Caging of carbonyl compounds as photolabile (2,5-dihydroxyphenyl)ethylene glycol acetals

Full text of DOI:10.1021/jo802612f

moderate to good yield upon 350 nm irradiation. The byproducts
of deprotection, however, contain a nitroso group and are not
always compatible with biological applications.2c,d The 6-bromo-
4-(1,2-dihydroxyethyl)-7-hydroxycoumarin-derived acetals of
aldehydes and ketones have good aqueous solubility and can
be cleaved under single (365 nm) or two photon (740 nm)
excitation conditions albeit in a moderate yield.10 5-Methoxy-
R,R-diphenylsalicylic alcohol readily forms acetals with alde-
hydes and ketones under mild conditions and releases substrates
in a good yield upon irradiation with λ > 280 nm.11 The
quantum efficiency of the photochemical cleavage of all these
acetals is rather low apparently due to the reversibility of the
formation of an intimate ion pair upon light-induced heterolysis
of a C-O bond.
Caging of Carbonyl Compounds as Photolabile
(2,5-Dihydroxyphenyl)ethylene Glycol Acetals
Alexey P. Kostikov, Natalia Malashikhina, and
Vladimir V. Popik*
Department of Chemistry, UniVersity of Georgia, Athens,
Georgia 30602
Vpopik@chem.uga.edu
ReceiVed NoVember 25, 2008
We have recently reported a design of PPGs for alcohols and
other types of hydroxy groups that utilize the excited state
intramolecular proton transfer (ESIPT) in o-hydroxybenzyl
alcohol analogues.12 ESIPT-induced C-O bond cleavage pro-
duces neutral intermediates and, therefore, proceeds with good
quantum efficiency. The PPG for glycols based on this design
was also developed.13 Since deprotection of glycols involves
photochemical cleavage of acetals, we decided to explore the
applicability of photolabile acetals for the protection of ketones
and aldehydes.
Aldehydes and ketones caged as 4-(2,5-dihydroxyphenyl)-
1,3-dioxolanes are efficiently (Φ ) 0.1-0.2) released in a
good to excellent chemical yield upon irradiation with 300
nm light. Caged carbonyl compounds are prepared by their
acetalization with (2,5-dimethoxyphenyl)ethylene glycol fol-
lowed by oxidative demethylation to produce corresponding
(1,3-dioxolane-4-yl)-1,4-benzoquinones. The latter acetals are
photochemically inert but can be converted into photolabile
hydroquinones by mild reduction in situ.
Here we report that 300 nm irradiation of (2,5-dihydrox-
yphenyl)ethylene glycol acetals of aldehydes and ketones 1a-e
results in their efficient cleavage and regeneration of the
(4) (a) Kaplan, J. H.; Forbush, B.; Hoffman, J. F. Biochemistry 1978, 17,
1929. (b) Walker, J. W.; Reid, G. P.; McGray, J. A.; Trentham, D. R. J. Am.
Chem. Soc. 1988, 110, 7170. (c) Furuta, T.; Torigai, H.; Sugimoto, M.; Iwamura,
M. J. Org. Chem. 1995, 60, 3953. (d) Hagen, V.; Bendig, J.; Frings, S.; Eckardt,
T.; Helm, S.; Reuter, D.; Kaupp, U. B. Angew. Chem., Int. Ed. 2001, 40, 1045.
(e) Corrie, J. E. T.; Trentham, D. R. J. Chem. Soc., Perkin Trans. 1 1992, 2409.
(f) Givens, R. S.; Athey, P. S.; Kueper, L. W., III; Matuszewski, B.; Xue, J.
J. Am. Chem. Soc. 1992, 114, 8708. (g) Park, C.-H.; Givens, R. S. J. Am. Chem.
Soc. 1997, 119, 2453. (h) Kla´n, P.; Pelliccioli, A. P.; Pos|Aapil, T.; Wirz, J.
Photochem. Photobiol. Sci. 2002, 1, 920.
(5) (a) Patchornik, A.; Amit, B. J.; Woodward, R. B. J. Am. Chem. Soc.
