N-Methyl-N-(o-nitrophenyl)carbamates as photolabile alcohol protecting groups

Article abstract of DOI:10.1016/S0040-4039(01)01700-2

N-Methyl-N-(o-nitrophenyl)carbamates represent new photoremovable alcohol protecting groups. This protecting group is easily incorporated by chemical coupling of the corresponding alcohol to N-methyl-N-(o-nitrophenyl)carbamoyl chloride. High yield and clean deprotection are induced by photolysis in protic solvents (water, ethanol or ethanol/water mixtures) from 254 to 365 nm.

Full text of DOI:10.1016/S0040-4039(01)01700-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 7957–7959
N-Methyl-N-(o-nitrophenyl)carbamates as photolabile alcohol
protecting groups
Sandra Loudwig and Maurice Goeldner*
Laboratoire de Chimie Bioorganique, UMR 7514 CNRS, Faculte´ de Pharmacie, Universite´ Louis Pasteur Strasbourg,
BP 24, 67401 Illkirch Cedex, France
Received 6 September 2001; revised 8 September 2001; accepted 10 September 2001
Abstract—N-Methyl-N-(o-nitrophenyl)carbamates represent new photoremovable alcohol protecting groups. This protecting
group is easily incorporated by chemical coupling of the corresponding alcohol to N-methyl-N-(o-nitrophenyl)carbamoyl chloride.
High yield and clean deprotection are induced by photolysis in protic solvents (water, ethanol or ethanol/water mixtures) from
254 to 365 nm. © 2001 Elsevier Science Ltd. All rights reserved.
Protecting groups represent useful tools in organic syn-
thesis provided they fulfil a series of criteria including a
convenient and efficient synthesis, chemical stability
and an efficient and selective removal. Many protecting
groups have been developed for alcohols, such as ester
and ether derivatives, to modulate their base and acid
sensitivity.1 Orthogonality of protecting groups was
also developed for alcohols2–4 to extend their synthetic
use.
nitroindolines amides12 prompted us to investigate the
possibility of extending such a photolytic reaction to
carbamates for an ultimate release of alcohols. The
present article describes the use of such carbamates as
photoremovable protecting groups of alcohols.
We studied first simple carbamate derivatives i.e. N-
methyl - N - (2 - nitrophenyl)methyloxycarboxamide 3a
and N-benzyl-N-(2-nitrophenyl)benzyloxycarboxamide
3b, to set up a convenient and easy synthesis of the
alcohol protection step, which is described in Scheme 1.
Photolytic removal of protecting groups represents an
interesting issue in synthetic organic chemistry, allow-
ing a very selective unmasking of a chemical function,5
while photolytic orthogonality was recently described
for the protection of carboxylic acids.6 The o-nitroben-
zyl group represents the most widely used photoremov-
able protecting group in organic chemistry. This
photolytic unmasking has also been extensively used in
biology to permit a spatio-temporal release of biologi-
cally active compounds from their precursors named
caged compounds.7 Very few examples used the photo-
chemical deprotection of alcohol groups to achieve the
functional masking of a biomolecule such as the photo-
chemical release of choline8 and glucose9 from o-
nitrobenzyl ether precursors and more recently of
adenosine from an anthraquinon-2-ylmethoxycarbonyl
precursor.10 Also, photochemical release of alcohols
from silyl protection was described using a hydrosilyla-
tion reaction of arylethynyl acetates.11 The description
of the photorelease of carboxylic acids from 1-acyl-7-
The N-methyl-2-nitroaniline 1 is quantitatively con-
verted to the N-methyl-N-(2-nitrophenyl)carbamoyl
NO2
N
Cl
NO2
O
N
OR
R
OH
O
hν 248-365 nm
(EtOH / H2O)
O
O
NO2
N
OR
NO2
N
Cl
NO2
ROH,
DMAP, Et3N
NH
or RO-Na+
COCl2
1
2
3
Scheme 1. N-Methyl-N-(o-nitrophenyl)carbamates as photo-
* Corresponding author. Tel.: +333 90 24 41 62; fax: +333 90 24 43
labile protecting groups. Principle and synthesis.
06; e-mail: goeldner@bioorga.u-strasbg.fr
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01700-2

