Aromatic Metamorphosis of Indoles into 1,2-Benzazaborins

Article abstract of DOI:10.1021/acs.orglett.9b01353

Among the plethora of aromatic compounds, indoles represent a privileged class of substructures that is ubiquitous in natural products and pharmaceuticals. While numerous exocyclic functionalizations of indoles have provided access to a variety of useful derivatives, endocyclic transformations involving the cleavage of the C2-N bond remain challenging due to the high aromaticity and strength of this bond in indoles. Herein, we report the "aromatic metamorphosis" of indoles into 1,2-benzazaborins via the insertion of boron into the C2-N bond. This endocyclic insertion consists of a reductive ring-opening using lithium metal and a subsequent trapping of the resulting dianionic species with organoboronic esters. Considering that 1,2-azaborins have attracted increasing academic and industrial attention as BN isosteres of benzene, the counterintuitive aromatic metamorphosis presented herein can feasibly be expected to substantially advance the promising chemistry of 1,2-azaborins.

Full text of DOI:10.1021/acs.orglett.9b01353

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Aromatic Metamorphosis of Indoles into 1,2-Benzazaborins
Shun Tsuchiya, Hayate Saito, Keisuke Nogi, and Hideki Yorimitsu*
Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan
*
S Supporting Information
ABSTRACT: Among the plethora of aromatic compounds, indoles represent a
privileged class of substructures that is ubiquitous in natural products and
pharmaceuticals. While numerous exocyclic functionalizations of indoles have
provided access to a variety of useful derivatives, endocyclic transformations
involving the cleavage of the C2−N bond remain challenging due to the high
aromaticity and strength of this bond in indoles. Herein, we report the “aromatic
metamorphosis” of indoles into 1,2-benzazaborins via the insertion of boron into
the C2−N bond. This endocyclic insertion consists of a reductive ring-opening
using lithium metal and a subsequent trapping of the resulting dianionic species with organoboronic esters. Considering that
1
,2-azaborins have attracted increasing academic and industrial attention as BN isosteres of benzene, the counterintuitive
aromatic metamorphosis presented herein can feasibly be expected to substantially advance the promising chemistry of 1,2-
azaborins.
mong aromatic compounds, indoles have received
Scheme 1. Optimization Study for the Insertion of Boron
into Indole 1a
A
particular attention due to their prevalence in natural
1
products and pharmaceuticals, and numerous methods have
2
been developed for the functionalization of indoles. However,
almost all these reactions are limited to the exocyclic
functionalization of indoles, which has been attributed to the
exceptional robustness of the indole skeleton (Figure 1a, left).
Conversely, endocyclic functionalizations such as atom
insertion and removal/substitution of endocyclic atoms have
not been accomplished (Scheme 1a, right), except for Studer’s
3
ring-opening silylation with silyllithium.
Recently, we have become interested in the development of
endocyclic transformations of aromatic compounds, which we
4
,5
have coined “aromatic metamorphosis”. We envisioned that
the endocyclic functionalization of indoles could become a
game-changing method for the synthesis of nitrogen-
containing cyclic molecules using readily available indoles as
a common platform. In particular, the insertion of a boron
atom into the C2−N bond would be interesting, considering
that the resulting benzo[e][1,2]azaborins are attractive BN
6
,7
isosteres of naphthalenes.
Over the past decade, 1,2-
8
azaborins, in which one of the CC units in the benzene
ring is replaced with a B−N unit, and their derivatives have
Figure 1. Functionalization of indoles. (a) Conventional exocyclic
and elusive endocyclic functionalization. (b) Insertion of boron into
the C2−N bond of indoles to generate benzo[e][1,2]azaborins.
Received: April 17, 2019
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01353
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Reaction Scope
a
b
c
d
1
0 mmol of 1a was used. 1.0 mmol of 1 was used. Determined by NMR spectroscopy. 0.50 mmol of 1d, 2.5 mmol of Li, and 0.25 mmol of 1,4-
e
bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene (2u) were used. 10 mmol of 1d, 50 mmol of Li, and 5.0 mmol of 1,4-dibromo-2,5-
bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene (2v) were used. 1.0 mmol of 1d, 5.0 mmol of Li, and 0.20 mmol of 1,3,5-tris(4,4,5,5-
f
tetramethyl-1,3,2-dioxaborolan-2-yl)benzene (2w) were used.
5
d,e
attracted increasing attention as promising functional mole-
reactions.
Unfortunately, these catalyst systems are
7
,9
cules with potential applications in bioactive molecules and
ineffective for the insertion of boron into indoles, and the
indole substrates were recovered in most cases. In general,
indoles should be expected to be less susceptible to ring-
opening than benzofurans, considering that the aromatic
stabilization energy of the pyrrole ring is higher than that of the
10
optoelectronic materials. The B−N unit induces local dipole
moments and/or polarization of the frontier orbitals, which
dramatically changes the optical and electronic properties of
the parent aromatic compounds.
1
4
Generally, benzo[e][1,2]azaborins are synthesized from the
furan ring. Moreover, given that strongly basic amide anions
would be formed as leaving groups, the cleavage of C−N
bonds remains considerably challenging.
