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org/joc

Photoenolization-Induced Oxirane Ring Opening in 2,5-Dimethylbenzoyl

Oxiranes To Form Pharmaceutically Promising Indanone Derivatives
Tom 
as Solomek,† 
Peter Stacko,†
Aneesh Tazhe Veetil,† Tomas Pospı́sil,† 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

[email protected]
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
groups10-14 by Kl an, Wirz, and co-workers, who demon-
reactions are important transformation steps in organic
strated that the 2,5-dimethylphenacyl (DMP) group can be
synthesis. It was demonstrated on many examples that the
used to protect moderately or good leaving groups, such as
specific reactivity of the electronically excited states enables
carboxylic acids,15-17 phosphates, sulfonates,18 alcohols as
the formation of complex and highly functionalized mole-
carbonates,19 or amines as carbamates.20
cules, thus shortening the number of synthetic steps.1,2
Indanone derivatives are key intermediates in the synthesis
Triplet excited 2-alkylacetophenones are known to under-
of some pharmaceutically important compounds, such as the
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 (8) Bergmark, W. R. J. Chem. Soc., Chem. Commun. 1978, 61.
completely suppressed, only the (Z)-enol is formed via the (9) Bergmark, W. R.; Barnes, C.; Clark, J.; Paparian, S.; Marynowski, S.
J. Org. Chem. 1985, 50, 5612.
excited singlet state; this isomer is a short-lived species that (10) Givens, R. S.; Conrad, P. G.; Yousef, A. L.; Lee, J.-I. In CRC
readily reketonizes.3 When a leaving group (LG) is present Handbook of Organic Photochemistry and Photobiology; Horspool, W. M.,
Lenci, F., Eds.; CRC Press: Boca Raton, 2004; Chapter 69, p 1.
in the R-position of 2-alkylacetophenones, a longer-lived (11) Goeldner, M.; Givens, R. S. Dynamic Studies in Biology; Wiley-
(E)-photoenol liberates the LG to give the corresponding WCH: Weinheim, 2005.
cyclization (indanone, in red) or solvolysis (in blue) products (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.
(1) Klan, P.; Wirz, J. Photochemistry of Organic Compounds: From Adv. Phys. Org. Chem. 2009, 43, 39.
Concepts to Practice; 1st ed.; John Wiley & Sons Ltd.: Chichester, 2009. (15) Klan, P.; Zabadal, M.; Heger, D. Org. Lett. 2000, 2, 1569.
(2) Hoffmann, N. Chem. Rev. 2008, 108, 1052. (16) Ruzicka, R.; Zabadal, M.; Klan, P. Synth. Commun. 2002, 32, 2581.
(3) Haag, R.; Wirz, J.; Wagner, P. J. Helv. Chim. Acta 1977, 60, 2595. (17) Zabadal, M.; Pelliccioli, A. P.; Klan, P.; Wirz, J. J. Phys. Chem. A
(4) Sammes, P. G. Tetrahedron 1976, 32, 405. 2001, 105, 10329.
(5) Das, P. K.; Encinas, M. V.; Small, R. D.; Scaiano, J. C. J. Am. Chem. (18) Klan, P.; Pelliccioli, A. P.; Pospisil, T.; Wirz, J. Photochem. Photo-
Soc. 1979, 101, 6965. biol. Sci. 2002, 1, 920.
(6) Small, R. D.; Scaiano, J. C. J. Am. Chem. Soc. 1977, 99, 7713. (19) Literak, J.; Wirz, J.; Klan, P. Photochem. Photobiol. Sci. 2005, 4, 43.
(7) Pelliccioli, A. P.; Klan, P.; Zabadal, M.; Wirz, J. J. Am. Chem. Soc. (20) Kammari, L.; Plistil, L.; Wirz, J.; Klan, P. Photochem. Photobiol. Sci.
2001, 123, 7931. 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

Solomek et al.
JOC Article
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
antihypertensive drug (þ)-indacrinone,21 the reversible acet- corresponding (E)-enol to relieve internal strain of a three-
ylcholinesterase inhibitor donepezil hydrochloride,22,23 and membered ring. This would eventually yield 2-hydroxymethylin-
the antibacterial and cytotoxic pterosines (Chart 1).24 For dan-1-one related, for example, to the pterosine derivatives
example, Wessig and co-workers used the phototransforma- (Chart 1). Since many reliable strategies for the preparation of
tion of 2-alkylacetophenone derivatives for the synthesis of benzoyl oxiranes (epoxy ketones), including some of a very high
two sesquiterpene indane derivatives, pterosine B or C,25 enantiomeric purity,41 are available, this strategy would be syn-
and other indanone derivatives.26 Kl an and co-workers thetically beneficial. We report on the synthesis of benzoyl
showed that photolysis of a 4,5-dimethoxyphenacyl deriva- oxiranes, their photochemical behavior, laser flash photolysis
tive can lead to an indanone precursor for the synthesis of experiments, and some quantum chemical calculations. The
donepezil.27 Wang and co-workers used this concept in polymer- possibility of utilizing the photoreaction of the benzoyl oxiranes
supported synthesis,28 and Park and co-workers utilized this in the synthesis of some structurally related pharmaceutically
reaction in photopolymerization29 and the synthesis of various active compounds is considered.
indanone and benzocyclobutenol derivatives.30,31
The synthesis of indanone building blocks using a photo- Results and Discussion
enolization step is generally designed to start from precur- Synthesis of 2,5-Dimethylbenzoyl Oxiranes. The 2,5-di-
sors, which do not possess functional groups susceptible to methylbenzoyl oxiranes 1a-d (Scheme 3) were prepared to
photochemical side reactions and responsible for slowing study their photochemical transformations. The synthesis
down or impeding the initial 1,5-hydrogen abstraction step started with the Friedel-Crafts acylation of p-xylene (2) to
(Scheme 1). However, various functional groups are a part of give 3a,c,d and 4b, followed by the aldol condensation-
the target indanones, such as those shown in Chart 1. There- elimination (4a) or Mannich (4c,d) reactions to introduce a
fore, new photochemical transformations that would gener- CdC bond. The subsequent nucleophilic epoxidation with
ate an indanone moiety possessing synthetically useful sub- aq H2O2 in methanol provided the target epoxy ketones
stituents in the corresponding positions are of considerable 1a-d in high overall yields (73-84%) and purity.
interest. Photochemistry of 1a-d. A degassed acetonitrile solution
In this work we wish to report that, analogously to of an epoxide (1a-d; ∼5  10-3 M) was irradiated through a
Scheme 1, various substituted indanone derivatives can be Pyrex filter (>290 nm) until >95% of the starting material
synthesized by photolysis of the 2,5-dimethylbenzoyl oxiranes 1 was consumed. Three products, 5-7, were isolated and
via the corresponding (E)-enol (Scheme 2). We expected that the identified (Scheme 4); the chemical yields are summarized
initial 1,5-hydrogen abstraction step would efficiently compete in Table 1. In all cases, the indanones 5 were the major
with the R-C-O bond scission in the excited state and subsequent photoproducts at high conversions and essentially the sole
skeletal rearrangements, which are archetypal transformation 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
(21) Dolling, U. H.; Davis, P.; Grabowski, E. J. J. J. Am. Chem. Soc. 1984,
106, 446. 1d and in very low chemical yields.
(22) Elati, C. R.; Kolla, N.; Chalamala, S. R.; Vankawala, P. J.; Sundaram, Exhaustive irradiation of 1c afforded a complex mixture
V.; Vurimidi, H.; Mathad, V. T. Synth. Commun. 2006, 36, 169. of compounds, from which only 5c was successfully isolated
(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, in 7% yield. Since the HPLC yield at a 40% conversion
M.; Dauphin, F.; Dallemagne, P.; Rault, S. Eur. J. Med. Chem. 2005, 40, was 82%, we assumed that this photoproduct underwent
1222.
(24) Kobayashi, A.; Egawa, H.; Koshimizu, K.; Mitsui, T. Agric. Biol.
Chem. 1975, 39, 1851. (34) Hallet, P.; Muzart, J.; Pete, J. P. J. Org. Chem. 1981, 46, 4275.
(25) Wessig, P.; Teubner, J. Synlett 2006, 1543. (35) Pappas, S. P.; Gresham, R. M.; Miller, M. J. J. Am. Chem. Soc. 1970,
(26) Wessig, P.; Glombitza, C.; Muller, G.; Teubner, J. J. Org. Chem. 92, 5795.
2004, 69, 7582. (36) Pappas, S. P.; Bao, L. Q. J. Am. Chem. Soc. 1973, 95, 7906.
(27) Pospisil, T.; Veetil, A. T.; Lovely Angel, P. A.; Klan, P. Photochem. (37) Paquette, L. A.; Nitz, T. J.; Ross, R. J.; Springer, J. P. J. Am. Chem.
Photobiol. Sci. 2008, 7, 625. Soc. 1984, 106, 1446.
(28) Du, L. H.; Zhang, S. H.; Wang, Y. G. Tetrahedron Lett. 2005, 46, (38) Hallet, P.; Muzart, J.; Pete, J. P. Tetrahedron Lett. 1979, 2723.
3399. (39) Williams, J. R.; Sarkisia, Gm; Quigley, J.; Hasiuk, A.; Vanderve, R J.
(29) Park, B. S.; Lee, H. M. Bull. Korean Chem. Soc. 2008, 29, 2054. Org. Chem. 1974, 39, 1028.
(30) Park, B. S.; Jeong, S. Bull. Korean Chem. Soc. 2009, 30, 3053. (40) Hasegawa, E.; Ishiyama, K.; Fujita, T.; Kato, T.; Abe, T. J. Org.
(31) Park, B. S.; Ryu, H. J. Tetrahedron Lett. 2010, 51, 1512. Chem. 1997, 62, 2396.
(32) Zimmerman, H. E.; Simkin, R. D. Tetrahedron Lett. 1964, 1847. (41) Lauret, C. Tetrahedron: Asymmetry 2001, 12, 2359.
(33) Zimmerman, H. E.; Cowley, B. R.; Tseng, C. Y.; Wilson, J. W. J. Am. (42) Wagner, P. J.; Kelso, P. A.; Kemppainen, A. E.; Zepp, R. G. J. Am.
Chem. Soc. 1964, 86, 947. Chem. Soc. 1972, 94, 7500.