7958
S. Loudwig, M. Goeldner / Tetrahedron Letters 42 (2001) 7957–7959
Table 1. Structure and yields of protection and photode-
protection of the different alcohols masked with 2. (a)
Those alcohols were too volatile and could not be satis-
factorily detected by UV and subsequently quantified by
HPLC. Their photodecomposition could be appreciated by
near UV spectra evolution and followed by HPLC: disap-
pearance of the starting material, together with the forma-
tion of N-methyl-2-nitrosoaniline. (b) The protected
choline 3c used the alternative synthetic pathway, starting
from the corresponding chloroformate and N-methyl-2-
nitroaniline 1 (see text).
The photochemical reactivity of these derivatives was
tested in different solvents and wavelengths using a
1000 W Xe-Hg lamp connected to a grating monochro-
mator. The light intensity was measured with a ther-
mopile coupled to a microvolmeter. These carbamates
were photolabile in different solvents but the best
results were obtained in protic solvents such as H2O,
EtOH or EtOH/H2O mixtures. The probes were sensi-
tive at the different wavelengths we tested, 365, 312 and
254 nm, respectively, corresponding to maximum emis-
sion lines of the Xe-Hg lamp. They showed a faster
decomposition at 254 nm (Table 2). Besides the desired
alcohol, N-methyl-2-nitrosoaniline was identified dur-
ing these photolytic reactions. The structure of this
compound was assessed by NMR, MS and IR.15 Its
strong UV absorbance umax 308 nm (m=11000 M−1
cm−1), 472 nm (m=5900 M−1 cm−1) should allow an easy
monitoring of the photolytic reaction by UV spec-
troscopy. However, the fragmentation mechanism of
these carbamates remains unclear and cannot be
deduced from the usual photolytic mechanism proposed
either on o-nitrobenzyl16 or on the 1-acyl-7-indoline
derivatives.12 Consequently, we did not take advantage
of the formation of this nitroso compound to monitor
the photolytic reaction.
We analyzed in more detail two photolytic reactions,
the protected choline and serine derivatives 3c and 3d,
respectively. Scheme 2 shows the UV spectra of the
photodecomposition of compound 3c in water. The
formation of isobestic points (202 and 276 nm) is
indicative of a clean photodecomposition process. The
photolytic reaction led to a quantitative formation of
choline tested by means of an enzymatic test.8
chloride 2 by treatment with phosgene (or a phosgene
substitute). This precursor, which solidifies at lower
temperature, can be stored for months when protected
from light. It is converted to the carbamate13 in high
yield either by treatment with an excess alcohol in the
presence of DMAP and NEt3 or with the corresponding
sodium alkoxide (Table 1). The carbamates are isolated
using standard purification procedures (i.e. silica gel
chromatography). Alternatively, the alcohols can also
be firstly converted to their chloroformate derivatives
with phosgene (or an equivalent) and treated subse-
quently with N-methyl-2-nitroaniline 1, as was the case
for the protected choline derivative 3c.14
The photolytic deprotection of the serine derivative 3d
could be fully monitored by HPLC, allowing visualiza-
tion of the disappearance of the starting compound 3d
with the concomitant formation of the unprotected
serine derivative and the N-methyl-2-nitrosoaniline
(Scheme 3).
The N-methyl-N-(o-nitrophenyl)carbamates are slightly
sensitive to hydrolytic conditions especially in basic
medium, therefore they cannot be used in a synthetic
strategy using such reaction conditions. This protecting
group is however compatible with strong non-nucle-
ophilic basic conditions, i.e. with lithium diisopropy-
lamide or lithium bis(trimethylsilyl)amide (THF, up to
0°C). As expected, these carbamates are also stable in
non-aqueous acidic conditions such as pure TFA or
TFA/CH2Cl2 mixtures.
Table 2. Deprotection yield generated by irradiation of 1.4
ml 10−4 M and 2×10−4 M solutions of compound 3c in
water, at different wavelengths, for 1 h. The amount of
released choline was assessed by an enzymatic test8
254 nm
312 nm
365 nm
1.10−4
2.10−4
M
M
100%
100%
100%
91%
76%
52%
Scheme 2. UV spectra of 3c photolysis (1.4 ml, 10−4 M in
water at 254 nm) as a function of time (0, 10, 20, 30, 45, 60
min).

