Photoreactivity of 2-pyridones with furan, benzene, and naphthalene. Inter- and intramolecular photocycloadditions

Article abstract of DOI:10.1021/jo9918394

Pyridones, well-known for their ability to photodimerize, have been found to undergo [4 + 4] photocycloaddition with furan and naphthalene but not with benzene. In some cases these reactions can be highly regio- and stereospecific. Intramolecular reaction with furan produces both cis and trans [4 + 4] products. The cycloaddition with naphthalene can occur both inter- and intramolecularly. The intermolecular reaction yields primarily the cis isomer, whereas the trans isomer is the major product from the intramolecular reaction. A mixture of 4-methoxy-2-pyridone and 2- methoxynaphthalene that could form up to eight regio- and stereoisomers forms largely one [4 + 4] product.

Full text of DOI:10.1021/jo9918394

1972
J . Org. Chem. 2000, 65, 1972-1977
P h otor ea ctivity of 2-P yr id on es w ith F u r a n , Ben zen e, a n d
Na p h th a len e. In ter - a n d In tr a m olecu la r P h otocycloa d d ition s
Scott McN. Sieburth,* Kevin F. McGee, J r., Fangning Zhang, and Yanping Chen
Department of Chemistry, State University of New York, Stony Brook, New York 11794-3400
Received November 30, 1999
Pyridones, well-known for their ability to photodimerize, have been found to undergo [4 + 4]
photocycloaddition with furan and naphthalene but not with benzene. In some cases these reactions
can be highly regio- and stereospecific. Intramolecular reaction with furan produces both cis and
trans [4 + 4] products. The cycloaddition with naphthalene can occur both inter- and intramolecu-
larly. The intermolecular reaction yields primarily the cis isomer, whereas the trans isomer is the
major product from the intramolecular reaction. A mixture of 4-methoxy-2-pyridone and 2-meth-
oxynaphthalene that could form up to eight regio- and stereoisomers forms largely one [4 + 4]
product.
Among the higher-order cycloadditions,1-3 2-pyridones
have long been recognized for their propensity to photo-
dimerize with a high level of regio- and stereoselectivity.4
At concentrations above 0.1 M, most 2-pyridones will
undergo photodimerization in high yield, forming exclu-
sively the head-to-tail regioisomers 2 and 3, with the
trans isomer 3 dominating. A less-well studied reactivity
of 2-pyridones is their photocycloaddition with other
polyunsaturated molecules such as 1,3-dienes and tri-
azolopyridines. Using an excess of a 1,3-diene, especially
cyclopentadiene, [4 + 4] products such as cis 4 and trans
5 have been prepared by Sato et al.,5 and intramolecular
reactions proceed similarly.6 Triazolopyridines, also known
to photodimerize,7 will yield cross [4 + 4] product 6 when
irradiated in the presence of a 2-pyridone (Figure 1).8The
symmetry of 2-pyridone photodimers 2 and 3, with a C2
axis and a center of inversion, respectively, limits the
potential application of this efficient [4 + 4] cycloaddition
because few synthetic targets are similarly symmetric.
One approach to eliminating the symmetry of pyridone/
pyridone photoproducts is to use pyridone mixtures.9
These photoreactions can yield densely functionalized [4
+ 4] products from simple and readily available aromatic
substances.10,11 Alternatively, new examples of 2-pyridone
cross-photocycloaddition with polyunsaturated species
F igu r e 1. Photodimerization of 2-pyridones and cross-reaction
wth 1.3-dienes and triazolopyridine.
would greatly expand the range of accessible products.
As part of our continuing investigations of 2-pyridone
photoreactivity, we have therefore surveyed its reactivity
with furan, benzene, and naphthalene and report the
results here.
Among this set of aromatics, furan, benzene, and
naphthalene, only naphthalene will photodimerize to give
structures such as 10 (Figure 2).2,3,12 This photo-[4 + 4]
reactivity is well-studied with three-atom tethered bis-
1-naphthalenes,13 and intermolecular photo-[4 + 4] dimer-
ization can also occur readily, especially with 2-methoxy-
naphthalene.14
* Ph: 631-632-7851. FAX: 631-632-8882. scott.sieburth@sunysb.edu.
(1) Rigby, J . H. Tetrahedron 1999, 55, 4521-4538.
(2) Sieburth, S. McN.; Cunard, N. T. Tetrahedron 1996, 52, 6251-
6282.
(3) McCullough, J . J . Chem. Rev. 1987, 87, 811-860.
(4) Sieburth, S. McN. The Inter- and Intramolecular [4 + 4]
Photocycloaddition of 2-Pyridones and Its Application to Natural
Product Synthesis. In Advances in Cycloaddition; Harmata, M., Ed.;
J AI: Greenwich, CT, 1999; Vol. 5, pp 85-118.
(5) Kanaoka, Y.; Ikeda, Y.; Sato, E. Heterocycles 1984, 21, 645. Sato,
E.; Ikeda, Y.; Kanaoka, Y. Heterocycles 1989, 28, 117-120. Sato, E.;
Ikeda, Y.; Kanaoka, Y. Liebigs Ann. Chem. 1989, 781-788.
(6) Sieburth, S. McN.; Zhang, F. Tetrahedron Lett. 1999, 40, 3527-
3530.
Furans (7) do not photodimerize, with the exception
of isobenzofuran,15 undergoing fragmentation and isomer-
ization reactions instead.16,17 West has found that furan
will photochemically yield intramolecular [4 + 4] adducts
(12) Rigby, J . H. [4 + 4] and [6 + 4] Cycloadditions. In Comprehen-
sive Organic Synthesis; Trost, B. M., Ed.; Pergamon: New York, 1991;
Vol. 5, pp 617-643.
(7) Nagano, T.; Hirobe, M.; Itoh, M.; Okamoto, T. Tetrahedron Lett.
1975, 3815-3818.
(8) Nagano, T.; Hirobe, M.; Okamoto, T. Tetrahedron Lett. 1977,
3891-3894.