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SCHEME 2. Photochemistry of o-Methylbenzoyl Oxiranes: TABLE 2. Quantum Yields (Φ) of 5a-d Formation from 1a-d
The Strategy compound Φa
5a 0.11 ( 0.01
5b 0.15 ( 0.01 (0.16 ( 0.01b)
5c 0.25 ( 0.01
5d 0.12 ( 0.01
a
Degassed 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
a
Reagents and conditions: (i) AlCl3, CS2, 0 °C; (ii) KOH, methanol,
allow elimination of water to form R,β-unsaturated ketones,
20 °C; (iii) H2O2, KOH, MeOH, 0 °C; (iv) aq CH2O, CH3CO2H (cat.), useful intermediates in organic synthesis. Thus 5b (∼1 
piperidine (cat.), MeOH; (v) aq CH2O, morpholine (cat.), CH3CO2H. 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
SCHEME 4. Photochemistry of 1a-d 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).
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)
irradiated epoxide % yield (5a-d) % yield (6a-d) % yield (7a-d) and that the excited (triplet) state lifetime is ∼2 ns, assuming
1a 74b,c [93d] n.d.f n.d.f that the energy transfer is diffusion-controlled (kq =1.5  109
1b 72b,c [85d] 7b 12b M-1 s-1 in benzene43). In addition, irradiation of 1b in neat
1c 7b [82e] n.d.f n.d.f acetone, acting as a triplet sensitizer, afforded the same photo-
1d 69b [93d] 8b 15b products as those obtained in acetonitrile by direct irradiation.
a
Degassed solutions of 1a-d (∼5  10-3 M) in acetonitrile were We concluded that the photoproducts are exclusively triplet-
irradiated at λ > 290 nm to >95% conversion. bIsolated by column
chromatography. cA pair of diastereomers in a ∼1:1 ratio (NMR,
state-derived. This is in agreement with the discussion of Park
HPLC). dThe optimized HPLC yields of the indanone 5 formation in and his co-workers who studied a structurally analogous
∼95% conversions. eThe optimized HPLC yields of the indanone 5 chromophore, 2-(o-tolyl)-2-benzoyloxirane (9, shown later in
formation in ∼40% conversions. fNot detected. Scheme 7), the photochemistry of which also occurs exclusively
from the triplet state.44
subsequent photochemical transformations. Indeed, pro-
longed irradiation of 5a or b in acetonitrile led to a complex
mixture of photoproducts, which were, however, produced (43) Montalti, M.; Credi, A.; Prodi, L.; Gandolfi, M. T. Handbook of
Photochemistry, 3rd ed.; CRC Press: Boca Raton, 2006.
with a lower efficiency than the primary photoproducts 5 (44) Kim, H.; Kim, T. G.; Hahn, J.; Jang, D. J.; Chang, D. J.; Park, B. S.
formed from 1. 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 FIGURE 1. Highest occupied molecular orbitals (HOMO-1 and
relative energies are strongly influenced by both the benzene HOMO) of the triplet 1g (n,π*) and 1f (π,π*).
ring substituents and the environment.45 Electron-donating
groups and polar solvents tend to stabilize the π,π* state.45-48 Formation of 6 and 7 (Schemes 4 and 6) suggests that a
The π,π* state of a phenyl ketone is generally far less reactive homolytic CR-O bond scission32-40 occurs at some stage of
than the n,π* state toward both electron and hydrogen-atom the reaction and competes with the 1,5-hydrogen atom shift.
abstraction reactions.49-52 According to Park and co-workers,44 only two competing
Because the major products obtained from photolysis of 1 chemical decay channels exist in the lowest triplet state of the
were the indanones 5, we assumed that they are produced via analogous 2-(o-tolyl)-2-benzoyloxirane 9 (Scheme 7): a 1,4-
photoenolization initiated by an intramolecular 1,5-hydrogen H atom shift (k = 6  107 s-1) from the methylene group of
abstraction (Scheme 1). The short lifetime of the triplet 1a thus the oxiranyl ring followed, by the CR-O bond scission and a
has to be related to an efficient intramolecular hydrogen 1,6-H atom shift (k=2.3  108 s-1) from the o-methyl group.
abstraction, which furthermore implies that the state is n,π* Scheme 8 shows three reaction pathways of the triplet excited
in character. The photochemistry of the epoxide 1e was studied 1g inspired by the photochemistry of 9 as obtained from our
to confirm our assumption that the π,π* excited epoxide will DFT quantum chemical calculations. As expected, the 1,5-H
not produce the corresponding indanone 5e (Scheme 6). In- atom shift (preceding the photoenolization reaction) is pre-
deed, irradiation of a degassed solution of 1e (∼5  10-3 M) at ferred to the direct CR-O bond homolysis by ∼2 kcal mol-1.
λ > 290 nm led to 6e as a major product regardless of what kind The CR-O bond was cleaved spontaneously in all of our
of solvent (acetonitrile, benzene, hexane, t-BuOH) was used attempts to locate the transition state of a 1,4-H atom shift in
(Scheme 6). The two electron-donating methoxy groups in 1e the triplet 1g. Therefore, the CR-O bond homolysis followed
evidently inverted the energy of the two states, rendering the by a 1,4-H atom shift (highlighted in red, Scheme 8) is a
π,π* state as the lowest (reactive) triplet state,45,48 which dominant photochemical channel to 6.
resulted in a CR-O bond scission.34,38 The excited state type The rate constants of 1,5-H atom shift, which is observed
was theoretically examined on an analogue 1f together with the in our system, are generally higher than those for less or more
unsubstituted o-methylbenzoyl oxirane 1g. The relevant mo- distant H-atom transfers due to the ring strain introduced in
lecular orbitals from the UB3LYP/6-31G* level of theory in the the transition state.53-55 Indeed, the rates of both the 1,6-H
gas phase are depicted in Figure 1. The results, according to atom shift (∼2  108 s-1) and 1,4-H atom shift (∼6  107 s-1)
which the lowest triplet states of 1f and 1g are of π,π* and n,π* in 9 are slower than that of the 1,5-H atom shift in 1a as
character, respectively, are consistent with our assumption. estimated from the Stern-Volmer analysis (∼5  108 s-1).
The compound 6 was preferentially formed only when the
(45) Wagner, P. J.; Park, B.-S. In Organic Photochemistry; Padwa, A., inversion of the triplet state levels in 1e decreased the rate
Ed.; Marcel Dekker, Inc.: New York, 1991; Vol. 11, p 227. constant of an H-atom abstraction (formation of the ben-
(46) Rauh, R. D.; Leermakers, P. A. J. Am. Chem. Soc. 1968, 90, 2246. zooxepinone 7e was not observed).
(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 A comprehensive reaction mechanism for the formation of
and Photobiology, 2nd ed.; Horspool, W. M., Lenci, F., Eds.; CRC Press 5 and 7 is demonstrated in Scheme 9 on the 2-methylbenzoyl
LLC: Boca Raton, 2003; Chapter 52, p 1. oxirane 1g photochemistry, which includes the results of our
(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. (53) Hayes, C. J.; Burgess, D. R. J. Phys. Chem. A 2009, 113, 2473.
(51) Zimmerman, H. E.; Steinmetz, M. G. J. Chem. Soc., Chem. Commun. (54) Dorigo, A. E.; Houk, K. N. J. Am. Chem. Soc. 1987, 109, 2195.
1978, 230. (55) Dorigo, A. E.; McCarrick, M. A.; Loncharich, R. J.; Houk, K. N.
(52) Zimmerman, H. E. Acc. Chem. Res. 1982, 15, 312. J. Am. Chem. Soc. 1990, 112, 7508.

