Copper-Catalyzed Aminoboration from Hydrazones to Generate Borylated Pyrazoles

Article abstract of DOI:10.1021/acs.orglett.8b04038

Herein we report an aminoboration reaction that employs inexpensive, Earth-abundant, and commercially available Cu(OTf)₂ as an effective catalyst in the direct addition of B-N σ bonds to C-C π bonds, generating borylated pyrazoles, which are us

Full text of DOI:10.1021/acs.orglett.8b04038

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Copper-Catalyzed Aminoboration from Hydrazones To Generate
Borylated Pyrazoles
Kim N. Tu, Scott Kim, and Suzanne A. Blum*
Department of Chemistry, University of California, Irvine, Irvine, California 92697-2025, United States
*
S Supporting Information
ABSTRACT: Herein we report an aminoboration reaction
that employs inexpensive, Earth-abundant, and commercially
available Cu(OTf)2 as an effective catalyst in the direct
addition of B−N σ bonds to C−C π bonds, generating
borylated pyrazoles, which are useful building blocks for drug
discovery. By nature of the mechanism, the reaction produces
exclusively one regioisomer and tolerates groups incompatible
with alternative lithiation/borylation and iridium-catalyzed C−H activation/borylation methods. The reaction can be scaled up,
and the resulting isolable pyrazole pinacol boronates can be further functionalized through palladium-catalyzed Suzuki cross-
coupling reactions.
minoboration of alkynes by B−N σ bond addition would
Scheme 1. Comparison of Previous Methods (a−c) and
This Aminoboration Method (d) with Earth-Abundant
Copper Catalyst
A
be a useful synthetic method to provide alternative routes
to borylated N-heterocycles that can be further functionalized
1
through metal-catalyzed cross-coupling reactions. Yet there
were only limited reports of direct addition of B−N σ bonds to
C−C π bonds prior to a report by our group in 2015,
demonstrating this aminoboration strategy for the synthesis of
2
borylated indoles. That reaction employed a precious-metal
catalyst IPrAuTFA. Replacement of this precious-metal catalyst
with an Earth-abundant metal catalyst is however desirable
from cost and sustainability standpoints, as is extension of this
chemistry to new substrate classes.
Subsequent to our report, there were two additional reports
3
,4
of aminoboration reactions in which boron trichloride was
used to activate the C−C π bonds toward cyclization without a
catalyst. However, due to its high reactivity, boron trichloride
might not tolerate other active sites on the same substrate. We
herein report the first example of copper as a catalyst in the
direct addition of B−N σ bonds to C−C π bonds. Cost
effective Cu(OTf) is an efficient catalyst obviating the need
2
for complicated organic ligands, further reducing catalyst cost
and increasing availability.
This aminoboration method is tolerant of a variety of
functional groups and generates exclusively the 4-borylated
regioisomer in one synthetic step, without the need to preform
the heterocyclic core. Products of this reaction are building
blocks toward potent medicinal scaffolds that exhibit a full
tivity. Alternatively, a sequential lithiation/borylation of 4-
1
6
5
bromopyrazoles has been used to access 4-borylated
pyrazoles (Scheme 1c), but this method does not tolerate
bromides and electrophilic functional groups.
spectrum of biological activities, such as antimicrobial,
6
7
8
9
antifungal, antiinflammatory, anticancer, and many others.
Pyrazoles are present in several FDA-approved drugs, for
1
0
11
On the basis of our previous borylative heterocyclization
example celecoxib (Celebrex), sildenafil citrate (Viagra),
2
,17−23
12
13
reactions,
we hypothesized that an analogous route to
tepoxalin (Zubrin), and also in pesticides. Currently,
borylated pyrazoles can be accessed through [3 + 2]
cycloaddition/retrocycloaddition of sydnones (Scheme 1a)1
borylated pyrazoles from hydrazones 1 may be amenable to a
1
4
5
or Ir-catalyzed borylation of pyrazoles (Scheme 1b).
Received: December 18, 2018
However, these methods are limited due to poor regioselec-
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b04038
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
22
a
direct borylation pathway. The aminoboration reaction
developed here starts from readily available hydrazones and
does not require isolation of synthetic intermediates (Scheme
Scheme 2. Reaction Substrate Scope
1
d).
The reaction was developed through a series of optimization
studies. We first investigated the formation of the requisite B−
N σ bond (Table S1, Supporting Information) through the
screening of different boron sources and bases using phenyl
3
3
hydrazone (R = Ph) and tosyl hydrazone (R = Ts) as initial
nitrogen substitution patterns. We determined that B-chloro-
catecholborane (ClBcat) and triethylamine together were
3
sufficient in forming the desired B−N σ bond in 2 (R =
Ts) at room temperature with complete consumption of 1.
