PubMed]
  15. Corey, E.J.; Watt, D.S. Total synthesis of (+−)- alpha-and (+−)- beta-copaenes and ylangenes. J. Am. Chem. Soc. 1973, 95, 2303–2311. [Google Scholar] [CrossRef]
  16. Ciganek, E. 2, 3, 4, 4a, 5, 6, 7, 7a-Octahydro-1H-benzofuro [3, 2-e] isoquinoline: A new morphine fragment. J. Am. Chem. Soc. 1981, 103, 6261–6262. [Google Scholar] [CrossRef]
  17. Martin, S.F.; Rüeger, H.; Williamson, S.A.; Grzejsczak, S. General strategies for the synthesis of indole alkaloids. Total synthesis of (+−)-reserpine and (+−)- alpha-yohimbine. J. Am. Chem. Soc. 1987, 109, 6124–6134. [Google Scholar] [CrossRef]
  18. Noguchi, M.; Kakimoto, S.; Kajigaeshi, S. Regio-and Stereoselective Introduction of Functional Groups into 1-Isoindolinone and 1 (2 H)-Isoquinolone Systems. Bull. Chem. Soc. Jpn. 1987, 60, 3261–3267. [Google Scholar] [CrossRef]
  19. Ahmed, S.A.; Bardshiri, E.; Simpson, T.J. A convenient synthesis of isotopically labelled anthraquinones, chrysophanol, islandicin, and emodin. Incorporation of [methyl-2H3]chrysophanol into tajixanthone in Aspergillus variecolor. J. Chem. Soc. Chem. Commun. 1987, 1995, 883–884. [Google Scholar] [CrossRef]
  20. Yamaguchi, R.; Otsuji, A.; Utimoto, K.; Kozima, S. 1, 2-Addition of Allyl and 2-Oxo-2 H-pyran-6-ylcarbonyl Groups to Cyclic C=N Double Bonds by Means of Organotin Reagent for Alkaloids Synthesis; A Facile Synthesis of 8-Oxoprotoberberine and Norketoyobirine (Demethoxycarbonyloxogambirtannine). Bull. Chem. Soc. Jpn. 1992, 65, 298–300. [Google Scholar] [CrossRef]
  21. Marko, I.E.; Seres, P.; Evans, G.R.; Swarbrick, T.M. Tandem pericylic reactions (TPR). A simple construction of functionalised [3n, 1] bicycles and a ready entry into the core of gibberellic acid and zizaene. Tetrahedron Lett. 1993, 34, 7305–7308. [Google Scholar] [CrossRef]
  22. Komiyama, T.; Takaguchi, Y.; Tsuboi, S. One-Pot Synthesis of 2-Arylthio-2-cyclohexenone Derivatives by the Diels–Alder Reaction of 4-Arylthio-3-hydroxy-2-pyrones. Synth. Commun. 2007, 37, 2131–2136. [Google Scholar] [CrossRef]
  23. Birch, A.M.; Birtles, S.; Buckett, L.K.; Kemmitt, P.D.; Smith, G.J.; Smith, T.J.D.; Turnbull, A.V.; Wang, S.J.Y. Discovery of a potent, selective, and orally efficacious pyrimidinooxazinyl bicyclooctaneacetic acid diacylglycerol acyltransferase-1 inhibitor. J. Med. Chem. 2009, 52, 1558–1568. [Google Scholar] [CrossRef] [PubMed]
  24. Posner, G.H.; Jeon, H.B. New A-ring analogs of the hormone 1α, 25-dihydroxyvitamin D3:(2’-hydroxymethyl) tetrahydrofuro [1, 2-a]-25-hydroxyvitamin D3. Tetrahedon 2009, 65, 1235–1240. [Google Scholar]