(13) Chandross, E. A.; Dempster, C. J . J . Am. Chem. Soc. 1970, 92,
703-704. Todesco, R.; Gelan, J .; Martens, H.; Put, J .; Boens, N.; De
Schryver, F. C. Tetrahedron Lett. 1978, 2815-2818.
(14) Bradshaw, J . S.; Hammond, G. S. J . Am. Chem. Soc. 1963, 85,
3953-3955. Selinger, B. K.; Sterns, M. J . Chem. Soc., Chem. Commun.
1969, 978-979.
(9) Sieburth, S. McN.; Lin, C.-H. Tetrahedron Lett. 1996, 37, 1141-
1144.
(10) Sieburth, S. McN.; Lin, C.-H.; Rucando, D. J . Org. Chem. 1999,
64, 950-953.
(11) Sieburth, S. McN.; Rucando, D.; Lin, C.-H. J . Org. Chem. 1999,
64, 954-959.
(15) Warrener, R. N.; Pitt, I. G.; Russell, R. A. Aust. J . Chem. 1993,
46, 1515-1534.
10.1021/jo9918394 CCC: $19.00 © 2000 American Chemical Society
Published on Web 03/16/2000

Photoreactivity of 2-Pyridones
J . Org. Chem., Vol. 65, No. 7, 2000 1973
F igu r e 2. Naphalene will undergo [4 + 4] photodimerization,
whereas benzene and furan will not.
F igu r e 3. Photosubstrate synthesis.
F igu r e 4. Photoreactions of pyridones tethered to phenyl (12),
furyl (14), and naphthalene (15) and Cope rearrangement of
the cis isomers.
with 2-pyrones.18 Benzene 8 has a wide range of photo-
reactivity, including [4 + 4] photocycloadditions with 1,3-
dienes and with furan, but it does not photodimerize.2,19
The photoreactivity of 2-pyridones with these three
substrates has not been tested, although benzene has
been used as a solvent. Nevertheless, the potential
intramolecular reaction of benzene and pyridone was
included in this study so that its reactivity could be
compared with the other aromatics studied here.
directly with benzyl chloride using phase-transfer etheri-
fication conditions22 to give ether 12. Conversion of
hydroxymethyl pyridone 11 to the corresponding chlo-
romethyl pyridone 1320 using thionyl chloride, followed
by phase-transfer mediated etherification with furfuryl
alcohol and 1-(hydroxymethyl)naphthalene, gave ethers
14 and 15, respectively. Each of these ethers was
subjected to ambient temperature, Pyrex-filtered irradia-
tion from a water-cooled 450 W medium-pressure mer-
cury lamp and monitored at intervals by TLC and/or
NMR.
Benzyl ether 12 was found to undergo a relatively slow
photoreaction. After 8.5 h of irradiation, the product
mixture was concentrated and purified by flash chroma-
tography. In addition to residual 12, only the cis and
trans [4 + 4] dimers 16 and 17 were isolated, in a ratio
of 2:3 (Figure 4); however, these had nearly identical Rf
values and were not separated. This dimerization was
not unexpected, as benzene has been found to be a
suitable solvent for 2-pyridone photochemistry, but it
establishes that even under ideal intramolecular circum-
stances, an unsubstituted phenyl group is inert to pho-
tocycloaddition with 2-pyridones.
Resu lts a n d Discu ssion
In tr a m olecu la r Rea ction s. Photosubstrates, with a
three-atom chain anchoring furan, benzene, and naph-
thalene at C-3 of 1-methyl-2-pyridone, were readily
prepared from the known 3-hydroxymethyl-1-methyl-2-
pyridone 11 (Figure 3).20,21 During the course of this work,
a new preparation of this useful intermediate was
developed, and it is included here. Alcohol 11 was coupled
(16) Lablache-Combier, A. Photoisomerization of Five-Membered
Heterocyclic Compounds. In Photochemistry of Heterocyclic Com-
pounds; Buchardt, O., Ed.; Wiley: New York, 1976; pp 123-206.
D′Auria, M. Heterocycles 1999, 50, 1115-1136.
(17) Furan and benzene will yield a [4 + 4] photoproduct, see:
Berridge, J . C.; Gilbert, A.; Taylor, G. N. J . Chem. Soc., Perkin Trans.
1 1980, 2174-2178.
In contrast to the phenyl group, the furan in 14 reacted
completely within 3 h to give photoproducts 18 and 19.18
These two products were formed in a ratio of 3:10,
favoring the trans isomer 19. Changing the solvent from
benzene to methanol did not alter significantly the rate
of the photoreaction or the ratio of the products. The cis
(18) West, F. G.; Chase, C. E.; Arif, A. M. J . Org. Chem. 1993, 58,
3794-3795. West, F. G.; Hartke-Karger, C.; Koch, D. J .; Kuehn, C.
E.; Arif, A. M. J . Org. Chem. 1993, 58, 6795-6803. Chase, C. E.;
Bender, J . A.; West, F. G. Synlett 1996, 1173-1175.
(19) Garcia, H.; Gilbert, A.; Griffiths, O. J . Chem. Soc., Perkin Trans
2 1994, 247-252. Yang, N. C.; Libman, J . Tetrahedron Lett. 1973,
1409-1412.
(20) Morrow, C. J .; Rapoport, H. J . Org. Chem. 1974, 39, 2116-
2118.
(21) Sieburth, S. McN.; Siegel, B. J . Chem. Soc., Chem. Commun.
1996, 2249-2250.
(22) Palmer, M. J .; Danilewicz, J . C.; Vuong, H. Synlett 1994, 171-
172.

1974 J . Org. Chem., Vol. 65, No. 7, 2000
Sieburth et al.
F igu r e 6. Methoxy substitution is tolerated in the cross-
photocycloaddition of a pyridone and a naphthalene and yields
a high level of regio- and stereoselectivity. Products 33 and
34 are comparable to the known 35, a dimer of 32, and its
Cope rearrangement product 36.
