Cross-coupling strategy for the synthesis of diazocines

Article abstract of DOI:10.1021/acs.orglett.0c00122

Ethylene bridged azobenzenes are novel, promising molecular switches that are thermodynamically more stable in the (Z) than in the (E) configuration, contrary to the linear azobenzene. However, their previous synthetic routes were often not general, and yields were poorly reproducible, and sometimes very low. Here we present a new synthetic strategy that is both versatile and reliable. Starting from widely available 2-bromobenzyl bromides, the designated molecules can be obtained in three simple steps.

Full text of DOI:10.1021/acs.orglett.0c00122

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Letter
Cross-Coupling Strategy for the Synthesis of Diazocines
Shuo Li, Nadi Eleya, and Anne Staubitz*
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ABSTRACT: Ethylene bridged azobenzenes are novel, promising
molecular switches that are thermodynamically more stable in the
(Z) than in the (E) configuration, contrary to the linear
azobenzene. However, their previous synthetic routes were often
not general, and yields were poorly reproducible, and sometimes
very low. Here we present a new synthetic strategy that is both versatile and reliable. Starting from widely available 2-bromobenzyl
bromides, the designated molecules can be obtained in three simple steps.
Scheme 1. Comparison of Strategies for the Synthesis of
cAB
he development of molecular switches that isomerize by
Tirradiation with light have gained much attraction in
recent years due to their numerous applications.1 In 2009, the
ethylene-bridged cyclic congener of azobenzene, 11,12-
dihydrodibenzo[c,g][1,2]diazocine (cAB, 1a), was observed
to have superior switching properties compared to linear
azobenzene.2 In particular, the high photoconversion (Z → E
92 3%, E → Z 100%), the good resolution of absorption
bands between isomeric states (Z to E isomer: 404 to 490 nm),
and photoisomerization quantum yields (Z → E 72 4%, E →
Z 50 10%) are much higher in cAB than in the nonbridged
azobenzene. Furthermore, in cAB, photochromism is achieved
solely by visible light: Blue light irradiation at 385 nm triggers
the nπ* excitation and transition to the (E) isomer, while
backswitching is accomplished by thermal relaxation or via
green light at a wavelength of 520 nm. In contrast to linear
azobenzene, the (Z) isomer of cAB is thermodynamically
favored over the (E) isomer by 37.08 kJ/mol.3 The switching
behavior of cAB has been examined in detail by quantumme-
chanical simulations4,5 and spectroscopic methods.6,7 How-
ever, compared to linear azobenzenes,8 diazocines have been
used to a much lesser extent (examples are a photocontrolled
switch in a peptide,9 in polyurea,10 on molecular platforms,11
and in oligonucleotides).12 The reason for this low level of
exploitation of these favorable properties is that although
syntheses exist, they tend to be low yielding and substrate
specific.
Synthetically, cAB can be understood as two rigid benzene
rings linked by a diazo and an ethylene group. These entities
are formed successively from 1,2-disubstituted arenes as
starting materials. Previous reports describe C−C coupling of
o-nitrotoluene (2) to establish the ethylene bridge (3) first
(Scheme 1).13,14 Then, the nitro groups were joined in an
intramolecular reduction step using lead as a reductant to
generate the diazo group in cAB in 51% yield.13,15 Very recent
approaches to the diazocine ring formation involve an
intramolecular oxidation of amino groups by Oxone16 (40%
yield) or by m-chloroperoxybenzoic acid (85% yield).17
Commonly, arenes containing nitro groups are often less
soluble in organic solvents. A further complication is that the
success of the reduction depends on the addition of specific
amounts of reductant or oxidant and the choice of defined
reaction conditions.13,17 To date, all procedures for cAB
preparation rely on an intramolecular redox reaction between
nitrogen-containing functional groups to establish the diazo-
cine ring.
Herein, we follow a novel retrosynthetic disconnection:
Instead of breaking the bond between the nitrogen atoms, we
aimed for the insertion of a diazo unit via consecutive C−N
cross-coupling reactions to construct the diazocine ring. Only a
few studies described the synthesis of heterocycles containing
diazo functions18,19 and azobenzenes20 via C−N bond
formation. In this report, an alternative facile synthesis of
functionalized cABs is presented.
Following the newly designed strategy, we started with
formation of the C−C bond in cAB from an initial 1,2-
disubstituted arene (Scheme 1). Thus, reduction of 2-
Received: January 15, 2020
https://dx.doi.org/10.1021/acs.orglett.0c00122
© XXXX American Chemical Society
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bromobenzyl bromide (4a) with n-butyllithium (n-BuLi)
