Photoenolization-induced oxirane ring opening in 2,5-dimethylbenzoyl oxiranes to form pharmaceutically promising indanone derivatives

Article abstract of DOI:10.1021/jo101515a

Irradiation of 2,5-dimethylbenzoyl oxiranes results in a relatively efficient and high-yielding formation of β-hydroxy functionalized indanones that structurally resemble biologically active pterosines. Nanosecond laser flash photolysis and quantum-chemical calculations based on density functional theory provided evidence that this photochemical transformation proceeds primarily via a photoenolization mechanism. Our study revealed considerable complexity of the mechanism and that structural modifications can significantly alter the reaction pathway and yield different products. The scope of this photochemical transformation for the synthesis of some pharmaceutically important compounds was investigated.

Full text of DOI:10.1021/jo101515a

pubs.acs.org/joc
Photoenolization-Induced Oxirane Ring Opening in 2,5-Dimethylbenzoyl
Oxiranes To Form Pharmaceutically Promising Indanone Derivatives
†
Tomas Solomek, Peter Stacko, Aneesh Tazhe Veetil, Tomas Pospı
†
†
†
sil, and Petr Klan*
,†,‡
ꢁ
ꢁ
ꢀꢁ
ꢀꢁ
ꢁ
ꢀ
´
†Department of Chemistry, Faculty of Science, Masaryk University, Kamenice 5/A8, 625 00 Brno,
Czech Republic, and ‡Research Centre for Toxic Compounds in the Environment, Faculty of Science,
Masaryk University, Kamenice 3, 625 00 Brno, Czech Republic
klan@sci.muni.cz
Received August 2, 2010
Irradiation of 2,5-dimethylbenzoyl oxiranes results in a relatively efficient and high-yielding
formation of β-hydroxy functionalized indanones that structurally resemble biologically active
pterosines. Nanosecond laser flash photolysis and quantum-chemical calculations based on density
functional theory provided evidence that this photochemical transformation proceeds primarily via a
photoenolization mechanism. Our study revealed considerable complexity of the mechanism and
that structural modifications can significantly alter the reaction pathway and yield different
products. The scope of this photochemical transformation for the synthesis of some pharmaceutically
important compounds was investigated.
Introduction
(Scheme 1). This reaction, introduced by Bergmark,8,9 was
later utilized in the field of photoremovable protecting
Thermally as well as photochemically initiated cyclization
reactions are important transformation steps in organic
synthesis. It was demonstrated on many examples that the
specific reactivity of the electronically excited states enables
the formation of complex and highly functionalized mole-
cules, thus shortening the number of synthetic steps.1,2
Triplet excited 2-alkylacetophenones are known to under-
go intramolecular 1,5-hydrogen abstraction to form a triplet
1,4-biradical (triplet enol) and subsequently the two isomeric
(E)- and (Z)-photoenols.1,3-7 When the triplet pathway is
completely suppressed, only the (Z)-enol is formed via the
excited singlet state; this isomer is a short-lived species that
readily reketonizes.3 When a leaving group (LG) is present
in the R-position of 2-alkylacetophenones, a longer-lived
(E)-photoenol liberates the LG to give the corresponding
cyclization (indanone, in red) or solvolysis (in blue) products
groups10-14 by Klan, Wirz, and co-workers, who demon-
ꢀ
strated that the 2,5-dimethylphenacyl (DMP) group can be
used to protect moderately or good leaving groups, such as
carboxylic acids,15-17 phosphates, sulfonates,18 alcohols as
carbonates,19 or amines as carbamates.20
Indanone derivatives are key intermediates in the synthesis
of some pharmaceutically important compounds, such as the
(8) Bergmark, W. R. J. Chem. Soc., Chem. Commun. 1978, 61.
(9) Bergmark, W. R.; Barnes, C.; Clark, J.; Paparian, S.; Marynowski, S.
J. Org. Chem. 1985, 50, 5612.
(10) Givens, R. S.; Conrad, P. G.; Yousef, A. L.; Lee, J.-I. In CRC
Handbook of Organic Photochemistry and Photobiology; Horspool, W. M.,
Lenci, F., Eds.; CRC Press: Boca Raton, 2004; Chapter 69, p 1.
(11) Goeldner, M.; Givens, R. S. Dynamic Studies in Biology; Wiley-
WCH: Weinheim, 2005.
(12) Bochet, C. G. J. Chem. Soc., Perkin Trans. 1 2002, 125.
(13) Pelliccioli, A. P.; Wirz, J. Photochem. Photobiol. Sci. 2002, 1, 441.
(14) Sankaranarayanan, J.; Muthukrishnan, S.; Gudmundsdottir, A. D.
Adv. Phys. Org. Chem. 2009, 43, 39.
(15) Klan, P.; Zabadal, M.; Heger, D. Org. Lett. 2000, 2, 1569.
(16) Ruzicka, R.; Zabadal, M.; Klan, P. Synth. Commun. 2002, 32, 2581.
(17) Zabadal, M.; Pelliccioli, A. P.; Klan, P.; Wirz, J. J. Phys. Chem. A
2001, 105, 10329.
(1) Klan, P.; Wirz, J. Photochemistry of Organic Compounds: From
Concepts to Practice; 1st ed.; John Wiley & Sons Ltd.: Chichester, 2009.
(2) Hoffmann, N. Chem. Rev. 2008, 108, 1052.
(3) Haag, R.; Wirz, J.; Wagner, P. J. Helv. Chim. Acta 1977, 60, 2595.
(4) Sammes, P. G. Tetrahedron 1976, 32, 405.
(5) Das, P. K.; Encinas, M. V.; Small, R. D.; Scaiano, J. C. J. Am. Chem.
Soc. 1979, 101, 6965.
(18) Klan, P.; Pelliccioli, A. P.; Pospisil, T.; Wirz, J. Photochem. Photo-
biol. Sci. 2002, 1, 920.
(6) Small, R. D.; Scaiano, J. C. J. Am. Chem. Soc. 1977, 99, 7713.
(7) Pelliccioli, A. P.; Klan, P.; Zabadal, M.; Wirz, J. J. Am. Chem. Soc.
2001, 123, 7931.
(19) Literak, J.; Wirz, J.; Klan, P. Photochem. Photobiol. Sci. 2005, 4, 43.
(20) Kammari, L.; Plistil, L.; Wirz, J.; Klan, P. Photochem. Photobiol. Sci.
2007, 6, 50.
7300 J. Org. Chem. 2010, 75, 7300–7309
Published on Web 10/01/2010
DOI: 10.1021/jo101515a
r
2010 American Chemical Society

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SCHEME 1. Photochemistry of o-Alkylphenacyl Derivatives
CHART 1. Biologically Active Indanone Derivatives
of benzoyl oxiranes.32-40 Despite the fact that alkoxides (as poor
leaving groups) are not liberated from the substituted o-alkyl-
phenacyl derivatives,19,20 we have also anticipated that the
R-C-O bond in 1 will be broken upon cyclization of the
corresponding (E)-enol to relieve internal strain of a three-
membered ring. This would eventually yield 2-hydroxymethylin-
dan-1-one related, for example, to the pterosine derivatives
(Chart 1). Since many reliable strategies for the preparation of
benzoyl oxiranes (epoxy ketones), including some of a very high
enantiomeric purity,41 are available, this strategy would be syn-
thetically beneficial. We report on the synthesis of benzoyl
oxiranes, their photochemical behavior, laser flash photolysis
experiments, and some quantum chemical calculations. The
possibility of utilizing the photoreaction of the benzoyl oxiranes
in the synthesis of some structurally related pharmaceutically
active compounds is considered.
antihypertensive drug (þ)-indacrinone,21 the reversible acet-
ylcholinesterase inhibitor donepezil hydrochloride,22,23 and
the antibacterial and cytotoxic pterosines (Chart 1).24 For
example, Wessig and co-workers used the phototransforma-
tion of 2-alkylacetophenone derivatives for the synthesis of
two sesquiterpene indane derivatives, pterosine B or C,25
and other indanone derivatives.26 Klan and co-workers
ꢀ
showed that photolysis of a 4,5-dimethoxyphenacyl deriva-
tive can lead to an indanone precursor for the synthesis of
donepezil.27 Wang and co-workers used this concept in polymer-
supported synthesis,28 and Park and co-workers utilized this
reaction in photopolymerization29 and the synthesis of various
indanone and benzocyclobutenol derivatives.30,31
Results and Discussion
The synthesis of indanone building blocks using a photo-
enolization step is generally designed to start from precur-
sors, which do not possess functional groups susceptible to
photochemical side reactions and responsible for slowing
down or impeding the initial 1,5-hydrogen abstraction step
(Scheme 1). However, various functional groups are a part of
the target indanones, such as those shown in Chart 1. There-
fore, new photochemical transformations that would gener-
ate an indanone moiety possessing synthetically useful sub-
stituents in the corresponding positions are of considerable
interest.
