The power of solvent in altering the course of photorearrangements

Article abstract of DOI:10.1021/ol102887f

A clean bifurcation between two important photochemical reactions through competition of a triplet state Type II H-abstraction reaction with a photo-Favorskii rearrangement for (o/p)-hydroxy-o-methylphenacyl esters that depends on the water content of the solvent has been established. The switch from the anhydrous Type II pathway that yields indanones to the aqueous-dependent pathway producing benzofuranones occurs abruptly at low water concentrations (～8%). The surprisingly clean yields suggest that such reactions are synthetically promising.

Full text of DOI:10.1021/ol102887f

ORGANIC
LETTERS
2011
Vol. 13, No. 4
644–647
The Power of Solvent in Altering the
Course of Photorearrangements
Peter Sebej,†,‡,§ Bum Hee Lim, Bong Ser Park,*, Richard S. Givens,*,‡ and
ꢀ
,†,§
ꢁ
Petr Klan*
Department of Chemistry, Faculty of Science, Masaryk University, Kamenice 5/A8, 625
00, Brno, Czech Republic, Department of Chemistry, University of Kansas, 1251 Wescoe
Hall Drive, 5010 Malott Hall, 66045 Lawrence, Kansas, United States, Research Centre
for Toxic Compounds in the Environment, Faculty of Science, Masaryk University,
Kamenice 126/3, 625 00 Brno, Czech Republic, Department of Chemistry, Dongguk
University, Seoul 100-715, Korea
parkbs@dongguk.edu; givensr@ku.edu; klan@sci.muni.cz
Received November 30, 2010
ABSTRACT
A clean bifurcation between two important photochemical reactions through competition of a triplet state Type II H-abstraction reaction with a
photo-Favorskii rearrangement for (o/p)-hydroxy-o-methylphenacyl esters that depends on the water content of the solvent has been established.
The switch from the anhydrous Type II pathway that yields indanones to the aqueous-dependent pathway producing benzofuranones occurs
abruptly at low water concentrations (∼8%). The surprisingly clean yields suggest that such reactions are synthetically promising.
An intramolecular Type II reaction of alkylphenones,
especially 2-methylacetophenones, produces high yields of
photoenols that have been shown to be valuable reactive
intermediates.1 When a leaving group (X) is present in the
R-position of 2-alkylacetophenones (1), longer-lived (E)-
photoenols liberate HX to give indanones2 (2; Scheme 1)
that can be employed as precursors to elaborate products
used in synthetic methodology.3 Likewise, the photo-
Favorskii rearrangement of R-substituted p-hydroxyace-
tophenones (3) to p-hydroxyphenylacetic acid (4), dis-
covered more recently, has enjoyed success in a variety of
applications because of its rapid release of nucleofuges
(Scheme 1).4 Both reactions have exhibited very good
photochemical efficiencies and are relatively free of side
reactions that produce complicated product mixtures.
The similarity of the chromophores, the common triplet
state origin for reaction, and the extensive understanding
of the mechanistic photochemistry5 have prompted us to
explore the intersection of the photochemical pathways to
uncover which parameters control the pathway followed
by a chromophore common to both.
† Department of Chemistry, Faculty of Science, Masaryk University.
‡ University of Kansas.
§ Research Centre for Toxic Compounds in the Environment, Faculty of
Science, Masaryk University.
Dongguk University.
(1) (a) Haag, R.; Wirz, J.; Wagner, P. J. Helv. Chim. Acta 1977, 60,
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Chem. Soc. 1979, 101, 6965.
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(b) Pelliccioli, A. P.; Klan, P. P.; Zabadal, M.; Wirz, J. J. Am. Chem. Soc.
2001, 123, 7931. (c) Zabadal, M.; Pelliccioli, A. P.; Klan, P.; Wirz, J. J.
