This journal is c The Royal Society of Chemistry 2012 Chem. Commun., 2012, 48, 10195–10197 10195

Cite this: Chem. Commun., 2012, 48, 10195–10197

Enantioselectivity in visible light-induced, singlet oxygen [2+4]

cycloaddition reactions (type II photooxygenations) of 2-pyridonesw

Christian Wiegand, Eberhardt Herdtweck and Thorsten Bach*

Received 2nd August 2012, Accepted 22nd August 2012

DOI: 10.1039/c2cc35621j

3-Substituted 2-pyridones were enantioselectively (68–90% ee)

converted into the respective 3-hydroxypyridine-2,6-diones by a

sequence consisting of a template-mediated type II photooxy-

genation and an acid-catalysed rearrangement.

Singlet oxygen belongs to the most versatile and most readily

available reagents to be generated by visible light irradiation.

The low energy gap between triplet and singlet oxygen allows

for a sensitised excitation, which can be achieved at long

wavelengths using low catalytic loadings of appropriate dyes

such as rose bengal, methylene blue or tetraphenylporphyrin

(TPP). Subsequent reaction pathways accessible to singlet

oxygen include the formation of hydroperoxides by an ene-type

reaction, the formation of 1,2-dioxetanes by a [2+2] cycloaddition

and the [2+4] cycloaddition to 1,3-dienes.1 In particular, the

latter reaction2,3 appealed as a way to prepare endoperoxides

enantioselectively in the presence of chiral complexing agent 14,5

(Scheme 1). Provided that the 1,3-diene structure of the

substrate was attached to an amide or embedded in a lactam

ring, one could hope for an enantioselective reaction course6 in

a 1 : 1 complex between the substrate and template 1. We now

show that this approach has indeed been successful and report

the first highly enantioselective (up to 90% ee) singlet oxygen

[2+4] cycloaddition reactions.7

2-Pyridones (pyridine-2(1H)-ones) were considered to be

particularly promising 1,3-diene substrates for this study. It has

previously been shown that they bind to bicyclic lactams such as

1 by two-point hydrogen bonding and that enantioselective

reactions can be achieved.8 In addition, there are a number of

biologically relevant pyridine-2,6-diones, such as hermidin9 and

the speranskatines,10 with a structural motif, which seemed

synthetically accessible via the respective endoperoxide. The type

II photooxygenation of 3- and 6-substituted 2-pyridones has

been previously studied by Kanaoka et al.11 They performed the

reaction in the presence of para-toluenesulfonic acid (TsOH)

and obtained directly the corresponding ring-opened products

(vide infra). Initially, we planned to access and isolate the

endoperoxides because we noted that both the parent pyridone

substrate 2 and its 3-methyl derivative 3 underwent a clean

[2+4] photocycloaddition with singlet oxygen, which in turn

was generated by TPP-sensitised visible light irradiation

(Scheme 2).

All attempts, however, to characterise endoperoxides rac-4

and rac-5 upon isolation were hampered by the fact that the

retro-[2+4] cycloaddition is relatively fast.12 It was therefore

decided to perform a consecutive reaction, which preserved at

least one of the newly generated stereogenic centers. Indeed, it

was confirmed that the acid-catalysed ring opening of product

rac-5 proceeded by the well known Kornblum–DeLaMare

rearrangement.3a–d,13 Pyridine-2,6-dione rac-6 was obtained

in 32% yield if the type II photooxygenation and the ring

opening reaction were conducted in successive order. Compound

rac-6 has been obtained previously by Kanaoka et al. employing

an in situ opening of the endoperoxide in 14% yield starting from

3-methyl-2-pyridone (3).11

Scheme 1 Binding of chiral template 1 to a prochiral lactam or amide

via two hydrogen bonds.

Scheme 2 Formation of endoperoxides rac-4 and rac-5 by singlet

oxygen addition and Kornblum–DeLaMare rearrangement of product

rac-5.

Department Chemie and Catalysis Research Center (CRC),Technische Universitat Munchen, 85747 Garching, Germany.E-mail: thorsten.bach@ch.tum.de; Fax: +49 89 28913315;Tel: +49 89 28913330w Electronic supplementary information (ESI) available. CCDC894230. For ESI and crystallographic data in CIF of other electronicformat see DOI: 10.1039/c2cc35621j

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10196 Chem. Commun., 2012, 48, 10195–10197 This journal is c The Royal Society of Chemistry 2012

Since neither of the yields was acceptable, optimisation

reactions were performed, which would also allow us to perform

the reaction in the presence of template 1. By following the

reaction of substrate 3 UV-spectroscopically in the presence of

0.1 mol% TPP at �25 1C (c = 0.11 M) it was observed that

endoperoxide formation was complete within 15 minutes.