In this work we wish to report that, analogously to
Scheme 1, various substituted indanone derivatives can be
synthesized by photolysis of the 2,5-dimethylbenzoyl oxiranes 1
via the corresponding (E)-enol (Scheme 2). We expected that the
initial 1,5-hydrogen abstraction step would efficiently compete
with the R-C-O bond scission in the excited state and subsequent
skeletal rearrangements, which are archetypal transformation
Synthesis of 2,5-Dimethylbenzoyl Oxiranes. The 2,5-di-
methylbenzoyl oxiranes 1a-d (Scheme 3) were prepared to
study their photochemical transformations. The synthesis
started with the Friedel-Crafts acylation of p-xylene (2) to
give 3a,c,d and 4b, followed by the aldol condensation-
elimination (4a) or Mannich (4c,d) reactions to introduce a
CdC bond. The subsequent nucleophilic epoxidation with
aq H2O2 in methanol provided the target epoxy ketones
1a-d in high overall yields (73-84%) and purity.
Photochemistry of 1a-d. A degassed acetonitrile solution
of an epoxide (1a-d; ∼5 ꢀ 10-3 M) was irradiated through a
Pyrex filter (>290 nm) until >95% of the starting material
was consumed. Three products, 5-7, were isolated and
identified (Scheme 4); the chemical yields are summarized
in Table 1. In all cases, the indanones 5 were the major
photoproducts at high conversions and essentially the sole
photoproducts at conversions below 20%. The oxiranyl-
ring-opening products 6 and the substituted 3,4-dihydrobenzo-
[c]oxepin-5(1H)-ones 7 were isolated only in the case of 1b and
1d and in very low chemical yields.
(21) Dolling, U. H.; Davis, P.; Grabowski, E. J. J. J. Am. Chem. Soc. 1984,
106, 446.
Exhaustive irradiation of 1c afforded a complex mixture
of compounds, from which only 5c was successfully isolated
in 7% yield. Since the HPLC yield at a 40% conversion
was 82%, we assumed that this photoproduct underwent
(22) Elati, C. R.; Kolla, N.; Chalamala, S. R.; Vankawala, P. J.; Sundaram,
V.; Vurimidi, H.; Mathad, V. T. Synth. Commun. 2006, 36, 169.
(23) Omran, Z.; Cailly, T.; Lescot, E.; Santos, J. S. D.; Agondanou, J. H.;
Lisowski, V.; Fabis, F.; Godard, A. M.; Stiebing, S.; Le Flem, G.; Boulouard,
M.; Dauphin, F.; Dallemagne, P.; Rault, S. Eur. J. Med. Chem. 2005, 40,
1222.
(24) Kobayashi, A.; Egawa, H.; Koshimizu, K.; Mitsui, T. Agric. Biol.
Chem. 1975, 39, 1851.
(25) Wessig, P.; Teubner, J. Synlett 2006, 1543.
(26) Wessig, P.; Glombitza, C.; Muller, G.; Teubner, J. J. Org. Chem.
2004, 69, 7582.
(34) Hallet, P.; Muzart, J.; Pete, J. P. J. Org. Chem. 1981, 46, 4275.
(35) Pappas, S. P.; Gresham, R. M.; Miller, M. J. J. Am. Chem. Soc. 1970,
92, 5795.
(36) Pappas, S. P.; Bao, L. Q. J. Am. Chem. Soc. 1973, 95, 7906.
(37) Paquette, L. A.; Nitz, T. J.; Ross, R. J.; Springer, J. P. J. Am. Chem.
Soc. 1984, 106, 1446.
(27) Pospisil, T.; Veetil, A. T.; Lovely Angel, P. A.; Klan, P. Photochem.
Photobiol. Sci. 2008, 7, 625.
(28) Du, L. H.; Zhang, S. H.; Wang, Y. G. Tetrahedron Lett. 2005, 46,
3399.
(38) Hallet, P.; Muzart, J.; Pete, J. P. Tetrahedron Lett. 1979, 2723.
(39) Williams, J. R.; Sarkisia, Gm; Quigley, J.; Hasiuk, A.; Vanderve, R J.
Org. Chem. 1974, 39, 1028.
(40) Hasegawa, E.; Ishiyama, K.; Fujita, T.; Kato, T.; Abe, T. J. Org.
Chem. 1997, 62, 2396.
(41) Lauret, C. Tetrahedron: Asymmetry 2001, 12, 2359.
(42) Wagner, P. J.; Kelso, P. A.; Kemppainen, A. E.; Zepp, R. G. J. Am.
Chem. Soc. 1972, 94, 7500.
(29) Park, B. S.; Lee, H. M. Bull. Korean Chem. Soc. 2008, 29, 2054.
(30) Park, B. S.; Jeong, S. Bull. Korean Chem. Soc. 2009, 30, 3053.
(31) Park, B. S.; Ryu, H. J. Tetrahedron Lett. 2010, 51, 1512.
(32) Zimmerman, H. E.; Simkin, R. D. Tetrahedron Lett. 1964, 1847.
(33) Zimmerman, H. E.; Cowley, B. R.; Tseng, C. Y.; Wilson, J. W. J. Am.
Chem. Soc. 1964, 86, 947.
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SCHEME 2. Photochemistry of o-Methylbenzoyl Oxiranes:
The Strategy
TABLE 2. Quantum Yields (Φ) of 5a-d Formation from 1a-d
compound
Φa
5a
5b
5c
5d
0.11 ( 0.01
0.15 ( 0.01 (0.16 ( 0.01b)
0.25 ( 0.01
0.12 ( 0.01
aDegassed solutions (∼5 ꢀ 10-3 M) in acetonitrile or benzene were
irradiated at λ = 313 ( 5 nm (optical bench). Φ was determined using
valerophenone as an actinometer (Φ of acetophenone formation is 0.33
in hexane42). The results are based on at least five independent measure-
ments; the relative standard deviations of the mean are shown. bBenzene
solution.
SCHEME 3. Preparation of the Epoxides 1a-da
SCHEME 5. Dehydration of 5b
The quantum yields of 5a-d formation in acetonitrile (and
benzene in the case of 5b) are listed in Table 2. Their mag-
nitude can be compared to that of the photorelease of
carboxylate ions from the corresponding 2,5-dimethylphe-
nacyl esters (Φ = 0.18-0.25) in benzene.17 The quantum
yields of LG release from 2,5-dimethylphenacyl chromo-
phore are known to be generally higher in nonpolar solvents
than in polar and protic solvents,17-19 which was, however,
not observed in the case of 1b (Table 2).
Both 5a and 5b possess an R-hydrogen atom, which may
allow elimination of water to form R,β-unsaturated ketones,
useful intermediates in organic synthesis. Thus 5b (∼1 ꢀ
10-2 M) was heated in methanolic KOH (0.2 M) at 40 °C for
20 min, and 8 was isolated as a sole product in 97% yield as a
mixture of (E)- and (Z)-diastereomers (∼16:1; GC; Scheme 5).
A more convenient one-pot procedure, in which a base is
directly added to the reaction mixture that is irradiated, has
been rejected because the product is a very reactive Michael
reaction substrate (a complex mixture of products was obtained
under such experimental conditions).
aReagents and conditions: (i) AlCl3, CS2, 0 °C; (ii) KOH, methanol,
20 °C; (iii) H2O2, KOH, MeOH, 0 °C; (iv) aq CH2O, CH3CO2H (cat.),
piperidine (cat.), MeOH; (v) aq CH2O, morpholine (cat.), CH3CO2H.
SCHEME 4. Photochemistry of 1a-d
Mechanistic Studies. Initially we wished to determine the
multiplicity of the excited state responsible for the photo-
products formation. Stern-Volmer analysis (see Supporting
Information, S41) using naphthalene as a triplet quencher
(ET = 60.5 kcal mol-1 43
) revealed that the photoreaction of
TABLE 1. Photochemical Formation of 5-7a
1a is fully quenched at high quencher concentrations (c >2 M)
and that the excited (triplet) state lifetime is ∼2 ns, assuming
that the energy transfer is diffusion-controlled (kq=1.5 ꢀ 109
M-1 s-1 in benzene43). In addition, irradiation of 1b in neat
acetone, acting as a triplet sensitizer, afforded the same photo-
products as those obtained in acetonitrile by direct irradiation.