  25. Larsson, R.; Scheeren, H.W.; Aben, R.W.M.; Johansson, M.; Sterner, O. Total Synthesis of Transtaganolide E and F: Insight in the Biosynthesis of the Transtaganolides. Eur. J. Org. Chem. 2013, 2013, 6955–6960. [Google Scholar] [CrossRef]
  26. Jung, Y.G.; Lee, S.C.; Cho, H.K.; Darvatkar, N.B.; Song, J.Y.; Cho, C.G. Total syntheses of (±)-α-lycorane and (±)-1-deoxylycorine. Org. Lett. 2013, 15, 132–135. [Google Scholar] [CrossRef]
  27. Slack, R.D.; Siegler, M.A.; Posner, G.H. Highly stereocontrolled and regiocontrolled syntheses of polyoxygenated [2.2. 2] oxabicyclic synthons. Tetrahedron Lett. 2013, 54, 6267–6270. [Google Scholar] [CrossRef]
  28. Cho, H.K.; Lim, H.Y.; Cho, C.G. (E)-β-Borylstyrene in the Diels–Alder Reaction with 3, 5-Dibromo-2-pyrone for the Syntheses of (±)-1-epi-Pancratistatin and (±)-Pancratistatin. Org. Lett. 2013, 15, 5806–5809. [Google Scholar] [CrossRef]
  29. Guney, T.; Lee, J.L.; Kraus, G.A. First Inverse Electron-Demand Diels–Alder Methodology of 3-Chloroindoles and Methyl Coumalate to Carbazoles. Organic Lett. 2014, 16, 1124–1127. [Google Scholar] [CrossRef]
  30. Okura, K.; Tamura, R.; Shigehara, K.; Masai, E.; Nakamura, M.; Otsuka, Y.; Katayama, Y.; Nakao, Y. Synthesis of Polysubstituted benzenes from 2-Pyrone-4, 6-dicarboxylic acid. Chem. Lett. 2014, 43, 1349–1351. [Google Scholar] [CrossRef]
  31. Min, L.; Zhang, Y.; Liang, X.F.; Huang, J.R.; Bao, W.L.; Lee, C.S. A Biomimetic Synthesis of (±)-Basiliolide B. Angew. Chem. Int. Edit. 2014, 53, 11294–11297. [Google Scholar] [CrossRef] [PubMed]
  32. Tong, H.; Liu, B. A Diels–Alder Approach toward the Scaffolds of Polycyclic Sesquiterpenoids with 2-Pyrone. Synlett 2014, 25, 681–686. [Google Scholar]
  33. Kondratov, I.S.; Tolmachova, N.A.; Dolovanyuk, V.G.; Gerus, I.I.; Daniliuc, C.G.; Haufe, G. Eur. Synthesis of isomeric (3,3,3-trifluoropropyl)anilines. J. Org. Chem. 2015, 11, 2482–2491. [Google Scholar]
  34. Usachev, B.I. 6-(Trifluoromethyl)-2H-pyran-2-ones: Promising CF3-bearing conjugated cyclic diene and electrophilic building-blocks. J. Fluor. Chem. 2015, 175, 36–46. [Google Scholar] [CrossRef]
  35. Zhao, P.; Beaudry, C.M. Total Synthesis of (+)-Cavicularin: The Pyrone Diels–Alder Reaction in Enantioselective Cyclophane Synthesis. Synlett 2015, 26, 1923–1929. [Google Scholar]
  36. Lee, J.H.; Cho, C.G. Total synthesis of (−)-Neocosmosin A via intramolecular Diels–Alder reaction of 2-Pyrone. Org. Lett. 2016, 18, 5126–5129. [Google Scholar] [CrossRef]
  37. Gan, P.; Smith, M.W.; Braffman, N.R.; Snyder, S.A. Pyrone Diels–Alder Routes to Indolines and Hydroindolines: Syntheses of Gracilamine, Mesembrine, and Δ7-Mesembrenone. Angew. Chem. Int. Ed. 2016, 55, 3625–3630. [Google Scholar] [CrossRef]