1970, 92, 6333. (b) Cameron, J. F.; Frechet, J. M. J. J. Am. Chem. Soc. 1991,
113, 4303. (c) Fodor, S. P. A.; Read, J. L.; Pirrung, M. C.; Stryer, L.; Lu, A. T.;
Solas, D. Science 1991, 251, 767. (d) Chee, M.; Yang, R.; Hubbell, E.; Berno,
A.; Huang, X. C.; Stern, D.; Winkler, J.; Lockhart, D. J.; Morris, M. S.; Fodor,
S. P. A. Science 1996, 274, 610. (e) Barltrop, J. A.; Schofield, P. Tetrahedron
Lett. 1962, 3, 697. (f) Chamberlin, J. W. J. Org. Chem. 1966, 31, 1658. (g)
Cameron, J. F.; Wilson, C. G.; Frechet, J. M. J. J. Am. Chem. Soc. 1996, 118,
12925.
(6) (a) Zehavi, U.; Amit, B.; Patchornik, A. J. Org. Chem. 1972, 37, 2281.
(b) Ohtsuka, E.; Tanaka, T.; Tanaka, S.; Ikehara, M. J. Am. Chem. Soc. 1978,
100, 4580. (c) Nicolaou, K. C.; Hummel, C. W.; Nakada, M.; Shibayama, K.;
Pitsinos, E. N.; Saimoto, H.; Mizuno, Y.; Baldenius, K.-U.; Smith, A. L. J. Am.
Chem. Soc. 1993, 115, 7625. (d) Suzuki, A. S.; Watanabe, T.; Kawamoto, M.;
Nishiyama, K.; Yamashita, H.; Ishii, M.; Iwamura, M.; Furuta, T. Org. Lett.
2003, 5, 4867. (e) Misetic, A.; Boyd, M. K. Tetrahedron Lett. 1998, 39, 1653.
(f) Furuta, T.; Hirayama, Y.; Iwamura, M. Org. Lett. 2001, 3, 1809. (g) Pirrung,
M. C.; Bradley, J.-C. J. Org. Chem. 1995, 60, 1116.
(7) (a) McHale, W. A.; Kutateladze, A. G. J. Org. Chem. 1998, 63, 9924.
(b) Mitkin, O. D.; Kurchan, A. N.; Wan, Y.; Schiwal, B. F.; Kutateladze, A. G.
Org. Lett. 2001, 3, 1841. (c) Li, Z.; Kutateladze, A. G. J. Org. Chem. 2003, 68,
8336.
Photoremovable protecting groups (PPGs) have found numer-
ous applications in organic synthesis, biochemistry, and bio-
technology as they allow for the spatial and temporal control
of substrate release, while the only reagent required is light.1,2
The majority of photolabile groups are designed to protect
carboxylic acids,3 phosphates,4 amines,5 and alcohols.6 The
choice of PPGs for caging of a carbonyl group, on the other
hand, is rather limited. Thus, carbonyl compounds can be
released from their dithiane adducts by using PET from suitable
internal or external donors.7 Three types of photolabile acetals
also have been reported. 4-(o-Nitrophenyl)-8 and 4,5-bis(o-
nitrophenyl)-1,3-dioxolanes9 release carbonyl compounds in a
(1) (a) Greene, T. W.; Wuts, P. G. M. Greene′s ProtectiVe Groups in Organic
Synthesis, 4th ed; Wiley: Hoboken, NJ, 2007. (b) Kocienski, P. J. Protecting
Goups; Thieme: Stuttgart, Germany, 2005.
(2) (a) Pelliccioli, A. P.; Wirz, J. Photochem. Photobiol. Sci. 2002, 1, 441.
(b) Bochet, C. G. J. Chem. Soc., Perkin Trans. 1 2002, 125. (c) Morrison, H.
Biological Applications of Photochemical Switches; Wiley: New York, 1993.
(d) Goeldner, M.; Givens, R. Dynamic Studies in Biology: Wiley: Weinheim,
Germany, 2005. (e) Mayer, G.; Heckel, A. Angew. Chem., Int. Ed. 2006, 45,
4900.
(8) Gravel, D.; Herbert, J.; Thoraval, D. Can. J. Chem. 1983, 61, 400.
(9) Blanc, A.; Bochet, C. G. J. Org. Chem. 2003, 68, 1138.
(10) Lu, M.; Fedoryak, O. D.; Moister, B. R.; Dore, T. M. Org. Lett. 2003,
5, 2119.
