2,5-Dimethylphenacyl as a New Photoreleasable Protecting Group for Carboxylic Acids

Article abstract of DOI:10.1021/ol005789x

(Matrix Presented) The 2,5-dimethylphenacyl chromophore, a new photoremovable protecting group for carboxylic acids, is proposed. Direct photolysis of various 2,5-dimethylphenacyl esters in benzene or methanol at 254-366 nm leads to the formation of the corresponding carboxylic acids in almost quantitative isolated yields. The photodeprotection is based on efficient intramolecular hydrogen abstraction without the necessity of introducing a photosensitizer.

Full text of DOI:10.1021/ol005789x

ORGANIC
LETTERS
2000
Vol. 2, No. 11
1569-1571
2,5-Dimethylphenacyl as a New
Photoreleasable Protecting Group for
Carboxylic Acids
Petr Kla´n,* Miroslav Zabadal, and Dominik Heger
Department of Organic Chemistry, Faculty of Science, Masaryk UniVersity,
Kotlarska 2, 611 37 Brno, Czech Republic
klan@sci.muni.cz
Received March 10, 2000
ABSTRACT
The 2,5-dimethylphenacyl chromophore, a new photoremovable protecting group for carboxylic acids, is proposed. Direct photolysis of various
2,5-dimethylphenacyl esters in benzene or methanol at 254−366 nm leads to the formation of the corresponding carboxylic acids in almost
quantitative isolated yields. The photodeprotection is based on efficient intramolecular hydrogen abstraction without the necessity of introducing
a photosensitizer.
There has been long-standing interest in photoreleasable
protecting groups, especially in terms of their applications
in various multistep organic syntheses or in biochemistry.1
The o-nitrobenzyl group, for example, is among the most
widely used.2
The photochemical release of phosphates and carboxylic
acids from the p-methoxyphenacyl esters has already been
reported.3 In the past three years, the photochemistry of
phenacyl and p-hydroxyphenacyl chromophores has received
considerable attention. Falvey and co-workers reported that
photolysis of electron-donating photosensitizers in the pres-
ence of various phenacyl derivatives resulted in release of
the corresponding carboxylic acids,4 alcohols, and phos-
phates5 in high yields. In addition, efficient photolysis of
phenacyl esters in the presence of hydrogen atom donors
has been described.6 Givens et al. proposed the p-hydroxy-
phenacyl group as an aqueous soluble, photoremovable,
protecting group for amino acids, peptides,7 and phosphates.8
Irradiation of those esters in the presence of water at 300-
350 nm triggered release of the corresponding acids with
high efficiency and at the same time resulted in formation
of biochemically benign byproducts. Recently, a mechanism
in which the primary photochemical step involves the singlet
excited state has been proposed.9 There are also a number
of nonphotochemical deprotection methods for the phenacyl
group described in the literature.10
(1) (a) ProtectiVe Groups in Organic Synthesis; Green, T. W., Wuts, P.
G. M., Eds.; Wiley: New York, 1991. (b) Pillai, V. N. R. In Organic
Photochemistry; Padwa, A., Ed.; Marcel Dekker: New York, 1987; Vol.
9, pp 225-323. (c) Corrie, J. E. T.; Trentham, D. R. In Biological
Applications of Photochemical Switches; Morrison, H., Ed.; Wiley: New
York, 1993; pp 243-305. (d) Willner, I.; Willner, B. In Biological
Applications of Photochemical Switches; Morrison, H., Ed.; Wiley: New
York, 1993; pp 1-110.
(4) (a) Banerjee, A.; Lee, K.; Yu, Q.; Fang, A. G.; Falvey, D. E.
Tetrahedron Lett. 1998, 39, 4635. (b) Banerjee, A.; Falvey, D. E. J. Org.
Chem. 1997, 62, 6245.
(5) Banerjee, A.; Lee, K.; Falvey, D. E. Tetrahedron 1999, 55, 12699.