We concluded that the photoproducts are exclusively triplet-
state-derived. This is in agreement with the discussion of Park
and his co-workers who studied a structurally analogous
chromophore, 2-(o-tolyl)-2-benzoyloxirane (9, shown later in
Scheme 7), the photochemistry of which also occurs exclusively
from the triplet state.44
irradiated epoxide % yield (5a-d) % yield (6a-d) % yield (7a-d)
1a
1b
1c
1d
74b,c [93d]
72b,c [85d]
7b [82e]
n.d.f
n.d.f
7b
12b
n.d.f
8b
n.d.f
15b
69b [93d]
aDegassed solutions of 1a-d (∼5 ꢀ 10-3 M) in acetonitrile were
irradiated at λ > 290 nm to >95% conversion. bIsolated by column
chromatography. cA pair of diastereomers in a ∼1:1 ratio (NMR,
HPLC). dThe optimized HPLC yields of the indanone 5 formation in
∼95% conversions. eThe optimized HPLC yields of the indanone 5
formation in ∼40% conversions. fNot detected.
subsequent photochemical transformations. Indeed, pro-
longed irradiation of 5a or b in acetonitrile led to a complex
mixture of photoproducts, which were, however, produced
with a lower efficiency than the primary photoproducts 5
formed from 1.
(43) Montalti, M.; Credi, A.; Prodi, L.; Gandolfi, M. T. Handbook of
Photochemistry, 3rd ed.; CRC Press: Boca Raton, 2006.
(44) Kim, H.; Kim, T. G.; Hahn, J.; Jang, D. J.; Chang, D. J.; Park, B. S.
J. Phys. Chem. A 2001, 105, 3555.
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SCHEME 6. Irradiation of 1e
SCHEME 7. Photochemistry of 2-(o-Tolyl)-2-benzoyloxirane 944
The phenacyl chromophore is known to have two nearly
isoenergetic triplet states that differ in polarity, and their
relative energies are strongly influenced by both the benzene
ring substituents and the environment.45 Electron-donating
groups and polar solvents tend to stabilize the π,π* state.45-48
The π,π* state of a phenyl ketone is generally far less reactive
than the n,π* state toward both electron and hydrogen-atom
abstraction reactions.49-52
FIGURE 1. Highest occupied molecular orbitals (HOMO-1 and
HOMO) of the triplet 1g (n,π*) and 1f (π,π*).
Formation of 6 and 7 (Schemes 4 and 6) suggests that a
homolytic CR-O bond scission32-40 occurs at some stage of
the reaction and competes with the 1,5-hydrogen atom shift.
According to Park and co-workers,44 only two competing
chemical decay channels exist in the lowest triplet state of the
analogous 2-(o-tolyl)-2-benzoyloxirane 9 (Scheme 7): a 1,4-
H atom shift (k = 6 ꢀ 107 s-1) from the methylene group of
the oxiranyl ring followed, by the CR-O bond scission and a
1,6-H atom shift (k=2.3 ꢀ 108 s-1) from the o-methyl group.
Scheme 8 shows three reaction pathways of the triplet excited
1g inspired by the photochemistry of 9 as obtained from our
DFT quantum chemical calculations. As expected, the 1,5-H
atom shift (preceding the photoenolization reaction) is pre-
Because the major products obtained from photolysis of 1
were the indanones 5, we assumed that they are produced via
photoenolization initiated by an intramolecular 1,5-hydrogen
abstraction (Scheme 1). The short lifetime of the triplet 1a thus
has to be related to an efficient intramolecular hydrogen
abstraction, which furthermore implies that the state is n,π*
in character. The photochemistry of the epoxide 1e was studied
to confirm our assumption that the π,π* excited epoxide will
not produce the corresponding indanone 5e (Scheme 6). In-
deed, irradiation of a degassed solution of 1e (∼5 ꢀ 10-3 M) at
λ> 290 nm led to 6e as a major product regardless of what kind
of solvent (acetonitrile, benzene, hexane, t-BuOH) was used
(Scheme 6). The two electron-donating methoxy groups in 1e
evidently inverted the energy of the two states, rendering the
π,π* state as the lowest (reactive) triplet state,45,48 which
resulted in a CR-O bond scission.34,38 The excited state type
was theoretically examined on an analogue 1f together with the
unsubstituted o-methylbenzoyl oxirane 1g. The relevant mo-
lecular orbitals from the UB3LYP/6-31G* level of theory in the
gas phase are depicted in Figure 1. The results, according to
which the lowest triplet states of 1f and 1g are of π,π* and n,π*
character, respectively, are consistent with our assumption.
ferred to the direct CR-O bond homolysis by ∼2 kcal mol-1
.
The CR-O bond was cleaved spontaneously in all of our
attempts to locate the transition state of a 1,4-H atom shift in
the triplet 1g. Therefore, the CR-O bond homolysis followed
by a 1,4-H atom shift (highlighted in red, Scheme 8) is a
dominant photochemical channel to 6.
The rate constants of 1,5-H atom shift, which is observed
in our system, are generally higher than those for less or more
distant H-atom transfers due to the ring strain introduced in
the transition state.53-55 Indeed, the rates of both the 1,6-H
atom shift (∼2 ꢀ 108 s-1) and 1,4-H atom shift (∼6 ꢀ 107 s-1
)
in 9 are slower than that of the 1,5-H atom shift in 1a as
estimated from the Stern-Volmer analysis (∼5 ꢀ 108 s-1).
The compound 6 was preferentially formed only when the
inversion of the triplet state levels in 1e decreased the rate
constant of an H-atom abstraction (formation of the ben-
zooxepinone 7e was not observed).
(45) Wagner, P. J.; Park, B.-S. In Organic Photochemistry; Padwa, A.,
Ed.; Marcel Dekker, Inc.: New York, 1991; Vol. 11, p 227.
(46) Rauh, R. D.; Leermakers, P. A. J. Am. Chem. Soc. 1968, 90, 2246.
(47) Li, Y. H.; Lim, E. C. Chem. Phys. Lett. 1970, 7, 15.
(48) Wagner, P. J.; Klan, P. In CRC Handbook of Organic Photochemistry
and Photobiology, 2nd ed.; Horspool, W. M., Lenci, F., Eds.; CRC Press
LLC: Boca Raton, 2003; Chapter 52, p 1.
(49) Hammond, G. S.; Leermakers, P. A. J. Am. Chem. Soc. 1962, 84, 207.
(50) DeBoer, C. D.; Herkstroeter, W. G.; Marchetti, A. G.; Schultz,
A. G.; Schlessinger, H. J. Am. Chem. Soc. 1973, 95, 3963.
(51) Zimmerman, H. E.; Steinmetz, M. G. J. Chem. Soc., Chem. Commun.
1978, 230.
A comprehensive reaction mechanism for the formation of
5 and 7 is demonstrated in Scheme 9 on the 2-methylbenzoyl
oxirane 1g photochemistry, which includes the results of our
(53) Hayes, C. J.; Burgess, D. R. J. Phys. Chem. A 2009, 113, 2473.
(54) Dorigo, A. E.; Houk, K. N. J. Am. Chem. Soc. 1987, 109, 2195.
(55) Dorigo, A. E.; McCarrick, M. A.; Loncharich, R. J.; Houk, K. N.
J. Am. Chem. Soc. 1990, 112, 7508.
(52) Zimmerman, H. E. Acc. Chem. Res. 1982, 15, 312.
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SCHEME 8. Formation of 6a
aThe activation Gibbs energies are shown. The fate of 3E is discussed later.
SCHEME 9. Formation of 5 and 7a
population analysis favors the mesomeric form 13b and the
formation of 5g. This is in agreement with our experiments
because we found no evidence that 14 was formed by irradia-
tion of 1. In addition, the production of the benzooxepinones 7
(Table 1) suggests that a ring closure of 12 competes with a
hydrogen shift to give 13b. A complete triplet potential energy
profile for the photochemistry of 1g, calculated at the BMK/
6-311þG(3df,2p) level of theory on B3LYP/6-31G* optimized
geometries, is then depicted in Figure 2. Other reaction path-
ways known from the literature, such as R-cleavage to give the
corresponding acyl and epoxy radicals,32,57,58 heterolytic,34 or
electron-transfer mediated oxirane ring-opening59 intermedi-
ates, are apparently not relevant for our systems.
Finally, we had to decide which of the two possible
mechanisms for the formation of 5, photoenolization or
3
homolytic CR-O bond scission in E, are favored. Regen-
eration of the starting ketone from the (E)-photoenol re-
quires a proton transfer through the solvent. When a suitable
deuteron donor is present in the solution, the incorporation
of deuterium into the o-methyl group can be detected by
NMR measurements.3 The m-methyl group signal in 1H
NMR spectra of 1a-d interferes with those of the products.
Therefore, epoxide 1h (Scheme 10), having only a single
methyl group, was synthesized and irradiated in a degassed
D2O/acetone-d6 mixture (1:20) at >290 nm in an NMR
cuvette. The ratio of the integrals, corresponding to the
o-methyl and CH (of the oxiranyl ring) signals, decreased
by ∼25%. We were unable to integrate the peaks properly at
longer irradiation times because of an overlap of the peaks
with those of the products; nevertheless, it was sufficient
evidence that photoenols are indeed formed in the solution
upon irradiation.