S. Loudwig, M. Goeldner / Tetrahedron Letters 42 (2001) 7957–7959
7959
7. Methods Enzymol.; Marriott, G., Ed.; Academic Press:
New York, 1998; Vol. 291.
8. Peng, L.; Goeldner, M. J. Org. Chem. 1996, 61, 185–191.
9. Corrie, J. E. T. J. Chem. Soc., Perkin Trans. 1 1993,
2161–2166.
10. Furuta, T.; Hirayama, Y.; Iwamura, M. Org. Lett. 2001,
3, 1809–1812.
11. Pirrung, M. C.; Fallon, L.; Zhu, J.; Lee, Y. R. J. Am.
Chem. Soc. 2001, 123, 3638–3643.
12. Papageorgiou, G.; Ogden, D. C.; Barth, A.; Corrie, E. T.
J. J. Am. Chem. Soc. 1999, 121, 6503–6504.
13. The NMR spectra of these carbamates and the starting
carbamoyl chloride 2 show the presence of rotamers
which collapse at higher temperature (DMSO-d6 at
80°C). N-Methyl-N-(2-nitrophenyl)carbamoyl chloride 2
could not be heated in DMSO due to its instability in this
solvent.
14. Protected methanol 3a. Methyl alcohol (0.2 M) with
metallic sodium (1.3 equiv.) and carbamoyl chloride 2 (1
equiv.) were stirred for 15 min at rt yielding 94% of 3a
after chromatography (CH2Cl2 as eluent).
Scheme 3. HPLC profiles at u=210 nm of photodeprotection
of the serine derivative 3d: 3d (tR=45 min); unprotected
serine (tR=36 min), N-methyl-2-nitrosoaniline (tR=33 min).
1.4 ml of a 1.5 M 3d solution in ethanol/water (1/1) was
irradiated for 3 h 30 at 254 nm. 100 ml samples were injected
on a C18 hypersil column with 1 ml/min flow rate using a
(H2O, 0.1% TFA):(CH3CN, 0.1% TFA) gradient from (100:0)
to (0:100) in 55 min. The slower photodecomposition process
observed for 3d compared to 3c (Table 2) is due to lower light
intensity used during this experiment (about 75% energy
weakening of the 1000 W lamp).
Protected benzyl alcohol 3b. Benzyl alcohol (3 equiv.),
DMAP (0.5 equiv.), Et3N (1.1 equiv.) and carbamoyl
chloride 2 (1 equiv.) in CH2Cl2 (0.2 M) were mixed for 1
night at rt and 94% of compound 3b was obtained, after
flash chromatography.
Protected choline 3c. The precursor of this derivative was
synthesized by condensing 2-nitro-N-methylaniline (1
equiv.) and 2-chloro-N,N-dimethylethylamine (1.25
equiv.) by reflux in xylene (0.2 M) for 1 night. After a
rapid filtration on silica gel, the isolated chloride product
was converted into its iodide derivative with NaI (10
equiv.) by 1 night reflux in acetone (0.2 M), followed by
silica gel flash chromatography. Finally, the quaternary
ammonium salt could be precipitated in toluene (0.05 M)
saturated with methyliodide and isolated by centrifuga-
tion. The obtained powder was rinsed with pentane (58%
overall yield).
We used the serine derivative 3d for a larger scale
photodecomposition reaction (27 mg in 400 ml EtOH)
using a quartz reactor. The irradiation was stopped
after 90 min photolysis. Evaporation of the solvent
followed by a rapid filtration over silica gel provided 15
mg (91%) of the desired serine compound.
In summary, the N-methyl-N-(o-nitrophenyl)carba-
mates represent a new class of photolabile alcohol
protecting groups, which are easily synthesized and can
be used at organic synthetic scale.
Protected serine 3d. N-Benzoyloxyserine carboxylate (1
equiv.) was transformed to its methyl ester by 1 night
stirring in methanol (0.2 M) with trimethylsilyl chloride
(4 equiv.) and isolated in 95% yield by flash chromatogra-
phy (TLC detection was ensured by spraying with a
solution of 1% Ce2(SO4)3, 38% (NH4)6Mo7O24·4H2O in
10% H2SO4 and then heating the plate). The protected
serine (1.5 equiv.), DMAP (0.5 equiv.), Et3N (1.2 equiv.)
and carbamoyl chloride 2 (1 equiv.) were stirred for 1
night at rt in CH2Cl2 (0.2 M) yielding 88% of compound
3d, after flash chromatography.
Acknowledgements
The authors thank James Pincock for critical reading of
the manuscript and the Association Franc¸aise contre les
Myopathies, the CNRS and the European Biotechnol-
ogy Programme N° 96081 for financial support.
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11.01 (s, 1H, NH); 8.70 (d, 1H, H3); 7.46 (ddd, 1H, H5);
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