(6) Banerjee, A.; Falvey, D. E. J. Am. Chem. Soc. 1998, 120, 2965.
(7) Givens, R. S.; Jung, A.; Park, C.-H.; Weber, J.; Bartlett, W. J. Am.
Chem. Soc. 1997, 119, 8369.
(8) Park, C.-H.; Givens, R. S. J. Am. Chem. Soc. 1997, 119, 2453.
(9) Zhang, K.; Corrie, J. E. T.; Munasinghe, V. R. N.; Wan, P. J. Am.
Chem. Soc. 1999, 121, 5625.
(2) (a) Engels, J.; Schlaeger, E.-J. J. Med. Chem. 1977, 20, 907. (b) Gee,
K. R.; Niu, L.; Schaper, K.; Hess, G. P. J. Org. Chem. 1995, 60, 4260 and
references therein.
(3) (a) Sheehan, J. C.; Umezawa, J. J. Org. Chem. 1973, 38, 3771 and
references therein. (b) Epstein, W. W.; Garrossian, M. J. Chem. Soc., Chem.
Commun. 1987, 532. (c) Baldwin, J. E.; McConnaughie, A.; Moloney, M.
C.; Pratt, A. J.; Shim, S. B. Tetrahedron 1990, 46, 6879.
(10) (a) Chivicas, C. J.; Hodges, J. C. J. Org. Chem. 1987, 52, 3591. (b)
Namikoshi, M.; Kundu, B.; Rinehart, K. L. J. Org. Chem. 1991, 56, 5464.
(c) Ueki, M.; Aoki, H.; Katoh, T. Tetrahedron Lett. 1993, 34, 2783. (d)
Hagiwara, D.; Neya, M.; Hashimoto, M. Tetrahedron Lett. 1990, 31, 6539.
10.1021/ol005789x CCC: $19.00 © 2000 American Chemical Society
Published on Web 05/05/2000

It is well-known that aryl ketones with o-alkyl groups
undergo an efficient photoinduced enolization (Scheme 1).11
Table 2. Photolysis of DMP Esters
ester
solvent
wavelength (nm)
yield (%)a
5a
5b
5b
5c
5d
5e
benzene
benzene
methanol
benzene
benzene
benzene
>280
>280
>254
>280
>280
>280
85b
86
92
91
95
90
Scheme 1
a Isolated yields of the crude acids (>95% purity). b Determined by GC.
solution of the DMP ester in benzene or methanol (∼250
mL) was irradiated in a quartz immersion well reactor using
a 125 W medium-pressure Hg lamp (>254 nm experiments)
or irradiated through a 2 mm borosilicate glass filter (>280
nm experiments) over 5 h. Irradiation was stopped when
conversion reached at least 96% (GC). For reactions in
benzene, the acid was isolated by washing with an Na2CO3
solution. The alkaline layer was then acidified with dilute
HCl, and the product was extracted into dichloromethane.
For reactions in methanol, solvent was evaporated, the
residue was dissolved in dichloromethane, and the following
extraction proceeded in a similar manner to that described
above. The crude acids were analyzed by GC, GC/MS, and
NMR, and the data were compared to those of the authentic
samples. The purity of the product was always found to be
higher than 95%.
We isolated and analyzed all significant photoproducts.
6-Methyl-1-indanone (4)15 was practically the only photo-
product found, in addition to the carboxylic acid, in nonpolar
benzene (Scheme 2). This parallels Bergmark’s results
obtained by irradiation of R-chloro-2′,5′-dimethylaceto-
phenone in benzene as previously mentioned.13 The reaction
obviously proceeds through triplet excited ester 6 and 1,4-
biradical 7, which loses the corresponding carboxylic acid
in the subsequent step of a possibly concerted rearrangement
of the enol. However, photosolvolysis seems to be a
dominant pathway when photolysis is accomplished in
nucleophilic methanol. Thus, along with indanone 4, 2-(meth-
oxymethyl)-5-methylacetophenone (8)16 was isolated in high
yields.