6
,11
12
corresponding o-vinyl-
or -alkynylanilines via Dewar’s
bora-Friedel−Crafts reaction, which intrinsically suffers from
the instability of the aniline substrates and the laborious
To cleave the robust indole cores, we focused on the strong
reducing ability of lithium metal. Yus has reported the
reductive cleavage of the C2−O bond in benzofuran using
an excess of lithium powder to furnish the corresponding
dianionic species of the type A that can be subsequently
trapped with electrophiles (Scheme 1a). Based on this
precedent, we began our investigation by establishing the
optimal conditions for the lithium-mediated reductive ring-
opening of N-phenylindole (1a). According to Yus’ method,
we conducted the ring opening of 1a at 0 °C using 10 equiv of
lithium powder and a catalytic amount of 4,4′-di-tert-
butylbiphenyl (DTBB) as an electron-transfer mediator. After
13
preparation of the starting materials. A synthetic route to
benzo[e][1,2]azaborins from stable and easily accessible
indoles should thus represent an attractive research target
and diversify the accessibility of the chemical space. Herein, we
report a new method for the synthesis of benzo[e][1,2]-
azaborins via the insertion of boron into the C2−N bond of
indoles. This transformation consists of two consecutive
reactions: a reductive ring-opening of indoles with lithium
metal that affords dianionic intermediates A (Figure 1b, step a)
followed by a trapping reaction with boron electrophiles such
as the commercially available organoboronic pinacol esters
15
(Figure 1b, step b).
quenching with H O, the ring-opened o-vinylaniline was
2
We have previously accomplished the insertion of boron into
benzofurans via nickel- or manganese-catalyzed ring-opening
obtained in 51% yield. Optimization of the reaction conditions
(cf. Tables S1 and S2) revealed an increased yield (84%) when
B
DOI: 10.1021/acs.orglett.9b01353
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
the reaction was conducted at −30 °C. It should also be noted
that the reaction proceeded smoothly even in the absence of
DTBB. The (Z)-configured dianionic intermediate was
generated in a stereoselective manner, and a subsequent
up: for example, 2.6 g (72% yield) of 3ak was obtained from 10
mmol of 1a. Moreover, naphthyl-, 3-thienyl-, and 4-
pyridylboronic acid esters 2m−p could be used as the boron
electrophiles to smoothly furnish 3am−ap. Apart from
arylboronic acid esters, alkynyl, alkenyl, and even alkylboronic
acid esters (2q−t) could be used to generate the
corresponding benzazaborins (3aq−at) in 80%, 82%, 81%,
and 82% yield, respectively.
treatment with D O exclusively provided (Z)-N-phenyl-2-
2
(
vinyl-2-d)aniline in 95% yield with 100% deuterium
incorporation (Scheme 1b).
We then attempted the synthesis of benzazaborin 3aa via the
electrophilic trapping of the dianionic species A with
commercially available phenylboronic acid pinacol ester
We then investigated the scope of this reaction with respect
to indoles 1 (Scheme 2b). The reactions of 5-butyl- and 5-
(trimethylsilyl)indole 1b and 1c with 2a afforded 3ba and 3ca
in good yield. The ring-opening of 5-fluoro-N-phenylindole did
not proceed; given that N-phenylindole was obtained after the
reaction, it seems feasible to conclude that a reductive
lithiation of the C−F bond occurs. Similarly, 5-methoxy- and
5-phenyl-substituted indoles did not undergo the ring-opening.
Instead of the targeted cleavage of the C2−N bond, Birch-type
reduction of their aromatic rings afforded complex product
mixtures (Figure S1). Substituents at the 2-position hamper
the ring opening of the corresponding 2-substituted indoles.
However, we found that the 2-position can be functionalized
after the insertion of boron into the C2−N bond (vide infra;
Scheme 3a). Subsequently, we explored the scope of this
transformation with respect to N-substituted indoles. Alkyl and
silyl substituents on the N-aryl ring did not hamper the
insertion of boron. On the other hand, methoxy groups
lowered the efficiency of the ring opening, which is reflected in
the low yields of benzazaborins 3ga (39%) and 3ja (21%).
Electron-withdrawing trifluoromethyl-substituted indole 1h
decomposed in the presence of lithium metal under the
conditions applied. The presence of an aryl ring on the
nitrogen atom seems to be indispensable, and a replacement
with alkyl or benzyl groups prevents the initial ring-opening
step (Figure S1).
(
PhB(pin), 2a). However, a simple addition of 2a to the
reaction mixture afforded a complex product mixture, and 3aa
was not observed (Scheme 1c), which we tentatively attributed
to the potential decomposition of the in situ generated 3aa by
the excess lithium powder. Therefore, we removed the
remaining lithium powder by filtration under an atmosphere
of argon using an H-type Schlenk tube, in which two glass
chambers are separated by a glass filter (Figure S2). Removing
the remaining lithium after the ring opening, before addition of
a solution of 2a in THF, afforded benzazaborin 3aa in 82%
16
yield (Scheme 1c).
