1-[2-(2-Hydroxyalkyl)phenyl]ethanone: A New Photoremovable Protecting Group for Carboxylic Acids

Article abstract of DOI:10.1021/ol035782q

(Equation presented) A new photoremovable protecting group for carboxylic acids is introduced. The protecting group 1-[2-(2-hydroxyalkyl)phenyl]ethanone, HAPE, is used to protect various carboxylic acids. When photolyzed, the protected compound releases the acid in 70-85% isolated yields. The synthesis and the results of photorelease of the protected acids are presented here.

Full text of DOI:10.1021/ol035782q

ORGANIC
LETTERS
2003
Vol. 5, No. 23
4469-4471
1-[2-(2-Hydroxyalkyl)phenyl]ethanone:
A New Photoremovable Protecting
Group for Carboxylic Acids
Walters N. Atemnkeng, Larry D. Louisiana II, Promise K. Yong,
Breanne Vottero, and Anamitro Banerjee*
Department of Chemistry, UniVersity of North Dakota,
Grand Forks, North Dakota 58202-9024
abanerjee@chem.und.edu
Received September 15, 2003
ABSTRACT
A new photoremovable protecting group for carboxylic acids is introduced. The protecting group 1-[2-(2-hydroxyalkyl)phenyl]ethanone, HAPE,
is used to protect various carboxylic acids. When photolyzed, the protected compound releases the acid in 70−85% isolated yields. The
synthesis and the results of photorelease of the protected acids are presented here.
Photoremovable protecting groups (PRPGs) have been used
in a variety of different applications.1 The temporal and
spatial resolution afforded by light along with wavelength
control gives PRPGs a distinct advantage over conventional
protecting groups in these applications. Despite considerable
design and development of PRPGs over the past three
decades,2 the pool of PRPGs is still very small. As a result,
there is still considerable interest in developing new PRPGs.3
In this paper, a new PRPG for carboxylic acids, 1-[2-(2-
hydroxyalkyl)phenyl]ethanone, HAPE (Figure 1), is intro-
duced. The HAPE esters, when photolyzed, are expected to
undergo a γ-H abstraction similar to a Norrish II reaction.
Figure 1. 1-[2-(2-Hydroxyalkyl)phenyl]ethanone (HAPE).
(1) (a) Givens, R. S.; Athey, P. S.; Matuszewski, B.; Kueper, L. W., III;
Xue, J.-y. J. Am. Chem. Soc. 1992, 114, 8708-8710. (b) Jayaraman, V.;
Hess, G. P. Biophys. J. 1998, 74, A344-A344. (c) Pirrung, M. C.; Fallon,
L.; McGall, G. J. Org. Chem. 1998, 63, 241-246. (d) Barnhurst, L. A.;
Kutateladze, A. G. Org. Lett. 2001, 3, 2633-2635. (e) Koglin, N.; Lang,
M.; Rennert, R.; Beck-Sickinger, A. G. J. Med. Chem. 2003, 46, 4369-
4372. (f) Kessler, M.; Glatthar, R.; Giese, B.; Bochet, C. G. Org. Lett. 2003,
5, 1179-1181. (g) Vazquez, M. E.; Nitz, M.; Stehn, J.; Yaffe, M. B.;
Imperiali, B. J. Am. Chem. Soc. 2003, 125, 10150-10151.
(2) (a) Pillai, V. N. R. Organic Photochemistry; Marcel Dekker: New
York, 1987; Vol. 9, pp 225-323. (b) Greene, T. W.; Wuts, P. G. M.
ProtectiVe Groups in Organic Synthesis; Wiley: New York, 1991; p 473.
(3) (a) Kla´n, P.; Zabadal, M.; Heger, D. Org. Lett. 2000, 2, 1569-1571.
(b) Lee, K.; Falvey, D. E. J. Am. Chem. Soc. 2000, 122, 9361-9366. (c)
Bochet, C. G. J. Chem. Soc., Perkin Trans. 1 2002, 125-142. (d) Ma, C.;
Steinmetz, M. G.; Cheng, Q.; Jayaraman, V. Org. Lett. 2003, 5, 71-74.
(e) Lu, M.; Fedoryak, O. D.; Moister, B. R.; Dore, T. M. Org. Lett. 2003,
5, 2119-2122.
This is followed by intersystem crossing to form the enol 1
(Scheme 1). The enol 1 may have two possible configura-
tions: E and Z.4 The enol can undergo a keto-enol
tautomerism to form the ketone (HAPE ester) or it can
eliminate the acid as observed for analogous nitro com-
pounds.5 Previous reports by Kla´n et al. indicate that a
(4) (a) Chen, C.-P.; Wagner, P. J. J. Am. Chem. Soc. 1976, 98, 239-
241. (b) Haag, R.; Wirz, J.; Wagner, P. J. HelV. Chim. Acta 1977, 60, 2595-
2607.
(5) Hasan, A.; Stengele, K. P.; Giegrich, H.; Cornwell, P.; Isham, K.
R.; Sachleben, R. A.; Pfleiderer, W.; Foote, R. S. Tetrahedron 1997, 53,
4247-4264.
10.1021/ol035782q CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/23/2003

