Formal anti-markovnikov hydroamination of terminal aryl alkynes with pinacolborane and hydroxylamines via Zr/Cu sequential catalysis

Article abstract of DOI:10.1246/cl.130485

We have explored a novel dry plasma process for the fabrication of electrodes on Nafion surfaces. Nanosized pillar structures were prepared through argon ion (Ar⁺) plasma treatment. The shear strengths of Au electrodes on plasma-treated Nafion surfaces were investigated. We found that the maximum shear strength (1.08 MPa) of Au-Nafion was observed under the optimal conditions (8 min, 100 W, 5 Pa, Ar⁺). Finally, we successfully prepared strongly bonded Au electrodes on Nafion through plasma surface treatment without using a wet plating process.

Full text of DOI:10.1246/cl.130485

doi:10.1246/cl.130485
1128
Published on the web June 20, 2013
Formal anti-Markovnikov Hydroamination of Terminal Aryl Alkynes
with Pinacolborane and Hydroxylamines via Zr/Cu Sequential Catalysis
Ryosuke Sakae, Koji Hirano,* Tetsuya Satoh, and Masahiro Miura*
Department of Applied Chemistry, Faculty of Engineering, Osaka University, Suita, Osaka 565-0871
(Received May 24, 2013; CL-130485; E-mail: miura@chem.eng.osaka-u.ac.jp)
H
We have developed sequential Zr/Cu catalysis involving
regioselective hydroboration and electrophilic amination for
the formal anti-Markovnikov hydroamination of terminal aryl
alkynes. The reaction system can provide a facile access to
enamines from terminal acetylenes with high regioselectivity
under mild conditions.
H
cat. Zr
Bpin
cat. Cu
Ar
R1
R2
Ar
Ar
R1
N
H
Bpin
BzO
N
R2
Scheme 1. A formal anti-Markovnikov hydroamination of
terminal aryl alkynes via sequential Zr/Cu catalysis. Bpin:
4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl.
Enamines are important building blocks in organic synthesis
because of their versatile reactivity directed toward alkylations,
cycloadditions, and some related bond-forming reactions for
heterocycle synthesis.1 In general, enamines are prepared by
condensation of the corresponding aldehydes or ketones and
amines in the presence of Brønsted acids or Lewis acids.2
However, due to relatively harsh reaction conditions, the above
processes sometimes suffer from low functional compatibility.
On the other hand, transition-metal-catalyzed hydroamination of
alkynes with amines has recently received significant attention
because it can complement the traditional condensation method-
ology and provide functional-group-tolerant approach to the
target enamines. To date, a variety of catalyst systems have been
reported.3 However, in view of regioselectivity and efficiency,
there still remains some room for the anti-Markovnikov hydro-
amination of terminal alkynes. Although Rh-,4 Ru-,5 and Zr-
based6 catalysts have been successfully employed,7 most of
them require elevated temperature.8 Thus, further developments
appear to be desired.
Ph
Cu(OAc)2•OH2 (10 mol%)
ligand (10 or 20 mol%)
LiO-t-Bu (2.0 equiv )
Bpin
+
BzO NEt2
THF, r.t., 4 h
Ph
PPh3 (20 mol%) 61%
1a
P(OEt)3 (20 mol%) 65%
xantphos (10 mol%) 59%
P(OEt)3 (20 mol%)a 76%
NEt2
2a
Scheme 2. Copper-catalyzed electrophilic amination of (E)-
4,4,5,5-tetramethyl-2-styryl-1,3,2-dioxaborolane (0.25 mmol)
with O-benzoyl-N,N-diethylhydroxylamine (1a, 0.30 mmol).