  38. Lee, J.-H.; Cho, C.-G. H-Bonding Mediated Asymmetric Intramolecular Diels–Alder Reaction in the Formal Synthesis of (+)-Aplykurodinone-1. Org. Lett. 2018, 20, 7312–7316. [Google Scholar]
  39. Wang, C.; Chen, Q.; Shin, S.; Cho, C. Total Synthesis of (±)-Clivonine via Diels–Alder Reactions of 3,5-Dibromo-2-Pyrone. J. Org. Chem. 2020, 85, 10035–10049. [Google Scholar] [CrossRef]
  40. Pfennig, T.; Chemburkar, A.; Cakolli, S.; Neurock, M.; Shanks, B.H. Improving Selectivity of Toluic Acid from Biomass-Derived Coumalic Acid. ACS Sustain. Chem. Eng. 2018, 6, 12855–12864. [Google Scholar] [CrossRef]
  41. Gambarotti, C.; Lauria, M.; Righetti, G.I.C.; Leonardi, G.; Sebastiano, R.; Citterio, A.; Truscello, A. Synthesis of Functionalized Aromatic Carboxylic Acids from Biosourced 3-Hydroxy-2-pyrones through a Base-Promoted Domino Reaction. ACS Sustain. Chem. Eng. 2020, 8, 11152–11161. [Google Scholar]
  42. Zhang, X.; Beaudry, C.M. Regioselective Synthesis of Benzofuranones and Benzofurans. J. Org. Chem. 2021, 86, 6931–6936. [Google Scholar] [CrossRef] [PubMed]
  43. Points, G.L., III; Stout, K.T.; Beaudry, C.M. Regioselective Formation of Substituted Indoles: Formal Synthesis of Lysergic Acid. Chem. Eur. J. 2020, 26, 16655–16658. [Google Scholar] [CrossRef] [PubMed]
  44. Points, G.L., III; Beaudry, C.M. Regioselective Synthesis of Substituted Carbazoles, Bicarbazoles, and Clausine C. Org. Lett. 2021, 23, 6882–6885. [Google Scholar] [CrossRef]
  45. Xu, M.-M.; You, X.-Y.; Zhang, Y.-Z.; Lu, Y.; Tan, K.; Yang, L.; Cai, Q. Enantioselective synthesis of axially chiral biaryls by Diels–Alder/Retro-Diels–Alder reaction of 2-pyrones with alkynes. J. Am. Chem. Soc. 2021, 143, 8993–9001. [Google Scholar] [CrossRef]
  46. Watanabe, S.; Nishikawa, T.; Nakazaki, A. Synthesis of Oxy-Functionalized Steroidal Skeletons via Mizoroki–Heck and Intramolecular Diels–Alder Reactions. Org. Lett. 2019, 21, 7410–7414. [Google Scholar] [CrossRef]
  47. Yu, H.; Kraus, G.A. Divergent pathways to isophthalates and naphthalate esters from methyl coumalate. Tetrahedron Lett. 2018, 59, 4008–4010. [Google Scholar] [CrossRef]
  48. Afarinkia, K.; Berna-Canovas, J. Diels–Alder cycloaddition of 5-aryl-2-pyrones. Tetrahedron Lett. 2000, 41, 4955–4958. [Google Scholar] [CrossRef]
  49. Afarinkia, K.; Daly, N.T.; Gomez-Farnos, S.; Joshi, S. Unusual stereoselectivity in Diels-Alder cycloadditions of 5-bromopyrone. Tetrahedron Lett. 1997, 38, 2369–2372. [Google Scholar] [CrossRef]