constructed the ethylene bridge of bibenzyl.21 Further addition
of n-BuLi and quenching with iodine converted the aryl
bromide into corresponding aryl iodide (5a) in an overall 81%
yield. The resulting dielectrophile then underwent Cu-
catalyzed cascade amidations with di-tert-butyl hydrazodicar-
boxylate (DBADH2) as a dinucleophilic hydrazine substrate in
which the second C−N coupling led to intramolecular
cyclization (6a) in 55% yield. This step followed a protocol
for diamine ligand-catalyzed Ullmann−Goldberg amidation
reactions22−24 except that a low-boiling solvent was used, i.e.,
acetonitrile. As the major byproduct of this reaction, we
detected the amidation product having consumed two
DBADH2 substrates, one on each aryl halide position.
Remaining tert-butyloxycarbonyl (Boc) groups on the
diazocine heterocycle were cleaved via Lewis acid promoted
hydrolysis using trimethylsilyl iodide (TMSI) before oxidation
of the exposed hydrazo group with NBS/Py, furnishing the
cAB product (1a) in 67% yield.
each benzene ring of the molecule such as 1m was prepared
from the combination of a benzyl bromide with a
benzaldehyde in a Wittig reaction. The resulting stilbene was
then hydrogenated to the desired bibenzyl compound 5m.26
Alongside benzyl coupling, we also established ethylene
bridges between heterocycles such as thiophene (5o) and
pyridine (5p).
Subsequently, we focused on the cyclization of ortho-
halogenated bibenzyl compounds using C−N coupling
chemistry (Scheme 3). Both electron-rich and electron-
Scheme 3. Synthesis of Various cABs from Bibenzyls
We sought to explore the scope of this new process by
fabrication of novel cAB derivatives containing functional
groups at convenient carbon positions 2, 3, 8, and 9.
Consequently, an array of 2-bromobenzyl bromides including
electron-donating and electron-withdrawing groups were
prepared (Scheme 2). Subsequent homocoupling to the
corresponding bibenzyls 5b−5n occurred in 41−82% yields.
Fusion of benzyl bromides containing reducible functional
groups such as methyl ester and nitrile was achieved by
employment of the reductive Zn/[NiCl2(PPh3)2] system.25
Asymmetric cAB carrying different substitution patterns on
Scheme 2. Synthesis of Various Bibenzyls from Benzyl
Bromides
a
b
4 equiv of TMSI used. 1 equiv of CuI used.
deficient arenes were readily transformed to the desired
diazocine products 6b−6n with similar efficiencies (35−70%).
However, when aryl bromides were used as electrophiles, the
desired cyclization product was only obtained in comparable
yields after addition of 1 equiv of CuI catalyst. Likewise,
heterocycles could also be annulated, delivering novel
condensed ring systems 6o and 6p. Deprotection of the Boc-
protected diazocine species and oxidation of the exposed
hydrazo to diazo furnished the cAB products 1b−1p in all
cases in good to excellent yields (33−92%). In the example of
the tert-butyl ether (6e), concomitant cleavage of ether and
carbamate groups finally resulted in the phenol (1e).
In all previous examples, the functional group substituents
are already present in the corresponding starting materials.
However, late-stage derivatization is extremely valuable in
terms of versatility and synthetic efficiency. Therefore,
capitalizing on the Cl functional group allowed the conversion
to amines (1q, 1r) using a Buchwald−Hartwig amination with
lithium bis(trimethylsilyl)amide (LHMDS) as the nucleophilic
cross-coupling partner in 51−58% yields (Scheme 4a).27 The
examples show that general cross-coupling chemistry is
possible for chlorinated cABs. Treatment of the methyl ester
functions such as basic hydrolysis and the reduction with
diisobutylaluminum hydride (DIBAL) were accomplished to
give cABs with carboxylic acid (1s, 1t) and benzyl alcohol (1u)
in good to excellent yields (70−91%) (Scheme 4b). Finally,
the photochromic properties of cABs were examined by UV−
a
1.5 equiv of Zn, 5 mol % [NiCl2(PPh3)2], 1 equiv of NEt4I, MeCN/
b
THF, 20 °C. Via Wittig reaction and alkene reduction; see the
Supporting Information. 0.5 equiv of n-BuLi, THF, −78 °C.
c
B
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Notes
Scheme 4. Transformation of Reactive cABs
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work has been supported by the German Research
Foundation (DFG) within the Collaborative Research Center
677 “Function by Switching” (subproject C14). N.E. would
like to thank the Philipp Schwartz Initiative of the Alexander
von Humboldt foundation for their support. This research has
been supported by the Institutional Strategy of the University
of Bremen, funded by the German Excellence Initiative.
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Anne Staubitz − Otto-Diels-Institute for Organic Chemistry,
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