F igu r e 5. Intermolecular photocycloaddition of 2-pyridones
and naphthalene can yield a single product.
Product 26 was unstable and underwent Cope rear-
rangement during purification over silica gel. Cope
rearrangement of cis-2-pyridone dimers (2) during silica
gel chromatography has been reported by Nakamura.25
Two alternative Cope rearrangements are possible for 26,
and the two isomeric cyclobutanes 28 and 29 were formed
in this rearrangement, with the R,â-unsaturated amide
28 favored by more than a factor of 7.
Hydrogenation of the unpurified photoproduct mixture
was readily accomplished, and the product 27 could then
be chromatographically purified in 32% overall yield,
based on pyridone 24 as the limiting reagent. Hydroge-
nation of the major Cope product 28 was also performed
for comparison with 27.
A complicating aspect of the intermolecular reaction
of 2-pyridone with naphthalene (Figure 5), was the need
to use an excess of naphthalene 25 to suppress photo-
dimerization of pyridone 24. Pyridone photodimerization
can also be avoided by using 4-methoxy-2-pyridone 31
(Figure 6). Pyridone 3124 will not photodimerize but will
undergo [4 + 4] photocycloaddition with other 2-pyri-
dones,9,10 and we anticipated that this reactivity might
also be available with non-pyridone reactants such as
naphthalene. Methoxynaphthalene 32 was chosen as a
reaction partner for 31.
Among the potential complications for photoreaction
of 31 and 32 was the known [4 + 4] dimerization of
naphthalene 32, the first naphthalene photodimerization
to be reported.14 Perhaps more significantly, however,
cross-photoreaction of 31 and 32, assuming an exclusively
[4 + 4] reaction manifold, could result in reaction at
either aromatic ring, and each of these reaction sites has
two possible regioisomers and two possible stereoisomers,
for a total of eight (racemic) [4 + 4] products. A 1:1 ratio
of 31 and 32 in methanol was irradiated for 72 h and
produced largely a single isomeric product 33. In contrast
isomer 18 was identified by heating benzene solutions
of each isomer to 100 °C in a sealed tube. Under these
conditions, the trans isomer 19 was unchanged but the
cis isomer underwent a Cope rearrangement23 to produce
the cyclobutane product 20.
Naphthylmethyl ether 15 proved to be similar in
reactivity to furfuryl ether 14. A solution of 15 in
benzene-d6 was completely converted to photoproducts
after 1 h of irradiation. Two isomers 21 and 22 were
formed in a ratio of 1:5, favoring the trans isomer. In
methanol-d4 the same isomers were produced, but this
required a slightly longer reaction time (3.5 h) and gave
a ratio of 1:2. Once again, the cis isomer was identified
by its facile Cope rearrangement. In this case, the
inseparable mixture of cis and trans isomers was heated
to 65 °C for 4.5 h. The trans isomer 22 remained
unchanged, and the cis isomer 21 was fully converted to
cyclobutane 23.
In ter m olecu la r Rea ction s. The photocycloaddition
of naphthalene with pyridone could also be performed
without the tether, using a mixture of the commercially
available substrates 2424 and 25 (Figure 5). The highly
dissimilar solubilities limited the solvent choice; however,
ethanol proved to be acceptable for both substrates. An
initial survey of relative concentrations led to the finding
that an excess of naphthalene 25 limited dimerization
of 24 and resulted in formation of largely one new
component. After irradiation of a 1:3 ratio of 24 and 25
in methanol (0.5 M in 25) for 24 h, little of the pyridone
remained. Unfortunately, purification of the resulting
photoproduct proved to be troublesome.
(23) Cope, A. C.; Hardy, E. M. J . Am. Chem. Soc. 1940, 62, 441-
444. For reviews see: Rhoads, S. J .; Raulins, N. R. Org. React. 1975,
22, 1-252. Hill, R. K. Cope, Oxy-Cope and Anionic Oxy-Cope Rear-
rangements. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Ed.; Pergamon: New York, 1991; Vol. 5, pp 785-826.
(24) Nitrogen substitution does not affect the photochemistry of
2-pyridones.
(25) Nakamura, Y.; Kato, T.; Morita, Y. J . Chem. Soc., Perkin Trans.
1 1982, 1187-1191.

Photoreactivity of 2-Pyridones
J . Org. Chem., Vol. 65, No. 7, 2000 1975
hydrochloric acid (2 mL) was added. The resulting suspension
was filtered to give 1-methyl 2-oxo-(1H)-pyridine-3-carboxylic
acid28-30 as a colorless solid (2.11 g, 96%): 1H NMR (D2O) δ
8.29 (d, J ) 7.4 Hz, 1H), 7.91 (d, J ) 6.6 Hz, 1H), 6.63 (dd, J
) 7.4, 6.6 Hz, 1H), 3.59 (s, 3H).
This acid (439 mg, 2.87 mmol) was dissolved in thionyl
chloride (6.5 mL) and refluxed for 1 h. After evaporation of
the excess thionyl chloride, methanol (10 mL) was added, and
the solution was refluxed for 0.5 h. The solvent was evapo-
rated, the residue was dissolved in chloroform, and the solution
was washed with saturated sodium bicarbonate solution and
then water. Concentration gave methyl 1-methyl-2-oxo-(1H)-
pyridine-3-carboxylate28,31 as a light yellow solid (442 mg,
92%): 1H NMR (CDCl3) δ 8.06 (dd, J ) 7.1, 2.2 Hz, 1H), 7.54
(dd, J ) 6.6, 2.2 Hz, 1H), 6.17 (dd, J ) 7.1, 6.6 Hz, 1H), 3.82
(s, 3H), 3.53 (s, 3H). 13C NMR (CDCl3) δ 165.6, 159.3, 144.6,
143.1, 120.2, 104.4, 52.1, 38.2.