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SCHEME 8. Formation of 6a

a
The 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
homolytic CR-O bond scission in 3E, 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
a
Structures in blue and red denote isolated and spectroscopically cuvette. The ratio of the integrals, corresponding to the
observed species, respectively; a putative (not observed) product is o-methyl and CH (of the oxiranyl ring) signals, decreased
shown in green. The operative pathway (vide infra) of the indanones by ∼25%. We were unable to integrate the peaks properly at
formation is depicted by bold arrows. The activation Gibbs energies are
shown. longer irradiation times because of an overlap of the peaks
with those of the products; nevertheless, it was sufficient
DFT calculations. The primary 1,4-biradical 3E, which was evidence that photoenols are indeed formed in the solution
formed from the triplet excited compound by a hydrogen upon irradiation.
shift (Scheme 8), can undergo either CR-O homolytic clea- In addition, the mechanism of the photoreactions of 1b
vage to 12 or intersystem cross to the ground state to produce was investigated by laser flash photolysis (Table 3; see also
two photoenols (in red). The rate of 3E decay for phenacyl Supporting Information, S41-44). The transient absorption
derivatives is known to depend on the presence of oxygen or spectrum of an aerated solution of 1b in acetonitrile obtained
other triplet quenchers (τ ∼16-300 ns).7,17,18,20 Compound 1 μs after the laser flash is shown in Figure 3. The absorption
12 possesses a reactive primary alkoxy radical center; a spectrum reproduces nicely that measured for both ground
simple H-atom shift between the two oxygen atoms with a state photoenols in previous studies.7,17-20 We were unable
calculated barrier of ΔGq =7.3 kcal mol-1 results in a more to see any significant absorption at ∼340-350 nm characteristic
stable radical (see Figure 2), whose two mesomeric forms, of 3E even at short time delays (15 ns). Such a remarkable short
13a and 13b, are shown in the scheme. This pathway can be lifetime of a 1,4-biradical is consistent with that reported by
considered as a spin-center shift mechanism, recently proposed Caldwell and co-workers for R-benzyloxyacetophenone60 or
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.
(56) Wessig, P.; Muehling, O. Eur. J. Org. Chem. 2007, 2219. Chem. 1991, 56, 1631.

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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
in less polar cyclohexane: lifetimes of 47 and 12.5 ns were solvent τ (3E) τ (Z)-photoenol τ (E)-photoenol
observed in the degassed and air-saturated solutions, respec- acetonitrile 23 (<10)b ns 8.8 μs 5 ms
tively. This transient intermediate was assigned to the triplet enol cyclohexane 47 (12.5)b ns 2.8 μs >40 msc
(3E) decay. The lifetimes of the other two components were not
a
Degassed solutions (∼1  10-4 M) in acetonitrile or cyclohexane
sensitive to the presence of oxygen. A shorter-lived intermediate measured at λ=390 nm after 266-nm laser flash. bThe lifetimes measured
for aerated solutions are in the parentheses. cThe lower limit estimated
with a lifetime of 8.8 and 2.8 μs in acetonitrile and cyclohexane from the exponential fit of the kinetic trace.
solution, respectively, was attributed to the ground state (Z)-
photoenol, which is expected to undergo fast intramolecular relevant intermediates shown in Figure 2. The results
reketonization,7,17 while the long-lived component was attrib- are summarized in the Supporting Information (S48). Only
uted to the (E)-photoenol. Its lifetime of 5.0 ms was observed in the photoenols and conformers of the triplet enol, 3E,
acetonitrile, whereas that in cyclohexane (>40 ms) could not showed a strong absorption at ∼390 nm (f ∼0.15-0.19;
be fit properly because of instability of our white light source at Figure 3) and ∼355-363 nm (f ∼0.1), respectively. The
such a long time scale. Our results resemble well those reported transitions for other relevant species are approximately
for the photoenolization in dimethylphenacyl chromophore 10 times weaker in this region. Regarding the absence of
substituted by different leaving groups in the R-position.7,17-20 significant spectral changes within the time of the experi-
Our assignments were also rationalized by performing ment or in the presence of oxygen, we conclude that both
TD-DFT calculations of the electronic transitions for all kinetic traces assigned to the decay of the 390 nm signal
belong to the photoenol intermediates, although the pre-
(60) Caldwell, R. A.; Majima, T.; Pac, C. J. Am. Chem. Soc. 1982, 104, sence of some other relevant species cannot be unambigu-
629. ously ruled out.
J. Org. Chem. Vol. 75, No. 21, 2010 7305
 
JOC Article Solomek et al.

