Tetrahedron Letters
Reevaluation of the 2-nitrobenzyl protecting group for nitrogen
containing compounds: an application of flow photochemistry
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Chloe I. Wendell, Michael J. Boyd
Vertex Pharmaceuticals Inc., 50 Northern Avenue, Boston, MA, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Photochemistry under continuous flow conditions has many potential benefits for photochemical reac-
tions that are problematic in batch. The 2-nitrobenzyl moiety is a photolabile protecting group for nitro-
gen. However, N-deprotection is generally impractical and, therefore, has not been extensively adopted.
This Letter reports significant improvements in the N-deprotection of the 2-nitrobenzyl group through
the application of continuous flow photolysis. This procedure was applied to a variety of substrates
including indoles, indazoles, pyrazoles and secondary amines. Significant improvement in yield, reaction
time and scalability was observed under continuous flow conditions.
Received 5 November 2014
Revised 18 December 2014
Accepted 2 January 2015
Available online 10 January 2015
Keywords:
Photochemistry
Flow
Ó 2015 Elsevier Ltd. All rights reserved.
Protecting group
o-Nitrobenzyl
R1
R2
Introduction
N
O
The 2-nitrobenzyl protecting group (o-NB) is photolabile and
removable under mild conditions (Fig. 1). Despite the fact that there
are many options for nitrogen protection,1 the use of ultraviolet
light as the sole deprotecting agent makes this protecting group
especially useful because the removal conditions are unlikely to
affect other functional groups or other protecting groups present
in a given substrate. Furthermore, the o-NB is stable to a variety of
conditions, including acid and base, so it is potentially of high value
to synthetic chemists. Its use was first reported by Barltrop in 1966
as the corresponding ester of benzoic acid,2 and it was subsequently
used for the protection of nitrogen containing compounds such as
amines, amides, histidine3 and various heterocycles.4
However, apart from amides, the use of the o-NB protecting
group on nitrogen is relatively uncommon. Potential reasons for
the relatively low use of this group for the protection of nitrogen
are: (1) removal is often low yielding; (2) long reaction times are
often required; (3) very low concentrations are used and (4) reac-
tions are generally limited to a small scale. Scale limitations are
due to the decrease of the surface area to reaction volume ratio in
conventional batch vessels that leads to decreased light exposure.
Many of the drawbacks seen in o-NB removal make the reaction
particularly suited to continuous flow photochemical conditions.5
In 2005, Booker-Milburn and co-workers6 described a practical
flow apparatus for organic photochemistry in which the reaction
R1
R2
hv
N
H
NO2
N
O
Figure 1. Scheme for the removal of the 2-nitrobenzyl protecting group.
mixture is pumped through UV transparent tubing wrapped
around a medium pressure mercury lamp. Compared to batch reac-
tions, photochemical reactions in continuous flow experience more
efficient irradiation due to a much higher surface area to volume
ratio4 and, importantly, this ratio is constant regardless of scale.
In addition, more efficient irradiation reduces the duration of the
reaction, which can minimize decomposition and side reactions.
To test whether the photolytic deprotection of o-NB-protected
nitrogen-containing compounds offers significant advantages in
flow, several indoles were deprotected in batch and flow and the
results were compared. The conditions were then applied to other
nitrogen containing compounds.
Batch and flow yields were obtained using the following proce-
dures. In batch reactions, the o-NB-protected compounds were
added to a 10 mL Pyrex tube under nitrogen. Degassed dioxane
(0.04 M) was added and the tube was placed into a Luzchem
LZC-4 photoreactor equipped with fourteen 8 W UV-A lamps. In
flow, the protected compounds were added to a round bottom flask
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