To a solution of methyl 1-methyl-2-oxo-(1H)-pyridine-3-
carboxylate (410 mg, 2.45 mmol) in THF (25 mL) at -5 °C
was added diisobutylaluminum hydride (5.40 mmol). After 3
h at 0 °C, methanol (1 mL), water (1 mL), sodium hydroxide
(15%, 1 mL), and water (2 mL) were added. The resulting
suspension was filtered, and the residue was washed with
methanol. The filtrate was concentrated, and the product was
purified by flash chromatography (3-5% gradient of methanol
in methylene chloride) to afford alcohol 1120,21 as a colorless
solid (160 mg, 47%): 1H NMR (CDCl3) δ 7.29 (d, J ) 6.9 Hz,
1H), 7.20 (d, J ) 6.9 Hz, 1H), 6.17 (t, J ) 6.9 Hz, 1H), 4.50 (s,
2H), 3.49 (s, 3H).
to 26, product 33 was stable to silica gel chromatography
and was isolated in 44% yield.
The proton NMR spectrum of 33 contained four aro-
matic protons, consistent with alkyl substitution (7.2-
6.8 ppm), and two enol ether vinyl protons (5.1 and 5.0
ppm). The methoxy groups had identical chemical shifts
(3.55 ppm), indicating that they were in similar environ-
ments and isolated from anisotropic influences of the
amide group and aromatic ring. These chemical shifts
are nearly identical to the corresponding data reported26
for the cis 2-methoxynaphthalene dimer 35, particularly
the chemical shift of the methoxy singlet at 3.58 ppm.
In chloroform-d at ambient temperature, this product
underwent a slow, quantitative rearrangement to cy-
clobutane 34, confirming the cis configuration of 33, with
the alkenes in close proximity as shown in Figure 6.
After this rearrangement, the chemical shift of the two
methoxy groups shifted substantially, one upfield and one
downfield (3.65 and 3.06 ppm). This pattern is identical
to that observed for the Cope rearrangement product 36,
with two methoxy singlets at 3.71 and 3.07 ppm.26 In
addition, three vinyl protons were now present and were
consistent with structure 34, with two “normal” alkene
protons (6.7 and 5.5 ppm) and a vinyl proton associated
with a â-alkoxy-R,â-unsaturated amide group (4.9 ppm).
Thermodynamically, this would be the expected product,
with an R,â-unsaturated amide rather than the alterna-
tive N-alkenyl amide, and it is consistent with the major
product formed upon rearrangement of 26 (Figure 5).
The high selectivity of this cycloaddition for the
substituted ring of 32 mirrors the photodimerization of
2-substituted naphthalenes. A variety of 2-substituted
naphthalenes undergo [4 + 4] photodimerization exclu-
sively across the substituted ring (see 35). Such head-
to-tail selectivity has also been observed in suitably
substituted anthracenes. Neither steric nor simple orbital
interactions have been found to adequately account for
the regioselectivity.27
Ben zyl (3-[1-Meth yl-2-oxo-(1H)-pyr idin yl])-m eth yl Eth er
12. To a solution of alcohol 11 (39 mg, 0.28 mmol) in methylene
chloride (10 mL) at 0 °C was added benzyl chloride (79 mg,
0.56 mmol), benzyltriethylammonium chloride (83 mg, 0.37
mmol), and 40% sodium hydroxide (0.56 mL). The mixture was
allowed to reach ambient temperature and stirred for 24 h.
The aqueous phase was extracted with methylene chloride,
and the combined organics were washed with water and then
dried over anhydrous sodium sulfate. The organics were
concentrated and purified by flash chromatography (3:97
methanol/methylene chloride) to give 12 as a colorless oil (34
1
mg, 50%): Rf ) 0.21 (3:97 methanol/methylene chloride); H
NMR (CDCl3) δ 7.50 (d, J ) 6.9 Hz, 1H), 7.39-7.27 (m, 5H),
7.21 (d, J ) 6.9 Hz, 1H), 6.18 (t, J ) 6.9 Hz, 1H), 4.65 (s, 2H),
4.52 (s, 2H), 3.53 (s, 3H); 13C NMR (CDCl3) δ 161.6, 138.2,
136.4, 135.4, 129.7, 128.3, 127.6, 127.5, 105.6, 73.0, 67.3, 37.4.
3-Ch lor om eth yl-1-m eth yl-2-(1H)-p yr id on e 13.20 To a
solution of alcohol 11 (0.728 g, 5.24 mmol) in methylene
chloride (15 mL) was added dropwise a solution of thionyl
chloride (0.42 mL) in methylene chloride (6 mL). The mixture
was stirred for 1.5 h, at which time TLC indicated an absence
of starting 11. The mixture was concentrated, and the result-
ing oil was purified by flash chromatography (5:95 methanol/
methylene chloride) to give 13 as an oil (0.725 g, 88%):20 Rf )
Con clu sion s
Pyridones are stable and readily available aromatics,
well-known for their [4 + 4] photocycloadditions, and the
experiments described here reveal a richer diversity for
this [4 + 4] reactivity. The readily available furans and
naphthalenes, in combination with pyridones, yield novel
and potentially useful new products. The high site, regio-,
and stereoselectivities leading to 33 are especially in-
triguing and further studies are in progress.
1
0.31 (3:97 methanol/methylene chloride); H NMR (CDCl3) δ
7.46 (dd, J ) 6.9, 1.8 Hz, 1H), 7.28 (dd, J ) 6.9, 1.8 Hz, 1H),
6.14 (t, J ) 6.9 Hz, 1H), 4.51 (s, 2H), 3.52 (s, 3H).
2-Fu r ylm eth yl (3-[1-Meth yl-2-oxo-(1H)-pyr idin yl])-m eth -
yl Eth er 14. To a solution of chloride 13 (82 mg, 0.52 mmol)
in methylene chloride (15 mL) at 0 °C was added furfural
alcohol (56 mg, 0.57 mmol), benzyltriethylammonium chloride
(150 mg, 0.68 mmol), and sodium hydroxide (1.8 mL of a 40%
aqueous solution). The mixture was allowed to reach ambient
temperature and stirred for 24 h. The aqueous phase was
extracted with methylene chloride, washed with water, dried
over anhydrous sodium sulfate, and concentrated in vacuo.
