Formation of α-Monosubstituted propargylamines from terminal alkynes and secondary amines using a (PNO)Rh/Cu Tandem catalyst system

Article abstract of DOI:10.1246/cl.170754

A novel (PNO)Rh/CuBr (PNO: phosphine-quinolinolate) tandem catalyst system was developed for facile synthesis of α-monosubstituted propargylamines from aliphatic terminal al-kynes and secondary amines. Various terminal alkynes and amines were applicable t

Full text of DOI:10.1246/cl.170754

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Formation of α-Monosubstituted Propargylamines from Terminal Alkynes and Secondary
Amines Using a (PNO)Rh/Cu Tandem Catalyst System
Shotaro Takano, Takuya Kochi, and Fumitoshi Kakiuchi*
Advance Publication on the web September 2, 2017
doi:10.1246/cl.170754
© 2017 The Chemical Society of Japan
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1
Formation of α-Monosubstituted Propargylamines from Terminal Alkynes and Secondary
Amines Using a (PNO)Rh/Cu Tandem Catalyst System
Shotaro Takano, Takuya Kochi, and Fumitoshi Kakiuchi*
Department of Chemistry, Faculty of Science and Technology, Keio University
3-14-1 Hiyoshi, Kohoku-ku, Yokohama, Kanagawa 223-8522
E-mail: kakiuchi@chem.keio.ac.jp
A
novel
(PNO)Rh/CuBr
(PNO:
phosphine-
hydroamination of terminal alkynes. Therefore, we
envisioned that the use of (PNO)Rh complex along with a
copper catalyst would provide a novel tandem catalyst
system which produce propargylamines via (PNO)Rh-
catalyzed anti-Markovnikov hydroamination and copper-
catalyzed alkyne addition.
quinolinolate) tandem catalyst system was developed for
facile synthesis of α-monosubstituted propargylamines from
aliphatic terminal alkynes and secondary amines. Various
terminal alkynes and amines were applicable to this reaction
and the corresponding propargylamines were obtained in
good yields.
Keywords: Rhodium catalysts
| Terminal alkynes |
Propargylamines |
Propargylamines are an important class of compounds
that have been used as intermediates for various nitrogen-
containing compounds.1 Direct addition of terminal alkynes
to imines or enamines can be regarded as one of the most
facile methods for the preparation of propargylamines and
has been extensively used in the synthesis of a variety of
amines.2-4 Since one of the most convenient, atom-efficient
ways to prepare imines or enamines is hydroamination of
alkynes, combinations of alkyne hydroamination and further
alkyne addition to imines or enamines have also been studied
to prepare propargylamines from alkynes and amines.5-7
Copper catalysts, known to catalyze both the hydroamination
and the alkyne addition, have mostly been employed for
these reactions.5,6 Most of the hydroamination/alkyne
addition reactions reported so far produced α,α-disubstituted
propargylamines because the hydroamination reactions
generally proceeds in a Markovnikov fashion.5 There have
been a few reports on one-step propargylamine syntheses via
anti-Markovnikov addition and alkyne addition using
Figure 1. Rhodium complexes bearing a PNO tridentate ligand
Here we report the novel (PNO)Rh/Cu tandem catalyst
system for facile synthesis of α-monosubstituted
propargylamines from aliphatic terminal alkynes and
secondary amines. The reaction is considered to proceed via
the rhodium-catalyzed anti-Markovnikov hydroamination of
terminal alkynes with secondary amines to form enamines,
followed by copper-catalyzed alkyne addition to the
enamines.
First, the reaction of 1-octyne (2a) with piperidine (3a)
was performed in the presence of 5 mol % dinuclear
(PNO)Rh complex 1a and 20 mol % CuBr (eq. 1), and α-
monosubstituted propargylamine 4aa, possibly formed by
the tandem anti-Markovnikov hydroamination/alkyne
addition, was obtained in 74% NMR yield along with dimers
of 2a. In this reaction, no α,α-disubstituted propargylamine,
which may be generated via the Markovnikov
hydroamination, was observed.
alkynes
possessing
aryl
or
electron-withdrawing
substituents,6,8 the corresponding high-yielding synthesis of
propargylamines via anti-Markovnikov addition to aliphatic
terminal alkynes has not been reported.
Our group has developed various transformations of
terminal alkynes catalyzed by 8-quinolinolatorhodium
complexes.9 For example, we found the combination of an 8-
quinolinolatorhodium complex bearing a cyclooctadiene
ligand (Rh(Q)(cod)) with triarylphosohines are effective
catalysts for the anti-Markovnikov hydroamination of
arylacetylenes with secondary amines at room temperature.9b
We recently synthesized novel rhodium(I) complexes
The reaction conditions for the anti-Markovnikov
hydroamination/alkyne addition was then examined (Table
1). Addition of 1 equiv of triethylamine slightly improved
the yield to 77% (entry 1). In the absence of rhodium catalyst
1a, the catalytic activity for the propargylamine formation
was decreased, and the Markovnikov hydroamination/alkyne
addition product became the major product (entry 2). When
only 1a was used as a catalyst, the propargylamine formation
did not proceed and a trace amount of hydroamination
bearing
a PNO tridentate ligand containing an 8-
quinolinolate and a phosphine moieties (Figure 1)10 and
found that the (PNO)Rh complexes can produce the anti-
Markovnikov hydroamination product from an aliphatic
terminal alkyne and piperidine at 110 ºC. It was also shown
that vinylidene-bridged dirhodium complexes and
(amino)carbene complexes can be prepared from (PNO)Rh
complex 1a with terminal alkynes and then with amines and
are important intermediates in the anti-Markovnikov

