New safety-catch photolabile protecting group

Article abstract of DOI:10.1021/ol702327c

Photolabile protecting groups have proven their usefulness on many occasions. Their versions as linkers are however less attractive, as robustness and real orthogonality become critical issues. Safety-catch systems, where a preliminary activation phase is necessary, circumvent the problem of premature cleavage. In this work, we introduce a new safety-catch photolabile protecting group, whose cleavage requires the simultaneous presence of light and a chemical promoter.

Full text of DOI:10.1021/ol702327c

ORGANIC
LETTERS
2007
Vol. 9, No. 26
5453-5456
New Safety-Catch Photolabile Protecting
Group
Emmanuel Riguet and Christian G. Bochet*
Department of Chemistry, UniVersity of Fribourg, chemin du Muse´e 9,
CH-1700 Fribourg, Switzerland.
christian.bochet@unifr.ch
Received September 26, 2007
ABSTRACT
Photolabile protecting groups have proven their usefulness on many occasions. Their versions as linkers are however less attractive, as
robustness and real orthogonality become critical issues. Safety-catch systems, where a preliminary activation phase is necessary, circumvent
the problem of premature cleavage. In this work, we introduce a new safety-catch photolabile protecting group, whose cleavage requires the
simultaneous presence of light and a chemical promoter.
Photolabile protecting groups exhibit numerous advantages
over their classical chemically labile counterparts, such as
the relatively soft conditions required for their deprotection
and orthogonality with respect to acid- or base-sensitive
groups.1 Nevertheless, to extend the scope of photolabile
protecting groups, there is an important need for new
methodologies to increase the selectivity of the deprotection
step. Our group developed the concept of chromatic or-
thogonality which established that the use of monochromatic
Figure 1. Photolabile derivatives of ortho-NBA.
light is a powerful strategy to achieve wavelength-selective
deprotection.2
We describe here a new strategy in which the release of
the protecting group requires the simultaneous presence of
light and a chemical activator. It is therefore a type of safety-
catch process.3 We based our work on the photochemical
reactivity of ortho-nitrobenzyl derivatives such as compounds
1 and 2 which are effectively cleaved upon irradiation into
amine, alcohol, or carboxylic acid, respectively (Figure 1).
Extensive studies on the photochemical behavior of such
compounds showed that substitution on the aromatic part
has an impact both on the absorption properties and on the
quantum yield for photocleavage.4 Typically, in the nitro-
veratryloxycarbonyl (NVOC) derivatives 2, the two methoxy
groups were introduced to increase the absorbance at
wavelengths longer than 320 nm. Consequently, the pho-
tolysis of NVOC derivatives 2 is possible at wavelengths
longer than normally required for the NBA derivatives 1.5
However, this modification also significantly decreased the
quantum yield of the reaction.6
(1) (a) Falvey, D. E.; Sundararajan, C. Photochem. Photobiol. Sci. 2004,
3, 831. (b) Pelliccioli, A. P.; Wirz, J. Photochem. Photobiol. Sci. 2002, 1,
441. (c) Bochet, C. G. J. Chem. Soc., Perkin Trans. 1 2002, 125. (d) Pillai,
V. N. R. Org. Photochem. 1987, 9, 225.
(2) (a) Blanc, A.; Bochet, C. G. Org. Lett. 2007, 9, 2649. (b) Blanc, A.;
Bochet, C. G. J. Org. Chem. 2002, 67, 5567. (c) Bochet, C. G. Angew.
Chem., Int. Ed. 2001, 40, 2071.
(3) Kenner, G. W.; McDermott, J. R.; Sheppard, R. C. Chem. Commun.
1971, 636. For a more recent overview, see: Seneci, P. Solid-Phase
Synthesis and Combinatorial Technologies; John Wiley: New York, 2000;
p 17.
(4) Bochet, C. G. Tetrahedron Lett. 2000, 41, 6341 and references therein.
(5) Patchornik, A.; Amit, B.; Woodward, R. B. J. Am. Chem. Soc. 1970,
92, 6333.
(6) Charier, S.; Ruel, O.; Baudin, J. B.; Alcor, D.; Allemand, J. F.;
Meglio, A.; Jullien, L.; Valeur, B. Chem.-Eur. J. 2006, 12, 1097-1113.
10.1021/ol702327c CCC: $37.00
© 2007 American Chemical Society
Published on Web 11/30/2007

We hypothesized that the excited state of derivatives
containing an electron-releasing group para to the nitro
function would have a strong charge-transfer character, which
should sufficiently decrease the quantum yield to almost
completely passivate the compound toward irradiation. If the
electron-releasing group is an amine, we anticipated that
protonation should restore the photoreactivity by cancelling
the charge-transfer character in the transition state (Scheme
1).
Scheme 2. Preparation of the Ester 3
Scheme 1. Inhibition of the Photoreactivity by Charge
Transfer
confirmed that protonation has the expected effect on the
rate of photolysis. Indeed, in the presence of 1 equiv of
To test our hypothesis, we synthesized the esters 3-5
which contain the piperidine, morpholine, and diethyl amine
subunit para to the nitro group (Figure 2).
Figure 3. Photolysis of compound 3 in the presence of increasing
amounts of trifluoromethane sulfonic acid. For compounds 4 and
5, see Supporting Information.
Figure 2. Safety-catch candidates.
trifluoromethane sulfonic acid or 10 equiv of HCl, the rate
of photolysis is close to that of the unsubstituted NBA
derivative 1 (Figure 3).
The potentially photolabile ester 3 was prepared by simple
acylation of the corresponding alcohol 10, itself prepared
by nucleophilic aromatic substitution of the 4-chloro-2-
nitrobenzaldehyde acetal 7 with piperidine, followed by
acidic hydrolysis and reduction with sodium borohydride,
according to Scheme 2. Esters 4 and 5 were prepared along
similar lines from alcohols 11 and 12, respectively.
The effect of protonation is particularly visible in the UV-
vis spectrum of 3. The intense charge-transfer band (λmax
)
395 nm) gradually decreases upon addition of increasing
amounts of a strong acid (Figure 4). Moreover, this effect is
also directly observable by the disappearance of the yellow
color (see pictures in the Supporting Information). The
spectrocopic results might, however, not fully reflect the
situation in the photolysis rate experiments because the
We first verified that compounds 3-5 are inert toward
irradiation at 300 nm in acetonitrile (Figure 3). We then
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Org. Lett., Vol. 9, No. 26, 2007

