Formal C-H-azidation-based shortcut to diazido building blocks for the versatile preparation of photoaffinity labeling probes

Article abstract of DOI:10.1002/ejoc.201402516

Short synthetic routes to diazido building blocks with different connectable groups were established on the basis of the sequential iridium-catalyzed C-H borylation and copper-catalyzed azidation of 1,3-disubstituted benzenes, followed by diverse azido-fr

Full text of DOI:10.1002/ejoc.201402516

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201402516
Formal C–H-Azidation-Based Shortcut to Diazido Building Blocks for the
Versatile Preparation of Photoaffinity Labeling Probes
Suguru Yoshida,[a] Yoshihiro Misawa,[a] and Takamitsu Hosoya*[a]
Keywords: Synthetic methods / Photoaffinity labeling / C–H borylation / Azides / Diazido building blocks
Short synthetic routes to diazido building blocks with dif-
ferent connectable groups were established on the basis of
the sequential iridium-catalyzed C–H borylation and copper-
These building blocks facilitate the rapid development of ef-
fective diazido photoaffinity labeling probes that are useful
for the identification of unknown target biomolecules of
catalyzed azidation of 1,3-disubstituted benzenes, followed bioactive compounds.
by diverse azido-friendly functional-group transformations.
Introduction
Photoaffinity labeling (PAL) is a useful method to ident-
ify the target biomolecule of target-unknown bioactive
compounds that are frequently observed in drugs, natural
products, and screening hit compounds.[1] PAL probes are
generally prepared by bifunctionalization of a bioactive
compound of interest with a photoreactive group and a de-
tectable tag. Aromatic azido, diazirinyl, diazocarbonyl, and
benzoylphenyl groups are commonly used photoreactive
groups that enable covalent bond formation between the
probe and target. Radioisotopes (RI) and a biotinyl group
are widely used detectable tags that facilitate the detection
and analysis of the photolabeled target.
Exploiting the higher photoreactivity of phenyl azide rel-
ative to that of benzyl azide, we previously developed a new
PAL method by using a compact “diazido probe” that bore
two types of azido groups: a photoreactive aromatic azido
group and a relatively photostable benzylic azido group
(Figure 1).[2,3] This second azido group served as a latent
detectable tag by means of Staudinger ligation[4] or click
Figure 1. Diazido PAL method and probes that we used for target
photolabeling. Each original bioactive compound and its target
protein are shown in square brackets; CG = connectable group.
reactions.[5] The RI-free method enabled the direct sequence
analysis of photolabeled targets. Moreover, the small low-
polarity azidomethyl tag preserved the bioactivity of the
original compound in the probe, which is particularly im-
portant for reliable target identification if compounds of
interest are small molecules.
Using the diazido probe PAL method, we identified some
target proteins of bioactive compounds (Figure 1).[2,6] The
probes were designed with a common (3-azido-5-azido-
methyl)phenyl substructure wherein all three substituents
were put in a meta relationship to each other to avoid unde-
sired side reactions under photoirradiation. The probes
were prepared by conjugating the diazido unit to the basic
skeleton of the original compound upon careful assessment
of the modifiable site to maintain bioactivity. In each case,
the appropriate diazido building block was synthesized on
demand with the most suitable connectable group (CG),
such as hydroxymethyl,[2a] bromomethyl,[2b,2e] iodo,[2d,2f] or
boryl[2d] groups, depending on the probe structure. To re-
spond more quickly to an increasing demand for target
identification of bioactive compounds, we felt a strong need
to streamline the synthetic route and assort various types
of diazido building blocks that can facilitate the preparation
[a] Laboratory of Chemical Bioscience, Institute of Biomaterials
and Bioengineering, Tokyo Medical and Dental University,
2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan
E-mail: thosoya.cb@tmd.ac.jp
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402516.
Eur. J. Org. Chem. 2014, 3991–3995
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3991