2
product was detected (entry 3). Then the copper catalysts
were screened for the propargylamine formation. The use of
other copper(I) catalysts such as CuCl, CuI, and CuCN gave
product 4aa in 40-74% yields (entries 4-6). Among the
copper(II) catalysts examined, CuCl2 and CuBr2 showed
similar catalytic activity to CuBr (entries 7 and 8), while the
product yields of the reactions using other copper(II) salts
such as Cu(OAc)2 and Cu(OTf)2 were significantly lower
than that with CuBr (entries 9 and 10). The reactions using
other (PNO)Rh catalysts were also conducted. The use of
triphenylphosphine complex 1b slightly improved the yield
of product 4aa to 83% (entry 11), while carbonyl complex 1c
showed lower catalytic activity (entry 12). The yield of 4aa
was further improved to 89% by reducing the amounts of the
catalysts (entry 13).11
2e also gave the corresponding propargylamines (entries 4
and 5). The reaction of a substrate containing a THP-
protected alcohol (2f) also proceeded efficiency (entry 6). In
contrast, phenylacetylene (2g) was not a suitable substrate
and gave only 10% NMR yield of the corresponding product
4ga (entry 7). In this case, various byproducts such as the
hydroamination product were observed.
Table 2. anti-Markovnikov Hydroamination/Alkyne Addition of
Various Terminal Alkynes with 3aa
Table 1. Screening of Catalysts for the anti-Markovnikov
Hydroamination/Alkyne Addition of 2a with 3aa
Entry
R
isolated yield (%)
2
4
1
2
C6H13
Cy
89
89
2a
2b
4aa
4ba
3
4
5
6
7
CyCH2
92
55
89
91
10b
2c
2d
2e
2f
4ca
4da
4ea
4fa
4ga
NC(CH2)3
MeO2C(CH2)3
THPO(CH2)3
Ph
Entry
Rh catalyst
1a (5 mol %)
none
Cu catalyst
CuBr
NMR yield (%)b
2g
1
2
77
4c
ndd
aReaction conditions: terminal alkyne (2.0 mmol), 3a (0.4 mmol), 1b
(0.02 mmol), CuBr (0.03 mmol), triethylamine (0.4 mmol), toluene 3.0
mL, 100 ºC, 2 h. bNMR yield determined by 1H NMR using 9H-fluorene
as an internal standard.
CuBr
3
1a (5 mol %)
none
4
CuCl
61
5
CuI
74
The scope of secondary amines were also investigated
(Table 3). When cyclic secondary amines (3b-3d) were used
as a substrate, the corresponding propargylamines (4ab-4ad)
were obtained in 79-89% yields (entries 1-3). The reaction
also proceeded using acyclic amines, N-benzylmethylamine
(3e) and N-butylmethylamine (3f), to provide amines 4ae
and 4af in 74 and 90% yields, respectively (entries 4 and 5).
6
CuCN
CuCl2
CuBr2
Cu(OAc)2
Cu(OTf)2
CuBr
40
7
77
8
75
9
24
10
11
12
13e
trace
83
1b
1c
1b
Table 3. anti-Markovnikov Hydroamination/Alkyne Addition of 2a with
Various Secondary Aminesa
CuBr
59
CuBr
89
aReaction conditions: 2a (1.0 mmol), 3a (0.2 mmol), Rh catalyst (0.02
mmol), Cu catalyst (0.04 mmol), triethylamine (0.2 mmol), toluene 1.5
b
c
mL, 100 ºC, 2 h. 9H-Fuluorene was used as an internal standard. The
Markovnikov hydroamination/alkyne addition product was formed in
16% NMR yield. dNot detected. ePerformed using 5 mol % of 1b and 7.5
mol % of CuBr.
Entry
1
HNR1R2
isolated yield (%)
89
3
4
3b
4ab
O
HN
Various propargylamines were isolated by performing
the anti-Markovnikov hydroamination/alkyne addition of
several terminal alkynes using 0.4 mmol of amine 3a (Table
2). Propargylamine 4aa was isolated in 89% yield from the
reaction of 2a with 3a (entry 1). The reactions of
cyclohexylacetylene (2b) and 3-cyclohexyl-1-propyne (2c)
also provided propargylamine products 4ba and 4ca in 89
and 92% yields, respectively (entries 2 and 3). Terminal
alkynes containing a polar functional group such as 2d and
2
3
89
79
3c
Me
4ac
4ad
O
HN
Me
3d