The reaction of 1 (X ) H, alkyl) involves triplet excited
ketone formation, which is followed by intramolecular
hydrogen abstraction yielding the biradical 2 and conse-
quently the triplet photoenol 3.12 In the absence of trapping
agents, photoenols decay by reverse hydrogen transfer to
regenerate the ketone. On the other hand, R-chloro-2′,5′-
dimethylacetophenone (1, X ) Cl) can lead to methyl-
indanone 4 as has been reported by Bergmark et al.13
Now we wish to report on the photochemistry of 2,5-
dimethylphenacyl (DMP) esters of carboxylic acids. We were
intrigued by the possibility that carboxylic acids might be
effectively released as a consequence of intramolecular
hydrogen abstraction; thus the DMP chromophore would be
a “self-photoreleasable” protecting group, i.e., without neces-
sity to introduce any photosensitizer or hydrogen atom donor.
The photochemistry of the DMP esters has been investigated
in terms of solvent and wavelength influence.
The esters (5a-e) were synthesized by refluxing a mixture
of R-chloro-2′,5′-dimethylacetophenone,14 the sodium salt of
the corresponding acid (1.2-2 equiv), sodium iodide (1.2
equiv), and triethylamine (1.2 equiv) in acetone and then
purifiying the product by recrystallization or column chro-
matography. The chemical yields are shown in Table 1.
Table 1. Synthesis of DMP Esters
(11) (a) Sammes, P. G. Tetrahedron 1976, 32, 405. (b) Wagner, P. J.;
Chen, C.-P. J. Am. Chem. Soc. 1976, 98, 239.
(12) (a) Wagner, P. J.; Chen, C.-P.. J. Am. Chem. Soc. 1976, 98, 239.
(b) Netto-Ferreira, J. C.; Scaiano, J. C. J. Am. Chem. Soc. 1991, 113, 5800
and references therein.
(13) Bergmark, W. R.; Barnes, C.; Clark, J.; Paparian, S.; Marynowski,
S. J. Org. Chem. 1985, 50, 5612.
(14) 2,5-Dimethyl-R-chloroacetophenone was synthesized according to
ref 13.
R
ester
yield (%)
CH3
C6H5
C6H5CH2
n-pentadecyl
5a
5b
5c
5d
5e
84
95
84
69
51
(15) Mp (from petroleum ether) 48-51 °C. 1H NMR (300 MHz, CDCl3)
δ (ppm) 2.40 (s, 3H), 2.65-2.69 (m, 2H), 3.08 (t, J ) 5.8 Hz, 2H), 7.35
(d, J ) 7.9 Hz, 1H), 7.40 (dd, J1 ) 7.9 Hz, J2 ) 1.5 Hz, 1H), 7.55 (broad
s, 1H). 13C NMR (75.5 MHz, CDCl3) δ (ppm) 21.1, 25.4, 36.6, 123.7, 126.4,
135.9, 137.2, 137.3, 152.5, 207.1. MS (EI) m/z 146 (M+), 118, 115, 103,
91. Anal. Calcd for C10H10O: C, 82.16; H, 6.89. Found: C, 82.39; H, 6.92.
(16) Mp. 31-32 °C. 1H NMR (300 MHz, CDCl3) δ (ppm) 2.39 (s, 3H),
2.57 (s, 3H), 3.42 (s, 3H), 4.70 (s, 2H), 7.29 (t, J1 ) 7.9 Hz, J2 ) 8.2 Hz,
1H), 7.50 (d, J ) 5.8 Hz, 2H); 13C NMR (75.5 MHz, CDCl3): δ (ppm)
21.0, 29.2, 58.6, 72.6, 128.0, 129.9, 132.5, 136.3, 136.6, 136.7, 201.6. MS
(EI) m/z 178 (M+), 163, 147, 117, 91. Anal. Calcd for C11H14O2: C, 74.13;
H, 7.92. Found: C, 73.91; H, 7.96.