The byproduct of this reaction, triethylammonium chloride,
was removed from the reaction mixture by filtration to prevent
the formation of the undesired protonated pyrazole 3a′.
We next targeted the aminoboration step for optimization. A
series of gold and copper catalysts with varying oxidation
states, counterions, and ligands were examined with 2a as the
model substrate. Previously, our group developed oxyboration
and aminoboration methods with IPrAuTFA as the optimal
2
,17,18,24
catalyst.
However, when IPrAuTFA was used in this
1
reaction, only a trace amount of 3a was observed by H and
B NMR spectroscopy (Table 1, entry 1). We switched to
1
1
Table 1. Selected Optimization Study for the Formation of
a
Borylated Pyrazole 3a
a
1
b
Isolated yield of 4 ( H NMR yield of 3). 110 °C.
cat. loading
(% mol)
percent
b
entry
catalyst
base T (°C) conversion to 3a
1
2
3
4
5
6
7
IPrAuTFA
IPrCuTFA
CuI
Cu(OAc)2
Cu(OTf)2
none
5
5
5
5
5
N/A
10
Et N
80
40
40
40
40
110
40
trace
0
20
24
70
3
the internal standard. The numbers outside the parentheses
correspond to the isolated yields of 4. The blue color in
Scheme 2 indicates compounds that would be incompatible
with previous lithiation or iridium-catalyzed synthetic methods
due to chemo- or regioselectivity.
Et N
3
Et N
3
Et N
3
Et N
3
Et N
3
trace
0
The aminoboration reaction provided 4 in moderate-to-
TfOH
Et N
3
1
good H NMR spectroscopy and isolated yields. The reaction
a
b
Reactions were carried out on a 0.10 mmol scale. Percent
was compatible with a variety of electron-rich (1b and 1k) and
conversion was determined based on the amount of desired product
formed with respect to the amounts of starting material and
byproduct 3a′.
1
2
electron-poor (1h) aryl substituents in R and R . Aliphatic
1c, 1g, and 1j) and heteroaryl (1e and 1f) substitution were
(
also tolerated with the reaction conditions. Thiophene-
substituted 4e and 4f demonstrated the complementary bond
disconnections that avoided potential competing ortho
study Cu(I) and Cu(II) catalysts due to an initial unpublished
hit in the oxyboration study of borylated isoxazoles and
found the inexpensive and commercially available Cu(OTf) to
18
25
borylation of the thiophene under the alternative lith-
1
iation/borylation method (73% and 80% H NMR spectros-
2
be the optimal catalyst, with 70% conversion to 3a at 40 °C in
copy yields of 3e and 3f, respectively; and 60% and 74%
isolated yields of 4e and 4f, respectively).
2
4 h (Table 1, entries 2−5). Control experiments without a
catalyst and with triflic acid were performed at 110 and 40 °C,
respectively (Table 1, entries 6 and 7). These control reactions
confirmed the vital role of the catalyst.
In addition, aryl bromide 1i smoothly undergoes amino-
1
boration to produce borylated pyrazole 3i (78% H NMR
yield, 68% isolated yield of 4i). Aryl bromides would not be
16
Under the optimized reaction conditions (Table 1, entry 5),
the substrate scope was examined (Scheme 2). Previously
unreported pyrazole catechol boronic esters 3a−3k were
generated and then transesterified to afford bench-stable and
silica-gel-column-chromatography-stable pyrazole pinacol bor-
onic esters 4a−4k. In Scheme 2, the numbers inside the
tolerated under an alternative lithiation/borylation sequence
because of competitive lithium−halogen exchange. Substrates
1d and 1j required an elevated reaction temperature (110 °C),
which may be caused by steric hindrance from the tert-butyl
and the silyl groups. Consistent with competing formation of
byproduct 3a′, substrates with enolizable protons did not yield
product 3a, presumably due to the acid sensitivity of the B−C
bond. Replacement of the tosyl on nitrogen with phenyl
1
parentheses denote the H NMR spectroscopy yields of
pyrazole catechol boronic esters 3 relative to phenanthrene as
B
DOI: 10.1021/acs.orglett.8b04038
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
3
1
resulted in no or incomplete deprotonation of the nitrogen
This salt, LiOTf, is capable of coordinating nitrogen;
from the requisite B−N bond by HBcat, ClBcat/NaH, or
therefore, any catalytic activity observed with LiOTf might
indicate an alternative mode of activation for this type of
reaction. However, we did not observe any boronate 3a
formation after heating 2a with LiOTf at 40 °C for 24 h. This
result does not eliminate the possibility of nitrogen activation
by the copper catalyst entirely, and future mechanistic study is
planned to provide insight into the role of the copper catalyst.
Synthetic Utility. The scale-up experiment of the amino-
boration reaction of 1f was successful to afford 816 mg of
pinacol boronate 4f on a 3 mmol scale (eq 2). This convenient
scalability demonstrates the efficiency of the method, in which
large quantities of these heterocyclic boronic ester building
blocks could be prepared for multistep downstream syntheses.