Purification by flash chromatography (3:97 methanol/methyl-
ene chloride) gave 14 (108 mg, 95%): Rf ) 0.40 (3:97 methanol/
Exp er im en ta l Section
3-Hyd r oxym eth yl-1-m eth yl-2-(1H)-p yr id on e 11.20,21 Fol-
lowing the method of Deady,28 to a solution of 2-hydroxy
nicotinic acid (2.0 g, 14.4 mmol) in a mixture of methanol (20
mL) and water (3 mL) was added powdered potassium
hydroxide (1.6 g, 28.6 mmol). This mixture was refluxed for
15 min. Iodomethane (10 mL, 161 mmol) was added, and the
resulting mixture was refluxed for 2 h. The resulting clear
solution was concentrated to half of its volume, and 10%
(26) Teitei, T.; Wells, D.; Sasse, W. H. F. Tetrahedron Lett. 1974,
367-370.
(29) Tomisawa, H.; Fujita, R.; Hongo, H.; Kato, H. Chem. Pharm.
Bull. 1974, 22, 2091-2096.
(30) Spa¨th, E.; Koller, G. Chem. Ber. 1923, 56, 880-887.
(31) Hardegger, E.; Nikles, E. Helv. Chim. Acta 1956, 39, 505-513.
Kitagawa, T.; Mizukami, S.; Hirai, E. Chem. Pharm. Bull. 1978, 26,
1403-1414. Newkome, G. R.; Kohli, D. K.; Kawato, T. J . Org. Chem.
1980, 45, 4508-4511.
(27) For a discussion and lead references, see: Teitei, T.; Wells, D.;
Spurling, T. H.; Sasse, W. H. F. Aust. J . Chem. 1978, 31, 85-96.
Ramesh, V.; Ramamurthy, V. J . Org. Chem. 1984, 49, 536-539. Albini,
A.; Fasani, E.; Gamba, A. J . Photochem. Photobiol. A 1988, 41, 215-
225. Ihmels, H. Eur. J . Org. Chem. 1999, 1595-1600.
(28) Deady, L. W. Aust. J . Chem. 1985, 38, 637-641.

1976 J . Org. Chem., Vol. 65, No. 7, 2000
Sieburth et al.
1
methylene chloride); mp ) 96.0-97.0 °C; H NMR (CDCl3) δ
Cop e Rea r r a n gem en t of 18. Photoproduct 18 (6.9 mg) was
dissolved in benzene-d6 and heated at 100 °C (sealed tube) for
8 h. Flash chromatography (3:97 methanol/methylene chloride)
gave 20 (2.7 mg, 39%): mp ) 168.5-169.5 °C; Rf ) 0.49 (5:95
methanol/methylene chloride); 1H NMR (CDCl3) δ 6.41 (m, 1H),
5.97 (d, J ) 8.2 Hz, 1H), 5.16 (m, 1H), 4.76 (dd, J ) 8.2, 5.2
Hz, 1H), 4.29 (d, J ) 9.1 Hz, 1H), 4.05 (d, J ) 9.6 Hz, 1H),
4.00 (d, J ) 9.1 Hz, 1H), 3.81 (d, J ) 9.6 Hz, 1H), 3.54 (m,
1H), 3.10 (dd, J ) 7.0, 5.2 Hz, 1H), 3.02(s, 3H); 13C NMR
(CDCl3) δ 165.1, 147.9, 131.0, 103.7, 101.7, 99.2, 77.2, 71.8,
56.6, 52.0, 39.7, 34.8. MS (DEI) m/z (%) 220 (MH+, 5), 138 (36),
123 (79), 122 (100).
P h otocycloa d d ition of 15. A solution of 15 (60.0 mg, 0.215
mmol) in benzene-d6 (4.3 mL, 50 mM in 15) was irradiated
with a Pyrex-filtered 450 W medium-pressure mercury lamp
for 1 h. The resulting mixture was purified by flash chroma-
tography (3:97 methanol/methylene chloride) to give an in-
separable 1:5 mixture of 21 and 22 (31.8 mg, 53%).
7.46 (dd, J ) 6.9, 1.9 Hz, 1H), 7.39 (m, 1H), 7.20 (dd, J ) 6.9,
1.9 Hz, 1H), 6.33 (m, 2H), 6.16 (t, J ) 6.9 Hz, 1H), 4.57 (s,
2H), 4.50 (s, 2H), 3.53 (s, 3H); 13C NMR (CDCl3) δ 161.7, 151.6,
142.8, 136.5, 135.6, 129.4, 110.2, 109.4, 105.6, 67.1, 64.8, 37.4;
MS (DCI/NH3) m/z 220 (MH+, 66), 138 (10), 123 (100), 95 (19),
81 (38); exact mass (DCI/NH3) calcd for C12H14NO3 220.0974,
found 220.0963.
(3-[1-Meth yl-2-oxo-(1H)-p yr id in yl])-m eth yl 1-Na p h th -
ylm eth yl Eth er 15. To a solution of chloride 13 (78.1 mg,
0.496 mmol) in methylene chloride (15 mL) at 0 °C was added
1-hydroxymethylnaphthalene (94.1 mg, 0.595 mmol), benzyl-
triethylammonium chloride (147 mg, 0.645 mmol), and 40%
sodium hydroxide (1.5 mL). The mixture was allowed to reach
ambient temperature and stirred for 9 h. The aqueous phase
was extracted with methylene chloride, washed with water,
dried over anhydrous sodium sulfate, and concentrated. Pur-
ification by flash chromatography (3:97 methanol/methylene
chloride) gave 15 as a colorless solid (99.5 mg, 72%): Rf ) 0.33
(3:97 methanol/methylene chloride); mp ) 102.4-103.4 °C; 1H
NMR (CDCl3) δ 8.14 (d, J ) 8.0 Hz, 1H), 7.83 (m, 2H), 7.56-
7.40 (m, 5H), 7.13 (dd, J ) 6.9, 1.6 Hz, 1H), 6.09 (t, J ) 6.9
Hz, 1H), 5.09 (s, 2H), 4.54 (s, 2H), 3.49 (s, 3H); 13C NMR
(CDCl3) δ 161.5, 136.3, 135.4, 133.6, 133.5, 131.6, 129.5, 128.4,
128.3, 126.3, 126.0, 125.6, 125.1, 123.9, 105.4, 71.4, 67.3, 37.2;
MS (DCI/NH3) m/z (%) 280 (MH+, 100), 141 (60), 123 (82); exact
mass (DCI/NH3) calcd for C18H18NO2 280.1338, found 280.1327.