(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 = 7.3 Hz),
6.96 (d, 1H, J = 7.8 Hz), 7.01 (d, 1H, J = 7.8 Hz), 7.31 (s, 1H). 13C
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.
1
H 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,
FIGURE 3. Transient absorption spectrum of 1b. The spectrum 121, 108, 93, 77, 65, 43, 39.
was taken 1 μs after the laser flash for an acetonitrile solution of 1b. (E)-1-(2,5-Dimethylphenyl)-3-phenylprop-2-en-1-one (4a). A
The red line shows the TD-DFT calculated transition of the E-enol solution of 3a (2.00 g, 13.5 mmol) in ethanol (15 mL) was added
derived from 1g (the intensity is arbitrarily scaled; see Supporting dropwise to aq KOH (40 mL, 10%) at 0 °C. Freshly distilled
Information, S48). benzaldehyde (1.43 g, 13.5 mmol) was then added dropwise to
the mixture in the period of 10 min. The reaction mixture was
In conclusion, four 2,5-dimethylbenzoyl oxiranes were stirred for 2 days at 20 °C and extracted with CH2Cl2 (3 
synthesized in high overall chemical yields, and their photo- 50 mL). The organic extracts were washed with brine (50 mL),
chemistry was explored. Irradiation of these epoxy ketones dried with MgSO4, and solvents were evaporated at reduced
resulted in indanone derivatives as major products, which pressure to give 4a. Yield: 94%; yellowish oil. 1H NMR (300
are structurally similar to some known pharmaceutically 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,
important compounds. In addition, a simple route to a
1H, 1H, J = 16.1 Hz), 7.57 (m, 2H). 13C NMR (75.5 MHz,
2-ethylidene-2,3-dihydro-1H-inden-1-one derivative from CDCl3): δ (ppm) 19.7, 20.9, 126.8, 128.4, 128.5, 128.8, 128.9,
the synthesized indanones was described. The laser flash 130.5, 131.2, 133.7, 134.7, 135.0, 139.1, 145.6, 196.6. MS (EI, 70
photolysis experiments and quantum-chemical calculations eV): m/z = 236, 145, 131, 103, 77.
provided solid evidence that the indanone photoproducts are (E)-1-(2,5-Dimethylphenyl)but-2-en-1-one (4b). The compound
formed via a photoenolization mechanism. A total synthesis was prepared from p-xylene (19.6 g, 185 mmol) and crotonyl
of several biologically active compounds, which is based on chloride (21.2 g, 224 mmol) according to the procedure described
the photochemical approach introduced here, is currently for 3a-e. Yield: 94%; colorless oil. 1H NMR (300 MHz, CDCl3):
under investigation in our laboratory. 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,
Experimental Section J1 = 15.6 Hz, J2 = 6.8 Hz), 7.10-7.16 (m, 2H), 7.17 (s, 1H). 13C
NMR (75.5 MHz, CDCl3): δ (ppm) 17.3, 18.7, 19.8, 127.6, 130.1,
General Procedure for the Synthesis of Acylphenones 3a-e. 130.2, 131.3, 132.6, 133.8, 138.1, 144.9, 194.9. MS (EI, 70 eV):
The corresponding acyl chloride (224 mmol) was added drop- m/z = 174, 159, 141, 131, 115, 15, 91, 79, 69, 41.
wise to a mixture of aluminum chloride (27.2 g, 204 mmol) and 1-(2,5-Dimethylphenyl)-2-phenylprop-2-en-1-one (4c). Piperi-
either p-xylene (19.6 g, 185 mmol) or 1,2-dimethoxy-4-methyl- dine (0.13 mL, 1.3 mmol), acetic acid (0.12 mL, 2.1 mmol),
benzene (28.2 g, 185 mmol) in CS2 (100 mL) under nitrogen and aq formaldehyde (37% solution, 4 mL, 50 mmol) were
atmosphere at 0-3 °C in a period of 1.5 h. The reaction mixture successively added to a magnetically stirred solution of 3c
was stirred for 1 h at 0 °C, warmed to 20 °C, stirred for (2.92 g, 13.0 mmol) in methanol (50 mL), and the resulting
additional 2 h, and then poured on ice (400 g). After the ice mixture was refluxed for 4 h and concentrated under reduced
melted, the aqueous layer was extracted with CH2Cl2 (3  100 mL). pressure. Water (50 mL) was added to the residue, and the
The combined organic extracts were washed with brine (100 mL) mixture was extracted with CH2Cl2 (3  30 mL). Combined
and dried with MgSO4. The solvent was evaporated under reduced organic extracts were washed with water (2  50 mL) and brine
pressure to give the crude title product, which was purified by (30 mL) and dried with MgSO4, and solvent was evaporated
vacuum distillation. under reduced pressure. The crude product was purified by flash
1-(2,5-Dimethylphenyl)ethanone (3a). Prepared from p-xylene column chromatography (silica, petroleum ether/ethyl acetate,
and acetyl chloride (15.9 mL, 224 mmol). Yield: 95%; colorless 8:1) to give the title product. Yield: 97%; white crystals, mp
oil. 1H NMR (300 MHz, CDCl3): δ (ppm) 2.35 (s, 3H), 2.47 178.3-181.0 °C. 1H NMR (300 MHz, CDCl3): δ (ppm) 2.33 (s,
(s, 3H), 2.55 (s, 3H), 7.10 (d, 1H, J = 7.8 Hz), 7.16 (d, 1H, J =7.8 3H), 2.42 (s, 3H), 5.75 (s, 1H), 6.17 (s, 1H), 7.14 (d, 1H, J = 7.8
Hz), 7.47 (s, 1H). 13C NMR (75.5 MHz, CDCl3): δ (ppm) 20.7, Hz), 7.19 (dd, 1H, J1 = 7.8 Hz, J2 = 1.3 Hz), 7.29 (d, 1H, J = 1.3
20.8, 29.3, 129.7, 131.8, 132.0, 135.0, 135.6 137.6, 201.6. MS (EI, Hz), 7.38 (m, 3H), 7.47 (dd, 1H, J1 = 7.9 Hz, J2 = 1.7 Hz). 13C
70 eV): m/z = 148, 133, 105, 79, 77, 51, 43. NMR (75.5 MHz, CDCl3): δ (ppm) 19.9, 21.0, 120.7, 128.1,
1-(2,5-Dimethylphenyl)-2-phenylethanone (3c). Prepared from 128.4, 128.5, 129.9, 131.2, 131.6, 134.4, 135.0, 137.0, 138.7,
p-xylene and phenylacetyl chloride (27.1 mL, 224 mmol). Yield: 149.8, 199.9. MS (EI, 70 eV): m/z = 236, 159, 145, 133, 105,
95%; colorless crystals, mp 30.2-31.6 °C. 1H NMR (300 MHz, 77, 63, 51.
CDCl3): δ (ppm) 2.42 (s, 3H), 2.46 (s, 3H), 4.25 (s, 2H), 7.16 (d, 1-(2,5-Dimethylphenyl)-2-methylprop-2-en-1-one (4d). Acetic
1H, J = 7.8 Hz,), 7.22 (dd, 1H, J1 = 7.8 Hz, J2 = 1.5 Hz), 7.31 acid (10 mL) was added to a magnetically stirred suspension of