aWith 0.30 mmol of the styrylboronate and 0.25 mmol of
hydroxylamine 1a.
4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (xantphos)
showed better activity, and the corresponding enamine 2a was
obtained in 59-65% yields, as judged by 1H NMR. In the case of
P(OEt)3, when 1a was used as the limiting agent (0.25 mmol),
the yield was further improved to 76%.12
Meanwhile, our group9 and others10 have recently focused
on the unique reactivity of chloramines and hydroxylamine
derivatives and succeeded in the catalytic C-N bond formation
through an electrophilic amination. In this context, we envi-
sioned that a combination of regioselective hydroboration of
terminal alkynes and electrophilic amination of preformed
alkenylborane intermediates could be a good alternative to the
above hydroamination protocols. Here, we report sequential Zr/
Cu catalysis for a formal anti-Markovnikov hydroamination of
terminal aryl alkynes. The process involves Zr-catalyzed hydro-
boration with pinacolborane and Cu-catalyzed electrophilic
amination with O-benzoylhydroxylamines, leading to the corre-
sponding enamines regioselectively under very mild conditions
(Scheme 1).11
To establish the second electrophilic amination step shown
in Scheme 1, we first chose (E)-4,4,5,5-tetramethyl-2-styryl-
1,3,2-dioxaborolane (0.25 mmol) and O-benzoyl-N,N-diethyl-
hydroxylamine (1a, 0.30 mmol) as model substrates and exten-
sively screened various reaction parameters such as catalysts,
bases, and solvents. It was found that the reaction proceeded in
THF smoothly even at room temperature in the presence of
a catalytic amount of Cu(OAc)2¢OH2 together with several
phosphorous ligands using LiO-t-Bu as the base (Scheme 2).
Among the phosphorus ligands we tested, P(OEt)3, PPh3, and
With the conditions in Scheme 2, we investigated the scope
of O-benzoylhydroxylamines 1 (Table 1). The optimal ligand
was highly dependent on the electronic and steric nature of
hydroxylamines. In addition to 2a (Entry 1), acyclic amines that
bear N,N-diallyl, N,N-dibenzyl, and N-benzyl-N-methyl sub-
stituents underwent the reaction with the styrylboronate to form
the corresponding enamines in moderate to good yields (Entries
2-4). The resultant allyl and benzyl moieties can be useful
synthetic handles after appropriate deprotection.13 The 4-
pentenylamine also reacted, and the usual aminated product 2e
was obtained exclusively (Entry 5). Thus, an aminyl radical
pathway is less likely.14 The cyclic pyrrolidine and azepane
also could be employed (Entries 6 and 7). In several cases,
products were isolated in a saturated alkylamine form after the
reduction with NaB(OAc)3H and AcOH. In most cases, the
corresponding homocoupling products, 1,4-diaryl-1,3-buta-
dienes, arising from alkenylboronates, were observed as a by-
product (ca. 10%). Regio- and stereoisomers of enamines were
not detected.
On the basis of the above success, we attempted the
hydroboration/electrophilic amination sequence for the formal
anti-Markovnikov hydroamination of terminal alkynes. Initially,
we focused on the catalyst-free mild hydroboration of alkynes
with two equivalents of pinacolborane, reported by Knochel.15
Chem. Lett. 2013, 42, 1128-1130
© 2013 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