S. Yoshida, Y. Misawa, T. Hosoya
SHORT COMMUNICATION
of effective PAL probes. Herein is described a short synthe-
After extensive studies, the azido group was successfully
sis of various diazido building blocks on the basis of the introduced to the 5-position of some 1,3-disubstituted benz-
formal C–H azidation strategy.[7]
enes with high efficiency by consecutive iridium-catalyzed
C–H borylation[9] and copper-catalyzed azidation[11]
(Table 1). Commercially available ethyl 3-iodobenzoate (4a),
methyl 3-bromobenzoate (4b), methyl m-toluate (4c), and
m-tolunitrile (4d) served as good substrates, and they pro-
vided 5-azidated products in good to excellent yields in a
simple two-step synthesis, which comprised borylation, sol-
vent removal, and azidation (Table 1, entries 1–4). These re-
actions were highly reproducible and could be performed at
the gram scale.[10] The key to this success was to avoid the
troublesome purification of the arylboronic ester intermedi-
ates and directly use these intermediates as a crude mixture
in the azidation step.[10,12,13] Fortunately, unlike in the direct
borylation of azido substrate (Scheme 1), no azido-reduced
product was formed despite the presence of residual bo-
rylation reagents such as the iridium catalyst and bis-
(pinacolato)diboron and their decomposed derivatives. This
result suggests that the iridium catalyst, which was unfavor-
able for the azido group, was deactivated by air exposure
during the workup. In contrast, tritylthio- or hydroxy-
methyl-bearing substrates, 5e and 5f, were found unsuitable
for this sequential transformation wherein their borylation
did not proceed effectively (Table 1, entries 5 and 6).
Results and Discussion
Considering that arylboronic acid and its derivatives are
good precursors for functionalized arenes,[8] direct boryl-
ation of the 5-position of 1-azido-3-(azidomethyl)benzene
(1) was initially attempted through iridium-catalyzed Smith/
Miyaura–Ishiyama–Hartwig C–H borylation.[9] Unfortu-
nately, rather than affording desired compound 2, a small
amount of aniline derivative 3 was produced presumably
through iridium-catalyzed reduction of the aromatic azido
group with diborane (Scheme 1).[10]
Scheme 1. Attempted direct C–H borylation of diazide 1; Bpin =
4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl, cod
tadiene, dtbpy = 4,4Ј-di-tert-butyl-2,2Ј-bipyridyl.
= 1,4-cyclooc-
Table 1. Formal C–H azidation of 1,3-disubstituted benzenes.
Given that the most straightforward approach failed, we
switched the strategy to the new one wherein the synthesis
started with indirect C–H azidation at the 5-position of
nonazidated 1,3-disubstituted benzenes equipped with a
one-carbon substituent (C1) and a functional group (FG,
Scheme 2). The C1 and FG moieties were intended to be
converted into an azidomethyl group and a connectable
group (CG), respectively. By this approach, we planned to
assort work-ready diazido building blocks with a variety of
CGs, such as boryl, hydroxy, amino, hydroxymethyl, bro-
momethyl, carboxyl, and activated esters. Our concern over
this approach was the sensitivity of azido groups to various
reaction conditions, including nucleophilic, acidic, basic,
hydrogenative, oxidative, high temperature, and photoirra-
diation conditions. Therefore, reaction conditions must be
set carefully to achieve all the desired transformations with-
out decomposing the aromatic and benzylic azido groups.
Entry
4
C1
FG
5
Yield [%][a]
1
2
3
4
5
6
4a
4b
4c
4d
4e
4f
CO2Et
CO2Me
CH3
CH3
CO2Et
CH3
I
Br
CO2Me
CN
SCPh3
CH2OH
5a
5b
5c
5d
5e
5f
91
96
95
70
0[b]
0[b]
[a] Yield of isolated product. [b] The borylation did not proceed
and the starting material was not consumed.
Next, transformation of each C1 moiety of 5a–d into an
azidomethyl group was examined, and under carefully
tuned reaction conditions, their ester moieties or methyl
groups were found readily convertible (Scheme 3). The
cautious reduction of esters 5a and 5b with diisobutylalumi-
num hydride (DIBAL-H, 4.0 equiv.) at –78 °C afforded 3-
azido-5-halobenzyl alcohols in sufficient yields, with only a
small amount of undesired azido-reduced aniline deriva-
tives. The byproduct was predominantly formed if other re-
ductants such as lithium borohydride were used. Subse-
quent azidation of the alcohols proceeded efficiently under
Mitsunobu–Merck conditions.[14] This sequential reduction/