7306 J. Org. Chem. Vol. 75, No. 21, 2010


Solomek et al.
JOC Article
3d (1.62 g, 10 mmol) and aq formaldehyde (37% solution, (2,5-Dimethylphenyl)(2-phenyloxiran-2-yl)methanone (1c). Pre-
2.4 mL, 30 mmol). A catalytic amount (few drops) of morpho- pared from 4c. Yield: 94%; colorless oil. 1H NMR (300 MHz,
line was then added, and the resulting mixture was refluxed for CDCl3): δ (ppm) 2.29 (s, 3H), 2.48 (s, 3H), 3.07 (d, 1H,
5 days. The reaction mixture was cooled to 20 °C, neutralized J = 5.6 Hz), 3.30 (d, 1H, J = 5.6 Hz), 7.11 (d, 1H, J = 7.8
with aq NaOH (20%), and extracted with CH2Cl2 (3  50 mL). Hz), 7.17 (d, 1H, J = 7.8 Hz), 7.30-7.41 (m, 3H), 7.48-7.56 (m,
Combined organic extracts were washed with brine (50 mL) and 3H). 13C NMR (75.5 MHz, CDCl3): δ (ppm) 20.8, 21.1, 54.9, 63.6,
dried with MgSO4, and solvent was evaporated under reduced 126.3, 128.3, 128.8, 131.0, 131.7, 132.8, 134.7, 135.1, 135.8, 136.4,
pressure. The flash column chromatography of the resulting 199.5. MS (EI, 70 eV: m/z = 252, 237, 193, 178, 133, 119, 105, 91,
mixture (silica, petroleum ether/ethyl acetate, 8:1) gave the 77, 65. UV-vis (acetonitrile): ε313 = 730 dm3 mol-1 cm-1, ε254 =
product. Yield: 96%; colorless oil. 1H NMR (300 MHz, CDCl3): 7160 dm3 mol-1 cm-1. HRMS (EIþ): calcd for C17H17O2 [M þ
δ (ppm) 1.99 (s, 3H), 2.19 (s, 3H), 2.25 (s, 3H), 5.53 (s, 1H), 5.89 Hþ] 253.1229, found 253.1223.
(s, 1H), 6.99 (s, 1H), 7.02 (d, 1H, J = 7.9 Hz), 7.06 (d, 1H, J = (2,5-Dimethylphenyl)(2-methyloxiran-2-yl)methanone (1d). Pre-
7.9 Hz). 13C NMR (75.5 MHz, CDCl3): δ (ppm) 17.0, 19.0, 20.6, pared from 4d. Yield: 80%; colorless oil. 1H NMR (300 MHz,
128.1, 129.5, 130.3, 130.5, 132.6, 134.3, 138.9, 145.0, 200.5. MS CDCl3): δ (ppm) 1.66 (s, 3H), 2.32 (s, 6H), 2.80 (d, 1H, J = 5.3
(EI, 70 eV): m/z = 174, 159, 145, 133, 115, 105, 91, 77, 65, 51, 41. Hz), 2.86 (d, 1H, J = 5.3 Hz), 7.08 (d, 1H, J = 7.8 Hz), 7.14 (dd,
(E)-1-(4,5-Dimethoxy-2-methylphenyl)-3-phenylprop-2-en-1-one 1H, J1 = 7.8 Hz, J2 = 1.8 Hz), 7.23 (d, 1H, J = 1.8 Hz). 13C NMR
(4e). Prepared as 4a from 3e (2.62 g, 13.5 mmol). Yield: 72%; (75.5 MHz, CDCl3): δ (ppm) 17.7, 19.6, 21.0, 52.4, 59.9, 128.3,
yellow solid; mp 107.1-109.8 °C. 1H NMR (300 MHz, CDCl3): δ 130.9, 131.6, 134.1, 134.8, 135.7, 204.5. MS (EI, 70 eV): m/z = 190,
(ppm) 2.45 (s, 3H), 3.89 (s, 3H), 3.93 (s, 3H), 6.75 (s, 1H), 7.10 (s, 174, 159, 145, 133, 105, 91, 77, 65, 51, 41. UV-vis (acetonitrile):
1H), 7.17 (d, 1H, J = 15.1 Hz), 7.39-7.40 (m, 3H), 7.53 (d, 1H, ε313 = 410 dm3 mol-1 cm-1, ε254 = 6120 dm3 mol-1 cm-1.
J = 15.1 Hz), 7.56-7.59 (m, 2H). 13C NMR (75.5 MHz, CDCl3): HRMS (EIþ): calcd for C12H15O2 [M þ Hþ] 191.1072, found
δ (ppm) 20.6, 56.1, 56.4, 112.4, 114.4, 126.7, 128.5, 129.1, 130.6, 191.1067.
131.3, 131.6, 135.0, 144.9, 146.7, 151.1, 194.7. MS (EI, 70 eV): m/z = (4,5-Dimethoxy-2-methylphenyl)(3-phenyloxiran-2-yl)methanone
282, 267, 251, 205, 191, 179, 165, 151, 131, 121, 103, 91, 77, 65, 51. (1e). Prepared from 4e. Yield: 77%; white crystals, mp 136.3-
(E)-3-Phenyl-1-o-tolylprop-2-en-1-one (4h). Prepared as 4a 137.7 °C. 1H NMR (300 MHz, CDCl3): δ (ppm) 2.51 (s, 3H), 3.80
from o-methylacetophenone (1.81 g, 13.5 mmol). Yield: 88%; (s, 3H), 3.91 (s, 3H), 4.05 (1H, J = 1.9 Hz), 4.06 (1H, J = 1.9 Hz),
colorless oil. 1H NMR (300 MHz, CDCl3): δ (ppm) 2.49 (s, 3H), 6.73 (s, 1H), 7.27 (s, 1H), 7.33-7.41 (m, 5H). 13C NMR (75.5 MHz,
7.17 (d, J = 16.0 Hz, 1H), 7.30-7.33 (m, 2H), 7.39-7.43 (m, CDCl3): δ (ppm) 21.3, 56.1, 56.3, 59.3, 62.7, 112.6, 114.7, 125.8,
4H), 7.57-7.60 (m, 3H). 13C NMR (75.5 MHz, CDCl3): δ (ppm) 127.54, 128.9, 129.1, 134.1, 135.8, 146.7, 152.4, 194.6. MS (EI, 70 eV):
20.3, 125.6, 126.9, 128.2, 128.5, 129.1, 130.6, 130.7, 131.4, 134.8, m/z = 282, 269, 191, 179, 152, 136, 121, 105, 91, 77, 65, 51. HRMS
137.1, 139.2, 145.9, 196.5. MS (EI, 70 eV): m/z = 222, 178, 145, (EIþ): calcd for C18H19O4 [M þ Hþ] 299.1283, found 299.1278.
131, 103, 91, 77, 65, 51. (3-Phenyloxiran-2-yl)(o-tolyl)methanone (1h). Prepared from
General Procedure for the Synthesis of Epoxides 1a-e,h. H2O2 4h. Yield: 94%; colorless oil. 1H NMR (300 MHz, CDCl3): δ