  50. Afarinkia, K.; Bearpark, M.; Ndibwami, A. Computational and Experimental Investigation of the Diels− Alder Cycloadditions of 4-Chloro-2 (H)-pyran-2-one. J. Org. Chem. 2003, 68, 7158–7166. [Google Scholar] [CrossRef]
  51. Afarinkia, K.; Bearpark, M.; Ndibwami, A. An Experimental and Computational Investigation of the Diels− Alder Cycloadditions of Halogen-Substituted 2 (H)-Pyran-2-ones. J. Org. Chem. 2005, 70, 1122–1133. [Google Scholar] [CrossRef] [PubMed]
  52. Afarinkia, K.; Posner, G.H. 5-Bromo-2-pyrone: An easily prepared ambiphilic diene and a synthetic equivalent of 2-pyrone in mild, thermal, Diels-Alder cycloadditions. Tetrahedron Lett. 1992, 33, 7839–7843. [Google Scholar] [CrossRef]
  53. Posner, G.H.; Nelson, T.D.; Kinter, C.M.; Afarinkia, K. 3-bromo-2-pyrone: An easily prepared chameleon diene and a synthetic equivalent of 2-pyrone in thermal Diels-Alder cycloadditions. Tetrahedron Lett. 1991, 32, 5295–5298. [Google Scholar] [CrossRef]
  54. Feng, M.; Jiang, X. Stereoselective construction of a key hydroindole precursor of epidithiodiketopiperazine (ETP) natural products. Chem. Commun. 2014, 50, 9690–9692. [Google Scholar] [CrossRef]
  55. Leonard, M.S.; Carroll, P.J.; Joullie, M.M. Synthesis of a pondaplin dimer and trimer. Aromatic interactions in novel macrocycles. J. Org. Chem. 2004, 69, 2526–2531. [Google Scholar] [CrossRef]
  56. Kirkham, J.D.; Leach, A.G.; Row, E.C.; Harrity, J.P.A. Investigation of the Origins of Regiochemical Control in [4+ 2] Cycloadditions of 2-Pyrones and Alkynylboronates. Synthesis 2012, 44, 1964–1973. [Google Scholar]
  57. Kirkham, J.D.; Delaney, P.M.; Ellames, G.J.; Row, E.C.; Harrity, J.P.A. An alkynylboronate cycloaddition strategy to functionalised benzyne derivatives. Chem. Commun. 2010, 46, 5154–5156. [Google Scholar] [CrossRef]
  58. Patrick, T.B.; Li, H. Cycloaddition reactions of 3-fluorobutenone. J. Fluor. Chem. 2009, 130, 544–546. [Google Scholar] [CrossRef]
  59. Danieli, B.; Lesma, G.; Martinelli, M.; Passarella, D.; Peretto, I.; Silvani, A. Application of the Pd-catalyzed heteroarylation to the synthesis of 5-(indol-2′-yl) pyridin-2-one and 5-(indol-2′-yl) pyran-2-one. Tetrahedron 1998, 54, 14081–14088. [Google Scholar] [CrossRef]
  60. Reus, C.; Liu, N.-W.; Bolte, M.; Lerner, H.-W.; Wagner, M. Synthesis of Bromo-, Boryl-, and Stannyl-Functionalized 1, 2-Bis (trimethylsilyl) benzenes via Diels–Alder or C–H Activation Reactions. J. Org. Chem. 2012, 77, 3518–3523. [Google Scholar] [CrossRef]
  61. Liu, C.-T. Studies toward the Synthesis of AB Ring System of Nagilactone. Ph.D. Thesis, University of Nebraska, Lincoln, NE, USA, 1980. Available online: http://digitalcommons.unl.edu/dissertations/AAI8101220 (accessed on 1 August 2022).