1129
Table 1. Copper-catalyzed electrophilic amination of (E)-
4,4,5,5-tetramethyl-2-styryl-1,3,2-dioxaborolane with O-benzo-
yl-N,N-diethylhydroxylamine (1a)a
Table 2. Sequential Zr/Cu catalysis for formal anti-
Markovnikov hydroamination of terminal alkynesa
cat. Cp2ZrHCl
R
+
H
Bpin
R
Cu(OAc)2•OH2 (10 mol%)
ligand (10 or 20 mol%)
toluene, r.t., 20 h
Bpin
R1
R2
Ph
R1
R2
LiO-t-Bu (2.0 equiv )
Ph
R1
R2
+
Bpin
BzO
N
N
1
THF, r.t., 4–8 h
BzO
N
1
2
Cu(OAc)2•OH2 (10 mol%)
P(OEt)3 (20 mol%)
Entry R1, R2 1
Ligand
P(OEt)3
Xantphos 2b, 65 (48)
PPh3
2c, (53)c
Xantphos 2d, 71 (65)c
2, Yieldb/%
R1 = R2 = Et (1a)
2a, 76 (65)
R
R1
R2
1
2
3
4
5
6
7
LiO-t-Bu (2.0 equiv )
R1 = R2 = allyl (1b)
R1 = R2 = benzyl (1c)
R1 = benzyl, R2 = Me (1d)
N
THF, r.t., 4 h
2
Entry
1
Alkyne
1
2, Yieldb/%
R1 = Bu, R2 = (CH2)3(CH=CH2) (1e) P(OEt)3
R1 = R2 = (CH2)5 (1f)
R1 = R2 = (CH2)6 (1g)
2e, 80 (66)c
Xantphos 2f, 45
Xantphos 2g, 72 (57)
F3C
Cl
F3C
Cl
1a
NEt2
2h, 76 (60)
2i, 64 (58)
aConditions: Cu(OAc)2¢OH2 (0.25 mmol), ligand (0.050 mmol
for P(OEt)3 and PPh3, 0.025 mmol for xantphos), styrylboronate
2
1a
1a
NEt2
(0.30 mmol),
1 (0.25 mmol), LiO-t-Bu (0.50 mmol), THF
(1.5 mL), r.t., 4-8 h. b 1H NMR yield. Isolated yield is in
c
parentheses. Isolated yield as the corresponding alkylamine 2¤.
3c
NEt2
See the Supporting Information for detailed procedures.
Br
2j, 69 (49)
Br
Me
However, impurities associated with residual excess of pinacol-
borane were detrimental to subsequent copper catalysis. After
evaluation of some reported catalytic hydroborations with nearly
one equivalent of pinacolborane to alkynes, we were pleased to
identify the Cp2ZrHCl catalysis, which was originally developed
by Srebnik,16 to be optimal for merging with the above
electrophilic amination process (Table 2). Namely, treatment
of 4-(trifluoromethyl)phenylacetylene (0.30 mmol) with pinacol-
borane (0.38 mmol) and Cp2ZrHCl (0.030 mmol) in toluene at
room temperature for 20 h afforded the corresponding alkenyl-
boronate with high regio- and stereoselectivities in a nearly
quantitative yield (judged by GC and GCMS analysis). Removal
of a small amount of the residual hydroborane and zirconium
salt through a pad of Celite and evaporation of volatile materials
were followed by the copper-catalyzed electrophilic amination
with O-benzoyl-N,N-diethylhydroxylamine (1a, 0.25 mmol) to
furnish the enamine 2h in 76% yield (based on 1a, Entry 1).17
The sequential catalysis was compatible with aryl chloride and
bromide functionalities (Entries 2 and 3). While the electron-
neutral 4-methylphenylacetylene was converted into the ena-
mines 2k, 2l, 2m, and 2n under the standard conditions (Entries
4-7), the electron-rich 4-methoxyphenylacetylene required a
higher catalyst loading for the satisfactory conversion (Entry 8).
Unfortunately, the reaction with aliphatic terminal alkynes such
as 1-hexyne was unsuccessful, despite the smooth hydroboration
confirmed by GC analysis (Entry 9). Thus, the present copper
catalysis apparently required aryl groups at the position ¢ to the
pinacolboryl unit.
Me
4
1a
1d
1e
NEt2
2k, 71 (45)
Me
Me
Me
N
5d
6
2l, 58 (47)
2m, (56)
Ph
Bu
N
Me
7d
1g
N
2n, 51 (46)
MeO
Bu
8e
9
1a
1a
MeO
Bu
NEt2
2o, 52 (32)
NEt2
2p, 0
aConditions; hydroboration: Cp2ZrHCl (0.030 mmol), alkyne
(0.30 mmol), HBpin (0.38 mmol), toluene (0.15 mL), r.t., 20 h;
amination: Cu(OAc)2¢OH2 (0.25 mmol), P(OEt)3 (0.050 mmol),
1 (0.25 mmol), LiO-t-Bu (0.50 mmol), THF (1.5 mL), r.t., 4 h.
b 1H NMR yield. Isolated yield as the corresponding alkylamine
2¤ is in parentheses. At 60 °C in the hydroboration step. With
0.025 mmol of xantphos instead of P(OEt)3. With 0.050 mmol
of Cu(OAc)2¢OH2 and 0.10 mmol of P(OEt)3.
c
d
e
This work was partly supported by Grants-in-Aid from the
Ministry of Education, Culture, Sports, Science and Technology,
Japan. K.H. acknowledges The Uehara Memorial Foundation for
financial support.
In conclusion, we have developed sequential Zr/Cu
catalysis for the formal anti-Markovnikov hydroamination of
terminal aryl alkynes. The catalytic system comprises Zr-
catalyzed regioselective hydroboration with pinacolborane and
Cu-catalyzed electrophilic amination with O-benzoylhydroxyl-
amines, and allows for the selective preparation of enamines
from terminal aryl alkynes under very mild conditions.18 Further
development of related electrophilic aminations is now in
progress in our laboratory.
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Chem. Lett. 2013, 42, 1128-1130
© 2013 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/