(30%, 2.9 mL, 28.9 mmol) was added dropwise to a stirred (ppm) 2.57 (s, 3H), 4.06 (d, 1H, J = 1.7 Hz), 4.13 (d, 1H, J = 1.7
solution of an enone (4a-e,h; 11 mmol) in methanol (60 mL) Hz), 7.29-7.32 (m, 2H), 7.37-7.44 (m, 6H), 7.71 (d, 1H, J = 7.8
cooled to 0 °C. Then a cooled solution (0 °C) of KOH (0.32 g, Hz). 13C NMR (75.5 MHz, CDCl3): δ (ppm) 21.1, 59.6, 62.5,
5.7 mmol) in methanol (20 mL) was added, and the mixture was 126.0, 128.9, 129.1, 129.2, 132.2, 132.4, 135.6, 139.0, 196.7. MS
stirred at 0 °C for 2 h. The reaction progress was monitored by (EI, 70 eV): m/z = 238, 119, 91, 77, 65, 51.
TLC. After completion, the reaction was quenched with water General Procedure for Irradiation of 1a-e; Preparation of
(100 mL) and extracted with CH2Cl2 (3  30 mL). The organic 5a-d, 6b,d,e and 7b,d. A degassed (N2) solution of the corre-
extracts were washed with brine (50 mL) and dried with MgSO4, sponding epoxide (1a-e, 5  10-3 M) in acetonitrile (200 mL)
and the solvents were evaporated under reduced pressure. The was irradiated with a 125- or 400-W Hg medium pressure UV
crude product mixture was separated using flash column chro- lamp through a Pyrex filter (λ < 290 nm) until ∼95% conver-
matography (silica, petroleum ether/ethyl acetate, 20:1 to 10:1) sion (HPLC) was reached (or ∼41% in the case of the epoxide
to give the title product. 1c). The solvent was removed under reduced pressure at the
(2,5-Dimethylphenyl)(3-phenyloxiran-2-yl)methanone (1a). Pre- temperature below 40 °C to prevent a retro-aldol reaction. The
pared from 4a (2.60 g, 11 mmol). Yield: 94%; white crystals, mp resulting mixture was separated by flash column chromatogra-
67.1-69.2 °C. 1H NMR (300 MHz, CDCl3): δ (ppm) 2.34 (s, 3H), phy (silica, petroleum ether/ethyl acetate, 20:1 to 5:1) to give the
2.49 (s, 3H), 4.05 (d, 1H, J = 1.8 Hz), 4.10 (d, 1H, J = 1.8 Hz), title photoproducts.
7.17 (d, 1H, J = 7.8 Hz), 7.24 (d, 1H, J = 7.8 Hz), 7.36-7.42 (m, 2-(Hydroxy(phenyl)methyl)-6-methyl-2,3-dihydro-1H-inden-1-
5H), 7.48 (s, 1H). 13C NMR (75.5 MHz, CDCl3): δ (ppm) 20.6, one (5a). Obtained from 1a. Yield: 67%; colorless oil; two
21.0, 59.6, 62.4, 126.0, 128.9, 129.0, 129.1, 129.5, 132.1, 133.1, diastereomers (a ∼1:1 ratio). 1H NMR (300 MHz, CDCl3): δ
135.6, 135.7, 135.7, 197.0. MS (EI, 70 eV): m/z = 252, 237, 222, (ppm) 2.41 (s, 3H), 2.43 (s, 3H), 2.65 (dd, J1 = 17.4 Hz, J2 = 4.4
207, 178, 148, 133, 119, 105, 91, 77, 51, 44. UV-vis (acetonitrile): Hz, 1H), 2.84-2.94 (m, 2H), 3.03-3.10 (m, 2H), 3.22 (dd, J1 =
ε313 = 1040 dm3 mol-1 cm-1, ε254 = 10 780 dm3 mol-1 cm-1. 16.8 Hz, J2 = 4.4 Hz, 1H), 4.80 (d, J = 9.7 Hz, 1H), 4.92 (s,
HRMS (EIþ): calcd for C17H17O2 [M þ Hþ] 253.1229, found broad), 5.59 (dd, J1 = 3.1 Hz, J2 = 3.1 Hz, 1H), 7.26-7.46 (m,
253.1222. 14H), 7.60 (s, 1H), 7.61 (s, 1H). 13C NMR (75.5 MHz, CDCl3): δ
(2,5-Dimethylphenyl)(3-methyloxiran-2-yl)methanone (1b). Pre- (ppm) 21.3, 21.3, 26.6, 29.8, 53.7, 55.3, 72.4, 76.1, 124.0, 124.3,
pared from 4b. Yield: 80%; colorless oil. 1H NMR (300 MHz, 125.8, 126.4, 126.5, 127.3, 127.6, 128.5, 128.7, 128.8, 136.5, 136.7,
CDCl3): δ (ppm) 1.47 (d, 3H, J = 5.1 Hz), 2.36 (s, 3H), 2.43 (s, 137.0, 137.5, 137.6, 138.0, 141.7, 142.8, 151.6, 152.3, 207.5, 210.0.
3H), 3.15 (dq, 1H, J1 = 5.1 Hz, J2 = 1.9 Hz), 3.74 (d, 1H, J = 1.9 MS (EI, 70 eV): m/z = 252, 234, 146, 132, 117, 104, 91, 77, 65, 51,
Hz), 7.13 (d, 1H, J = 7.8 Hz), 7.21 (d, 1H, J = 7.8 Hz), 7.44 (s, 32. UV-vis (acetonitrile): ε313 = 2520 dm3 mol-1 cm-1, ε254 =
1H). 13C NMR (75.5 MHz, CDCl3): δ (ppm) 17.5, 20.2, 20.9, 55.8, 9390 dm3 mol-1 cm-1. HRMS (EIþ): calcd for C17H17O2 [M þ
59.7, 129.1, 131.7, 132.7, 135.2, 135.3, 135.8, 198.8. MS (EI, Hþ] 253.1229, found 253.1221.
70 eV): m/z=175, 133, 117, 115, 105, 103, 79, 77, 58, 43. UV-vis 2-(1-Hydroxyethyl)-6-methyl-2,3-dihydro-1H-inden-1-one (5b).
(acetonitrile): ε313 = 775 dm3 mol-1 cm-1, ε254 = 8820 dm3 mol-1 Obtained from 1b. Yield: 64%; colorless oil; two diastereomers
cm-1. HRMS (EIþ): calcd for C12H15O2 [M þ Hþ] 191.1072, (a ∼1:1 ratio). Diastereomer A: 1H NMR (300 MHz, CDCl3):
found 191.1060. δ (ppm) 1.29 (d, 3H, J = 6.2 Hz), 2.41 (s, 3H), 2.65 (ddd, 1H,

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JOC Article Solomek et al.