3
4
74
90
3e
3f
4ae
4af
N
Rh
C
O
5
Ph2P
1.7 equiv P(4-CF3C6H4)3
N
benzene-d6, 90 °C, 4 days
89% NMR yield
C6H13
N
aReaction condition: 2a (2.0 mmol), secondary amine (0.4 mmol), 1b
(0.02 mmol), CuBr (0.03 mmol), triethylamine (0.4 mmol), toluene 3.0
mL, 100 ºC, 2 h.
C6H13
6
5
1.1 equiv CuBr
1.1 equiv 2a
1.1 equiv NEt3
A plausible mechanism of the anti-Markovnikov
hydroamination/alkyne addition is shown in Figure 2. As we
previously reported for the (PNO)Rh-catalyzed anti-
Markovnikov hydroamination of terminal alkynes,10
enamines were considered to be produced in this reaction as
well via formation of a vinylidene intermediate and then
conversion to an (amino)carbene complex, followed by 1,2-
β-H shift. In the presence of a copper catalyst, a copper
acetylide may be generated by the reaction with a terminal
alkyne and a base. Addition of the acetylide to an iminium
ion, formed by protonation of the enamine, would provide
the propargylamine product. Reactions of enamines with
copper acetylides to produce propargylamines have already
been reported.4
N
C6H13
benzene-d6, 90 °C, 2 days
43% NMR yield
C6H13
4aa
Scheme 1. The generation of enamine 6 from (amino)carbene complex 5
and the reaction of 6 with terminal alkyne 2a, CuBr and triethylamine
In conclusion, a facile method for the synthesis of α-
monosubstituted propargylamines from aliphatic terminal
alkynes and secondary amines was developed using the
novel (PNO)Rh/Cu tandem catalyst system. Various terminal
alkynes as well as secondary amines were applicable to this
reaction. The reaction is considered to proceed via the
(PNO)Rh-catalyzed anti-Markovnikov hydroamination to
form enamines and copper-catalyzed alkyne addition to the
enamines. Further developments of novel reactions via
enamine intermediates are currently in progress by taking
advantage of the excellent utility of the (PNO)Rh complexes
in tandem catalysis.
HNR1R2
1R2RN
R
H
R
[Rh]
[Rh]
[Rh]
NR1R2
base • H
base
R
R
R
This work was supported in part by JSPS KAKENHI
Grant Numbers JP16H04150 and JP15H05839 (Middle
Molecular Strategy). T.K. is also grateful for support by
JSPS KAKENHI Grant Number JP16H01040 (Precisely
Designed Catalysts with Customized Scaffolding).
NR1R2
[Cu]
R
base • H
Supporting
http://dx.doi.org/10.1246/cl.******.
Information
is
available
on
+ base
[Cu]
NR1R2
R
R
References and Notes
1
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R
Figure 2.
A proposed mechanism for tandem anti-Markovnikov
hydroamination/alkyne addition catalyzed by (PNO)Rh complexes and
copper co-catalyst
To examine the validity of the anti-Markovnikov
hydroamination/alkyne addition mechanism, enamine 6 was
generated in situ by the reaction of (amino)carbene complex
2
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5
with tris(4-trifluoromethylphenyl)phosphine and then
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indeed formed in 43% NMR yield.12
3

4
4
5
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6
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8
9
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10
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12
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See the Supporting Information for more details on the
optimization of the reaction conditions.
See the Supporting Information for other experimental result that
support the proposed mechanism.