Trans-Aminoboration across Internal Alkynes Catalyzed by B(C6F5)3 for the Synthesis of Borylated Indoles

Article abstract of DOI:10.1021/acs.orglett.7b00437

We report here a facile B(C₆F₅)₃ catalyzed trans-aminoboration of internal alkynes, furnishing 3-position borylated indoles at ambient temperature. This reaction proceeds with the breaking of a B-N bond and the formation of N-C and B-C bonds to produce indole and derivatives in one step. It works well for various boron reagents and alkynyl-anilines. The borylated indoles can be further derivatized to give column stable organoboron compounds that can be used for future functionalization.

Full text of DOI:10.1021/acs.orglett.7b00437

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Letter
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trans-Aminoboration across Internal Alkynes Catalyzed by B(C F5)3
6
for the Synthesis of Borylated Indoles
†
,†,‡
Kang Yuan and Suning Wang*
†
Department of Chemistry, Queen’s University, Kingston, Ontario K7L 3N6, Canada
‡
Beijing Key Laboratory of Photoelectronic/Electrophotonic Conversion Materials, School of Chemistry, Beijing Institute of
Technology, Beijing 100081, P. R. China
*
S Supporting Information
ABSTRACT: We report here a facile B(C F ) catalyzed trans-aminoboration
6
5 3
of internal alkynes, furnishing 3-position borylated indoles at ambient
temperature. This reaction proceeds with the breaking of a B−N bond and
the formation of N−C and B−C bonds to produce indole and derivatives in one
step. It works well for various boron reagents and alkynyl-anilines. The
borylated indoles can be further derivatized to give column stable organoboron
compounds that can be used for future functionalization.
ndole and its derivatives have important applications in
biological systems and materials science. Borylated indoles
applied to the generation of lactones, and thiophenes at high
1
6
I
temperature, while borylation with BCl can proceed readily at
3
room temperature to yield borylated benzofurans or
are of particular interest, as they are versatile building blocks for
7
2
benzothiophenes. However, when the same strategy was
the construction of functional molecules. Currently, iridium
applied to a dimethylaniline derivative to generate indole with7
boron trichloride, only a haloboration product was obtained.
One known example of borylative cyclization toward indole
formation requires the use of gold catalysts for the addition of a
catalyzed borylation represents one of the most powerful
methods in obtaining boron derivatized indoles. In addition,
electrophilic borylation with borenium species has been
3
demonstrated as an alternative method to introduce boronic4
8
B−N σ bond across the C−C triple bond (Scheme 1b). In
acid/boronate ester groups on heterocycles, including indole.
addition to the catalyst, high temperature (80 °C) is also
required for the previously reported borylative cyclization
toward indole. Frustrated Lewis pairs (FLPs) have been
demonstrated recently to be highly effective in activating
Nonetheless, both methods require the preformation of the
heterocyclic substrate.
Recently, Lewis acidic boron reagents such as boron
trichloride or B-chlorocatecholborane (ClBcat) have been
shown to be effective in promoting borylative cyclization of
alkynes to give borylated species, including borylated
9
small molecules and catalysis. For example, intramolecular
FLPs have been successfully used as highly effective catalysts for
10
C−H bond activation and borylation of heteroarenes. The
5
−7
heterocyclics (Scheme 1a).
ClBcat has been successfully
combination of borane and phosphine has also been shown to
be effective in activating alkynes intramolecularly or inter-
11
Scheme 1. Borylative Cyclization towards Heterocycles
molecularly. Similar alkyne activation was also achieved with
12
N, O, or S Lewis bases to form heterocyclic compounds.
Borylative cyclization of o-(phenylethynyl)-N,N-dimethyl tolui-
dine with stoichiometric B(C F ) was reported previously,
6
5 3
which led to the formation of a cyclized zwitterionic product
13
(
Scheme 1c), which is not known for use in cross-coupling
reactions for further functionalization.
We report herein a trans-aminoboration of internal alkynes
catalyzed by a catalytic amount of B(C F ) under mild
6
5 3
conditions, affording borylated indoles via a straightforward
borylative cyclization.
The trans-aminoboration reaction was discovered initially
from our investigation on whether an internal arylamine unit
can facilitate trans-hydroboration in a similar manner as
14
pyridine. Instead of hydroboration, the reaction mixture of
Received: February 13, 2017
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00437
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
alkynyl arylamine and 9-borabicyclo[3.3.1]nonane (9-BBN)
15
produced the dehydrogenation product a readily (Scheme 2).
Scheme 2. Dehydrogenation and B(C F ) Catalyzed
6
5 3
Aminoboration/Hydroamination of Internal Alkynes
Figure 1. Stacked 11B NMR spectra showing the transformation of 1a
to 1b in C D upon the addition of B(C F ) at ambient temperature.