Phys. Chem. A 2001, 105, 10329. (d) Klan, P.; Pelliccioli, A. P.; Pospisil,
T.; Wirz, J. Photochem. Photobiol. Sci. 2002, 1, 920. (e) Literak, J.; Wirz,
J.; Klan, P. Photochem. Photobiol. Sci. 2005, 4, 43. (f) Kammari, L.;
Plistil, L.; Wirz, J.; Klan, P. Photochem. Photobiol. Sci. 2007, 6, 50.
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Chem. 2006, 71, 8050. (b) Pospisil, T.; Veetil, A. T.; Antony, L. A. P.;
Klan, P. Photochem. Photobiol. Sci. 2008, 7, 625. (c) Solomek, T.;
Stacko, P.; Veetil, A. T.; Pospisil, T.; Klan, P. J. Org. Chem. 2010, 75,
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Chem. 2004, 69, 7582.
r
10.1021/ol102887f
Published on Web 01/14/2011
2011 American Chemical Society

Scheme 1. Photochemistry of Phenacyl Derivatives
Scheme 2. Synthesis of Hydroxy-2-methylphenacyl Esters
It is a rare occurrence in organic photochemistry when
one can completely and cleanly divert the reaction or re-
arrangement pathway from a single product type to an
alternative pathway yielding an entirely different structure
by addition of H2O to the solvent.3a Since it is well-known
that electron-donating hydroxy and methoxy groups sup-
press Type II reactivity6 and nearly as well-known that
the photo-Favorskii rearrangement has a strong affinity
for water,4k,7 we assumed that these two reaction path-
ways might be separated by the water content of the sol-
vent media. In this work, the analogues of 4-hydroxyphe-
nacyl derivatives with good leaving groups necessary for
the photo-Favorskii process were fitted with 2-methyl sub-
stituent for efficient Type II hydrogen abstraction reaction
to compete with the photo-Favorskii rearrangement. As
an extension, a similar design, in which the 2-hydroxyphe-
nacyl derivatives were fitted with a 6-methyl group, was
also examined.
A Comparison of the Photochemistry of 2- and 4-Hydro-
xy-o-methylphenacyl Esters (9a-c, 14) and Their Benzyl
(10) and Methyl Ethers (13b). Solutions (∼10 mM) of each
of the phenacyl esters in a series of solvents were irra-
diated at λ = 300 or 313 nm until more than 95% of the
starting material had disappeared. All of the esters re-
leased the corresponding acid in nearly quantitative yield.
The hydroxyphenacyl chromophores were transformed
Synthesis of Phenacyl Esters. 4-Hydroxy-2-methyl (9a-c)
and 2-hydroxy-4,6-dimethylphenacyl (14) esters, and the
corresponding benzyl (10) and methyl (13) ethers were
prepared by R-bromination of acetophenones 5, 6, and 11
and then SN2 reaction with formate, acetate, benzoate, or
mesylate (Scheme 2). Overall yields ranged from 18% to
50%.
Scheme 3. Photochemistry of 9a-c, 10, 13b, and 14
(4) (a) Givens, R. S.; Park, C. H. Tetrahedron Lett. 1996, 37, 6259. (b)
Givens, R. S.; Jung, A.; Park, C. H.; Weber, J.; Bartlett, W. J. Am. Chem.
Soc. 1997, 119, 8369. (c) Park, C. H.; Givens, R. S. J. Am. Chem. Soc.
1997, 119, 2453. (d) Conrad, P. G.; Givens, R. S.; Hellrung, B.; Rajesh,
C. S.; Ramseier, M.; Wirz, J. J. Am. Chem. Soc. 2000, 122, 9346. (e)
Conrad, P. G.; Givens, R. S.; Weber, J. F. W.; Kandler, K. Org. Lett.
2000, 2, 1545. (f) Givens, R. S.; Weber, J. F. W.; Conrad, P. G.; Orosz, G.;
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R. S.; Heger, D.; Hellrung, B.; Kamdzhilov, Y.; Mac, M.; Conrad, P. G.;
Cope, E.; Lee, J. I.; Mata-Segreda, J. F.; Schowen, R. L.; Wirz, J. J. Am.