In the consecutive acid-catalysed reaction the competing

retro-[2+4] cycloaddition compromised the yield. A relatively

large amount of TsOH (40 mol%) was found to be required to

enable a rapid rearrangement. Still, the retro-cycloaddition

was observed. In order to increase the yield, it was mandatory

to repeat the irradiation – now in the presence of acid – at low

temperature and the hydrolysis at room temperature. A third

cycle (irradiation, hydrolysis) helped to increase the yield even

further. This optimised procedure was subsequently applied to

the enantioselective irradiation in the presence of template 1

(Table 1). To our delight, significant enantioselectivities were

achieved, which reached up to 90% ee. Toluene (entries 1 and 2)

delivered moderate yields but had the benefit that the irradiation

could be performed at temperatures as low as �70 1C. The

enantioselectivity increased only slightly, however, when decreasing

the irradiation temperature from �25 1C (81% ee) to �70 1C

(85% ee). Carbon tetrachloride (entry 3) was inferior to

toluene as the solvent and product formation occurred with

only 73% ee, albeit at a higher yield. As in several other

lactam-mediated reactions14 trifluorotoluene (entry 4) turned

out to be the solvent of choice. The yield was almost quanti-

tative and product 6 was isolated in 90% ee. The result is

particularly remarkable as the second and third irradiation

runs were performed in the presence of a Brønsted acid, which

potentially disturbs the hydrogen bonding. In order to ensure

that the enantioselectivity in the studied reaction was due to

two-point hydrogen bonding, we performed an experiment with

the N-methyl derivative 7 of 3-methyl-2-pyridone (entry 5).

Expectedly, the reaction proceeded in high yield but without

any detectable enantioselectivity delivering product 8 as a

racemate. Based on the assumption of a 1 : 1 complex formed

between pyridone 3 and template 1 it was assumed that the

photooxygenation occurs from the Si face relative to carbon

atom C3 leading predominantly to the (S)-enantiomer. This

assumption was confirmed by anomalous X-ray diffraction

(Fig. 1)15 performed with a homochiral crystal of the major

product obtained in the reaction of pyridone 3 (Table 1,

entry 4).

When applying the reaction conditions to other 2-pyri-

dones, we noted varying yields and enantioselectivities

(Table 2). With 3-ethyl-2-pyridone (9)16 the reaction sequence

worked – as expected given its similarity to 3 – in the same

yield (entry 1) and with similar enantioselectivity for the final

product 10 (86% ee). In the case of the benzyl-substituted

substrate 1117 (entry 2) a significant decrease in chemo- and

enantioselectivity was noted. Indeed, the acidic conditions

Table 1 Enantioselective type II photooxygenation/Kornblum–DeLaMare rearrangement with 3-methyl-2-pyridones 3 and 7 underoptimised conditions in various solvents

Entrya R1 Solvent Temp. [1C] Yieldb [%] eec [%]

1 H PhCH3 �25 62 812 H PhCH3 �70 53 853 H CCl4 �25 80 734 H PhCF3 �25 99 905 Me PhCF3 �25 96 o5

a Reactions were performed at a substrate concentration of 0.11 M in

the given solvent. Irradiation was performed for 20 min at the

indicated temperature. Upon warming to room temperature the

mixture was treated with acid for 12 h before repeating the sequence

(cooling, irradiation, warming to rt) twice (for further details, see ESI).b Yield of the isolated product. c The enantiomeric excess (ee) was

determined by chiral HPLC analysis.

Fig. 1 Single crystal structure analysis of the enantiomerically pure

tertiary alcohol 6.

Table 2 Sequence of template-mediated enantioselective type IIphotooxygenation/Kornblum–DeLaMare rearrangement performedwith different 2-pyridones under optimised conditions (see Table 1)

Entry Substratea Product c [mM] Yieldb [%] eec [%]

1 110 99 86

2 37 73 69

3 33 30 79

4 23 38 85

5 34 46 71

a Reactions were performed at the indicated substrate concentration in

trifluorotoluene as the solvent employing 2.5 equivalents of template 1

and 0.1 mol% of TPP. The irradiation was performed for 20 min at

�25 1C. Upon warming to room temperature the mixture was treated

with TsOH (40 mol%) for 12 h before repeating the sequence (cooling,

irradiation, warming to rt) twice (for further details, see ESI). b Yield

of the isolated product. c The enantiomeric excess (ee) was determined

by chiral HPLC analysis.