(3) (a) Furuta, T.; Wang, S. S.-H.; Dantzker, J. L.; Dore, T. M.; Bybee, W. J.;
Callaway, E. M.; Denk, W.; Tsien, R. Y. Proc. Natl. Acad. Sci. U.S.A. 1999,
96, 1193. (b) Sheehan, J. C.; Wilson, R. M.; Oxford, A. W. J. Am. Chem. Soc.
1971, 93, 7222. (c) Kla´n, P.; Zabadal, M.; Heger, D. Org. Lett. 2000, 2, 1569.
(11) Wang, P.; Hu, H.; Wang, Y. Org. Lett. 2007, 9, 1533.
(12) (a) Kostikov, A. P.; Popik, V. V. J. Org. Chem. 2007, 72, 9190. (b)
Kulikov, A.; Arumugam, S.; Popik, V. V. J. Org. Chem. 2008, 73, 7611.
(13) Kostikov, A. P.; Popik, V. V. Org. Lett. 2008, 10, 5277.
1802 J. Org. Chem. 2009, 74, 1802–1804
10.1021/jo802612f CCC: $40.75 2009 American Chemical Society
Published on Web 01/15/2009

SCHEME 1. Cleavage of Photolablie Acetals
chloride biphasic system afforded the target 4-(2,5-dihydrox-
yphenyl)-1,3-dioxolanes 1a-e (Scheme 3). The yields of
conversion of carbonyl compounds 5a-e into acetals 1a-e are
summarized in the Table 1.
TABLE 1. Preparative Yields of Acetals 1a-e and Quantum and
Chemical Yields of the Photochemical Release of Carbonyl
Compounds at >97% Conversion
yield of formation,
% (over 3 steps)
yield of
deprotection, %
acetal
Φ300
1a
1b
1c
1d
1e
37
40
39
47
43
∼90a
59b
94
0.08
0.12
0.04
0.15
0.17
88
carbonyl compound (Scheme 1). This reaction apparently
proceeds via photoinduced transfer of the phenolic proton to
the dioxolane oxygen in the 3-position, followed or accompanied
by the C-O bond cleavage and the formation of an intermediate
o-quinone methide 2. o-Quinone methide is very reactive14 and
can undergo rapid hydration or tautomerization to form unstable
hemiacetals 3 and/or 4 correspondingly.12a The hydrolysis of 3
and 4 liberates the carbonyl compound (Scheme 1). The
advantages of this new PPG for carbonyl compounds are in its
good aqueous solubility, efficiency of deprotection, and potential
for the in situ reductive arming (vide infra).
Preparation of (2,5-dimethoxyphenyl)ethylene glycol 6, which
was required for the synthesis of 4-(2,5-dihydroxyphenyl)-1,3-
dioxolanes 1a-e, is outlined in Scheme 2. 2,5-Dimethoxyben-
zaldehyde was converted into 2,5-dimethoxystyrene15 under
standard Wittig conditions.16,17 Hydroxylation of the latter with
sodium periodate in hot acetic acid, followed by the hydrolysis
of the resulting mixture of acetates with potassium carbonate
in methanol18 afforded 6 in 75% yield (Scheme 2).
100
a Measured by NMR. b Measured by GC.
4-(2,5-Dihydroxyphenyl)-1,3-dioxolanes 1a-e are stable in
the dark in the solid state, as well as in aqueous methanol
solutions. UV spectra of these compounds contain the charac-
teristic p-benzohydroquinone band at 293 nm (log ε ) 3.53,
Figure 1). Irradiation of solutions of acetals 1a-e in 30%
aqueous methanol with 300 nm light results in the efficient
release of the carbonyl compound. Figure 1 shows the growth
of the characteristic 251 nm band of acetophenone in the course
of the photolysis.
SCHEME 2. Synthesis of the Glycol 6
SCHEME 3. Synthesis of Acetals 1a-e
FIGURE 1. UV spectra of 1d (solid line, ca. 1 × 10-4 M in 30%
aqueous methanol) and its 300 nm photolysis (dashed lines, every 10
min).
Acid-catalyzed acetalization of aldehydes (5b,e) and ketones
(5a,c,d) with glycol 6 in the presence of triethyl orthoformate
resulted in the formation of 4-(2,5-dimethoxyphenyl)-1,3-
dioxolanes 7a-e (Scheme 3).17 Oxidative demethylation of the
latter with silver oxide/nitric acid19 produced (1,3-dioxolane-
4-yl)-1,4-benzoquinones 8a-e in good yield. It is interesting
to note that p-benzoquinone-substituted acetals 8a-e are
photochemically stable in degassed aqueous methanol solutions.
