Copper-catalyzed intermolecular regioselective hydroamination of styrenes with polymethylhydrosiloxane and hydroxylamines

Article abstract of DOI:10.1002/anie.201304365

Playing Reversi with H and N: A copper-catalyzed intermolecular regioselective hydroamination of styrenes with polymethylhydrosiloxane and hydroxylamine derivatives has been developed. The catalysis accommodates challenging β-substituted substrates. Moreover, the chiral biphosphine-ligated copper complex successfully forms benzylamines with good enantiomeric ratios. Copyright

Full text of DOI:10.1002/anie.201304365

Angewandte
Chemie
DOI: 10.1002/anie.201304365
Synthetic Methods
Copper-Catalyzed Intermolecular Regioselective Hydroamination of
Styrenes with Polymethylhydrosiloxane and Hydroxylamines**
Yuya Miki, Koji Hirano,* Tetsuya Satoh, and Masahiro Miura*
The catalytic hydroamination reaction of carbon–carbon
double bonds has recently received significant attention, as
it allows relatively simple starting materials to be readily
transformed into alkylamines, which are of great importance
in both the fine and chemicals industries. To date, numerous
catalytic systems, including various transition-metal catalysts,
have been widely developed.[1] However, the intermolecular
hydroamination of alkenes still remains a challenge, although
there are some successful examples with strained alkenes,[2]
1,3-dienes,[3] allenes,[4] styrenes,[5] and simple alkenes.[6] For
example, even in the hydroamination of styrenes, b-substi-
tuted substrates are an inaccessible substrate class.[5] In
addition, most catalytic systems reported were based on
precious metals and required elevated temperatures. Thus,
further development of the catalytic intermolecular hydro-
amination of alkenes is strongly desired.
Scheme 1. Working hypothesis. Bz=benzoyl, L=ligand.
Herein, we report a copper-catalyzed formal intermolec-
ular hydroamination of styrenes with polymethylhydrosilox-
ane (PMHS) and hydroxylamines, providing hydroaminated
products, namely benzylamines, with high regioselectivity.[7]
The catalytic system consists common, inexpensive, and
abundant copper salts, and the reaction proceeds smoothly
even at room temperature. This method also accommodates
challenging b-substituted styrene derivatives. Moreover, the
catalytic asymmetric hydroamination also becomes possible
by using an appropriate chiral biphosphine ligand. Although
there are many precedents for the preparation of optically
active benzylamines, the hydroamination approach to these
chiral compounds still remains somewhat challenging, in view
of substrate scope and selectivity.[5a,d,i] Additionally, to the best
of our knowledge, this is the first copper-based catalysis for
the enantioselective intermolecular hydroamination of styr-
enes.
formation of [LnCuOtBu] species A[9] from a CuX precursor,
ligand, and M1OtBu, followed by reaction with an appropriate
hydride source, generates an active copper hydride species
B.[10] Subsequent insertion of a styrene derivative into the
À
LnCu H bond of B provides alkylcopper intermediates C or
C’.[11] Electrophilic amination[12,13] with an O-benzoylhydrox-
ylamine then occurs to deliver the desired formal hydro-
amination product, together with a [LnCuOBz] complex D.
Finally, ligand exchange with M1OtBu regenerates the start-
ing copper alkoxide A to complete the catalytic cycle.[14] If the
regioselectivity issue in the insertion step was addressed by
the proper choice of ligands,[15] and a chemoselective reaction
À
of the Cu H species toward styrenes over hydroxylamines
was feasible, the formal regioselective hydroamination could
be achieved.[16]
On the basis of the above scenario, we selected styrene
(1a), O-benzoyl-N,N-diethylhydroxylamine (2a), and triphe-
nylsilane as model substrates, and began optimization studies
(Table 1). In an early experiment, treatment of 1a with 2a and
We have recently developed a copper-catalyzed three-
component-coupling aminoboration of styrenes with bis(pi-
nacolato)diboron and hydroxylamines.[8] In the course of this
study, we envisioned our blueprint for the catalytic intermo-
lecular hydroamination with hydrides and hydroxylamines.
Our working hypothesis is illustrated in Scheme 1. Initial
triphenylsilane in the presence of
a Cu(OAc)2/dppbz
(dppbz = 1,2-bis(diphenylphosphino)benzene) catalyst and
LiOtBu as the base in THF at room temperature afforded
the desired hydroaminated product 3aa in 41% yield
(Table 1, entry 1). Although the yield was moderate, our
postulated catalytic cycle could be operating. Moreover, 3aa
was obtained as a single regioisomer. Thus, in the insertion
step (Scheme 1, B to C), the copper species and the hydride
can be regioselectively added to the a and b positions,
respectively, of the styrene.[17] With this preliminary but
promising result in hand, we next screened phosphorous-
based ligands (entries 2–7). Some biphosphines promoted the
hydroamination; for dppbz derivatives, CF3-dppbz proved to
be optimal (entry 7). The origin of the beneficial effects of
[*] Y. Miki, Dr. K. Hirano, Prof. Dr. T. Satoh, Prof. Dr. M. Miura
Department of Applied Chemistry, Faculty of Engineering, Osaka
University, Suita, Osaka 565-0871 (Japan)
E-mail: k_hirano@chem.eng.osaka-u.ac.jp
miura@chem.eng.osaka-u.ac.jp
[**] This work was partly supported by Grants-in-Aid from MEXT and
JSPS (Japan). K.H. acknowledges The Uehara Memorial Foundation
for financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201304365.