6
6
6 5 3
deboronated indole product 3b, which provides indirect
support for the formation of the borylated indole in the
reaction. In the absence of B(C F ) , no cyclization or
6
5 3
We then considered the possibility of obtaining zwitterionic
species I similar to that reported by Stephan (Scheme 1c) by
reacting a with 1 equiv of B(C F ) . Surprisingly, this attempt
borylative cyclization is observed for 1a, which supports the
important role of B(C F ) in the formation of 1b.
6
5 3
6
5 3
Next, the reaction of 2-(phenylethynyl)aniline L2 with 9-
led to the isolation of borylated indoles b. Most interesting is
the observation that the borylated indoles can be obtained in
the presence of 5 mol % of B(C F ) . Since metal-free
BBN and B(C F ) was examined. The dehydrogenation occurs
6
5 3
at room temperature and was completed within 24 h to give
1
6
5 3
compound 2a quantitatively, based on H NMR data (see
borylative cyclization of internal alkynes for the synthesis of
borylated indoles has not been reported previously, we decided
to study this interesting reaction further to establish the scope
and to understand the mechanism of this B(C F ) promoted
borylative cyclization. The results of our investigation are
presented here.
Figure S9). In contrast to 1a, the addition of a catalytic amount
of B(C F ) to the solution of 2a leads to hydroamination and
6
5 3
the formation of 2b exclusively in 95% yield at ambient
temperature. Compound 2b has a 11B peak at 53 ppm, similar
6
5 3
11
to a previously reported chemical shift of 4 B with 9-BBN
b
directly bound to the nitrogen in indole. The exclusive
First, the reaction of N-methyl-2-(phenylethynyl)aniline L1
with 9-BBN and B(C F ) was examined and monitored by
NMR spectroscopy. The mixing of L1 and 9-BBN at 50 °C for
formation of 2b indicates that the proton transfer is much more
favorable than the borinium transfer. We also investigated the
reactivity of L1 in the presence of 5 mol % of B(C F ) . In
6
5 3
6
5 3
2
days afforded a dehydrogenation product 1a quantitatively as
contrast to 9-BBN, NMR data indicate that B(C F ) forms a
6 5 3
1
11
confirmed by H and B NMR spectral data (see Supporting
simple Lewis acid−base adduct first with L1, which is stable at
room temperature (see SI, Figures S4 and S5). Heating the
mixture of L1 and its adduct with B(C F ) at 80 °C results in
1
1
Information (SI)). The characteristic B NMR chemical shift
49 ppm) of 1a indicates a partial double bond character of the
(
6
5 3
1
5
B−N bond. 1a is not stable under ambient conditions and
was used for the subsequent reaction without being isolated.
Addition of 5 mol % B(C F ) into the solution of 1a in C D
6
the dissociation of the Lewis acid−base adduct and affords 2-
phenyl-indole quantitatively, which is mechanistically related to
intermolecular hydroamination of terminal alkynes involving
arylamines and a catalytic amount of B(C F ) reported
6
5 3
6
at ambient temperature immediately leads to the appearance of
6
5 3
a sharp 11B peak at −16 ppm, which is similar to that reported
16,17
previously by Stephan and co-workers.
These results show consistently that B(C F ) can effectively
13
for the zwitterionic species by Stephan [Scheme 1c], an
indication that the borate compound I is likely produced via
cyclization (Figure 1). As the reaction proceeds further, a new
6
5 3
promote trans-aminoboration across internal alkynes to afford a
borylated indole in the case of secondary amines such as L1.
However, the sensitivity of 3-position borylated indole 1b
toward moisture makes it difficult in handling and storing the
borylated product for further use, even though examples of
utilizing 9-BBN derivatized compounds for Suzuki−Miyaura
cross-coupling reactions under anhydrous conditions are
1
1
B peak at 77 ppm appears while the peak at 49 ppm decreases
in intensity. At the end of the reaction (∼5 h), the peak at 49
ppm in the 11B NMR spectrum completely vanishes and is
replaced by the peak at 77 ppm while the sharp peak at −16
1
11
ppm remains. The combination of H and B NMR spectral
1
1
18
analysis confirms that the species with a B chemical shift at 77
ppm is the 9-BBN borylated 2-phenyl-indole (1b), which is
formed nearly quantitatively. Considering the relatively strong
bond strength of the B−N bond, it is quite remarkable that the
borylated cyclization reaction is completed within a few hours
at ambient temperature. Unfortunately, due to the high
sensitivity of 1b toward moisture, it cannot be purified by the
general purification procedures. Attempts to purify 1b using a
silica column leads to the quantitative isolation of the
known in the literature. Thus, we sought to extend the
scope of the reaction with an alternative boron reagent such as
catecholborane with the aim to achieve stable borylated indoles.