Irradiation of a solution of 15 (35.1 mg, 0.126 mmol) in
methanol-d4 (2.52 mL, 50 mM in 15) for 3.5 h under the
conditions described above, followed by flash chromatography,
gave a 1:2 mixture of 21 and 22 (18.8 mg, 53%).
Cop e Rea r r a n gem en t of 21. The 1:2 mixture of 21 and
22 was dissolved in chloroform-d1 and heated to 65 °C for 4.5
h. The resulting mixture was purified by flash chromatography
(3:97 methanol/methylene chloride) to give trans isomer 22
(36%) and Cope product 23 (23%). P h otop r od u ct 22: Rf )
1
0.39 (3:97 methanol/methylene chloride); H NMR (CDCl3) δ
P h otocycloa d d ition of Ben zyl Eth er 12. A stream of dry
nitrogen was passed for 15 min through a solution of 12 (25.7
mg, 0.11 mmol) in benzene-d6 (50 mM in 12), and the Pyrex
test tube was then sealed with a septum. This tube was taped
to the side of a water-cooled quartz cooling jacket surrounding
a 450 W medium-pressure mercury Hanovia lamp fitted with
a Pyrex filter and irradiated for 8.5 h. The photoreaction was
periodically monitored by 1H NMR. The solvent was removed,
and the crude mixture was purified with silica gel chroma-
tography (3:97 methanol/methylene chloride) to give an in-
separable mixture of 16 and 17 (12.3 mg, 48%): Rf ) 0.43 (3:
97 methanol/methylene chloride); 1H NMR (CDCl3) δ 7.37-
7.27 (m, 10H), 6.64 (d, J ) 2.4 Hz, 1.2H), 6.57 (m, 1.2H), 6.50
(m, 0.8H), 6.20 (d, J ) 8.4 Hz, 0.8H), 4.60 (m, 4H), 4.27 (d, J
) 2.4 Hz, 1.2H), 3.94-3.88 (m, 2H), 3.81-3.74 (m 2H), 3.68
(d, J ) 9.9 Hz, 0.8H), 2.80 (s, 3.6H), 2.76 (s, 2.4H).
7.28 (m, 1H), 7.17-7.09 (m, 3H), 6.57 (t, J ) 7.5 Hz, 1H), 6.27
(d, J ) 8.2 Hz, 1H), 5.81 (t, J ) 7.3 Hz, 1H), 5.38 (d, J ) 8.2
Hz, 1H), 4.76 (d, J ) 9.1 Hz, 1H), 4.63 (d, J ) 9.6 Hz, 1H),
4.00-3.81 (m, 4H), 2.94 (s, 3H); 13C NMR (CDCl3) δ 173.9,
144.3, 143.9, 140.2, 137.0, 134.8, 133.1, 126.2, 125.9, 125.9,
123.7, 75.5, 75.4, 65.0, 62.0, 60.8. 47.8, 35.9; MS (DCI/NH3)
m/z (%) 280 (MH+, 84), 141 (53), 123 (100); exact mass (DCI/
NH3) calcd for C18H18NO2 280.1338, found 280.1329. Cop e
p r od u ct 23: Rf ) 0.57 (3:97 methanol/methylene chloride);
1H NMR (CDCl3) δ 7.11-7.06 (m, 3H), 6.95-6.92 (m, 1H), 6.38
(d, J ) 9.9 Hz, 1H), 5.72 (dd, J ) 8.2, 1.4 Hz, 1H), 5.54 (dd, J
) 9.9, 5.2 Hz, 1H), 4.83 (d, J ) 9.3 Hz, 1H), 4.76 (dd, J ) 8.2,
3.8 Hz, 1H), 4.13 (d, J ) 9.1 Hz, 1H), 3.98 (d, J ) 9.3 Hz, 1H),
3.70 (d, J ) 9.3 Hz, 1H), 3.62 (dd, J ) 9.1, 5.2 Hz, 1H), 3.22
(ddd, J ) 9.1, 3.8, 1.4 Hz, 1H), 2.70 (s, 3H); 13C NMR (CDCl3)
δ 165.5, 133.6, 130.2, 129.6, 128.3, 127.6, 127.5, 127.4, 127.4,
123.8, 104.4, 80.1, 78.1, 61.6, 59.1, 43.4, 42.2, 34.6; MS (DCI/
NH3) m/z (%) 280 (MH+, 100), 141 (66), 123 (69); exact mass
(DCI/NH3) calcd for C18H18NO2 280.1338, found 280.1340.