In addition, the mechanism of the photoreactions of 1b
was investigated by laser flash photolysis (Table 3; see also
Supporting Information, S41-44). The transient absorption
spectrum of an aerated solution of 1b in acetonitrile obtained
1 μs after the laser flash is shown in Figure 3. The absorption
spectrum reproduces nicely that measured for both ground
state photoenols in previous studies.7,17-20 We were unable
to see any significant absorption at ∼340-350 nm characteristic
of 3E even at short time delays (15 ns). Such a remarkable short
lifetime of a 1,4-biradical is consistent with that reported by
Caldwell and co-workers for R-benzyloxyacetophenone60 or
aStructures in blue and red denote isolated and spectroscopically
observed species, respectively; a putative (not observed) product is
shown in green. The operative pathway (vide infra) of the indanones
formation is depicted by bold arrows. The activation Gibbs energies are
shown.
DFT calculations. The primary 1,4-biradical 3E, which was
formed from the triplet excited compound by a hydrogen
shift (Scheme 8), can undergo either CR-O homolytic clea-
vage to 12 or intersystem cross to the ground state to produce
3
two photoenols (in red). The rate of E decay for phenacyl
derivatives is known to depend on the presence of oxygen or
other triplet quenchers (τ ∼16-300 ns).7,17,18,20 Compound
12 possesses a reactive primary alkoxy radical center; a
simple H-atom shift between the two oxygen atoms with a
calculated barrier of ΔGq=7.3 kcal mol-1 results in a more
stable radical (see Figure 2), whose two mesomeric forms,
13a and 13b, are shown in the scheme. This pathway can be
considered as a spin-center shift mechanism, recently proposed
by Wessig and co-workers.56 Subsequent radical recombina-
tion and ISC may lead to 5g or 14g (in green). The spin
(57) Dunston, J. M.; Yates, P. Tetrahedron Lett. 1964, 505.
(58) Padwa, A. Tetrahedron Lett. 1964, 813.
(59) Hasegawa, E.; Ishiyama, K.; Horaguchi, T.; Shimizu, T. J. Org.
Chem. 1991, 56, 1631.
(56) Wessig, P.; Muehling, O. Eur. J. Org. Chem. 2007, 2219.
7304 J. Org. Chem. Vol. 75, No. 21, 2010

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FIGURE 2. Triplet potential energy surface profile of 1g photoreactions. The Gibbs energies (in kcal mol-1) were calculated at the BMK/
6-311þG(3df,2p) level of theory on B3LYP/6-31G* optimized geometries.
the 1,5-biradical in Scheme 7 found by Park et al.44 A similar
SCHEME 10. Deuterium Incorporation in 1h
spectrum has been measured for 1a. The kinetic trace at λ=390
nm contained three exponential components: a very fast singly
exponential rise and a biexponential decay. The lifetime of the
former, short-lived component was sensitive to the presence of
oxygen. Its lifetime of 23 ns in degassed solutions dropped to
<10 ns in air-saturated solutions, which we could not resolve
because of limitations of our apparatus. However, the antici-
TABLE 3. Lifetimes τ of the Transients of 1ba
pated decrease of the rate constant for this component occurred
solvent
τ (3E)
τ (Z)-photoenol
τ (E)-photoenol
in less polar cyclohexane: lifetimes of 47 and 12.5 ns were
observed in the degassed and air-saturated solutions, respec-
tively. This transient intermediate was assigned to the triplet enol
(3E) decay. The lifetimes of the other two components were not
sensitive to the presence of oxygen. A shorter-lived intermediate
with a lifetime of 8.8 and 2.8 μs in acetonitrile and cyclohexane
solution, respectively, was attributed to the ground state (Z)-
photoenol, which is expected to undergo fast intramolecular
reketonization,7,17 while the long-lived component was attrib-
uted to the (E)-photoenol. Its lifetime of 5.0 ms was observed in
acetonitrile, whereas that in cyclohexane (>40 ms) could not
be fit properly because of instability of our white light source at
such a long time scale. Our results resemble well those reported
for the photoenolization in dimethylphenacyl chromophore
substituted by different leaving groups in the R-position.7,17-20
Our assignments were also rationalized by performing
TD-DFT calculations of the electronic transitions for all
acetonitrile
cyclohexane
23 (<10)b ns
8.8 μs
2.8 μs
5 ms
>40 msc
47 (12.5)b ns
aDegassed solutions (∼1 ꢀ 10-4 M) in acetonitrile or cyclohexane
measured at λ=390 nm after 266-nm laser flash. bThe lifetimes measured
for aerated solutions are in the parentheses. cThe lower limit estimated
from the exponential fit of the kinetic trace.
relevant intermediates shown in Figure 2. The results
are summarized in the Supporting Information (S48). Only
the photoenols and conformers of the triplet enol, 3E,
showed a strong absorption at ∼390 nm (f ∼0.15-0.19;
Figure 3) and ∼355-363 nm (f ∼0.1), respectively. The
transitions for other relevant species are approximately
10 times weaker in this region. Regarding the absence of
significant spectral changes within the time of the experi-
ment or in the presence of oxygen, we conclude that both
kinetic traces assigned to the decay of the 390 nm signal
belong to the photoenol intermediates, although the pre-
sence of some other relevant species cannot be unambigu-
ously ruled out.
(60) Caldwell, R. A.; Majima, T.; Pac, C. J. Am. Chem. Soc. 1982, 104,
629.
J. Org. Chem. Vol. 75, No. 21, 2010 7305

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Solomek et al.
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(m, 3H, J = 7.0 Hz), 7.36 (d, 2H, J = 7.0 Hz), 7.58 (d, 1H, J =
1.5 Hz). 13C NMR (75.5 MHz, CDCl3): δ (ppm) 20.8, 21.0, 48.4,
126.9, 128.6, 129.2, 129.6, 131.9, 132.1, 134.7, 135.1, 135.3, 137.8,
201.6. MS (EI, 70 eV): m/z = 224, 133, 105, 91, 77, 65, 51, 39.
1-(2,5-Dimethylphenyl)propan-1-one (3d). Prepared from
p-xylene and propionyl chloride (17.8 mL, 224 mmol). Yield:
96%; colorless oil. 1H NMR (300 MHz, CDCl3): δ (ppm) 1.08 (t,
3H, J =7.3 Hz), 2.22(s, 3H), 2.34 (s, 3H), 2.75 (q, 2H, J = 7.3Hz),
6.96 (d, 1H, J = 7.8 Hz), 7.01 (d, 1H, J = 7.8 Hz), 7.31 (s, 1H). 13
C
NMR (75.5 MHz, CDCl3): δ (ppm) 8.0, 20.3, 20.4, 34.1, 128.5,
131.3, 131.4, 134.2, 134.7, 137.7, 204.1. MS (EI, 70 eV): m/z = 162,
133, 105, 91, 77, 65, 51, 41.
1-(4,5-Dimethoxy-2-methylphenyl)ethanone (3e). Prepared
from 1,2-dimethoxy-4-methylbenzene and acetyl chloride (15.9
mL, 224 mmol). Yield: 84%; white crystals, mp 70.6-72.3 °C.
1H NMR (300 MHz, CDCl3): δ (ppm) 2.44 (s, 3H), 2.47 (s, 3H),
3.82 (s, 3H), 3.83 (s, 3H), 6.62 (s, 1H), 7.18 (s, 1H). 13C NMR (75.5
MHz, CDCl3): δ (ppm) 21.8, 29.3, 55.8, 56.2, 113.4, 114.6, 129.4,
133.4, 146.3, 151.6, 199.4. MS (EI, 70 eV): m/z=194, 179, 151, 136,
121, 108, 93, 77, 65, 43, 39.
FIGURE 3. Transient absorption spectrum of 1b. The spectrum
was taken 1 μs after the laser flash for an acetonitrile solution of 1b.
The red line shows the TD-DFT calculated transition of the E-enol
derived from 1g (the intensity is arbitrarily scaled; see Supporting
Information, S48).
(E)-1-(2,5-Dimethylphenyl)-3-phenylprop-2-en-1-one (4a). A
solution of 3a (2.00 g, 13.5 mmol) in ethanol (15 mL) was added
dropwise to aq KOH (40 mL, 10%) at 0 °C. Freshly distilled
benzaldehyde (1.43 g, 13.5 mmol) was then added dropwise to
the mixture in the period of 10 min. The reaction mixture was
stirred for 2 days at 20 °C and extracted with CH2Cl2 (3 ꢀ
50 mL). The organic extracts were washed with brine (50 mL),
dried with MgSO4, and solvents were evaporated at reduced
In conclusion, four 2,5-dimethylbenzoyl oxiranes were
synthesized in high overall chemical yields, and their photo-
chemistry was explored. Irradiation of these epoxy ketones
resulted in indanone derivatives as major products, which
are structurally similar to some known pharmaceutically
important compounds. In addition, a simple route to a
2-ethylidene-2,3-dihydro-1H-inden-1-one derivative from
the synthesized indanones was described. The laser flash
photolysis experiments and quantum-chemical calculations
provided solid evidence that the indanone photoproducts are
formed via a photoenolization mechanism. A total synthesis
of several biologically active compounds, which is based on
the photochemical approach introduced here, is currently
under investigation in our laboratory.
