The N-(2-acetoxyethyl) group as a new photolabile protecting group

Article abstract of DOI:10.1016/S0040-4039(00)00108-8

The N-(2-acetoxyethyl) group can be cleaved by a photoinduced single electron transfer to 4,4'-dimethoxybenzophenone. (C) 2000 Published by Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00108-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 2097–2099
The N-(2-acetoxyethyl) group as a new photolabile protecting
group
Janine Cossy ∗ and Haja Rakotoarisoa
Laboratoire de Chimie Organique associé au CNRS, ESPCI, 10 rue Vauquelin-75231, Paris Cedex 05, France
Received 21 December 1999; accepted 12 January 2000
Abstract
The N-(2-acetoxyethyl) group can be cleaved by a photoinduced single electron transfer to 4,40-
dimethoxybenzophenone. © 2000 Published by Elsevier Science Ltd. All rights reserved.
Keywords: N-(2-acetoxyethyl); protection; deprotection; 4,40-dimethoxybenzophenone; photo-induced electron transfer.
Numerous protecting groups for basic nitrogen can be found in the literature attesting to the importance
of this aspect of amine chemistry.1 The most frequently used amino protecting groups are Bn,2 Boc,3
Cbz,4 and Fmoc.5 Since removal of these groups can be problematic with highly functionalized and
sensitive substrates, new protecting groups are still needed.
In this letter, we disclose that the N-(2-acetoxyethyl) group can be used as an efficient protecting group
for the amino function. It has the advantage of being cleaved easily on irradiation of amines of type A in
the presence of 4,40-dimethoxybenzophenone at 350 nm in wet acetonitrile.
The N-(2-acetoxyethyl) derivatives of type A are easily obtained by treating amines of type B in
acetonitrile with 2-bromoethyl acetate.6 After heating the mixture under reflux for 5 h, followed by
standard aqueous extractive work-up and chromatography, protected amines of type A were obtained in
good yields. Several examples are shown in Table 1. Amines of type A (1 mmol) were deprotected
when irradiated in the presence of 4,40-dimethoxybenzophenone (1 mmol) and water (0.1 mL) in
acetonitrile (2×10−2 M) at 350 nm.7 After 3 h, the corresponding amines B were isolated in good yields.
This photochemical process was very regioselective as cleavage of the alkyl group R1 or R2 was not
observed. Furthermore, when an optically active amine of type A was irradiated, no epimerization was
observed (entry 5). This process was also very chemoselective as secondary amines were recovered
∗
Corresponding author.
0040-4039/00/$ - see front matter © 2000 Published by Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00108-8
tetl 16387

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Table 1
Irradiation of amine of type A at 350 nm in the presence of 4,40-dimethoxybenzophenone
unchanged (entry 6). The deprotection of amines of type A was accompanied by the reduction of 4,40-
dimethoxybenzophenone into the corresponding alcohol. The formation of B from A can be explained
by a photoinduced single electron transfer (SET) (cf. Scheme 1). Extensive investigations of the
photoreduction of aromatic ketones by amines have been carried out,8 and it has been shown that an
initial electron transfer to generate a radical ion pair is followed by a proton transfer to give a ketyl
radical and an α-aminoalkyl radical (tertiary amine). This radical pair can undergo disproportionation
to regenerate starting materials in competition with reaction of the α-aminoalkyl radical. It seems that
the acetyl group enhances the acidity of the proton at C-1 and, consequently, the transfer of one proton
to the ketyl radical-anion can produce radicals C and D which can be converted into alcohol E and
intermediates G and F. After hydrolysis, these intermediates can be transformed to B (Scheme 1, path
a). A second possibility is the abstraction of a hydrogen by the ketyl radical anion9 that will lead to the
iminium ion F, which can be stabilized by the acetyl group to form intermediate F0. These intermediates
can produce the deprotected amines after hydrolysis (Scheme 1, path b).
Scheme 1. Mechanism for the transformation of amines of type A to amines of type B
In summary, a photolabile protecting group for basic nitrogen has been developed. Applications of the
N-(2-acetoxyethyl) group as a protecting group to other synthetic situations are under study and will be
reported in due course.

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Acknowledgements
We thank Rhône-Poulenc Industrialisation for financial support.
References
1. (a) Greene, T.W.; Wuts, P. G. M. Protective Groups in Organic Synthesis; Wiley: New York, 1991, 2nd ed.; (b) Kocienski, P.
J. Protecting Group; Thieme: Stuttgart, 1994.
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Ichihara, O. Tetrahedron Asymmetry 1991, 2, 183–186.
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4. Bergmann, M.; Zervas, L. Ber. 1932, 65, 1192–1201.
5. Carpino, L. A.; Han, G. Y. J. Org. Chem. 1972, 37, 3404–3409.
6. Preparation of N-(acetoxyethyl)amines (general procedure): A mixture of amine (10 mmol), K2CO3 (2.7 g, 19.53 mmol),
NaI (0.15 g, 1 mmol) and 2-bromoethyl acetate (1.2 mL, 10.88 mmol) in acetonitrile (20 mL) was heated at 60°C for 5–6 h.
After cooling to rt, ethyl acetate (30 mL) and water (20 mL) were added. The organic layer was separated, dried over MgSO4,
filtered and the solvent was removed in vacuo. The N-(acetoxyethyl)amine was isolated after flash chromatography on silica
gel.
7. The irradiations were performed in a Rayonet RPR-200 equipped with six low-pressure mercury lamps (RPR-3500A, 350
nm, 24 W). The solutions were introduced into 1 cm inside diameter quartz tubes.
8. Inbar, S.; Linschitz, H.; Cohen, S. G. J. Am. Chem. Soc. 1981, 103, 1048–1054.
9. Cossy, J.; Guha, M. Unpublished results.