azidation transformation was performed without purifica-
Scheme 2. Short route to various diazido building blocks; C1
one-carbon substituent that is convertible into an azidomethyl
group, FG = functional group, LG = leaving group.
=
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Formal C–H-Azidation Based Shortcut to Diazido Building Blocks
tion of the alcohol intermediates to afford diazido com-
pounds 6a[2d] and 6b in reasonable yields (Scheme 3, a).[10]
The synthetic efficiency of 6a increased significantly relative
to that previously reported by us:[2d] from approximately
32% (6 steps) to approximately 70% (4 steps) in overall
yields from the commercial materials. Furthermore, radical
bromination of the benzylic methyl groups in ester 5c and
nitrile 5d by using N-bromosuccinimide (NBS) in the pres-
ence of a catalytic amount of 2,2Ј-azobis(isobutyronitrile)
(AIBN) provided benzyl bromides 7c and 7d in moderate
yields with a certain amount of recovered starting materials
(Scheme 3, b). Subsequent nucleophilic displacement by so-
dium azide proceeded smoothly to afford diazido products
6c[6c,12] and 6d almost quantitatively.
Scheme 3. Transformations of the C1 moieties into azidomethyl
groups, yields are based on isolated products; DIBAL-H = diiso-
butylaluminum hydride, DPPA = diphenylphosphoryl azide, DBU
= 1,8-diazabicyclo[5.4.0]undec-7-ene, NBS = N-bromosuccinimide,
AIBN = 2,2Ј-azobis(isobutyronitrile), brsm = based on the reco-
vered starting material.
With diazido compounds 6a–d in hand, methods to
transform the functional groups into a variety of connect-
able groups were explored. After a broad search, iodo, ester,
and cyano substituents of 6a, 6c, and 6d, respectively, were
found convertible into several work-ready connectable groups
without affecting the azido functionalities (Scheme 4).
Scheme 4. Further transformations of diazido compounds 6a–d
into various diazido building blocks, yields are based on isolated
products, unless otherwise noted. The yield of 11 was determined
after reaction with an excess amount of diethylamine; dppf = 1,1Ј-
bis(diphenylphosphanyl)ferrocene, SuOH = N-hydroxysuccinimide,
EDC = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, DMP =
Dess–Martin periodinane.
As we previously showed,[2d,2f] the diazido unit was toler-
ant to Pd-catalyzed cross-coupling reactions such as the Su-
zuki–Miyaura reaction[15] and Miyaura borylation.[16] For
example, borylation of iodide 6a provided boronic acid pin-
acol ester 2 in moderate yield (Scheme 4, a).[2d] Subsequent
Under previously reported basic conditions,[6c] methyl es-
oxidation of 2 with aqueous hydrogen peroxide smoothly ter 6c was hydrolyzed to diazidobenzoic acid 9 wherein the
afforded diazido phenol 8,[10] which is applicable to the cou- base-sensitive azidomethyl group remained intact (Scheme 4,
pling reactions such as etherification and esterification for b).[17] Acid 9 can be either directly subjected to coupling re-
the PAL probe synthesis.
actions for probe synthesis or derivatized into more reactive
Eur. J. Org. Chem. 2014, 3991–3995
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S. Yoshida, Y. Misawa, T. Hosoya
SHORT COMMUNICATION
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building blocks substituted with diverse connectable groups
were established through a formal C–H azidation strategy
and several azido-friendly functional-group transforma-
tions. Given that phenotypic high-throughput screening as-
says with the use of huge chemical libraries have become
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azido PAL probes from bioactive compounds, and target
identifications in collaboration with biological research
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[6]
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures and characterization for new com-
pounds including copies of the NMR spectra.
Acknowledgments
This work was partially supported by Platform for Drug Discovery,
Informatics, and Structural Life Science and a Grant-in-Aid for
Scientific Research on Innovative Areas, “Chemical Biology of
Natural Products” from the Ministry of Education, Culture,
Sports, Science and Technology (MEXT), Japan.
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Received: April 30, 2014
Published Online: May 28, 2014
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