1
pressure to give 4a. Yield: 94%; yellowish oil. H NMR (300
MHz, CDCl3): δ (ppm) 2.37 (s, 3H), 2.41 (s, 3H), 7.14 (d, 1H,
J = 16.1 Hz), 7.18 (m, 2H), 7.30 (s, 1H), 7.41 (m, 3H), 7.48 (d,
1H, 1H, J = 16.1 Hz), 7.57 (m, 2H). 13C NMR (75.5 MHz,
CDCl3): δ (ppm) 19.7, 20.9, 126.8, 128.4, 128.5, 128.8, 128.9,
130.5, 131.2, 133.7, 134.7, 135.0, 139.1, 145.6, 196.6. MS (EI, 70
eV): m/z = 236, 145, 131, 103, 77.
(E)-1-(2,5-Dimethylphenyl)but-2-en-1-one (4b). The compound
was prepared from p-xylene (19.6 g, 185 mmol) and crotonyl
chloride (21.2 g, 224 mmol) according to the procedure described
for 3a-e. Yield: 94%; colorless oil. 1H NMR (300 MHz, CDCl3):
δ (ppm) 1.95 (dd, 3H, J1 = 6.8 Hz, J2 = 1.4 Hz), 2.33 (s, 3H), 2.34
(s, 3H), 6.49 (dd, 1H, J1 = 15.6 Hz, J2 = 1.4 Hz), 6.73 (qd, 1H,
J1 = 15.6 Hz, J2 = 6.8 Hz), 7.10-7.16 (m, 2H), 7.17 (s, 1H). 13
C
Experimental Section
NMR (75.5 MHz, CDCl3): δ (ppm) 17.3, 18.7, 19.8, 127.6, 130.1,
130.2, 131.3, 132.6, 133.8, 138.1, 144.9, 194.9. MS (EI, 70 eV):
m/z = 174, 159, 141, 131, 115, 15, 91, 79, 69, 41.
General Procedure for the Synthesis of Acylphenones 3a-e.
The corresponding acyl chloride (224 mmol) was added drop-
wise to a mixture of aluminum chloride (27.2 g, 204 mmol) and
either p-xylene (19.6 g, 185 mmol) or 1,2-dimethoxy-4-methyl-
benzene (28.2 g, 185 mmol) in CS2 (100 mL) under nitrogen
atmosphere at 0-3 °C in a period of 1.5 h. The reaction mixture
was stirred for 1 h at 0 °C, warmed to 20 °C, stirred for
additional 2 h, and then poured on ice (400 g). After the ice
melted, the aqueous layer was extracted with CH2Cl2 (3ꢀ 100 mL).
The combined organic extracts were washed with brine (100 mL)
and dried with MgSO4. The solvent was evaporated under reduced
pressure to give the crude title product, which was purified by
vacuum distillation.
1-(2,5-Dimethylphenyl)-2-phenylprop-2-en-1-one (4c). Piperi-
dine (0.13 mL, 1.3 mmol), acetic acid (0.12 mL, 2.1 mmol),
and aq formaldehyde (37% solution, 4 mL, 50 mmol) were
successively added to a magnetically stirred solution of 3c
(2.92 g, 13.0 mmol) in methanol (50 mL), and the resulting
mixture was refluxed for 4 h and concentrated under reduced
pressure. Water (50 mL) was added to the residue, and the
mixture was extracted with CH2Cl2 (3 ꢀ 30 mL). Combined
organic extracts were washed with water (2 ꢀ 50 mL) and brine
(30 mL) and dried with MgSO4, and solvent was evaporated
under reduced pressure. The crude product was purified by flash
column chromatography (silica, petroleum ether/ethyl acetate,
8:1) to give the title product. Yield: 97%; white crystals, mp
178.3-181.0 °C. 1H NMR (300 MHz, CDCl3): δ (ppm) 2.33 (s,
3H), 2.42 (s, 3H), 5.75 (s, 1H), 6.17 (s, 1H), 7.14 (d, 1H, J = 7.8
Hz), 7.19 (dd, 1H, J1 = 7.8 Hz, J2 = 1.3 Hz), 7.29 (d, 1H, J = 1.3
1-(2,5-Dimethylphenyl)ethanone (3a). Prepared from p-xylene
and acetyl chloride (15.9 mL, 224 mmol). Yield: 95%; colorless
1
oil. H NMR (300 MHz, CDCl3): δ (ppm) 2.35 (s, 3H), 2.47
(s, 3H), 2.55 (s, 3H), 7.10 (d, 1H, J = 7.8 Hz), 7.16 (d, 1H, J =7.8
Hz), 7.47 (s, 1H). 13C NMR (75.5 MHz, CDCl3): δ (ppm) 20.7,
20.8, 29.3, 129.7, 131.8, 132.0, 135.0, 135.6 137.6, 201.6. MS (EI,
70 eV): m/z = 148, 133, 105, 79, 77, 51, 43.
1-(2,5-Dimethylphenyl)-2-phenylethanone (3c). Prepared from
p-xylene and phenylacetyl chloride (27.1 mL, 224 mmol). Yield:
95%; colorless crystals, mp 30.2-31.6 °C. 1H NMR (300 MHz,
CDCl3): δ (ppm) 2.42 (s, 3H), 2.46 (s, 3H), 4.25 (s, 2H), 7.16 (d,
1H, J = 7.8 Hz,), 7.22 (dd, 1H, J1 = 7.8 Hz, J2 = 1.5 Hz), 7.31
Hz), 7.38 (m, 3H), 7.47 (dd, 1H, J1 = 7.9 Hz, J2 = 1.7 Hz). 13
C
NMR (75.5 MHz, CDCl3): δ (ppm) 19.9, 21.0, 120.7, 128.1,
128.4, 128.5, 129.9, 131.2, 131.6, 134.4, 135.0, 137.0, 138.7,
149.8, 199.9. MS (EI, 70 eV): m/z = 236, 159, 145, 133, 105,
77, 63, 51.
1-(2,5-Dimethylphenyl)-2-methylprop-2-en-1-one (4d). Acetic
acid (10 mL) was added to a magnetically stirred suspension of
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Solomek et al.
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(2,5-Dimethylphenyl)(2-phenyloxiran-2-yl)methanone (1c). Pre-
3d (1.62 g, 10 mmol) and aq formaldehyde (37% solution,
2.4 mL, 30 mmol). A catalytic amount (few drops) of morpho-
line was then added, and the resulting mixture was refluxed for
5 days. The reaction mixture was cooled to 20 °C, neutralized
with aq NaOH (20%), and extracted with CH2Cl2 (3 ꢀ 50 mL).
Combined organic extracts were washed with brine (50 mL) and
dried with MgSO4, and solvent was evaporated under reduced
pressure. The flash column chromatography of the resulting
mixture (silica, petroleum ether/ethyl acetate, 8:1) gave the
product. Yield: 96%; colorless oil. 1H NMR (300 MHz, CDCl3):
δ (ppm) 1.99 (s, 3H), 2.19 (s, 3H), 2.25 (s, 3H), 5.53 (s, 1H), 5.89
(s, 1H), 6.99 (s, 1H), 7.02 (d, 1H, J = 7.9 Hz), 7.06 (d, 1H, J =
7.9 Hz). 13C NMR (75.5 MHz, CDCl3): δ (ppm) 17.0, 19.0, 20.6,
128.1, 129.5, 130.3, 130.5, 132.6, 134.3, 138.9, 145.0, 200.5. MS
(EI, 70 eV): m/z = 174, 159, 145, 133, 115, 105, 91, 77, 65, 51, 41.
(E)-1-(4,5-Dimethoxy-2-methylphenyl)-3-phenylprop-2-en-1-one
(4e). Prepared as 4a from 3e (2.62 g, 13.5 mmol). Yield: 72%;
yellow solid; mp 107.1-109.8 °C. 1H NMR (300 MHz, CDCl3): δ
(ppm) 2.45 (s, 3H), 3.89 (s, 3H), 3.93 (s, 3H), 6.75 (s, 1H), 7.10 (s,
1H), 7.17 (d, 1H, J = 15.1 Hz), 7.39-7.40 (m, 3H), 7.53 (d, 1H,
J = 15.1 Hz), 7.56-7.59 (m, 2H). 13C NMR (75.5 MHz, CDCl3):
δ (ppm) 20.6, 56.1, 56.4, 112.4, 114.4, 126.7, 128.5, 129.1, 130.6,
131.3, 131.6, 135.0, 144.9, 146.7, 151.1, 194.7. MS (EI, 70 eV): m/z=
282, 267, 251, 205, 191, 179, 165, 151, 131, 121, 103, 91, 77, 65, 51.