Chem. Soc. 2008, 130, 3307. (h) Stensrud, K. F.; Heger, D.; Sebej, P.;
Wirz, J.; Givens, R. S. Photochem. Photobiol. Sci. 2008, 7, 614. (i) Ma,
C. S.; Kwok, W. M.; Chan, W. S.; Du, Y.; Kan, J. T. W.; Toy, P. H.;
Phillips, D. L. J. Am. Chem. Soc. 2006, 128, 2558. (j) Ma, C. S.; Kwok,
W. M.; Chan, W. S.; Zuo, P.; Kan, J. T. W.; Toy, P. H.; Phillips, D. L. J.
Am. Chem. Soc. 2005, 127, 1463. (k) Stensrud, K.; Noh, J.; Kandler, K.;
Wirz, J.; Heger, D.; Givens, R. S. J. Org. Chem. 2009, 74, 5219.
(5) Klan, P.; Wirz, J., Photochemistry of Organic Compounds: From
Concepts to Practice, 1st ed.; John Wiley & Sons Ltd.: Chichester, UK,
2009; p 584.
(6) Wagner, P. J. Acc. Chem. Res. 1971, 4, 168.
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Chem. Soc. 1976, 98, 6203.
Org. Lett., Vol. 13, No. 4, 2011
645

into two distinct solvent-dependent sets of rearranged pho-
toproducts (Scheme 3; Tables 1 and 2). Indanones (17 and
19) were formed in low water (<5%) content acetonitrile
or benzene. In methanol, 9 gave a complex mixture of un-
identified products, which may be due to photoaddition
of methanol to the enol.3a The ethers 10 and 13b gave only
the indanone products (18 and 22) in all solvents; benzo-
cyclobutanol 23 was produced only from 13b. In contrast,
2-methyl-4-hydroxyphenylacetic acid 15 and 2-methyl-4-
hydroxybenzyl alcohol 16 were formed from 9, while 4,
6-dimethylbenzofuran-3(2H)-one 20 and 4,6-dimethyl-
benzofuran-2(3H)-one 21 were produced from 14 in
aqueous-based solutions.
Table 1. Photoproducts Formed by Irradiation of 9a-c and 10
chemical yields/%a
Figure 1. Yields of 15 (b, red) and 17 (9) obtained by irradiation
of 9c in aq acetonitrile at λ = 313 nm. The photochemical
conversions were kept between 50% and 70% in all solvent
mixtures (and 30% in acetonitrile to avoid secondary reactions).
The standard deviation of the mean for each point was <10%.
compd
solvent (ratio)
15
16
17 or 18
b
9a
9b
9c
H2O/CH3CN (3:1)
H2O/CH3CN (3:1)
H2O/CH3CN (3:1)
CH3CN or C6H6
H2O/CH3CN (1:1)
C6H6
79
82
8
8
9
-
-
-
b
b
80 (80c)
With 9c, the reaction efficiencies of the two competing
processes coalesced at ∼8% aq acetonitrile and 15 and 16
became the sole products when water content reached
∼30% in degassed solutions. It is noteworthy that for the
irradiations of 14, the crossover point from the Type II
process to photo-Favorskii, where 20/21 replaces 19 as
the dominant pathway, was nearly the same.
b
b
-
-
-
-
-
-
80 d (17)
>80 d (18)
84 d (18)
b
b
10
b
b
a Irradiated at λ = 300 nm in nondegassed solutions to >95%
conversion; the chemical yields were determined by 1H NMR and are the
average of two measurements. b Not observed. c Isolated yield as the
methyl ester of 15 (see the Supporting Information). d Indanones 17 and
18 decompose under prolonged irradiation.