With the optimal conditions in hand, we explored the
substrate scope (Scheme 2). A variety of arylboronates 2 can
be used in the present method (Scheme 2a). The formation of
the C−B−N linkage between the dianionic intermediate A and
2
should be expected to be fast, and various functional groups
such as benzoyl, ester, amide, and cyano groups in 3ae−ah
were well tolerated. Halogen and triflyloxy substituents at the
ortho positions of the B(pin) unit did not hamper the
electrophilic trapping to afford the corresponding benzazabor-
ins (3ai−al) in high yield. The remaining halogen moieties in
3
ai−al can be used for further derivatization into, e.g., BN-
containing polyaromatic compounds (vide infra; Scheme 3b).
Interestingly, this boron-insertion method can also be scaled
To our delight, p-diborylbenzenes 2u and 2v reacted with 2
equiv of dianionic A, which was derived from indole 1d, to
afford 3du and 3dv in 86% and 51% yield, respectively
Scheme 3. Derivatization of 3 into Further π-Extended
Molecules
(
Scheme 2c). Moreover, 1,3,5-triborylbenzene 2w reacted with
3
equiv of dianionic A to furnish 3dw in 56% yield.
As previously mentioned, we failed to convert 2-substituted
indoles into the corresponding 3-substituted benzazaborins
using the method presented herein. However, the 3-position of
benzazaborin can be readily functionalized via bromination and
subsequent cross-coupling with a modification of the
17
procedure reported by Molander. Benzazaborin 3da under-
went an electrophilic bromination with N-bromosuccinimide
(
NBS) and AlCl to afford 3-brominated 1,2-benzazaborin
3
4
da, and a subsequent Suzuki−Miyaura coupling afforded
1,2,3-triarylbenzazaborin 5da in 74% yield over two steps
(
Scheme 3a). This bromination/Suzuki−Miyaura coupling
sequence represents a powerful tool for the subsequent
decoration of benzazaborins 3.
Next, we attempted the synthesis of BN-embedded
polyaromatic hydrocarbons (PAHs) via further cyclization of
1,2-diarylbenzazaborins 3. PAHs have garnered increasing
attention as intriguing π-conjugated molecules in materials
science, and replacement of a CC bond in PAHs with a B−
N bond should represent an effective means to modulate their
original properties while maintaining structural similari-
8c,d,10h−w,18
ty.
With these considerations in mind, we decided
to synthesize BN-embedded PAHs 6 via cyclization of 1,2-
diarylbenzazaborins 3.
C
DOI: 10.1021/acs.orglett.9b01353
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Initially, we attempted a Scholl-type dehydrogenative
Accession Codes
cyclization of 3aa, as fused PAHs are often synthesized via
CCDC 1885774−1885775 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
19
oxidative intramolecular reactions. However, the azaborin
scaffold is generally incompatible with oxidative conditions,
and complex mixtures were obtained from all reactions. We
thus focused on the redox-neutral palladium-catalyzed intra-
molecular C−H arylation of 2-bromophenyl-substituted
20
benzazaborin 3ak. After extensive screening, we identified
the optimal reaction conditions: treatment of benzazaborin
AUTHOR INFORMATION
Corresponding Author
■
3
ak with 5 mol % of Pd(OAc) , 10 mol % of PPh , and 1 equiv
2 3
of K CO in toluene (0.04 M) at 120 °C for 14 h furnished a
2
3
*
E-mail: yori@kuchem.kyoto-u.ac.jp.
BN isostere of benzo[g]chrysene 6ak in 95% yield (Scheme
b). Using phosphine ligands other than PPh3 induced
ORCID
3
undesired Suzuki−Miyaura coupling between the C−Br and
Hayate Saito: 0000-0002-4549-7917
Keisuke Nogi: 0000-0001-8478-1227
Hideki Yorimitsu: 0000-0002-0153-1888
the peripheral C−B bonds, which prevented the formation of
6ak (Table S4). Yet, the present palladium-catalyzed intra-
molecular C−H arylation can be used for a 2-fold cyclization:
under more dilute conditions (0.01 M in toluene), 3dv
underwent cyclization to furnish B N -embedded PAH 6dv in
Notes
The authors declare no competing financial interest.
2
2
8
3% yield. The fused structures of 6ak and 6dv were
ACKNOWLEDGMENTS
■
unambiguously determined by single-crystal X-ray diffraction
analysis (Figures S3 and S5).
This work was supported by JSPS KAKENHI Grant Numbers.
JP16H04109, JP18H04254, JP18H04409, and JP18K14212.
H.Y. thanks The Asahi Glass Foundation for financial support.
H.S. acknowledges a predoctoral fellowship from the JSPS.
The photophysical properties of 1,2-diphenylbenzazaborin
aa and BN-embedded PAHs 6ak and 6dv are summarized in
3
Figure S7. Planar 6ak, which exhibits an extended π-
conjugation, showed bathochromically shifted longest wave-
length absorption (λmax = 337 nm) and emission (λem = 401
nm) bands relative to those of 3aa (λmax = 316 nm; λem = 367
nm), while the fluorescence quantum yields (Φ ) of 3aa and
6
REFERENCES
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