(E)-3-Phenyl-1-o-tolylprop-2-en-1-one (4h). Prepared as 4a
from o-methylacetophenone (1.81 g, 13.5 mmol). Yield: 88%;
colorless oil. 1H NMR (300 MHz, CDCl3): δ (ppm) 2.49 (s, 3H),
7.17 (d, J = 16.0 Hz, 1H), 7.30-7.33 (m, 2H), 7.39-7.43 (m,
4H), 7.57-7.60 (m, 3H). 13C NMR (75.5 MHz, CDCl3): δ (ppm)
20.3, 125.6, 126.9, 128.2, 128.5, 129.1, 130.6, 130.7, 131.4, 134.8,
137.1, 139.2, 145.9, 196.5. MS (EI, 70 eV): m/z = 222, 178, 145,
131, 103, 91, 77, 65, 51.
General Procedure for the Synthesis of Epoxides 1a-e,h. H2O2
(30%, 2.9 mL, 28.9 mmol) was added dropwise to a stirred
solution of an enone (4a-e,h; 11 mmol) in methanol (60 mL)
cooled to 0 °C. Then a cooled solution (0 °C) of KOH (0.32 g,
5.7 mmol) in methanol (20 mL) was added, and the mixture was
stirred at 0 °C for 2 h. The reaction progress was monitored by
TLC. After completion, the reaction was quenched with water
(100 mL) and extracted with CH2Cl2 (3 ꢀ 30 mL). The organic
extracts were washed with brine (50 mL) and dried with MgSO4,
and the solvents were evaporated under reduced pressure. The
crude product mixture was separated using flash column chro-
matography (silica, petroleum ether/ethyl acetate, 20:1 to 10:1)
to give the title product.
1
pared from 4c. Yield: 94%; colorless oil. H NMR (300 MHz,
CDCl3): δ (ppm) 2.29 (s, 3H), 2.48 (s, 3H), 3.07 (d, 1H,
J = 5.6 Hz), 3.30 (d, 1H, J = 5.6 Hz), 7.11 (d, 1H, J = 7.8
Hz), 7.17 (d, 1H, J = 7.8 Hz), 7.30-7.41 (m, 3H), 7.48-7.56 (m,
3H). 13C NMR (75.5MHz, CDCl3): δ (ppm) 20.8, 21.1, 54.9, 63.6,
126.3, 128.3, 128.8, 131.0, 131.7, 132.8, 134.7, 135.1, 135.8, 136.4,
199.5. MS (EI, 70 eV: m/z = 252, 237, 193, 178, 133, 119, 105, 91,
77, 65. UV-vis (acetonitrile): ε313 = 730 dm3 mol-1 cm-1, ε254
=
7160 dm3 mol-1 cm-1. HRMS (EIþ): calcd for C17H17O2 [M þ
Hþ] 253.1229, found 253.1223.
(2,5-Dimethylphenyl)(2-methyloxiran-2-yl)methanone (1d). Pre-
1
pared from 4d. Yield: 80%; colorless oil. H NMR (300 MHz,
CDCl3): δ (ppm) 1.66 (s, 3H), 2.32 (s, 6H), 2.80 (d, 1H, J = 5.3
Hz), 2.86 (d, 1H, J = 5.3 Hz), 7.08 (d, 1H, J = 7.8 Hz), 7.14 (dd,
1H, J1 =7.8Hz, J2 = 1.8 Hz), 7.23 (d, 1H, J =1.8Hz). 13CNMR
(75.5 MHz, CDCl3): δ (ppm) 17.7, 19.6, 21.0, 52.4, 59.9, 128.3,
130.9, 131.6, 134.1, 134.8, 135.7, 204.5. MS(EI, 70 eV): m/z = 190,
174, 159, 145, 133, 105, 91, 77, 65, 51, 41. UV-vis (acetonitrile):
ε313 = 410 dm3 mol-1 cm-1, ε254 = 6120 dm3 mol-1 cm-1
.
HRMS (EIþ): calcd for C12H15O2 [M þ Hþ] 191.1072, found
191.1067.
(4,5-Dimethoxy-2-methylphenyl)(3-phenyloxiran-2-yl)methanone
(1e). Prepared from 4e. Yield: 77%; white crystals, mp 136.3-
137.7 °C. 1H NMR (300 MHz, CDCl3): δ (ppm) 2.51 (s, 3H), 3.80
(s, 3H), 3.91 (s, 3H), 4.05 (1H, J = 1.9 Hz), 4.06 (1H, J = 1.9 Hz),
6.73 (s, 1H), 7.27 (s, 1H), 7.33-7.41 (m, 5H). 13C NMR (75.5 MHz,
CDCl3): δ (ppm) 21.3, 56.1, 56.3, 59.3, 62.7, 112.6, 114.7, 125.8,
127.54, 128.9, 129.1, 134.1, 135.8, 146.7, 152.4, 194.6. MS (EI, 70 eV):
m/z = 282, 269, 191, 179, 152, 136, 121, 105, 91, 77, 65, 51. HRMS
(EIþ): calcd for C18H19O4 [M þ Hþ] 299.1283, found 299.1278.
(3-Phenyloxiran-2-yl)(o-tolyl)methanone (1h). Prepared from
1
4h. Yield: 94%; colorless oil. H NMR (300 MHz, CDCl3): δ
(ppm) 2.57 (s, 3H), 4.06 (d, 1H, J = 1.7 Hz), 4.13 (d, 1H, J = 1.7
Hz), 7.29-7.32 (m, 2H), 7.37-7.44 (m, 6H), 7.71 (d, 1H, J = 7.8
Hz). 13C NMR (75.5 MHz, CDCl3): δ (ppm) 21.1, 59.6, 62.5,
126.0, 128.9, 129.1, 129.2, 132.2, 132.4, 135.6, 139.0, 196.7. MS
(EI, 70 eV): m/z = 238, 119, 91, 77, 65, 51.
General Procedure for Irradiation of 1a-e; Preparation of
5a-d, 6b,d,e and 7b,d. A degassed (N2) solution of the corre-
sponding epoxide (1a-e, 5 ꢀ 10-3 M) in acetonitrile (200 mL)
was irradiated with a 125- or 400-W Hg medium pressure UV
lamp through a Pyrex filter (λ < 290 nm) until ∼95% conver-
sion (HPLC) was reached (or ∼41% in the case of the epoxide
1c). The solvent was removed under reduced pressure at the
temperature below 40 °C to prevent a retro-aldol reaction. The
resulting mixture was separated by flash column chromatogra-
phy (silica, petroleum ether/ethyl acetate, 20:1 to 5:1) to give the
title photoproducts.
(2,5-Dimethylphenyl)(3-phenyloxiran-2-yl)methanone (1a). Pre-
pared from 4a (2.60 g, 11 mmol). Yield: 94%; white crystals, mp
67.1-69.2 °C. 1H NMR (300 MHz, CDCl3): δ (ppm) 2.34 (s, 3H),
2.49 (s, 3H), 4.05 (d, 1H, J = 1.8 Hz), 4.10 (d, 1H, J = 1.8 Hz),
7.17 (d, 1H, J = 7.8 Hz), 7.24 (d, 1H, J = 7.8 Hz), 7.36-7.42 (m,
5H), 7.48 (s, 1H). 13C NMR (75.5 MHz, CDCl3): δ (ppm) 20.6,
21.0, 59.6, 62.4, 126.0, 128.9, 129.0, 129.1, 129.5, 132.1, 133.1,
135.6, 135.7, 135.7, 197.0. MS (EI, 70 eV): m/z = 252, 237, 222,
207, 178, 148, 133, 119, 105, 91, 77, 51, 44. UV-vis (acetonitrile):
2-(Hydroxy(phenyl)methyl)-6-methyl-2,3-dihydro-1H-inden-1-
one (5a). Obtained from 1a. Yield: 67%; colorless oil; two
1
diastereomers (a ∼1:1 ratio). H NMR (300 MHz, CDCl3): δ
(ppm) 2.41 (s, 3H), 2.43 (s, 3H), 2.65 (dd, J1 = 17.4 Hz, J2 = 4.4
Hz, 1H), 2.84-2.94 (m, 2H), 3.03-3.10 (m, 2H), 3.22 (dd, J1 =
16.8 Hz, J2 = 4.4 Hz, 1H), 4.80 (d, J = 9.7 Hz, 1H), 4.92 (s,
broad), 5.59 (dd, J1 = 3.1 Hz, J2 = 3.1 Hz, 1H), 7.26-7.46 (m,
14H), 7.60 (s, 1H), 7.61 (s, 1H). 13C NMR (75.5 MHz, CDCl3): δ
(ppm) 21.3, 21.3, 26.6, 29.8, 53.7, 55.3, 72.4, 76.1, 124.0, 124.3,
125.8, 126.4, 126.5, 127.3, 127.6, 128.5, 128.7, 128.8, 136.5, 136.7,
137.0, 137.5, 137.6, 138.0, 141.7, 142.8, 151.6, 152.3, 207.5, 210.0.