N-(tert-butoxycarbonyl)-L-phenylalanine
The corresponding carboxylic acids were obtained in
nearly quantitative isolated yields (Table 2) when irradiated
according to the representative procedure: a ∼5 × 10-3
M
1570
Org. Lett., Vol. 2, No. 11, 2000

Scheme 2
Table 3. Quantum Yields in Benzene at >366 nm
ester
Φ
1 (X ) Cl)
5b
5c
0.11a
0.23b
0.18b
a From ref 13. Quantum yields for the ester degradation. The reproduci-
b
bility was (9%.
5b and 5c in benzene were found to be higher approximately
by a factor of 2 than that of 1 (X ) Cl). Initially, we
anticipated an opposite tendency since the carboxylate is a
poorer leaving group than chloride and there might be a
higher probability of reverse hydrogen transfer in 7 causing
a drop in the quantum yield. A quantum yield of ∼20%
makes our DMP chromophore as photochemically efficient
as the R-phenyl-o-nitrobenzyl moiety.20 On the other hand,
an unexpected decrease in quantum yields by a factor of
approximatelly 1.5 in methanol compared to that of benzene
was found, and it will be examined thoroughly in the
forthcoming research.
In conclusion, we propose a new type of photoreleasable
protecting group (photochemical switch)1 for carboxylic
acids, the 2,5-dimethylphenacyl chromophore, which afford
almost quantitative yields of deprotection. Practical applica-
tions perfectly fulfill all the criteria for the good protecting
group in organic synthesis: very high yields of deprotection,
high photochemical efficiency, a possibility of using wave-
lengths in the broad range of 254-366 nm thanks to the
absorption characteristics of the group, good stability, and
simplicity of the experiment. Furthermore,similar to some
other groups (e.g., 2-nitrobenzyl2 or 7-nitroindolyl21), the
DMP group is “self-removable” because the photoreaction
is intramolecular. Our future research is directed at other
DMP derivatives than carboxylic acid esters as well as at a
detailed kinetic analysis of this reaction.
In quantum yield measurements, benzene or methanol
solutions (0.005 M) of 5b and 5c were irradiated simulta-
neously with valerophenone solutions used as an actinom-
eter17 at >366 nm.18 The reaction conversion was kept under
20% to avoid interference from the photoproducts. The low
concentrations also reduced the probability of energy transfer
during a solution encounter as well as intermolecular
reactions. It is expected that intramolecular triplet energy
transfer in 5b and 5c (with the phenylacetic and benzoic
chromophores, respectively) is endothermic and thus negli-
gible.19 The results from our as well as Bergmark’s13 quantum
yield measurements are listed in Table 3. The values for both
Acknowledgment. We thank the Czech Ministry of
Education, Youth and Sport (CEZ: J07/98:143100005) for
support of this research. We thank J. Kuban for the elemental
analysis measurements.
OL005789X
(17) Wagner, P. J.; Kochevar, I. E.; Kemppainen, A. E. J. Am. Chem.
Soc. 1972, 94, 7489.
(18) Samples in Pyrex tubes were degassed in three freeze-pump-thaw
cycles before being sealed and were irradiated in a “merry-go-round”
apparatus immersed in a water bath. The 366 nm band from a medium-
pressure 125 W Teslamp mercury lamp was isolated by filtration with
Corning CS 0-52 and CS 7-37 filters.
(19) (a) Wagner, P. J.; Kla´n, P. J. Am. Chem. Soc. 1999, 121, 9626. (b)
Kla´n, P.; Wagner, P. J. J. Am. Chem. Soc. 1998, 120, 2198 and references
therein.
(20) Zhu, Q. Q.; Schnabel, W.; Schupp. H. J. Photochem. 1987, 39, 317.
(21) Papageorgiu, G.; Ogden, D. C.; Barth, A.; Corrie, J. E. T. J. Am.
Chem. Soc. 1999, 121, 6503.
Org. Lett., Vol. 2, No. 11, 2000
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