We first attempted to prepare the precursors such as 4a-Bcat,
an analogue of 1a through dehydrogenation of anilines and
catecholborane (HBcat) in a similar manner as the 9-BBN
reaction. However, the dehydrogenation of the HBcat reaction
requires elevated temperatures, and under this condition not
only dehydrogenation occurs but also degradation of
B
DOI: 10.1021/acs.orglett.7b00437
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
catecholborane arises simultaneously. Thus, we prepared the
Mechanistically, we suggest that the borylative cyclization
proceeds via a key zwitterionic borate-borenium intermediate I
based on the NMR data. Two possible reaction pathways based
on the intermediate I are proposed and shown in Scheme 4. In
precursors 4a-Bcat and related compounds by aminolysis of
8
ClBcat. The resulting aminoboronic esters have a characteristic
1
1
B NMR chemical shift at ∼29 ppm, similar to that reported
8
previously. Upon addition of a catalytic amount of B(C F )
into the amino-Bcat compounds, the B NMR spectrum
displays a similar change as the amino-9-BBN compounds. A
6
5 3
1
1
Scheme 4. Proposed Mechanism of trans-Aminoboration
11
borate peak at ∼ −15 ppm appears immediately, and a new B
peak at ∼32 ppm also appears as the reaction proceeds, which
is similar to that observed by Blum and co-workers (Scheme
8
1
b) and assigned to the borylated indole product (e.g., 4b-
Bcat in Scheme 3). NMR data indicated that the Bcat borylated
Scheme 3. Scope of trans-Aminoboration Reaction
pathway I, the borenium ion in the intermediate I transfers to
the 3-position of indole to replace B(C F ) , forming the
6
5 3
product b. The freed B(C F ) can then promote a second
6
5 3
cyclization reaction, continuing the catalytic cycle. In pathway
19
II, the highly electrophilic borenium ion in I attacks molecule
a, promoting cyclization and the formation of a cationic species
−
I′ and its counterion, [In−B(C F ) ] . The borenium ion in I′
6
5 3
could attack another molecule of a, releasing the product b,
while the reproduced I′ continues the catalytic cycle until all
starting material a is consumed. To support our hypothesis,
attempts were made to react the aminoboronic ester 4a-Bcat
with borenium generated from the reaction of ClBcat, AlCl ,
and triethylamine as reported by Ingleson and co-workers.
However, no borylative cyclization was observed from this
reaction even at 90 °C. Based on this observation, the catalytic
pathway I is most likely for the room temperature borylative
cyclization reported herein.
indoles are formed in greater than 90% yield (see Figure S6, for
example), and the reaction is completed within 5 h at room
temperature.
3
4
c
The Bcat borylated indoles are also highly prone to
protodeboronation due to the electron-rich environment,
making their isolation and purification difficult. One common
strategy to overcome this problem is to convert the Bcat group
to more stable boronic esters such as pinacolboronates by
transesterification. Another commonly used protecting group
for boronic acid is 1,8-diaminonaphthalene (dan), and the
resulting B(dan) unit can be used in iterative cross-coupling
In summary, we have established a facile trans-aminoboration
reaction catalyzed by B(C F ) under ambient temperature.
6
5 3
The scope of the reaction is quite general with different boron
reagents and alkynyl-aniline derivatives. This borylative
cyclization reaction provides an efficient strategy for the
construction of boron derivatized indoles. Future work will
be focused on the synthesis of other heterocycles employing a
similar strategy.
1
8
reactions. We therefore used 1,8-diaminonaphthalene to
protect the boron unit in the borylated indoles. The Bcat to
B(dan) conversion reaction (e.g., 4b-Bcat to 4b in Scheme 3)
occurs smoothly at ambient temperature in the presence of
triethylamine. The resulting B(dan) borylated indoles have
sufficient stability for purification and isolation via standard
procedures in good isolated yields as shown in Scheme 3. They
can also be fully characterized by NMR and HRMS analyses.
To probe the scope of the trans-aminoboration reaction, a
variety of aniline-alkyne derivatives are examined. The
borylative cyclization reaction is in fact applicable to all the
secondary arylamine-alkynes we examined. This reaction shows
tolerance to not only aryl substituents on the triple bond but
also alkyl substituents (9b). Alkynes that bear functional groups
such as bromo (7b) or a bulky ferrocenyl (8b) are also
compatible with the borylative cyclization.
ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b00437.
Experimental details for the synthesis of all compounds,
NMR and HRMS data (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*sw17@queensu.ca
C
DOI: 10.1021/acs.orglett.7b00437
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
ORCID
Letter
(19) De Vries, T. S.; Prokofjevs, A.; Vedejs, E. Chem. Rev. 2012, 112,
4
246.
Suning Wang: 0000-0003-0889-251X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank the Natural Science and Engineering
Research Council of Canada (RGPIN1193993-2013) for
financial support.
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D
DOI: 10.1021/acs.orglett.7b00437
Org. Lett. XXXX, XXX, XXX−XXX