MS (EI, 70 eV): m/z = 252, 234, 146, 132, 117, 104, 91, 77, 65, 51,
ε313 = 1040 dm3 mol-1 cm-1, ε254 = 10 780 dm3 mol-1 cm-1
.
HRMS (EIþ): calcd for C17H17O2 [M þ Hþ] 253.1229, found
253.1222.
(2,5-Dimethylphenyl)(3-methyloxiran-2-yl)methanone (1b). Pre-
pared from 4b. Yield: 80%; colorless oil. H NMR (300 MHz,
1
CDCl3): δ (ppm) 1.47 (d, 3H, J = 5.1 Hz), 2.36 (s, 3H), 2.43 (s,
3H), 3.15 (dq, 1H, J1 = 5.1 Hz, J2 = 1.9 Hz), 3.74 (d, 1H, J = 1.9
Hz), 7.13 (d, 1H, J = 7.8 Hz), 7.21 (d, 1H, J = 7.8 Hz), 7.44 (s,
1H). 13C NMR (75.5 MHz, CDCl3): δ (ppm) 17.5, 20.2, 20.9, 55.8,
59.7, 129.1, 131.7, 132.7, 135.2, 135.3, 135.8, 198.8. MS (EI,
70 eV): m/z=175, 133, 117, 115, 105, 103, 79, 77, 58, 43. UV-vis
(acetonitrile):ε313 = 775 dm3 mol-1 cm-1, ε254 = 8820 dm3 mol-1
cm-1. HRMS (EIþ): calcd for C12H15O2 [M þ Hþ] 191.1072,
found 191.1060.
32. UV-vis (acetonitrile): ε313 = 2520 dm3 mol-1 cm-1, ε254
=
9390 dm3 mol-1 cm-1. HRMS (EIþ): calcd for C17H17O2 [M þ
Hþ] 253.1229, found 253.1221.
2-(1-Hydroxyethyl)-6-methyl-2,3-dihydro-1H-inden-1-one (5b).
Obtained from 1b. Yield: 64%; colorless oil; two diastereomers
1
(a ∼1:1 ratio). Diastereomer A: H NMR (300 MHz, CDCl3):
δ (ppm) 1.29 (d, 3H, J = 6.2 Hz), 2.41 (s, 3H), 2.65 (ddd, 1H,
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Solomek et al.
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J1 = 9.0Hz, J2 = 8.0 Hz, J3 = 4.5 Hz) 2.75 (dd, 1H, J1 = 17.0 Hz,
J2 = 4.5 Hz), 3.24 (dd, 1H, J1 = 17.0 Hz, J2 = 8.0 Hz), 3.98 (dq,
1H, J1 = 9.0 Hz, J2 = 6.2 Hz), 4.36 (broad, 1H), 7.36 (d, 1H, J =
7.9 Hz), 7.44 (d, 1H, J = 7.9 Hz), 7.56 (s, 1H). 13C NMR (75.5
MHz, CDCl3): δ (ppm) 21.1, 21.6, 29.5, 53.8, 69.2, 124.0, 126.2,
136.7, 136.9, 137.8, 151.3, 210.0. Diastereomer B: 1H NMR (300
MHz, CDCl3): δ (ppm) 1.28 (d, 3H, J = 6.4 Hz), 2.40 (s, 3H), 2.80
(ddd, 1H, J1=8.0 Hz, J2=4.5 Hz, J3=3.6 Hz) 3.07 (dd, 1H, J1 =
17.0 Hz, J2 = 4.5 Hz), 3.17 (dd, 1H, J1 = 17.0 Hz, J2 = 8.0 Hz),
4.46 (dq, 1H, J1 = 6.4 Hz, J2 = 3.6 Hz), 7.36 (d, 1H, J = 7.9 Hz),
7.44 (d, 1H, J = 7.9 Hz), 7.56 (s, 1H). 13C NMR (75.5 MHz,
CDCl3): δ (ppm) 20.8, 21.1, 27.3, 54.3, 67.4, 123.7, 126.4, 136.3,
136.6, 137.4, 152.0, 208.4. MS (EI, 70 eV, m/z): 190, 175, 133, 129,
105, 91, 77, 69, 43. UV-vis (acetonitrile): ε313 = 1340 dm3 mol-1
cm-1, ε254 = 8030 dm3 mol-1 cm-1. HRMS (EIþ): calcd for
C12H15O2 [M þ Hþ] 191.1072, found 191.1056.
1H, J1 = 13.5 Hz, J2 = 5.8 Hz), 3.16 (dd, 1H, J1 = 13.5 Hz, J2 =
5.5 Hz), 4.24 (tq, 1H, J1 = 6.3 Hz, J2 = 6.1 Hz,), 4.84 (d, 1H,
J = 15.3 Hz), 4.94 (d, 1H, J = 15.3 Hz), 7.12 (d, 1H, J = 7.7 Hz),
7.26 (d, 1H, J = 7.7 Hz), 7.66 (s, 1H). 13C NMR (75.5 MHz,
CDCl3): δ (ppm) 21.1, 21.3, 50.0, 69.4, 71.4, 127.8, 129.2, 132.9,
137.5, 137.9, 139.6, 200.5. MS (EI, 30 eV): m/z = 190, 149, 119,
103, 91, 77, 65, 51, 39. HRMS (EIþ): calcd for C12H15O2 [M þ
Hþ] 191.1072, found 191.1062.
4,7-Dimethyl-3,4-dihydrobenzo[c]oxepin-5(1H)-one (7d). Ob-
tained from 1d.Yield: 15%; colorless oil. 1H NMR (300 MHz,
CDCl3): δ (ppm) 1.14 (d, 3H, J=6.7 Hz), 2.37 (s, 3H), 3.26-3.38
(m, 1H), 3.65 (dd, 1H, J1 = 10.7 Hz, J2 = 10.7 Hz), 4.00 (dd, 1H,
J1 = 10.7 Hz, J2 = 6.8 Hz), 4.83 (d, 1H, J = 15.2 Hz), 4.94 (d,
1H, J = 15.2 Hz), 7.10 (d, 1H, J = 7.7 Hz), 7.24 (d, 1H, J = 7.7
Hz), 7.58 (s, 1H). 13C NMR (75.5 MHz, CDCl3): δ (ppm) 11.6,
21.1, 46.6, 71.9, 72.8, 127.4, 129.3, 132.3, 137.7, 138.5, 138.7,
204.1. MS (EI, 30 eV, m/z): 190, 149, 119, 103, 91, 77, 65, 51, 39.
HRMS (EIþ): calcd for C12H15O2 [M þ Hþ] 191.1072, found
191.1053.
(E)-2-Ethylidene-6-methyl-2,3-dihydro-1H-inden-1-one (8).
KOH (0.10 g, 1.7 mmol) was added to a stirred solution of 2b
(50 mg, 0.26 mmol) in methanol (30 mL). The reaction mixture
was heated to 40 °C in the period of 20 min and then extracted
with CH2Cl2 (3 ꢀ 10 mL). The combined organic layers
were washed with brine (30 mL) and dried with MgSO4, and
the solvent was evaporated under reduced pressure. The
crude product was purified by flash chromatography (silica,
petroleum ether/ethyl acetate, 10:1) to give 8. Yield: 97%; color-
less oil. GC showed a mixture of the (E)- and (Z)-isomers in a
94:6 ratio. 1H NMR (300 MHz, CDCl3): δ (ppm) 1.97 (dt, 3H,
J1 = 7.2 Hz, J2 = 2.1 Hz), 2.43 (s, 3H), 3.62 (broad s, 2H), 6.94
(tq, 1H, J1 = 7.1 Hz, J2 = 2.1 Hz), 7.38-7.43 (m, 2H), 7.67
(s, 1H). 13C NMR (75.5 MHz, CDCl3): δ (ppm) 15.54, 21.38,
29.70, 124.6, 126.2, 132.9, 135.8, 137.6, 138.3, 139.3, 146.8, 193.5.
MS (EI, 70 eV): m/z = 172, 157, 143, 129, 115, 102, 77, 63, 51.
HRMS (EIþ): calcd for C12H13O [M þ Hþ] 173.0966, found
173.0962.