In ter m olecu la r P h otocycloa d d ition of 2-P yr id on e 24
a n d Na p h th a len e 25. A solution of naphthalene (239.7 mg,
1.87 mmol) and 2-pyridone 2 (59.4 mg, 0.625 mmol) in
methanol (5 mL, overall 0.5 M in 24 + 25) was irradiated for
24 h with a water-cooled Pyrex-filtered 450 W medium-
pressure mercury lamp. The crude mixture was cooled to 0 °C
overnight, and the crystalline naphthalene 25 was removed
by filtration. Concentration of the filtrate gave a mixture
containing largely photoproduct 26 plus residual 25. P h oto-
p r od u ct 26: Rf ) 0.71 (1:9 methanol/methylene chloride). In
addition to absorbances due to naphthalene, the 1H NMR
exhibited the following (CDCl3): δ 7.25 (m, 1 H), 7.03 (m, 2
H), 6.94 (m, 1 H), 6.60 (t, J ) 8.1 Hz, 1 H), 6.40 (t, J ) 7.2 Hz,
1 H), 6.27 (bs, 1 H, NH), 6.24 (t, J ) 7.2 Hz, 1 H), 6.05 (t, J )
7.5 Hz, 1 H), 4.03-3.96 (m, 1 H), 3.83-3.73 (m, 2 H), 3.45-
3.39 (m, 1 H). MS (FAB+) m/z (%) 224 (MH+, 30), 128 (13), 96
(100); exact mass (CI) calcd for C15H14NO 224.1075, found
224.1077.
P h otocycloa d d ition of 14. A stream of dry nitrogen was
passed for 15 min through a solution of 14 (51.6 mg, 0.235
mmol) in benzene-d6 (50 mM in 14), and the Pyrex test tube
was then sealed with a septum. This tube was taped to the
side of a water-cooled quartz cooling jacket surrounding a 450
W medium-pressure mercury lamp inside of a Pyrex filter and
irradiated. After 3 h, 1H NMR indicated that all of 14 had been
consumed. The solution was concentrated and purified by flash
chromatography (3:97 methanol/methylene chloride) to give a
difficultly separable 3.4:1 mixture (NMR) of 18 and 19 (37.2
mg, 72%). Cis isom er 18: Rf ) 0.34 (3:97 methanol/methylene
1
chloride); mp ) 129.5-130.5 °C; H NMR (CDCl3) δ 6.49 (dd,
J ) 5.8, 1.9 Hz, 1H), 6.44 (t, J ) 7.8 Hz, 1H), 5.97 (d, J ) 5.8
Hz, 1H), 5.87 (dd, J ) 7.8, 1.6 Hz, 1H), 4.84 (d, J ) 9.3 Hz,
1H), 4.62 (dd, J ) 6.3, 1.9 Hz, 1H), 3.96 (d, J ) 9.9 Hz, 1H),
3.82 (d, J ) 9.9 Hz, 1H), 3.73 (dt, J ) 6.3, 1.6 Hz, 1H), 3.65 (d,
J ) 9.3 Hz, 1H), 3.04 (s, 3H); 13C NMR (CDCl3) δ 175.0, 136.8,
135.8, 135.2, 134.7, 96.7, 78.2, 71.4, 70.8, 65.5, 61.9, 33.9; MS
(DEI) m/z (%) 220 (MH+, 9), 138 (32), 123 (100), 95 (63), 81
(48); exact mass (DEI) calcd for C12H14NO3 220.0974, found
220.0982. Tr a n s isom er 19: mp ) 129.2-130.4 °C; Rf ) 0.36
1
(3:97 methanol/methylene chloride); H NMR (CDCl3) δ 6.60
Hyd r ogen a tion of P h otop r od u ct 26. To a degassed
solution of crude photoproduct 26 (558 mg, 2.5 mmol) in
methanol (20 mL) was added 10% Pd/C (56 mg), and the flask
was fitted with a hydrogen balloon. After stirring for 19 h the
solution was filtered through Celite, concentrated in vacuo,
and purified by flash chromatography (1:9 methanol/methylene
chloride) to give 183.8 mg (32%) of 27 as an eggshell white
(dd, J ) 7.5, 6.6 Hz, 1H), 6.41 (d, J ) 5.6 Hz, 1H), 6.36 (dd, J
) 5.6, 1.6 Hz, 1H), 6.14 (dd, J ) 7.5, 1.4 Hz, 1H), 4.58 (dd, J
) 5.6, 1.6 Hz, 1H), 4.44 (d, J ) 9.7 Hz, 1H), 3.94 (d, J ) 9.7
Hz, 1H), 3.86 (d, J ) 10.1 Hz, 1H), 3.74 (d, J ) 10.1 Hz, 1H),
3.67 (dt, J ) 6.6, 1.4 Hz, 1H), 2.77 (s, 3H); 13C NMR (CDCl3)
δ 173.9, 137.2, 135.2, 132.6, 130.8, 91.4, 77.9, 72.2, 71.7, 65.5,
62.6, 35.3; MS (DEI) m/z (%) 220 (MH+, 4), 138 (20), 123 (100),
1
solid: Rf ) 0.73 (1:9 methanol/methylene chloride); H NMR
95 (55), 81 (40); exact mass (DEI) calcd for
220.0974, found 220.0984.
C
12H14NO3
(CDCl3) δ 7.20-7.16 (m, 2 H), 6.97-6.94 (m, 2H), 5.46 (bs, 1H,
NH), 3.87 (m, 1H), 3.44 (d, J ) 3.6 Hz, 1H), 3.40 (d, J ) 3.9

Photoreactivity of 2-Pyridones
J . Org. Chem., Vol. 65, No. 7, 2000 1977
Hz, 1H), 3.04 (dd, J ) 10.5, 4.2 Hz, 1H), 2.32-2.24 (m, 4H),
1.88-1.80 (m, 2H), 1.61-1.53 (m, 2H); 13C NMR (CDCl3) δ
176.4, 141.5, 140.1, 127.4, 127.1, 126.9, 126.8, 51.2, 45.4, 43.0,
38.6, 23.8, 23.2, 21.7, 20.4; MS (CI) m/z (%) 227 (M+, 13), 130
(33), 99 (100); exact mass (CI) calcd for C15H17NO 227.1310,
found 227.1311.