Scheme 1. Proposed Pathway for the Release of Acids from
Scheme 2. Synthesis of HAPE Esters
HAPE Esters
structurallysimilar E-enol of 2′-methylphenacyl esters reke-
tonizes slowly while the Z-form undergoes a rapid tautomer-
ization.6 Although at present we cannot rule out the
possibility of the elimination process from the Z-form (dashed
arrow), it is likely that the elimination of the carboxylic acid
occurs only from the E form.7 The elimination leads to the
rearomatization of the protecting group. Structurally similar
benzophenone derivatives have been shown to release
aromatic acids and secondary amines.8 Recently, Pelliccioli
and Wirz have reported the release of HCl from o-(2-chloro-
ethyl)acetophenone via a similar photoenol intermediate.9 A
variety of carboxylic acids protected as HAPE esters, when
photolyzed released the carboxylic acids in high yields.
This new protecting group offers flexibility to adapt to
different application requirements. For example, the R group
in HAPE (Figure 1) can be chosen as per the requirements
of an application without significantly affecting the overall
deprotection reaction.
1-[2-(2-Methyl[1,3]dioxolan-2-yl)phenyl]propan-2-ol (4a)
and 1-[2-(2-methyl-[1,3]dioxolan-2-yl)phenyl]butan-2-ol (4b)
were synthesized by reacting an organolithium compound
with the appropriate epoxide. 2′-Bromoacetophenone was
first protected as an ethylene glycol ketal (Scheme 2).10 The
ketal 3 was treated with excess lithium metal in dry diethyl
ether and then with the appropriate epoxide. The isolated
yields of this reaction varied between 64% (4a) and 61%
(4b). To protect acetic acid, the ketal 4a,b was then refluxed
with acetic anhydride for 5 h. The oily product was refluxed
with benzene and water mixture for 24 h in the presence of
1 g of p-toluenesulfonic acid. The benzene layer was dried,
and the solvent was removed to obtain protected acetic acid
(yields: 92% for 5a from 4a and 86% for 5b from 4b). All
attempts to remove the ketal from 4a or 4b to form HAPE
(Figure 1) led to its decomposition. Protected acids 6 were
obtained by treating 4a with the acids in the presence of
1,3-dicyclohexylcarbodiimide (DCC) and catalytic amounts
of 4-(dimethylamino)pyridine (DMAP) in CH2Cl2 11 (gener-
ally 53-86% yield, optimized only for benzoic acid). The
ketal was then removed by p-toluenesulfonic acid (as
described above) or wet silica gel hydrolysis in the presence
of oxalic acid (40 °C, 4-5 h, 85-96% yield).12
The protected compounds 5a (4.3 mg in 1.0 mL of
CD3CN) and 5b (4.6 mg in 1.0 mL of CD3CN) were
photolyzed in NMR tubes (λ > 320 nm) under air and under
1
nitrogen. The progress of the reaction was followed by H
NMR. In a dark control, 5b (4.3 mg in 1.0 mL of CD3CN)
was wrapped in Al foil and placed in front of the light source
along with the samples photolyzed. The protected acid 5b
did not decompose in the control experiment. This implies
that the protected acids are stable in the dark and can
withstand minor temperature fluctuations (that are sometimes
experienced during photolysis). The compound 5b photo-
lyzed under nitrogen decomposed to release acetic acid while
no such decomposition occurred when photolyzed under air.
This indicates that HAPE releases the carboxylic acid via a
(6) Zabadal, M.; Pelliccioli, A. P.; Kla´n, P.; Wirz, J. J. Phys. Chem. A
2001, 105, 10329-10333.
(7) Pelliccioli, A. P.; Kla´n, P.; Zabadal, M.; Wirz, J. J. Am. Chem. Soc.
2001, 123, 7931-7932.
(8) Tseng, S.-S.; Ullman, E. F. J. Am. Chem. Soc. 1976, 98, 541-544.
(9) Pelliccioli, A. P.; Wirz, J. Photochem. Photobiol. Sci. 2002, 1, 441-
458.
(11) Grewer, C.; Ja¨ger, J.; Carpenter, B. K.; Hess, G. P. Biochemistry
2000, 39, 2063-2070.
(12) Huet, F.; Lechevallier, A.; Pellet, M.; Conia, J. M. Synthesis 1978,
63-65.
(10) Vogel, A. I. Textbook of Practical Organic Chemistry, 4th ed.;
Longman Group Limited: London, 1978; p 1371.
4470
Org. Lett., Vol. 5, No. 23, 2003