  62. Pirkle, W.; Eckert, C.A.; Turner, W.V.; Scott, B.A.; McKendry, L.H. High pressure thermal and the photosensitized dimerizations of 2-pyrones. J. Org. Chem. 1976, 41, 2945–2946. [Google Scholar] [CrossRef]
  63. White, D.L.; Seyfert, D. Diels-Alder dimerization of 2-pyrone. J. Org. Chem. 1972, 37, 3545–3546. [Google Scholar] [CrossRef]
  64. Williams, J.D.; Otake, Y.; Coussanes, G.; Saridakis, I.; Maulide, N.; Kappe, C.O. Towards a Scalable Synthesis of 2-Oxabicyclo [2.2. 0] hex-5-en-3-one Using Flow Photochemistry. ChemPhotoChem 2019, 3, 229–232. [Google Scholar] [CrossRef] [PubMed]
  65. Pfaff, E.; Plieninger, H. Synthese einer Reihe von 3-Oxo-2-oxabicyclo [2.2.2] oct-7-en-Derivaten und Versuche zu deren Umwandlung in 3-Oxo-2-oxabicyclo [2.2. 2] octa-5, 7-dien. Chem. Ber. 1982, 115, 1967–1981. [Google Scholar] [CrossRef]
  66. Marko, I.E.; Seres, P.; Swarbrick, T.M.; Staton, I.; Adams, H. Tandem pericyclic reactions. Novel and efficient methodology for the Rapid assembly of complex polycyclic systems. Tetrahedron Lett. 1991, 32, 2452–2549. [Google Scholar]
  67. Hashimoto, Y.; Abe, R.; Morita, N.; Tamura, O. Inverse-electron-demand Diels–Alder reactions of α, β-unsaturated hydrazones with 3-methoxycarbonyl α-pyrones. Org. Bio. Chem. 2018, 16, 8913–8916. [Google Scholar] [CrossRef]
  68. Posner, G.H.; Ishihara, Y. Lewis acid-catalyzed, high pressure, stereospecific, regiospecific, Diels-Alder cycloaddition of unsubstituted 2-pyrone: Short synthesis of a racemic A-ring precursor to physiologically active 1-hydroxyvitamin D3 steroids. Tetrahedron Lett. 1994, 35, 7545–7548. [Google Scholar] [CrossRef]
  69. Chen, C.; Liao, C. One-pot stereoselective synthesis of tricyclic bislactones from 2-pyrones and 2-methoxyfuran. Org. Lett. 2000, 2, 2049–2052. [Google Scholar] [CrossRef]
  70. Aggarwal, V.K.; Gultekin, Z.; Grainger, R.S.; Adams, H.; Spargo, P.L. (1 R, 3 R)-2-Methylene-1, 3-dithiolane 1, 3-dioxide: A highly reactive and highly selective chiral ketene equivalent in cycloaddition reactions with a broad range of dienes. J. Chem. Soc. Perkin Trans. 1 1998, 17, 2771–2782. [Google Scholar] [CrossRef]
  71. Posner, G.H.; Nelson, T.D.; Kinter, C.M.; Johnson, N. Diels-Alder cycloadditions using nucleophilic 3-(p-tolylthio)-2-pyrone. Regiocontrolled and stereocontrolled synthesis of unsaturated, bridged, bicyclic lactones. J. Org. Chem. 1992, 57, 4083–4088. [Google Scholar] [CrossRef]
  72. Posner, G.H.; Wettlaufer, D.G. Asymmetric Diels-Alder cycloadditions using chiral alkyl vinyl ethers and a dienyl sulfone. Tetrahedron Lett. 1986, 27, 667–670. [Google Scholar]
  73. Kraus, G.A.; Wang, S. Synthesis of isophthalates from methyl coumalate. RSC Adv. 2017, 7, 56760–56763. [Google Scholar]
  74. Geist, E.; Berneaud-Koetz, H.; Baikstis, T.; Draeger, G.; Kirschning, A. Toward chromanes by de novo construction of the benzene ring. Org. Lett. 2019, 21, 8930–8933. [Google Scholar] [PubMed]
  75. Jung, M.E.; Street, L.J.; Usui, J. Chemoselective cycloadditions of 3, 4-dialkoxyfurans and alkyl coumalates. Novel loss of aromaticity of two nonbenzenoid aromatic rings in a mild thermal process. J. Am. Chem. Soc. 1986, 108, 6810–6811. [Google Scholar]
  76. Lantos, I.; Sheldrake, P.W.; Wells, A.S. Novel cage compounds from inter-and intra-molecular Diels–Alder reactions of heteroaromatic azadienes and methyl coumalate with cyclo-octa-1, 5-diene. J. Chem. Soc. Perkin Trans. 1 1990, 7, 1887–1890. [Google Scholar]
  77. Hatsui, T.; Hashiguchi, T.; Takeshita, H. Total Synthesis of (+−)-Shizuka-Acoradienol. Chem. Express 1993, 8, 581–584. [Google Scholar]
  78. Smith, M.W.; Snyder, S.A. A concise total synthesis of (+)-scholarisine A empowered by a unique C–H arylation. J. Am. Chem. Soc. 2013, 135, 12964–12967. [Google Scholar]
  79. Saktura, M.; Grzelak, P.; Dybowska, J.; Albrecht, L. Asymmetric Synthesis of [2.2. 2]-Bicyclic Lactones via All-Carbon Inverse-Electron-Demand Diels–Alder Reaction. Org. Lett. 2020, 22, 1813–1817. [Google Scholar]
  80. Obata, T.; Shimo, T.; Suishu, T.; Somekawa, K. Stereoselective photo[4+2]cycloadditions of 2-pyrone-5-carboxylates with maleimides in the solid state and in solution. J. Het. Chem. 1998, 35, 1361–1364. [Google Scholar]
Molecules 27 05666 sch001 550
Scheme 1. Applications of 2(H)-pyran-2-one in chemical synthesis.