Mildreductionof8a-ebysodiumdithioniteinawater-methylene
The yields of the substrates release were determined by using
either NMR spectroscopy (5a), GC (5c), or HPLC (5b,d,e); the
quantum efficiencies were measured with ferrioxalate chemical
actinometry (Table 1).20
The quantum yields of the carbonyl compounds release from
the photolabile acetals 1a-e is somewhat lower than were
observed for other 2,5-dihydroxybenzyl alcohol-based cages.12a,13
This phenomenon apparently can be explained by the intramo-
lecular nucleophilic attack by the hydroxy group on the
intermediate o-quinone methide 2. This reaction results in the
ring closure and the regeneration of starting material, and
efficiently competes with the hydration of 2 to form hemiace-
tal 3.
(14) (a) Diao, L.; Yang, C.; Wan, P. J. Am. Chem. Soc. 1995, 117, 5369. (b)
Wan, P.; Brousmiche, D. W.; Chen, C. Z.; Cole, J.; Lukeman, M.; Xu, M. Pure
Appl. Chem. 2001, 73, 529. (c) Chiang, Y.; Kresge, A. J.; Zhu, Y. J. Am. Chem.
Soc. 2000, 122, 9854. (d) Leo, E. A.; Delgado, J.; Domingo, L. R.; Espinos, A.;
Miranda, M. A.; Tormos, R. J. Org. Chem. 2003, 68, 9643.
(15) Parker, K. A.; Ruder, S. M. J. Am. Chem. Soc. 1989, 111, 5948.
(16) Wright, J. A.; Gaunt, M. J.; Spencer, J. B. Chem. Eur. J. 2006, 12, 949.
(17) Experimental details are presented in the Supporting Information.
(18) Emmanuvel, L.; Ali Shaikh, T. M.; Sudalai, A. Org. Lett. 2005, 7, 5071.
(19) Giles, R. G. F.; Rickards, R. W.; Senanayake, B. S. J. Chem. Soc., Perkin
Trans. 1 1997, 3361.
(20) Murov, S. L.; Carmichael, I.; Hug, G. L. In Handbook of Photochemistry;
Marcel Dekker: New York, 1993; p 299.
J. Org. Chem. Vol. 74, No. 4, 2009 1803

dimethoxyphenyl)-2,2-diethyl-1,3-dioxolane (7a, 2.05 g, 7.7 mmol)
in dioxane (50 mL) followed by nitric acid (6 M, 1 mL). The
resulting suspension was stirred for 30 min and then quenched with
sodium bicarbonate (10%, 100 mL). The product was extracted with
dichloromethane (3 × 30 mL) and the combined organic phases
were washed with NaHCO3 (10%, 2 × 50 mL), dried over
anhydrous Na2SO4 and evaporated in vacuo. Column chromatog-
raphy of the residue afforded 1.3 g (5.5 mmol, 71%) of 8a as a
The release of ketone is not accompanied by the bleaching
of the 293 nm band. This observation indicates that p-
benzohydroquinone chromophore is preserved in the course of
the reaction and that the hydration of initially formed o-quinone
methide 2 to the hydroquinone 3 is faster than tautomerization
to 4 (Scheme 1). In other words, the reactivity of 2 is drastically
different from that of o-quinone methide produced in the pho-
tolysis of 2,5-dihydroxy benzyl ether and esters.12a In the latter
case tautomerization to methyl-1,4-benzoquinone was the pre-
dominant pathway of the reaction. This reactivity difference is
probably due to the inductive effect of the additional oxygen
atom in 2, which increases nucleophilicity of the methide carbon.
In conclusion, a new photolabile acetal was developed for
caging of carbonyl compounds. We have shown that ketones
and aldehydes can be readily converted into acetals of (2,5-
dimethoxyphenyl)ethylene glycol. The p-benzoquinone precur-
sor of the 4-(2,5-dihydroxyphenyl)-1,3-dioxolane cage is pho-
tochemically inert but can be quantitatively converted in situ
into a photoreactive hydroquinone form by using mild reducing
agents. The latter acetals efficiently release substrates upon 300
nm irradiation in a good to excellent yield.