These experiments are compatible with our central hy-
pothesis. The photoreactivity of NBA-derived esters such
as 3, in which an amino group para to the nitro group
quenches the photoreactivity, can be restored efficiently by
a chemical activator such as a proton.
We then looked for a milder reagent to activate the
photolysis. We found that CuII could be used for this purpose.
Even 1 equiv of Cu(ClO4)2 or Cu(OTf)2 almost fully restored
the reactivity on 3 (Figure 5). Surprisingly, other metallic
Figure 4. UV spectra of 3 (10-4 M) in CH3CN upon addition of
trifluoromethane sulfonic acid (0-2 equiv).
concentrations are very different (0.1 mM for the UV-vis
vs 5 mM for the photolysis). Either the protonation is nearly
complete in the photolysis (as suggested by the totally
colorless solution) or the fraction of reactive species is
sufficient to drive the reaction to completion after re-
equilibration. In any case, the rates parallel the ones from
NBA derivative 1 (Figure 3). It is worth pointing out that
an accelerating effect of acids on NBA derivatives 1 has
already been reported, but it was shown that it occurred
downstream from the initial photochemical event.7 In our
case, as the starting material is observed, the rates of the
chemical steps following the first hydrogen abstraction are
irrelevant. In the case of 3, protonation clearly leads to an
acceleration of the photochemical step, i.e., the photoinduced
benzylic hydrogen abstraction.
Figure 5. Photolysis of compound 3 in the presence of a copper-
(II) source.
cations such as Zn2+ or Ni2+ did not increase the reactivity.
It is thus not ruled out that pathways more convoluted than
simple complexation are involved such as, for example,
single electron transfer from copper.8
As a negative control, we verified that compound 3 did
not undergo acid-catalyzed hydrolysis by adding up to 2
equiv of trifluoromethanesulfonic acid and stirring at 40 °C
1
for 3 h. No reaction was detected by H NMR. To further
check the compatibility with hydrolyzable functional groups
(Scheme 3), we photolyzed the diester 13 without detecting
Scheme 3. Verification of Chemical Orthogonality
Figure 6. Further analogues of 3.
An important application of this strategy would be its use
as a part of a photolabile safety-catch linker for solid-phase
synthesis.9 Thus piperazine analogues such as 15a,b would
have both the inhibiting amine and an anchor point for a
resin (Figure 6). Thus compounds such as 16a,b were
prepared (see Supporting Information). Both esters were
dodecanol (70% isolated yield of 14, after esterification with
trimethylsilyldiazomethane).
(7) (a) Hellrung, B.; Kamdzhilov, Y.; Schwo¨rer, M.; Wirz, J. J. Am.
Chem. Soc. 2005, 127, 8934. (b) Corrie, J. E. T.; Barth, A.; Munasinghe,
V. R. N.; Trentham, D. R.; Hutter, M. C. J. Am. Chem. Soc. 2003, 125,
8546.
(8) Aniline radical cations can be generated by Cu(II) under specific
circumstances, as shown recently. See: Kirchgessner, M.; Sreenath, K.;
Gopidas, K. R. J. Org. Chem. 2006, 71, 9849.
Org. Lett., Vol. 9, No. 26, 2007
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photochemically unreactive. On the other hand, in acidic
media, the reactivity of 16b was restored. 16a remained
photoinert, probably because the protonation occurs on the
unconjugated amine.
The combination of high chemical/photolytic stability and
mild hydrolysis conditions makes this new photolabile pro-
tecting group an interesting platform for further optimization
in diverse fields of application, such as photolithography,
combinatorial chemistry, or organic synthesis.
Acknowledgment. Financial support from the Swiss
National Science Foundation (grant 620-066063) and the
State Secretariat for Education and Research (grant C03.0025)
is gratefully acknowledged.
Supporting Information Available: Selected experi-
mental procedures and spectral data. This material is available
free of charge via the Internet at http://pubs.acs.org.
(9) Efficient, safety-catch photolabile linkers have been described
recently, triggered by the hydrolysis of thioketals or ketals: (a) Cano, M.;
Ladlow, M.; Balasubramanian, S. J. Org. Chem. 2002, 67, 129-135.
(b) Flickinger, S. T.; Patel, M.; Binkowski, B. F.; Lowe, A. M.; Li, M. H.;
Kim, C.; Cerrina, F.; Belshaw, P. J. Org. Lett. 2006, 8, 2357-2360.
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