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This journal is c The Royal Society of Chemistry 2012 Chem. Commun., 2012, 48, 10195–10197 10197

required for endoperoxide opening may in this case lead to

elimination of the tertiary alcohol 12. The sensitivity towards

acidic conditions was even more pronounced for ether substrates

13 (entry 4) and 15 (entry 5).18 Again, elimination reactions are

likely to account for a loss of the respective products 14 and 16. It

must be said, however, that an increased yield could have possibly

been achieved in these cases, if the standard reaction protocol had

been modified. The emphasis of the present study was on the

enantioselectivity, however, which remained in a relatively high

range for all substrates (69–86% ee). A bicyclic substrate (17,

entry 5)19 also exhibited a significant face differentiation

delivering product 18 in 46% yield and with 71% ee. The

assignment of the absolute configuration for the respective

major enantiomers as depicted in Table 2 is based on analogy

to the transformation 3 - 6. Indeed, all products (6, 10, 12,

14, 16, 18) have been shown to be consistently levorotatory

indicating that the major enantiomers possess identical absolute

configurations. The chiral template remained unaffected by singlet

oxygen and was recovered chromatographically in yields between

80–90%. The varying enantioselectivities are very likely due to the

different association constants, with which the substrates bind to

template 1. Pyridones with sterically bulkier substituents suffer

from a repulsive van der Waals interaction with the tricyclic

10-oxa-30-azacyclopenta[b]naphthalene group of template 1.

For these cases, substrate dimerisation by hydrogen bonding

becomes significant,14c which in turn leads to an ee decrease

because reactions occurring in the dimer do not proceed

enantioselectively.

In summary, it was shown that visible light irradiation can

be successfully employed for the enantioselective synthesis of

3-hydroxypyridine-2,6-diones from the respective pyridones

via type II photooxygenation intermediates. In an optimised

reaction protocol high yields and enantioselectivities could be

obtained for the selected substrates 3 and 9. In order to guarantee

high yields for other substrates the reaction conditions need to be

modified.20 In particular the acidic conditions employed for

endoperoxide opening are not compatible with every substitution

pattern and induce side reactions, which in turn compromise the

yield. Enantioselectivities have been consistently above 65% ee,

however, indicating that a high enantioface differentiation is

mediated upon binding of the substrate to template 1.

This project was supported by the Deutsche Forschungsge-

meinschaft (Ba 1372-10; Graduiertenkolleg GRK 1626 Chemical

Photocatalyis). C. Cornaggia andM. Cakmak are acknowledged

for preliminary studies on 4 and 5.

Notes and references

1 Reviews: (a) M. R. Iesce and F. Cermola, in CRC Handbook ofOrganic Photochemistry and Photobiology, ed. A. Griesbeck,M. Oelgemoller and F. Ghetti, CRC Press, Boca Raton, 3rd ed.,2012, pp. 727–764; (b) M. Zamadar and A. Greer, in Handbookof Synthetic Photochemistry, ed. A. Albini and M. Fagnoni,Wiley-VCH, Weinheim, 2010, pp. 353–386; (c) E. L. Clennanand A. Pace, Tetrahedron, 2005, 61, 6665–6691.

2 Pioneering studies: (a) M. Fritzsche, C. R. Acad. Sci., 1867, 64,1035–1037; (b) A. Windaus and J. Brunken, Liebigs Ann. Chem.,1928, 460, 225–235; (c) C. Dufraisse and A. Etienne, C. R. Acad.

Sci., 1935, 201, 280; (d) G. O. Schenck, Naturwissenschaften, 1954,32, 452–453.

3 Recent examples of singlet oxygen [2+4] cycloaddition reactions:(a) M. J. Palframan, G. Kociok-Kohn and S. E. Lewis, Chem.–Eur.J., 2012, 18, 4766–4774; (b) K. C. Nicolaou, S. Totokotsopoulos,D. Giguere, Y.-P. Sun and D. Sarlah, J. Am. Chem. Soc., 2011,133, 8150–8153; (c) G. S. Buchanan, K. P. Cole, Y. Tang andR. P. Hsung, J. Org. Chem., 2011, 76, 7027–7039; (d) V. L.Paddock, R. J. Phipps, A. Conde-Angulo, A. Blanco-Martin,C. Giro-Manas, L. J. Martin, A. J. P. White and A. C. Spivey,J. Org. Chem., 2011, 76, 1483–1486; (e) N. Charbonnet, E. Riguetand C. G. Bochet, Synlett, 2011, 2231–2233; (f) G. Mehta andP. Maity, Tetrahedron Lett., 2011, 52, 5161–5165; (g) J. A. Celaje,D. Zhang, A. M. Guerrero and M. Selke, Org. Lett., 2011, 13,4846–4849.