1
yellow oil. H NMR δ 0.95 (m, 6H), 1.72 (m, 4H), 3.56 (t, 1H),
4.49 (td, 1H), 4.99 (td, 1H), 6.76 (d, 2H), 6.96 (d, 1H); 13C NMR
δ 8.2, 8.4, 29.1, 29.8, 70.2, 72.5, 114.1, 130.7, 136.6, 137.0, 147.6,
187.5, 187.7; MS 207 (26, [M - 29]+), 152 (17), 135 (10), 133
(38), 123 (11), 107 (6), 77 (6), 57 (100); HRMS calcd for
C13H16O4Na+ 259.0946, found 259.0948.
2,2-Diethyl-4-(2,5-dihydroxyphenyl)-1,3-dioxolane (1a). An
aqueous solution of sodium dithionite (1.74 g, 10 mmol, 25 mL)
was added to a solution of 2-(2,2-diethyl-1,3-dioxolan-4-yl)benzo-
1,4-quinone (7a, 1.3 g, 5.5 mmol) in dichloromethane (25 mL).
The resulting suspension was vigorously stirred for 5 min and the
layers were separated. The product was extracted with ether (3 ×
30 mL) and the combined organic layers were washed with brine,
dried over anhydrous Na2SO4, and evaporated in vacuo. Column
chromatography of the residue afforded 875 g of hydroquinone 1a
1
(3.7 mmol, 67%) as a white solid. H NMR (acetone-d6) δ 0.95
Experimental Section
(m, 6H), 1.71 (m, 4H), 3.48 (t, 1H), 4.41 (td, 1H), 5.27 (td, 1H),
6.58 (dd, 1H), 6.67 (d, 1H), 7.01 (d, 1H), 7.81 (s, br, 1H), 7.93 (s,
br, 1H); 13C NMR δ 7.86, 7.94, 29.5, 29.9, 71.0, 74.0, 112.5, 112.9,
114.6, 115.8, 127.2, 147.1, 150.7; MS 238 (13, M+), 209 (11), 152
(90), 135 (62), 123 (42), 107 (32), 95 (6), 77 (13), 57 (100); HRMS
calcd for C13H18O4Na+ 261.1103, found 261.1105.
Representative Procedures:17 4-(2,5-Dimethoxyphenyl)-2,2-
diethyl-1,3-dioxolane (7a). p-Toluenesulfonic acid (ca. 25 mg) was
added to a solution of 3-pentanone (4a, 950 mg, 11 mmol), (2,5-
dimethoxyphenyl)ethylene glycol (6, 2 g, 10 mmol), and triethyl
orthoformate (1.8 mL, 1.62 g, 11 mmol) in dichloromethane (10
mL). The reaction mixture was stirred at room temperature over-
night and then purified by chromatography. A 2.05 g sample of
Acknowledgment. The authors thank the Georgia Cancer
Coalition and donors of the ACS Petroleum Research Fund
(48353-AC4), administered by the American Chemical Society,
for support of this project.
1
acetal 7a (7.7 mmol, 77%) was obtained as colorless liquid. H
NMR δ 0.99 (m, 6H), 1.77 (m, 4H), 3.55 (t, 1H), 3.77 (s, 3H),
3.79 (s, 3H), 4.45 (td, 1H), 5.30 (td, 1H), 6.77 (d, 2H), 7.19 (d,
1H); 13C NMR δ 8.4, 8.5, 29.7, 30.1, 55.9, 56.0, 71.3, 73.6, 111.1,
112.1, 112.9, 113.0, 129.8, 150.7, 154.0; MS 266 (44, M+), 238
(14), 237 (100), 181 (35), 151 (14), 149 (17), 121 (19), 100 (20),
91 (20), 77 (20); HRMS calcd for C15H22O4Na+ 289.1416, found
289.1416.
Supporting Information Available: Synthesis and charac-
terization of the compounds 1b-e, 6, 7b-e, and 8b-e and
photolyses protocols. This material is available free of charge
via the Internet at http://pubs.acs.org.
2-(2,2-Diethyl-1,3-dioxolan-4-yl)benzo-1,4-quinone (8a). Silver
oxide (1.22 g, 10 mmol) was added to the solution of 4-(2,5-
JO802612F
1804 J. Org. Chem. Vol. 74, No. 4, 2009