2-(Hydroxymethyl)-6-methyl-2-phenyl-2,3-dihydro-1H-inden-
1-one (5c). Obtained from 1c. Yield: 82% (at a 41% conversion
of 1c); colorless oil. 1H NMR (300 MHz, CDCl3): δ (ppm) 2.43
(s, 3H), 3.97 (d, 1H, J = 17.0 Hz), 4.13 (d, 1H, J = 17.0 Hz), 4.15
(d, 1H, J = 10.9 Hz), 4.27 (d, 1H, J = 10.9 Hz), 7.27-7.46(m,
7H), 7.63 (s, 1H). 13C NMR (75.5 MHz, CDCl3): δ (ppm) 21.2,
38.8, 58.6, 68.0, 124.5, 126.2, 127.0, 127.3, 128.9, 136.6, 136.9,
137.9, 140.4, 150.7, 208.3. MS (EI, 70 eV): m/z = 238, 119, 91,
77, 65. UV-vis (acetonitrile): ε313 = 2270 dm3 mol-1 cm-1, ε254
= 10 140 dm3 mol-1 cm-1. HRMS (EIþ): calcd for C17H17O2
[M þ Hþ] 253.1229, found 253.1223.
2-(Hydroxymethyl)-2,6-dimethyl-2,3-dihydro-1H-inden-1-one
(5d). Obtained from 1d. Yield: 66%; colorless oil. 1H NMR (300
MHz, CDCl3): δ (ppm) 1.24 (s, 3H), 2.39 (s, 3H), 2.84 (d, 1H,
J = 17.0 Hz), 3.18 (d, 1H, J = 17.0 Hz), 3.62 (d, 1H, J = 10.7
Hz), 3.81 (d, 1H, J = 10.7 Hz), 7.34 (d, 1H, J = 7.8 Hz), 7.43 (d,
1H, J = 7.8 Hz), 7.53 (s, 1H). 13C NMR (75.5 MHz, CDCl3): δ
(ppm) 14.2, 20.7, 37.7, 51.1, 67.9, 124.1, 126.3, 136.0, 136.5,
137.4, 150.6, 211.1. MS (EI, 70 eV): m/z = 190, 172, 159, 145,
132, 129, 115, 105, 91, 77, 51, 32. UV-vis (acetonitrile): ε313
=
880 dm3 mol-1 cm-1, ε254 = 6560 dm3 mol-1 cm-1. HRMS
(EIþ): calcd for C12H15O2 [M þ Hþ] 191.1072, found 191.1067.
1-(2,5-Dimethylphenyl)-3-hydroxybut-2-en-1-one (6b). Ob-
Irradiation Experiment in an NMR Cuvette. D2O (25 μL) was
added to a solution of 1h (20 mg) in acetone-d6 (500 μL) in an
NMR cuvette. The resulting solution was purged with argon for
10 min. 1H NMR was measured in 15-min intervals of irradia-
tion by a 125-W medium pressure Hg UV lamp through a Pyrex
filter (λ < 290 nm).
1
tained from 1b. Yield: 7%; colorless oil. H NMR (300 MHz,
CDCl3): δ (ppm) 2.17 (s, 3H), 2.34 (s, 3H), 2.45 (s, 3H), 5.84 (s,
1H), 7.11 (d, 1H, J = 7.8 Hz), 7.15 (d, 1H, J = 7.8 Hz), 7.28 (s,
1H), 15.96 (broad, 1H). 13C NMR (75.5 MHz, CDCl3): δ (ppm)
20.3, 21.0, 25.8, 101.0, 129.0, 131.5, 131.6, 134.1, 135.5, 136.0,
188.4, 193.2. MS (EI, 70 eV): m/z = 190, 172, 132, 129, 115, 104,
77, 43, 32. HRMS (EIþ): calcd for C12H15O2 [M þ Hþ]
191.1072, found 191.1059.
Quantum Yield Measurements. The quantum yield measure-
ments were performed on an optical bench consisting of high
pressure 350- or 450-W UV lamps, a 1/8 m monochromator with
200-1600 nm grating, set to 313 nm, and a 1.0-cm matched
quartz cell containing a solution degassed by purging with argon
for 10 min. The sample temperature was maintained using a
Peltier thermo block set to 20 °C. The light intensity was
monitored by a Si photodiode detector (UV enhanced) with a
multifunction optical power meter. The concentration of all
sample solutions was in the interval of 1 ꢀ 10-3 and 5 ꢀ 10-4 M,
containing hexadecane (10-3 M; GC) or acetone (10-2 M;
HPLC) as internal standards. Valerophenone was used as an
actinometer in all cases.42 The reaction conversions were always
kept below 10% to avoid the interference of photoproducts. The
relative standard deviations of the mean for multiple (at least
five) samples were found below 10% in all analyses.
Steady-State Quenching Experiments. Stern-Volmer anal-
ysis was performed with naphthalene as a triplet quencher in a
merry-go-round apparatus (see also the Supporting Informa-
tion, S41). Samples in Pyrex tubes (13 ꢀ 120 mm) were degassed
by purging with argon for 10 min. The concentration of all
sample solutions was approximately 5 ꢀ 10-3 M, and they
contained hexadecane (10-3 M) as an internal standard for
GC measurements. Three degassed tubes for a given naph-
thalene concentration were irradiated using a medium pressure
1-(2,5-Dimethylphenyl)-3-hydroxy-2-methylprop-2-en-1-one (6d).
Obtained from 1d. Yield: 7%; colorless oil. 1H NMR (300 MHz,
CDCl3):δ(ppm) 1.68 (s, 3H), 2.26 (s, 3H), 2.33 (s, 3H), 6.99 (s, 1H),
7.13 (s, 2H), 8.54 (d, 1H, J= 4.8 Hz), 14.94 (d, 1H, J=4.8Hz). 13C
NMR (75.5 MHz, CDCl3): δ (ppm) 13.2, 18.8, 21.1, 127.3, 130.5,
130.7, 135.4, 136.3, 184.4, 208.1. MS (EI, 70 eV): m/z = 190, 172,
159, 145, 132, 129, 115, 104, 91, 77, 32. HRMS (EIþ): calcd for
C12H15O2 [M þ Hþ] 191.1072, found 191.1067.
1-(4,5-Dimethoxy-2-methylphenyl)-3-hydroxy-3-phenylprop-2-
1
en-1-one (6e). Obtained from 1e. Yield: 70%; colorless oil. H
NMR (300 MHz, CDCl3): δ (ppm) 2.54 (s, 3H), 3.91 (s, 3H), 3.92
(s, 3H), 6.51 (s, 1H), 6.74 (s, 1H), 7.15 (s,1H), 7.44-7.54 (m, 3H),
7.95 (m, 2H). 13C NMR (75.5 MHz, CDCl3): δ (ppm) 21.0, 56.2,
56.4, 97.2, 112.0, 114.5, 127.2, 128.9, 131.3, 132.5, 135.7, 147.1,
151.3, 184.3, 190.0 (see an HMBC spectrum in the Supporting
Information, S30). MS (EI, 70eV): m/z = 298, 283, 267, 221, 192,
179, 150, 136, 121, 105, 91, 77, 69, 51. HRMS (EIþ): calcd for
C18H19O4 [M þ Hþ] 299.1283, found 299.1278.
3,7-Dimethyl-3,4-dihydrobenzo[c]oxepin-5(1H)-one (7b). Ob-
tained from 1b. Yield: 12%; colorless oil. 1H NMR (300 MHz,
CDCl3): δ (ppm) 1.33 (d, 3H, J = 6.3 Hz), 2.38 (s, 3H), 2.85 (dd,
7308 J. Org. Chem. Vol. 75, No. 21, 2010

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400-W Hg lamp; the λ = 366 nm band was isolated by an optical
filter in order to avoid the absorption by naphthalene.
measurements, fruitful discussions, and chemical analyses.
T.S. acknowledges the Scholarship for talented Ph.D. stu-
dents of the Brno City. The University of Fribourg is greatly
acknowledged for computational resources.
Acknowledgment. Support for this work was provided
by the Grant Agency of the Czech Republic (203/09/0748),
the Ministry of Education, Youth and Sports of the
Czech Republic (MSM0021622413), the European Union
(CETOCOEN, CZ.1.05/2.1.00/01.0001; administered by the
Ministry of Education, Youth and Sports of the Czech
Republic), and by the Rector’s Program to Support Masaryk
University Students’ Creative Work. The authors express
their thanks to Lubica Klicova, Peter Sebej, Lukas Maier,
Jaromir Literak, Dominik Heger, and Blanka Hegrova for
their help with the laser flash photolysis experiments, NMR
Supporting Information Available: 1H and 13C NMR spec-
tra of new compounds; 1H-1H COSY and 1H-13C HMBC
NMR correlations; Stern-Volmer analysis; kinetic traces
from laser flash photolysis experiments; UV-vis spectra of
1a-d and 5a-d; total Gibbs free energies (with scaled thermal
corrections) of calculated species discussed in the article;
TD-DFT electronic transitions; Cartesian coordinates of opti-
mized structures with the corresponding transition states. This
material is available free of charge via the Internet at http://
pubs.acs.org.
J. Org. Chem. Vol. 75, No. 21, 2010 7309