Table 2. Photoproducts from Irradiation of 14 and 13b
chemical yields/%a
compd
solvent (ratio)
19 or 22
20
21
23
b
14
benzene
59 (19)
9
8
-
b
b
CH3OH
-
28
5
62
9
-
b
CH3CN
60 (19)
-
b
b
H2O/CH3CN (1:1)
benzene
-
30
55
-
b
b
b
13b
79 (22)
65 (22)
41 (22)
-
-
-
-
-
-
-
b
b
CH3CN
15
b
b
H2O/CH3CN (1:1)
13
a Degassed solutions irradiated at λ = 300 nm to >95% conversion.
Isolated yields; the average of two measurements. b Not observed.
What is clearly apparent is the remarkable influence
that water plays in changing the course from classic Type
II photochemistry to the photo-Favorskii rearrangement.
Phenylacetic acid (15), as established earlier,4a,c and di-
methylbenzofuranones 20 and 21, in this study, were formed
via the photo-Favorskii rearrangement, whereas the in-
danones 17, 18, 19, and 22 were apparently derived from
classic Type II photoenolization2a,b,8 (Scheme 1 and 3).
Figures 1 and 2 further demonstrate that the two com-
peting pathways can be “titrated” by careful addition of
water to the reaction media in the photolysis of 9c and 14.
Figure 2. Yields of 19 (9), 20 (b, red), and 21 (2, blue)
determined by 1H NMR from irradiation of 14 in aqueous
acetonitrile at λ = 313 nm to >90% conversion. The standard
deviation of the mean for each point was <10%.
Anhydrous Media: The Photoenolization Pathway.
Photoenolization to isomeric (E)- and (Z)-dienols from
2-alkylphenones is a well-established, triplet state path-
way.1,5 Strategic positioning of a leaving group R to the
carbonyl (1, Scheme 1) sets the stage for an elimination
cascade from the (E)-photoenol, whereas the (Z)-isomer
rapidly reverts to the alkylphenone via 1,5-sigmatropic
hydrogen transfer. The (E)-photoenol’s longer lifetime is
(8) Bergmark, W. R. J. Chem. Soc., Chem. Commun 1978, 61.
646
Org. Lett., Vol. 13, No. 4, 2011

ments4b,c,g,i-k of the 2-alkyl-4-hydroxyphenacyl derivatives
9a-c, bearing the nucleofuge R to the carbonyl, formed
15 when photolyzed in mixed aqueous organic solvents
(Scheme 3). Givens, Wirz, and co-workers recently re-
counted the vital role that water plays in this rearrange-
ment.4h,k The process relies on a triplet state proton loss
from the hydroxy group to solvent water, which is
thought to be in concert with solvent-assisted release of
the nucleofuge forming a triplet biradical intermediate.
The biradical relaxes to a putative spirodienedione inter-
mediate (Scheme 1) that either opens to the phenylacetic
acid or loses CO to form a quinomethane.
Scheme 4. Photo-Favorskii and Photoenolization Intermediates
The fact that this process dominates when the water
content is significant is not surprising. Both photo-
Favorskii and photoenolization transformations are pri-
marily triplet reactions. A triplet lifetime of τ = 340-770
ps4k was reported for the 4-hydroxyphenacyl carboxylate
analogues, which is nearly an order of magnitude shorter
than the triplet (τ ≈ 3 ns2c) invoked for photoenolization
of 2,5-dimethylphenacyl carboxylate. This would imply
that the reaction of 9c in water should favor the photo-
Favorskii process. Therefore, decreasing the solvent water
content disfavors the photo-Favorskii process and en-
courages photoenolization, which is largely independent
of the presence of water.