ClBcat/NEt presumably due to the higher pK of the N−H
3
a
bond (see Supporting Information Table S1 for details);
however, N-tosylpyrazoles can be detosylated after down-
stream coupling of the pinacol boronate if desired, using
2
6
known procedures.
We propose a plausible catalytic cycle for the copper-
catalyzed aminoboration reaction in Scheme 3. The Lewis
Scheme 3. Proposed Mechanism
The pinacol boronate 4f could be further functionalized via
Suzuki cross-coupling to add more structural complexity to the
pyrazole core, showcasing the applicability of the amino-
boration products. This coupling reaction afforded 11 in 63%
yield (eq 3). Pinacol boronate 4i could be transformed into
32
bromide 12 (63%), the detosylation of which yielded 13
26
(
54%) using standard procedures (eq 4).
27,28
acidic Cu(OTf) activates the C−C π bond
to form
2
intermediate 5, to which the N−B σ bond is subsequently
added to generate intermediate 6, which then separates into a
neutral organocopper intermediate 7 and electrophilic boron
intermediate 8. The organocopper intermediate is primed for
transmetalation with 8 in the next step to produce the desired
boronate 3 and regenerate Cu(OTf) , which would be an early
2
example of organocopper-to-boron transmetalation reaction.
Organocopper-to-boron transmetalation is not well-estab-
lished, but the reverse reaction from organoboron-to-copper
2
9,30
is better studied.
The aminoboration reaction also provides complementary
The viability of copper catalysis in this reaction was
considered further. Interestingly, this direct borylative
heterocyclization did not proceed with IPrAuTFA as the
catalyst, in contrast to four examples of oxyboration and
regioselectivity to the alternative Ir-catalyzed C−H activation/
15,33
borylation reaction sequence,
as highlighted in the reaction
shown in eq 5. Protonated pyrazole 3f′, a byproduct from the
aminoboration reaction of 1f, was reacted with pinacolborane
17
2
aminoboration to make borylated benzofurans, indoles,
1
8
24
isoxazoles, and dihydrofurans. The origin of this difference
in the presence of [Ir(COD)OMe] (3 mol %) and 4,4′-di-tert-
2
remains unclear. In an unpublished result from borylated
butyl-2,2′-dipyridyl (3 mol %) at 25 °C, which are the
literature conditions for the C−H activation/borylation
isoxazoles, we found that Cu(OTf) could also catalyze this
2
33
oxyboration, albeit with a much slower rate than IPrAuTFA.
proceedure. After 1 h, the crude reaction mixture was
1
8
Isoxazoles and pyrazoles are the only two substrate classes
from this set that contain two consecutive heteroatoms in each
of their core structures. This structural similarity may play a
role in their susceptibility toward copper catalysis. We
hypothesize that copper might coordinate to the far-left
nitrogen atom (highlighted in a red box, Scheme 3) and
activate the system toward B−N σ bond addition across the
C−C π bond (shown in alternative intermediate 9). In order to
test this hypothesis, LiOTf (5 mol %) was examined as a
catalyst for the aminoboration reaction instead of Cu(OTf)2.
1
examined by H NMR spectroscopy, which showed formation
of only one new product plus unreacted starting material 3f′.
Purification of this mixture resulted in a 30% yield of 12 and
6% recovery of unreacted 3f′. The borylation reaction
occurred exclusively at the thiophene instead of the pyrazole
in contrast to the aminoboration reaction to yield 4f. Thus,
borylated pyrazoles that are not accessible by this previous
iridium-catalyzed route can be accessed in a straightforward
manner by copper-catalyzed aminoboration.
4
C
DOI: 10.1021/acs.orglett.8b04038
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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an important heterocyclic core for drug discovery. The
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ASSOCIATED CONTENT
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The Supporting Information is available free of charge on the
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Full experimental procedures, characterization data, and
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AUTHOR INFORMATION
Corresponding Author
E-mail: blums@uci.edu.
■
*
(
27) da Silva, V. D.; de Faria, B. M.; Colombo, E.; Ascari, L.; Freitas,
G. P. A.; Flores, L. S.; Cordeiro, Y.; Romao
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ORCID
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Suzanne A. Blum: 0000-0002-8055-1405
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The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
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(32) Thompson, A. L. S.; Kabalka, G. W.; Akula, M. R.; Huffman, J.
W. Synthesis 2005, 2005, 547−550.
We thank the National Science Foundation (CHE-1665202)
and the University of California, Irvine (UCI), for funding.
S.K. thanks the Allergan Foundation for a fellowship.
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DOI: 10.1021/acs.orglett.8b04038
Org. Lett. XXXX, XXX, XXX−XXX