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Table 1: Optimization studies for the copper-catalyzed regioselective
hydroamination of styrene (1a) with O-benzoyl-N,N-diethylhydroxyl-
amine (2a) and hydrosilane.[a]
usual hydroaminated product exclusively, and no cyclic
products arising from a 5-exo radical cyclization were
detected (entry 4). Thus, an aminyl radical pathway is less
likely.[21] Moreover, the cyclic hydroxylamines of piperizine,
azepane, and morpholine could be employed for the catalytic
hydroamination (entries 5–7). Avariety of styrene derivatives
could also be employed.[22] Not only electron-rich 1b, but also
electron-deficient 1c and 1d reacted smoothly with 2h, to
form the corresponding hydroaminated products 3bh–dh in
high yields (entries 8–10). Notably, the copper catalyst was
compatible with aryl chloride and bromide functional groups
(entries 11 and 12), providing additional opportunities for
further transformations with palladium catalysts. The fused
naphthalene system could also be employed (entries 13 and
14). This process accommodated b-substituted styrenes 1h–k
(entries 15–18), which were an inaccessible substrate class
under the previously reported palladium-catalyzed condi-
tions.[5] In particular, the challenging substrates cinnamyl
methyl ether (1l) and cinnamyl acetate (1m) could be
successfully hydroaminated; their allylic moieties tend to
Entry
Ligand
dppbz
R3SiH
Solvent
Yield [%][b]
1
Ph3SiH
Ph3SiH
Ph3SiH
Ph3SiH
Ph3SiH
Ph3SiH
Ph3SiH
Ph3SiH
Ph3SiH
Ph3SiH
Ph3SiH
Ph2MeSiH
PhMe2SiH
PMHS
THF
THF
THF
THF
THF
THF
THF
toluene
DCE
DMF
DMSO
DCE
DCE
DCE
DCE
41
0
[c]
2
PPh3
3
dppe
0
4
5
6
7
8
9
10
11
12
13
14
15[d]
dppf
30
40
22
56
73
85
0
xantphos
MeO-dppbz
CF3-dppbz
CF3-dppbz
CF3-dppbz
CF3-dppbz
CF3-dppbz
CF3-dppbz
CF3-dppbz
CF3-dppbz
CF3-dppbz
0
67
58
53
>99
PMHS
[a] Reaction conditions: Cu(OAc)2 (0.025 mmol), ligand (0.025 mmol),
LiOtBu (0.60 mmol), 1a (0.25 mmol), 2a (0.30 mmol), hydrosilane
(0.30 mmol), solvent (1.5 mL), N2, RT, 4 h. [b] Yield estimated by GC
analysis with dibenzyl as the internal standard. [c] With PPh3
(0.050 mmol). [d] With PMHS (0.75 mmol) and LiOtBu (0.75 mmol).
dppbz=1,2-bis(diphenylphosphino)benzene, dppe=1,2-bis(diphenyl-
phosphino)ethane, dppf=1,1’-bis(diphenylphosphino)ferrocene, xant-
phos=4,5-bis(diphenylphosphino)-9,9’-dimethylxanthene.
CF3-dppbz is not clear at present, but its steric bulk and
electron-deficient nature may suppress undesirable aggrega-
tion of the copper hydride species B (Scheme 1). The choice
of solvent was also critical for the reaction efficiency
(entries 8–11): Less polar toluene and 1,2-dichloroethane
(DCE) improved the yield, whereas more polar N,N-dime-
thylformamide (DMF) and dimethylsulfoxide (DMSO) com-
pletely shut down the reaction. An additional screen of
hydride sources revealed that, to our delight, the much less
expensive
and
abundant
polymethylhydrosiloxane
(PMHS)[18] showed acceptable reactivity (entries 12–14).
Finally, we obtained 3aa in > 99% yield (by GC analysis),
using Cu(OAc)2/CF3-dppbz (10 mol%), PMHS (3.0 equiv),
and LiOtBu (entry 15). On the other hand, other bases such as
LiOMe, NaOtBu, and LiF did not form 3aa at all (data not
shown).[19]
Based on the optimization studies (Table 1), we evaluated
the scope of the amine coupling partners with styrene (1a;
Table 2). With hydroxylamines other than 2a, a slight excess
of styrene and 4.0 equivalents of LiOtBu generally gave
better results. Acyclic amines that bear N,N-dibenzyl, N-
benzyl-N-methyl, and N,N-diallyl substituents participated in
the reaction (entries 1–3). The resultant benzyl and allyl
moieties can be a useful synthetic handle for further
manipulation after a selective deprotection.[20] The reaction
with 2e, which contains a pendant olefin moiety, gave the
Scheme 2. Catalytic asymmetric hydroamination. The chiral biphos-
phine employed is given in parentheses. [a]Æ5%.