Even more intriguing are the pathways for formation of
20 and 21. They were formed in parallel (generally 21 do-
minates) as the major products in aqueous solvents,
although a small amount was also observed in anhydrous
solvents (Table 2). We posit that, based on the analogy
with the photo-Favorskii reaction, the putative spirodie-
nedione intermediate 26 serves as a common intermediate
for both 20 and 21 in the irradiation of 14 (Scheme 4). The
proposed ring expansion of the cyclopropanone by nu-
cleophilic attack of the cyclohexadienone carbonyl on
either one of the benzylic bonds (blue and red bond scis-
sions) but predominantly on the one attached to the cyclo-
propanone carbonyl (blue scission) leads to the two products.
The rearrangement of 26 to 20 and 21 does not require large
amounts of water, i.e. the water-assisted ring-opening as seen
for formation of 15 from 9a-c is overridden by the intra-
molecular nature of this novel rearrangement step. These pro-
cesses are currently under investigation in our laboratories.
sufficient to permit the release of modest to very good
nucleofuges2,8 generating primarily indanone 2 (Scheme 1)
in nonaqueous and non-nucleophilic solvents.3a As expected,
the presence of either the o- or p-hydroxy groups on 14
(Scheme 4) and 9, respectively, did not influence the
dominance of the photoenol pathway. The compounds
10 and 13b, in which the photo-Favorskii pathway was
suppressed by replacing the hydroxy with an alkoxy
group, also followed the photoenolization pathway. Cy-
clobutanol 23 along with indanone 22 were formed from
13b in dry or aqueous acetonitrile, apparently via photo-
enol 25 (Scheme 4) similar to the cyclobutanols produced
from 2,4,6-trialkylphenacyl benzoates.9
Phenyl ketones are known to have two nearly isoener-
getic triplet states and their relative energies are strongly
influenced by both the aryl substituents and the solvent.10
Electron-donating substituents and polar solvents tend to
stabilize the π,π* state,11 which is generally far less reactive
toward H-atom abstraction than the n,π* state withits half
vacant, nonbonding p orbital on the carbonyl oxygen.6 To
our surprise, 14, having three electron-donating substitu-
ents (and largely a π,π* configuration), still underwent
photoenolization in acetonitrile, although the reaction was
much less efficient (by a factor of 10 compared with those
carried out in aqueous organic solvents).
Acknowledgment. Support for this work was provided
by the Ministry of Education, Youth and Sports of the
Czech Republic: ME09021 (KONTAKT/AMVIS) and
MSM0021622413, the project CETOCOEN (CZ.1.05/
2.1.00/01.0001) granted by the European Regional Devel-
opment Fund, the Grant Agency of the Czech Republic:
203/09/0748 (P.S., P.K.), Dongguk University (Seoul
Campus) (B.S.P.), and the NIH grants GM069663 and
R01 GM72910 (R.S.G.).
Aqueous Media: Photo-Favorskii Pathway. In stark
contrast to photoenolization, photo-Favorskii rearrange-
(9) Park, B. S.; Ryu, H. J. Tetrahedron Lett. 2010, 51, 1512.
(10) (a) Wagner, P. J.; Park, B.-S. Photoinduced Hydrogen Atom
Abstraction by Carbonyl Compounds. In Organic Photochemistry; Padwa,
A., Ed.; Marcel Dekker, Inc.: New York, 1991; Vol. 11, p 227. (b) Wagner,
P. J.; Klan, P. Norrish Type II Photoelimination of Ketones: Cleavage of
1,4-Biradicals Formed by a-Hydrogen Abstraction. In CRC Handbook of
Organic Photochemistry and Photobiology, 2nd ed.; Horspool, W. M.,
Lenci, F., Eds.; CRC Press LLC: Boca Raton, FL, 2003; Chapter 52, p 1.
(11) (a) Rauh, R. D.; Leermakers, P. A. J. Am. Chem. Soc. 1968, 90,
2246. (b) Li, Y. H.; Lim, E. C. Chem. Phys. Lett. 1970, 7, 15.
Supporting Information Available. Experimental de-
tails and characterization data for products. This material
is available free of charge via the Internet at http://pubs.
acs.org.
Org. Lett., Vol. 13, No. 4, 2011
647