J1 = 9.0 Hz, J2 = 8.0 Hz, J3 = 4.5 Hz) 2.75 (dd, 1H, J1 = 17.0 Hz, 1H, J1 = 13.5 Hz, J2 = 5.8 Hz), 3.16 (dd, 1H, J1 = 13.5 Hz, J2 =
J2 = 4.5 Hz), 3.24 (dd, 1H, J1 = 17.0 Hz, J2 = 8.0 Hz), 3.98 (dq, 5.5 Hz), 4.24 (tq, 1H, J1 = 6.3 Hz, J2 = 6.1 Hz,), 4.84 (d, 1H,
1H, J1 = 9.0 Hz, J2 = 6.2 Hz), 4.36 (broad, 1H), 7.36 (d, 1H, J = J = 15.3 Hz), 4.94 (d, 1H, J = 15.3 Hz), 7.12 (d, 1H, J = 7.7 Hz),
7.9 Hz), 7.44 (d, 1H, J = 7.9 Hz), 7.56 (s, 1H). 13C NMR (75.5 7.26 (d, 1H, J = 7.7 Hz), 7.66 (s, 1H). 13C NMR (75.5 MHz,
MHz, CDCl3): δ (ppm) 21.1, 21.6, 29.5, 53.8, 69.2, 124.0, 126.2, CDCl3): δ (ppm) 21.1, 21.3, 50.0, 69.4, 71.4, 127.8, 129.2, 132.9,
136.7, 136.9, 137.8, 151.3, 210.0. Diastereomer B: 1H NMR (300 137.5, 137.9, 139.6, 200.5. MS (EI, 30 eV): m/z = 190, 149, 119,
MHz, CDCl3): δ (ppm) 1.28 (d, 3H, J = 6.4 Hz), 2.40 (s, 3H), 2.80 103, 91, 77, 65, 51, 39. HRMS (EIþ): calcd for C12H15O2 [M þ
(ddd, 1H, J1=8.0 Hz, J2=4.5 Hz, J3=3.6 Hz) 3.07 (dd, 1H, J1 = Hþ] 191.1072, found 191.1062.
17.0 Hz, J2 = 4.5 Hz), 3.17 (dd, 1H, J1 = 17.0 Hz, J2 = 8.0 Hz), 4,7-Dimethyl-3,4-dihydrobenzo[c]oxepin-5(1H)-one (7d). Ob-
4.46 (dq, 1H, J1 = 6.4 Hz, J2 = 3.6 Hz), 7.36 (d, 1H, J = 7.9 Hz), tained from 1d.Yield: 15%; colorless oil. 1H NMR (300 MHz,
7.44 (d, 1H, J = 7.9 Hz), 7.56 (s, 1H). 13C NMR (75.5 MHz, CDCl3): δ (ppm) 1.14 (d, 3H, J=6.7 Hz), 2.37 (s, 3H), 3.26-3.38
CDCl3): δ (ppm) 20.8, 21.1, 27.3, 54.3, 67.4, 123.7, 126.4, 136.3, (m, 1H), 3.65 (dd, 1H, J1 = 10.7 Hz, J2 = 10.7 Hz), 4.00 (dd, 1H,
136.6, 137.4, 152.0, 208.4. MS (EI, 70 eV, m/z): 190, 175, 133, 129, J1 = 10.7 Hz, J2 = 6.8 Hz), 4.83 (d, 1H, J = 15.2 Hz), 4.94 (d,
105, 91, 77, 69, 43. UV-vis (acetonitrile): ε313 = 1340 dm3 mol-1 1H, J = 15.2 Hz), 7.10 (d, 1H, J = 7.7 Hz), 7.24 (d, 1H, J = 7.7
cm-1, ε254 = 8030 dm3 mol-1 cm-1. HRMS (EIþ): calcd for Hz), 7.58 (s, 1H). 13C NMR (75.5 MHz, CDCl3): δ (ppm) 11.6,
C12H15O2 [M þ Hþ] 191.1072, found 191.1056. 21.1, 46.6, 71.9, 72.8, 127.4, 129.3, 132.3, 137.7, 138.5, 138.7,
2-(Hydroxymethyl)-6-methyl-2-phenyl-2,3-dihydro-1H-inden- 204.1. MS (EI, 30 eV, m/z): 190, 149, 119, 103, 91, 77, 65, 51, 39.
1-one (5c). Obtained from 1c. Yield: 82% (at a 41% conversion HRMS (EIþ): calcd for C12H15O2 [M þ Hþ] 191.1072, found
of 1c); colorless oil. 1H NMR (300 MHz, CDCl3): δ (ppm) 2.43 191.1053.
(s, 3H), 3.97 (d, 1H, J = 17.0 Hz), 4.13 (d, 1H, J = 17.0 Hz), 4.15 (E)-2-Ethylidene-6-methyl-2,3-dihydro-1H-inden-1-one (8).
(d, 1H, J = 10.9 Hz), 4.27 (d, 1H, J = 10.9 Hz), 7.27-7.46(m, KOH (0.10 g, 1.7 mmol) was added to a stirred solution of 2b
7H), 7.63 (s, 1H). 13C NMR (75.5 MHz, CDCl3): δ (ppm) 21.2, (50 mg, 0.26 mmol) in methanol (30 mL). The reaction mixture
38.8, 58.6, 68.0, 124.5, 126.2, 127.0, 127.3, 128.9, 136.6, 136.9, was heated to 40 °C in the period of 20 min and then extracted
137.9, 140.4, 150.7, 208.3. MS (EI, 70 eV): m/z = 238, 119, 91, with CH2Cl2 (3  10 mL). The combined organic layers
77, 65. UV-vis (acetonitrile): ε313 = 2270 dm3 mol-1 cm-1, ε254 were washed with brine (30 mL) and dried with MgSO4, and
= 10 140 dm3 mol-1 cm-1. HRMS (EIþ): calcd for C17H17O2 the solvent was evaporated under reduced pressure. The
[M þ Hþ] 253.1229, found 253.1223. crude product was purified by flash chromatography (silica,
2-(Hydroxymethyl)-2,6-dimethyl-2,3-dihydro-1H-inden-1-one petroleum ether/ethyl acetate, 10:1) to give 8. Yield: 97%; color-
(5d). Obtained from 1d. Yield: 66%; colorless oil. 1H NMR (300 less oil. GC showed a mixture of the (E)- and (Z)-isomers in a
MHz, CDCl3): δ (ppm) 1.24 (s, 3H), 2.39 (s, 3H), 2.84 (d, 1H, 94:6 ratio. 1H NMR (300 MHz, CDCl3): δ (ppm) 1.97 (dt, 3H,
J = 17.0 Hz), 3.18 (d, 1H, J = 17.0 Hz), 3.62 (d, 1H, J = 10.7 J1 = 7.2 Hz, J2 = 2.1 Hz), 2.43 (s, 3H), 3.62 (broad s, 2H), 6.94
Hz), 3.81 (d, 1H, J = 10.7 Hz), 7.34 (d, 1H, J = 7.8 Hz), 7.43 (d, (tq, 1H, J1 = 7.1 Hz, J2 = 2.1 Hz), 7.38-7.43 (m, 2H), 7.67
1H, J = 7.8 Hz), 7.53 (s, 1H). 13C NMR (75.5 MHz, CDCl3): δ (s, 1H). 13C NMR (75.5 MHz, CDCl3): δ (ppm) 15.54, 21.38,
(ppm) 14.2, 20.7, 37.7, 51.1, 67.9, 124.1, 126.3, 136.0, 136.5, 29.70, 124.6, 126.2, 132.9, 135.8, 137.6, 138.3, 139.3, 146.8, 193.5.
137.4, 150.6, 211.1. MS (EI, 70 eV): m/z = 190, 172, 159, 145, MS (EI, 70 eV): m/z = 172, 157, 143, 129, 115, 102, 77, 63, 51.
132, 129, 115, 105, 91, 77, 51, 32. UV-vis (acetonitrile): ε313 = HRMS (EIþ): calcd for C12H13O [M þ Hþ] 173.0966, found
880 dm3 mol-1 cm-1, ε254 = 6560 dm3 mol-1 cm-1. HRMS 173.0962.
(EIþ): calcd for C12H15O2 [M þ Hþ] 191.1072, found 191.1067. Irradiation Experiment in an NMR Cuvette. D2O (25 μL) was
1-(2,5-Dimethylphenyl)-3-hydroxybut-2-en-1-one (6b). Ob- added to a solution of 1h (20 mg) in acetone-d6 (500 μL) in an
tained from 1b. Yield: 7%; colorless oil. 1H NMR (300 MHz, NMR cuvette. The resulting solution was purged with argon for
CDCl3): δ (ppm) 2.17 (s, 3H), 2.34 (s, 3H), 2.45 (s, 3H), 5.84 (s, 10 min. 1H NMR was measured in 15-min intervals of irradia-
1H), 7.11 (d, 1H, J = 7.8 Hz), 7.15 (d, 1H, J = 7.8 Hz), 7.28 (s, tion by a 125-W medium pressure Hg UV lamp through a Pyrex
1H), 15.96 (broad, 1H). 13C NMR (75.5 MHz, CDCl3): δ (ppm) filter (λ < 290 nm).
20.3, 21.0, 25.8, 101.0, 129.0, 131.5, 131.6, 134.1, 135.5, 136.0, Quantum Yield Measurements. The quantum yield measure-
188.4, 193.2. MS (EI, 70 eV): m/z = 190, 172, 132, 129, 115, 104, ments were performed on an optical bench consisting of high
77, 43, 32. HRMS (EIþ): calcd for C12H15O2 [M þ Hþ] pressure 350- or 450-W UV lamps, a 1/8 m monochromator with
191.1072, found 191.1059. 200-1600 nm grating, set to 313 nm, and a 1.0-cm matched
1-(2,5-Dimethylphenyl)-3-hydroxy-2-methylprop-2-en-1-one (6d). quartz cell containing a solution degassed by purging with argon
Obtained from 1d. Yield: 7%; colorless oil. 1H NMR (300 MHz, for 10 min. The sample temperature was maintained using a
CDCl3): δ (ppm) 1.68 (s, 3H), 2.26 (s, 3H), 2.33 (s, 3H), 6.99 (s, 1H), Peltier thermo block set to 20 °C. The light intensity was
7.13 (s, 2H), 8.54 (d, 1H, J = 4.8 Hz), 14.94 (d, 1H, J = 4.8 Hz). 13C monitored by a Si photodiode detector (UV enhanced) with a
NMR (75.5 MHz, CDCl3): δ (ppm) 13.2, 18.8, 21.1, 127.3, 130.5, multifunction optical power meter. The concentration of all
130.7, 135.4, 136.3, 184.4, 208.1. MS (EI, 70 eV): m/z = 190, 172, sample solutions was in the interval of 1  10-3 and 5  10-4 M,
159, 145, 132, 129, 115, 104, 91, 77, 32. HRMS (EIþ): calcd for containing hexadecane (10-3 M; GC) or acetone (10-2 M;
C12H15O2 [M þ Hþ] 191.1072, found 191.1067. HPLC) as internal standards. Valerophenone was used as an
1-(4,5-Dimethoxy-2-methylphenyl)-3-hydroxy-3-phenylprop-2- actinometer in all cases.42 The reaction conversions were always
en-1-one (6e). Obtained from 1e. Yield: 70%; colorless oil. 1H kept below 10% to avoid the interference of photoproducts. The
NMR (300 MHz, CDCl3): δ (ppm) 2.54 (s, 3H), 3.91 (s, 3H), 3.92 relative standard deviations of the mean for multiple (at least
(s, 3H), 6.51 (s, 1H), 6.74 (s, 1H), 7.15 (s,1H), 7.44-7.54 (m, 3H), five) samples were found below 10% in all analyses.
7.95 (m, 2H). 13C NMR (75.5 MHz, CDCl3): δ (ppm) 21.0, 56.2, Steady-State Quenching Experiments. Stern-Volmer anal-
56.4, 97.2, 112.0, 114.5, 127.2, 128.9, 131.3, 132.5, 135.7, 147.1, ysis was performed with naphthalene as a triplet quencher in a
151.3, 184.3, 190.0 (see an HMBC spectrum in the Supporting merry-go-round apparatus (see also the Supporting Informa-
Information, S30). MS (EI, 70 eV): m/z = 298, 283, 267, 221, 192, tion, S41). Samples in Pyrex tubes (13  120 mm) were degassed
179, 150, 136, 121, 105, 91, 77, 69, 51. HRMS (EIþ): calcd for by purging with argon for 10 min. The concentration of all
C18H19O4 [M þ Hþ] 299.1283, found 299.1278. sample solutions was approximately 5  10-3 M, and they
3,7-Dimethyl-3,4-dihydrobenzo[c]oxepin-5(1H)-one (7b). Ob- contained hexadecane (10-3 M) as an internal standard for
tained from 1b. Yield: 12%; colorless oil. 1H NMR (300 MHz, GC measurements. Three degassed tubes for a given naph-
CDCl3): δ (ppm) 1.33 (d, 3H, J = 6.3 Hz), 2.38 (s, 3H), 2.85 (dd, thalene concentration were irradiated using a medium pressure