triplet excited state (Scheme 1). In the presence of oxygen,
the triplet excited state is quenched and no acid is released.
A solution of each of the protected acids 6 (ca. 80 mg in
500 mL of CH3CN, 2.5 × 10-4 to 6 × 10-4 M) was
photolyzed with a 450 W mercury lamp using a Pyrex filter
for 3-6h. The solvent was removed under reduced pressure,
and the residue was dissolved in 20 mL of ethyl acetate or
benzene. The solution was then washed with saturated
NaHCO3 solution (2 M NaOH solution was used in case of
the phenylacetic acid). The organic layer was dried over
anhydrous MgSO4 and analyzed for byproducts. The aqueous
layer was acidified by dropwise addition of concentrated HCl.
The acidified aqueous layer was washed with ethyl acetate
or benzene. The organic layer was dried and the solvent was
removed under reduced pressure. The recovered acids were
HAPE-N-t-BOC-GABA and HAPE-N-fmoc-glycine showed
no decomposition in CD3CN when kept in the dark for nearly
1
4 h (analyzed by H NMR and 13C NMR). Attempts were
made to isolate the free acids from unphotolyzed samples
of HAPE-phenylacetate and HAPE-N-t-BOC-GABA using
the base extraction technique described for the photolyzed
samples. No detectable free acid could be isolated in the
control samples. These experiments rule out the possibility
of base-catalyzed hydrolysis of protected acids under the
conditions employed for product isolation.
A variety of byproducts were detected in small amounts
that were difficult to isolate and characterize. These products
formed the bulk of the byproducts. The expected byproduct
2 could not be detected in the mixture although its formation
cannot be ruled out. It is possible that 2, if formed, could
act as an internal filter and undergo an efficient secondary
photolysis to form oligomers.13 This along with the compet-
ing reketonization could result in low quantum yield for the
deprotection reaction as reflected in long photolysis times
(3-6 h). The GC-MS analysis of byproducts of the
photolysis of 5a showed a mixture of compounds whose
structures could not be conclusively determined.
1
analyzed by H and 13C NMR spectroscopy. The yields,
determined gravimetrically, are listed in Table 1. The
Table 1. Photolysis Times and Deprotection Yields of the
HAPE-Protected Carboxylic Acids
A variety of different carboxylic acids have been protected
by HAPE as esters in relatively high yields. All the HAPE
esters released the free acids in high isolated yields under
nitrogen. Efforts are currently ongoing to characterize the
byproducts of this reaction and to determine the quantum
yield of the deprotection reaction. The mechanism of the
deprotection reaction is currently under investigation. We
hope to trap the enol 1 by Diels-Alder reaction. The results
will be reported in the future.
Acknowledgment. We thank ND-EPSCoR, the ND-
EPSCoR “Network in Catalysis” program (NSF-EPS-
0132289), and the University of North Dakota for funding
this research. B.V. was supported by NSF REU Grant No.
CHE-0243832.
Supporting Information Available: Synthesis and NMR
spectra of 4ab, 5ab, and 6. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL035782Q
recovered yield for N-fmoc-glycine is lower than others
probably due to the instability of the fmoc group in the basic
medium during the extraction. This led to only a partial
recovery of the released acid.
(13) (a) DeCosta, D. P.; Bennett, A. K.; Pincock, J. A. J. Am. Chem.
Soc. 1999, 121, 3785-3786. (b) Yu, X.; Scheller, D.; Rademacher, O.;
Wolff, T. J. Org. Chem. 2003, 68, 7386-7399.
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