Scheme 1. Applications of 2(H)-pyran-2-one in chemical synthesis.
Molecules 27 05666 sch001
Molecules 27 05666 sch002 550
Scheme 2. Preparation of tert-butyl(2-oxo-2H-pyran-5-yl)carbamate.
Scheme 2. Preparation of tert-butyl(2-oxo-2H-pyran-5-yl)carbamate.
Molecules 27 05666 sch002
Molecules 27 05666 sch003 550
Scheme 3. All four cycloaddition products between 8 methyl acrylate and butyl vinyl ether.
Scheme 3. All four cycloaddition products between 8 methyl acrylate and butyl vinyl ether.
Molecules 27 05666 sch003
Molecules 27 05666 g001 550
Figure 1. Comparison between the rates of cycloaddition of 8 with dienophiles at 100 °C.
Figure 1. Comparison between the rates of cycloaddition of 8 with dienophiles at 100 °C.
Molecules 27 05666 g001
Molecules 27 05666 sch004 550
Scheme 4. Dimerization of compound 8.
Scheme 4. Dimerization of compound 8.
Molecules 27 05666 sch004
Molecules 27 05666 g002 550
Figure 2. Electron demand in the cycloadditions of 3-phenylsulfenyl-2(H)pyran-2-one and 3-phenylsulfonyl-2(H)pyran-2-one.
Figure 2. Electron demand in the cycloadditions of 3-phenylsulfenyl-2(H)pyran-2-one and 3-phenylsulfonyl-2(H)pyran-2-one.
Molecules 27 05666 g002
Table
Table 1. Results from cyloadditions of 5-(BocNH)-2(H)pyran-2-one, 8, with various dienophiles.
Table 1. Results from cyloadditions of 5-(BocNH)-2(H)pyran-2-one, 8, with various dienophiles.
DienophileYield * (%)Cycloadduct5-endo:5-exo:6-endo:6-exo
Methyl acrylate791091:9:0:0
Methyl metacrylate721293:7:0:0
Acrylonitrile761350:50:0:0
Styrene671470:30:0:0
Vinyl acetate651525:63:12:0
Vinylene carbonate511667:33: 0:0
Butyl vinyl ether541180:20:0:0
* Combined isolated yield of all stereoisomers following chromatography.
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Omar, Y.M.; Santucci, G.; Afarinkia, K. tert-Butyl(2-oxo-2H-pyran-5-yl)carbamate as the First Chameleon Diene Bearing an Electron-Donating Substituent. Molecules 2022, 27, 5666. https://doi.org/10.3390/molecules27175666

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Omar YM, Santucci G, Afarinkia K. tert-Butyl(2-oxo-2H-pyran-5-yl)carbamate as the First Chameleon Diene Bearing an Electron-Donating Substituent. Molecules. 2022; 27(17):5666. https://doi.org/10.3390/molecules27175666

Chicago/Turabian Style

Omar, Yasser M., Giulia Santucci, and Kamyar Afarinkia. 2022. "tert-Butyl(2-oxo-2H-pyran-5-yl)carbamate as the First Chameleon Diene Bearing an Electron-Donating Substituent" Molecules 27, no. 17: 5666. https://doi.org/10.3390/molecules27175666

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