7308 J. Org. Chem. Vol. 75, No. 21, 2010


Solomek et al.
JOC Article
400-W Hg lamp; the λ = 366 nm band was isolated by an optical measurements, fruitful discussions, and chemical analyses.
filter in order to avoid the absorption by naphthalene. T.S. acknowledges the Scholarship for talented Ph.D. stu-
dents of the Brno City. The University of Fribourg is greatly
Acknowledgment. Support for this work was provided acknowledged for computational resources.
by the Grant Agency of the Czech Republic (203/09/0748),
the Ministry of Education, Youth and Sports of the Supporting Information Available: 1H and 13C NMR spec-
Czech Republic (MSM0021622413), the European Union tra of new compounds; 1H-1H COSY and 1H-13C HMBC
(CETOCOEN, CZ.1.05/2.1.00/01.0001; administered by the NMR correlations; Stern-Volmer analysis; kinetic traces
from laser flash photolysis experiments; UV-vis spectra of
Ministry of Education, Youth and Sports of the Czech
1a-d and 5a-d; total Gibbs free energies (with scaled thermal
Republic), and by the Rector’s Program to Support Masaryk corrections) of calculated species discussed in the article;
University Students’ Creative Work. The authors express TD-DFT electronic transitions; Cartesian coordinates of opti-
their thanks to Lubica Klicova, Peter Sebej, Lukas Maier, mized structures with the corresponding transition states. This
Jaromir Literak, Dominik Heger, and Blanka Hegrova for material is available free of charge via the Internet at http://
their help with the laser flash photolysis experiments, NMR pubs.acs.org.

J. Org. Chem. Vol. 75, No. 21, 2010 7309