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which gives the desired products, albeit in low to moderate
yields.[21,27] Therefore, major improvements are urgently
required to stimulate simple, future application of red-shifted,
azobenzene derivatives in chemical biology and medicine.
Moreover, the synthesis of red-shifted unsymmetric azoben-
zenes (Ar1 ¼ Ar2, Figure 1C) is needed to enable selective
functionalization and fine-tuning of optical properties.
Herein, we report a versatile, direct synthesis of a multi-
tude of structurally diverse, visible- and red-light-switchable
azobenzenes using directed ortho-lithiation of aromatic
precursors, followed by their reaction with aryldiazonium
salts. The azobenzenes are obtained in short time (< 3 h) with
good to excellent yields, following straightforward purifica-
tion methods.
We focused our attention on a simple and efficient
method for the preparation of sterically encumbered, tetra-
ortho-substituted azobenzenes, taking advantage of coupling
reactions with organolithium reagents. These coupling reac-
tions have seen increased interest in the past years,[28,29] and
were recently shown to be particularly suited for congested
systems.[28] 1,3-Disubstituted aromatic compounds, bearing
methoxy, fluoro or chloro substituents were identified as
potential substrates, since they can undergo facile ortho-
lithiation.[30–32] We anticipated that the resulting 2,6-disubsti-
tuted lithium species could be used as nucleophiles in the
direct reaction with 2,6-disubstituted aryldiazonium salts,
yielding highly substituted azobenzenes. Early literature on
the reaction of Grignard and organozinc reagents[33–35] with
aryldiazoniums salts, despite receiving little attention, indi-
cated that the use of organolithium reagents might be
a feasible approach towards the synthesis of hindered, red-
shifted azobenzenes. This notion was further supported by
two known examples of related procedures, in which lithiated
species react with diazonium salts to provide heterocyclic
azobenzene derivatives, as shown by Herges and co-work-
ers,[36] and in the preparation of two azobenzene intermedi-
ates as part of a procedure for the synthesis of 1-iodo-2,6-
bispropylthiobenzenes, as reported by Kaszynski and co-
workers.[37] Since the ortho-lithiation procedure is known to
have a broad substrate tolerance,[30] and the preparation of
aryldiazonium tetrafluoroborate salts is well established,[38]
we expected that our methodology might yield interesting
novel azobenzene structures with potentially bathochromi-
cally shifted absorption spectra.
tolerated but did not improve the yield, mainly due to
increasing amounts of side-products (see Table S2 in the
Supporting Information). Excess of n-butyllithium was tol-
erated in the ortho-lithiation, however, in the subsequent
reaction with the aryldiazonium salt, the liberation of N2 was
observed leading to a significant drop in isolated yield (see
Table S2). Therefore, equimolar amounts of the lithiation
precursor, n-butyllithium and aryldiazonium salt are used
throughout, yielding tetra-ortho-methoxyazobenzene 3a in
86% isolated yield.
After establishing the optimized conditions, we studied
the scope of the reaction by diversifying both the substrate for
lithiation and the aryldiazonium salt. As shown in Figure 2,
a multitude of diazonium salts could be efficiently coupled to
1,3-dimethoxybenzene 1a in good to excellent yields. More-
over, both cyano-substituted (2d) and nitro-substituted (2e)
aryldiazonium salts were well tolerated, which are potential
precursors for para-aminomethylene- and para-amino-azo-
benzene derivatives. Both tert-butoxy-carbonyl- (2 f) and
chloro-substituted (2g) aryldiazoniums were converted with
satisfying yields, with the potential for subsequent function-
alization of the products using amide formation and cross-
coupling reactions. Successful preparation of compounds 3d–
3g highlights the functional group tolerance, which is of
particular importance for the application of our method to the
synthesis of photoresponsive materials and drugs. The azo-
benzene derivatives were purified using either extraction/
washing or short flash chromatography allowing the rapid
syntheses (2–3 h total time) of these functionalized photo-
switches.
Inspired by earlier reports by Woolley and co-workers,[4,24]
we aimed next at installing additional methoxy substituents to
obtain more bathochromically shifted absorption bands of the
azobenzenes. Therefore, the scope of the lithiation and
subsequent coupling was tested with different methoxy-
substituted benzene derivatives. 1,3,5-Trimethoxybenzene
1b could be readily lithiated and reacted with aryldiazonium
salts to give moderate to excellent yields (41–86%). More-
over, lithiation of 1,3,4-trimethoxybenzene 1c selectively at
the 2-position led, after quenching with the different aryldia-
zonium salts, to novel azobenzenes (3k–m) in good yields
(58–76%).
Subsequently, we attempted the synthesis of ortho-fluo-
roazobenzenes, because of their promising photochemical
properties, as reported by Hecht and co-workers.[21] In line
with earlier reports,[39] difluorobenzene 1d underwent a regio-
selective lithiation at the 2-position, due to the coordinating
potential of the two fluoro-substituents to lithium. Using our
method, 3n was synthesized in high yield (82%) and short
reaction times (< 2 h). Moreover, tetra-ortho-fluoroazoben-
zene 3o was synthesized starting from difluorobenzene 1d
and difluoro-substituted aryldiazonium salt 2h yielding the
product in excellent yield (77% after 2 h) without the need
for laborious purification. However, it has to be noted that
lower temperatures (up to ꢀ508C) were required for the
lithiation of 1d to prevent the formation of benzyne.[39]
Due to the recent application of red-shifted tetra-ortho-
chloro-derivatives,[23,25,26] we applied our method to synthe-
size these azobenzenes. Lithiation of dichlorobenzene 1e at
In the initial investigations, we focused on the synthesis of
tetra-ortho-methoxyazobenzene (Figure 1C, R = OMe). The
synthesis of this compound requires the ortho-lithiation of
1,3-dimethoxybenzene (Figure 2, 1a), followed by reaction of
the formed metallo-organic species with 2,6-dimethoxyben-
zenediazonium tetrafluoroborate 2a. We used a slight excess
of aryldiazonium salt, inspired by the well-known reaction of
aryldiazoniums with phenolates.[16] Treating compound 2a
(1.2 equiv) with 1 equiv of the metallated 1,3-dimethoxyben-
zene, produced the desired product 3a in 71% isolated yield
after 90 minutes total reaction time, requiring only simple
purification (extraction followed by precipitation). Further
optimization of the procedure was performed using, among
others, additional equivalents of aryldiazonium salt (2a) for
the coupling reaction, showing that an excess of the salt was
2
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Angew. Chem. Int. Ed. 2016, 55, 1 – 6
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