naphthalene (127 mg, 0.8 mmol) and 4-methoxy-2-pyridone
(100 mg, 0.8 mmol) in methanol (6 mL), and the Pyrex test
tube was then sealed with a septum. This solution was
irradiated with a 450 W medium-pressure mercury lamp for
20 h, at which time all of the 2-methoxynaphthalene had been
consumed (TLC). The solution was concentrated and purified
by preparative TLC (2:1 ethyl acetate/hexanes) to give recov-
ered 31 (28 mg) and adduct 33 (72 mg, 32%, 44% based on
Cop e Rea r r a n gem en t of P h otop r od u ct 26. A solution
of 2-pyridone 24 (59.4 mg, 0.625 mmol) and naphthalene 25
(239.7 mg, 1.87 mmol) in methanol (5 mL, overall 0.5 M in 24
+ 25) was irradiated for 24 h with a water-cooled, Pyrex-
filtered 450 W medium-pressure mercury lamp. The crude
mixture was purified by flash chromatography (1:9 methanol/
methylene chloride) to give 16.5 mg of 28 and 2.3 mg of 29
(7.2:1, 13% from 24) as a light brown solid. 28: Rf ) 0.65 (1:9
1
recovered 30): Rf ) 0.52 (2:1 ethyl acetate/hexane); H NMR
(CDCl3) δ 7.18 (m, 1H), 7.00 (m, 2H), 6.89 (m, 1H), 5.29 (bs,
1H), 5.13 (d, J ) 7.2 Hz, 1H), 5.01 (d, J ) 7.2 Hz, 1H), 3.98
(m, 1H), 3.74 (m, 1H), 3.55 (m, 1H), 3.55 (s, 6H), 3.30 (m, 1H);
IR (KBr) 3300, 3245, 2934, 1677, 1652, 1216 cm-1
.
Photoproduct 33 rearranged on standing in CDCl3 at ambi-
ent temperature to give cyclobutane product 34: Rf ) 0.35 (2:1
ethyl acetate/ hexanes); 1H NMR (CDCl3) δ 7.17 (m, 2H), 7.05
(m, 1H), 6.96 (m, 1H), 6.67 (d, J ) 10.2 Hz, 1H), 5.45 (d, J )
10.2 Hz, 1H), 4.93 (s, 1H), 4.57 (br, 1H), 4.27 (dd., J ) 9.0 Hz,
7.5 Hz, 1H), 3.80 (d, J ) 7.5 Hz, 1H), 3.65 (s, 3H), 3.50 (d, J
) 9.0 Hz, 1H), 3.06 (s, 3H); 13C NMR (CDCl3) δ 164.6, 133.8,
132.7, 128.6, 128.4, 128.1, 127.6, 126.3, 123.2, 93.4, 78.7, 55.4,
50.8, 47.7, 46.7, 46.5, 29.7; IR (KBr) 3504, 3448, 3231, 1667,
1221 cm-1; MS (DEI) m/z (%) 282 (M+ - H, 0.5), 158 (100),
115 (82); exact mass (DEI) calcd for C17H16NO3 282.1130, found
282.1118.
1
methanol/methylene chloride); H NMR (CDCl3) δ 7.08-7.04
(m, 2 H), 6.90 (dd, J ) 5.1, 3.6 Hz, 1H), 6.80 (m, 1H), 6.40 (dd,
J ) 9.9, 3.6 Hz, 1H), 6.35 (d, J ) 9.9 Hz, 1H), 5.91 (bs, 1H,
NH), 5.58 (m, 2H), 4.51 (t, J ) 2.7 Hz, 1H), 3.96 (m, 1H), 3.60
(m, 1H); 13C NMR (CDCl3) δ 164.8, 139.6, 129.2, 128.8, 127.8,
127.7, 127.3, 125.7, 123.7, 53.8, 42.4, 40.1, 38.2; MS (CI) m/z
(%) 224 (MH+, 28), 128 (20), 96 (100); exact mass (CI) calcd
for C15H14NO 224.1075, found 224.1076. 29: Rf ) 0.79 (1:9
1
methanol/methylene chloride); H NMR (CDCl3) δ 7.10-7.05
(m, 2 H), 6.98 (m, 1H), 6.90 (m, 1H), 6.36 (d, J ) 9.6 Hz, 1H),
6.3 (bs, 1H), 5.79 (dd, J ) 7.8, 5.1 Hz, 1H), 5.66 (dd, J ) 4.5,
9.9 Hz, 1H), 4.80 (dd, J ) 4.2, 8.1 Hz, 1H), 4.21 (bt, J ) 9.9
Hz, 1H), 3.65 (m, 2H).
Ack n ow led gm en t. This work was supported by the
National Institutes of Health (GM45214). NMR spec-
trometers used in this study were purchased with
funding from the National Science Foundation (CHE941-
3510).
Hyd r ogen a tion of 28. Following the procedure described
for hydrogenation of 26, Cope rearrangement product 28 was
reduced to give 30: Rf ) 0.83 (1:9 methanol/methylene
1
chloride); H NMR (CDCl3) δ 7.11-7.09 (m, 2 H), 6.96-6.93
(m, 2H), 5.35 (bs, 1H, NH), 4.19 (dt, J ) 7.5, 2.1 Hz, 1H), 3.86
(t, J ) 8.4 Hz, 1H), 3.09-3.03 (m, 1H), 2.88-2.82 (m, 1H),
2.73-2.66 (m, 1H), 2.58-2.48 (m, 1H), 2.30 (t, J ) 3.3 Hz, 1H),
2.25 (t, J ) 3.3 Hz, 1H), 2.08-1.73 (m, 4H); MS (EI) m/z (%)
228 (MH+, 100), 130 (16); exact mass (CI) calcd for C15H18NO
228.1388, found 228.1379.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra for
11-20, 22, 23, 26-30, 33, and 34; COSY spectra for 18, 20,
22, 23, 27-30, 33 and 34; and 13C NMR spectra for 27 and
28. This material is available free of charge via the Internet
at http://pubs.acs.org.
P h otocycloa d d ition of 4-Meth oxy-2-p yr id on e 31 a n d
2-Meth oxyn a p h th a len e 32. A stream of dry nitrogen was
passed for several minutes through a solution of 2-methoxy-
J O9918394