4 T. Bach, H. Bergmann, B. Grosch, K. Harms and E. Herdtweck,Synthesis, 2001, 1395–1405.

5 Examples: (a) T. Bach, H. Bergmann and K. Harms, Angew.Chem., Int. Ed., 2000, 39, 2302–2304; (b) T. Bach, T. Aechtnerand B. Neumuller, Chem. Commun., 2001, 607–608; (c) T. Bach,H. Bergmann, B. Grosch and K. Harms, J. Am. Chem. Soc., 2002,124, 7982–7990; (d) T. Aechtner, M. Dressel and T. Bach, Angew.Chem., Int. Ed., 2004, 43, 5849–5851; (e) P. Selig and T. Bach,Angew. Chem., Int. Ed., 2008, 47, 5082–5084; (f) K. A. B. Austin,E. Herdtweck and T. Bach, Angew. Chem., Int. Ed., 2011, 50,8416–8419.

6 Review: C. Muller and T. Bach, Aust. J. Chem., 2008, 62, 557–564.7 For an enantioselective access to endoperoxides by an auxiliary-based method, see: W. Adam, M. Guthlein, E.-M. Peters, K. Petersand T. Wirth, J. Am. Chem. Soc., 1998, 120, 4091–4093.

8 (a) T. Bach, H. Bergmann and K. Harms, Org. Lett., 2001, 3,601–603; (b) D. Albrecht, F. Vogt and T. Bach, Chem.–Eur. J.,2010, 16, 4284–4296; (c) P. Fackler, S. M. Huber and T. Bach,J. Am. Chem. Soc., 2012, 134, 12869–12878.

9 (a) G. A. Swan, Experientia, 1984, 40, 687–688; (b) G. A. Swan,J. Chem. Soc., Perkin Trans. 1, 1985, 1757–1766.

10 (a) J.-G. Shi, H.-Q. Wang, M. Wang and Y. Zhu, Phytochemistry,1995, 40, 1299–1302; (b) J.-G. Shi, H.-Q. Wang, M. Wang,Y.-C. Yang, W.-Y. Hu and G.-X. Zhou, J. Nat. Prod., 2000, 63,782–786.

11 E. Sato, Y. Ikeda and Y. Kanaoka, Chem. Pharm. Bull., 1987, 35,507–513.

12 M. Matsumoto, M. Yamada and N. Watanabe, Chem. Commun.,2005, 483–485.

13 (a) N. Kornblum and H. E. DeLaMare, J. Am. Chem. Soc., 1951,73, 880–881; (b) S. T. Staben, X. Linghu and F. D. Toste, J. Am.Chem. Soc., 2006, 128, 12658–12659.

14 (a) M. Dressel and T. Bach, Org. Lett., 2006, 8, 3145–3148;(b) C. Muller, A. Bauer and T. Bach, Angew. Chem., Int. Ed.,2009, 48, 6640–6642; (c) A. Bakowski, M. Dressel, A. Bauer andT. Bach, Org. Biomol. Chem., 2011, 9, 3516–3529; (d) C. Muller,M. M. Maturi, A. Bauer, M. C. Cuquerella, M. A. Miranda andT. Bach, J. Am. Chem. Soc., 2011, 133, 16689–16697.

15 The asymmetric unit contains two crystallographically independentbut chemically identical molecules. CCDC 894230 (6); for moredetails see ESIw.

16 S. Yamaguchi, E. Hamade, H. Yokoyama, Y. Hirai andS. Shiotani, J. Heterocycl. Chem., 2002, 39, 335–339.

17 L. I. Kruse, C. Kaiser, W. E. DeWolf, J. A. Finkelstein,J. S. Frazee, E. L. Hilbert, S. T. Ross, K. E. Flaim andJ. L. Sawyer, J. Med. Chem., 1990, 33, 781–789.

18 Compounds 13 and 15 were prepared in analogy to a knownprocedure (see ESIw for further information): D. B. Moran,G. O. Morton and J. D. Albright, J. Heterocycl. Chem., 1986,23, 1071–1077.

19 E. Ochiai and Y. Kawazoe, Pharm. Soc. Jpn, 1957, 5, 606–610.20 For singlet oxygen reactions, performed in a continuous flow

system, see: (a) F. Levesque and P. H. Seeberger, Org. Lett.,2011, 13, 5008–5011; (b) F. Levesque and P. H. Seeberger, Angew.Chem., Int. Ed., 2012, 51, 1706–1709; (c) K. Booker-Milburn, Nat.Chem., 2012, 4, 433–435.

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