2
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Table 2: Copper-catalyzed regioselective hydroamination of styrene derivatives 1 with various O-benzoylhydroxylamines 2.[a]
Entry
1
1
2
3
Yield
[%][b]
Entry
11[d]
1
2
3
Yield
[%][b]
81
2h
91
2[c]
3[d]
4
1a
1a
1a
89
72
85
12[d]
13
2h
2a
2h
91
72
63
14
1g
5
1a
1a
80
78
15[d]
2h
2h
85
50
6[d]
16
7
1a
95
97
17
2h
2h
2h
82
87
98
8
2h
2h
18
9[d]
>99
19[d]
10
2h
83
20[d]
2b
57
[a] Reaction conditions: Cu(OAc)2 (0.025 mmol), CF3-dppbz (0.025 mmol), LiOtBu (1.0 mmol), 1 (0.30 mmol), 2 (0.25 mmol), PMHS (0.75 mmol),
DCE (1.5 mL), N2, RT, 4 h. [b] Yield of isolated product. [c] With Ph3SiH (0.30 mmol) and LiOtBu (0.60 mmol). [d] With 1 (0.38 mmol). [e] E/Z=96:4.
[f] E/Z=92:8.
undergo oxidative addition to low valent metal complexes,
such as palladium(0). Additionally, in most cases, the hydro-
aminated products were readily isolated by a simple acid/base
workup without purification by column chromatography on
silica gel (see the Supporting Information for details).
Finally, we developed an asymmetric variant of this
method by using an appropriate optically active ligand.
Pleasingly, good efficiency and enantioselectivity were
observed with a combination of CuCl and (S,S)-Me-Duphos
(L1) in THF at room temperature (Scheme 2).[23] The copper-
catalyzed asymmetric hydroamination of styrene (1a) gave
optically active benzylamines 3ab–ah with enantiomeric
ratios (e.r.) of 87:13–93:7. With electron-deficient styrenes,
(R,R)-Ph-BPE (L2) gave better enantioselectivities than L1
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(1b) and electron-neutral 2-vinylnaphthalene (1g) underwent
hydroamination with good e.r. values under the same
conditions using L1 (3bh and 3gh). The trans b-methylstyr-
enes 1h and 1j were also suitable substrates for this
enantioselective reaction (3hh and 3jh). The asymmetric
catalyst accommodated more sterically demanding 1k, which
bears an iPr substituent (3kh). Moreover, the optically active
1,3-aminoalcohol scaffold 3lh was readily accessible by the
enantioselective hydroamination of cinnamyl ether 1l.[24]
In conclusion, we have developed a copper-catalyzed
intermolecular regioselective formal hydroamination of styr-
enes with PMHS and O-benzoylhydroxylamines. The method
makes use of common and less expensive copper salts as the
metal catalyst and PMHS as the hydride source, and allowed
some challenging b-substituted substrates to be successfully
hydroaminated. Electrophilic amination with hydroxylamines
(umpolung) was the key to success. Moreover, catalytic
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Published online: && &&, &&&&
Keywords: amines · copper · hydroamination ·
.
synthetic methods · umpolung
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À
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[22] Preliminary attempts to apply cis olefins and aliphatic alkenes
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[23] See the Supporting Information for detailed optimization studies
for the catalytic asymmetric reaction.
[24] The enantiomeric ratios were determined by HPLC analysis on
a chiral stationary phase. The absolute configuration of (R)-3ah
was determined by comparison of the optical rotation with the
reported value, and those of other amines were tentatively
assigned by analogy. See the Supporting Information for details.
À
[18] For leading work on the generation of Cu H species with
PMHS, see: a) B. H. Lipshutz, K. Noson, W. Chrisman, J. Am.
Chem. Soc. 2001, 123, 12917; b) B. H. Lipshutz, A. Lower, K.
Nolan, Org. Lett. 2002, 4, 4045; c) B. H. Lipshutz, J. M. Servesko,
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
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Angewandte
Communications
Communications
Synthetic Methods
Y. Miki, K. Hirano,* T. Satoh,
M. Miura*
&&&& — &&&&
Copper-Catalyzed Intermolecular
Regioselective Hydroamination of
Styrenes with Polymethylhydrosiloxane
and Hydroxylamines
Playing Reversi with H and N: A copper-
catalyzed intermolecular regioselective
hydroamination of styrenes with polyme-
thylhydrosiloxane and hydroxylamine
derivatives has been developed. The
catalysis accommodates challengingb-
substituted substrates. Moreover, the
chiral biphosphine-ligated copper com-
plex successfully forms benzylamines
with good enantiomeric ratios.
6
www.angewandte.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
These are not the final page numbers!