Ruthenium-catalyzed regio- and enantioselective allylic amination of racemic 1-arylallyl esters

Article abstract of DOI:10.1021/ol5002768

The regio- and enantioselective allylic amination of racemic monosubstituted allylic esters, such as 1-arylallyl acetates, with cyclic secondary amines has been accomplished. The RuCl₃/(S,S)-ip-pybox catalyst system has effectively catalyzed th

Full text of DOI:10.1021/ol5002768

Letter
pubs.acs.org/OrgLett
Ruthenium-Catalyzed Regio- and Enantioselective Allylic Amination
of Racemic 1‑Arylallyl Esters
Motoi Kawatsura,*,† Kenta Uchida,‡ Shou Terasaki,† Hiroaki Tsuji,‡ Maki Minakawa,†
and Toshiyuki Itoh*,‡
†Department of Chemistry, College of Humanities & Sciences, Nihon University, Sakurajosui, Setagaya-ku, Tokyo 156-8550, Japan
‡Department of Chemistry and Biotechnology, Graduate School of Engineering, Tottori University, Koyama, Tottori 680-8552, Japan
S
* Supporting Information
ABSTRACT: The regio- and enantioselective allylic amination of racemic
monosubstituted allylic esters, such as 1-arylallyl acetates, with cyclic secondary
amines has been accomplished. The RuCl3/(S,S)-ip-pybox catalyst system has
effectively catalyzed the reaction to afford the enantiomerically enriched branch-type
allylic amines with perfect regioselectivity and high enantioselectivity.
he transition-metal-catalyzed allylic amination of allylic
substrates1 is one of the most useful reactions to construct
reaction using RuCl2(cod) or RuCl3 effectively increased the
branch selectivity (entries 6 and 8), and we observed a
moderate enantioselectivity (54% ee) for the reaction using the
RuCl3 precatalyst with L. The higher enantioselectivity was
attained by reducing the amount of DBU from 2 to 1 equiv at
40 °C (entries 9 and 10), and the highest enantioselectivity
(85% ee) was obtained when the amount of L was increased
from 5 to 10 mol % (2 equiv to Ru) (entry 11). We also
examined other additives, such as DABCO, Et3N, DMAP, or
Cs2CO3, and confirmed that the DBU is a crucial additive for
the perfect branch selectivity and high enantioselectivity
(entries 12−15).
With these optimized reaction conditions in hand, we
investigated the ruthenium catalyzed intermolecular asymmet-
ric allylic amination of several racemic 1-arylallyl acetates 1a−j
with six-membered aliphatic amines, such as 2a−f (Table 2).
Most of the reactions proceeded smoothly, and we succeeded
in obtaining the desired product in high yield with a high
enantiomeric excess. Especially, the reaction of 1a with
phenylpiperazine (2d) gave the highest enantioselectivity
(94% ee) (Table 2, entry 3). The reactions of 1b−d, which
have an electron-withdrawing group at the para-position on the
phenyl group, also afforded good results (entries 6−11). On the
other hand, we confirmed that the reaction of 1e, which has a
methoxy group at the para-position on the phenyl group, gave
3ea in 60% yield with 12% ee (entry 12), but increasing the
amount of ligand from 10 to 20 mol % significantly increased
the enantiomeric excess up to 85% ee (entry 13). Furthermore,
we examined the reaction of allyl acetates 1f−i and succeeded
in obtaining the intended enantiomercially enriched products
with both acceptable yields and enantiomeric excess (entries
14−21). Unfortunately, the reactions of the 1-naphthyl group
substituted allyl acetate 1j gave the desired products in low
yield with low ee (entries 22 and 23).
T
allylic amines, and its asymmetric reaction2 is also a powerful
method to prepare enantiomerically enriched allylic amines. For
such a transition-metal-catalyzed asymmetric allylic amination,
several types of allylic substrates can be used, including
symmetrical 1,3-disubstituted allylic substrates, but the reaction
of the unsymmetrical monosubstituted substrates is a more
challenging system because the reaction requires controlling
both the regioselectivity and enantioselectivity. To the best of
our knowledge, only palladium3 and iridium4−10 are known as
effective catalysts for such an intermolecular asymmetric allylic
amination of monosubstituted allylic substrates. The first
example of the palladium-catalyzed reaction was reported by
Hayashi and Ito in 1990.3a More recently, Hartwig’s group
investigated the highly enantioselective allylic amination of
monosubstituted allylic esters and alcohols by an iridium
catalyst.4
However, still it is a challenging topic to discover an
alternative transition metal catalyst, which allows the
asymmetric allylic amination of racemic monosubstituted allylic
compounds. Although there are several studies on the
ruthenium-catalyzed asymmetric allylic substitution11−17 after
Onitsuka and Takahashi’s report in 2001,12a there are still no
reports about the intermolecular asymmetric allylic amination
of racemic monosubstituted allylic substrates. During the
course of our study on the ruthenium-catalyzed regioselective
allylic substitution,18 we succeeded in the intermolecular
enantioselective allylic amination of racemic monosubstituted
allylic esters with cyclic secondary amines.
We first examined the allylic amination of the racemic 1-
phenyl-2-propenyl acetate (1a) with morpholine (2a) by
several chiral ruthenium catalysts, which were generated in
situ from the ruthenium precatalyst and (S,S)-ip-pybox (L). As
shown in Table 1, when the reactions were conducted without
an additive, the desired branch-type product 3aa was obtained
in low yield or as a mixture of linear-type products 4aa (entries
1−4). However, the addition of DBU (2 equiv to 1a) to the
Received: January 26, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ol5002768 | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Ru Catalysts for the Alkylation of 1a with 2a
Table 2. Ruthenium-Catalyzed Enantioselective Allylic
a
Amination of Racemic 1-Arylallyl Acetates with Amines
a
additive
yield (%)
ee (%)
entry
[Ru]
(2 equiv)
3aa
<2
4aa
of 3aa
b
b
entry
1
2
yield (%) of 3
% ee of 3
1
2
3
4
5
6
7
8
9
[Ru-1]
−
−
−
−
<2
39
73
40
<2
4
nd
0
RuCl2(cod)
Ru3(CO)12
RuCl3
47
7
1
1a
1a
1a
1a
1a
1b
1b
1b
1c
1c
1d
1e
1e
1f
2b
2c
2d
2e
2f
91 (3ab)
84 (3ac)
90 (3ad)
90 (3ae)
93 (3af)
88 (3ba)
87 (3bc)
87 (3bd)
83 (3cc)
88 (3cd)
81 (3dd)
60 (3ed)
87 (3ed)
77 (3fb)
74 (3fd)
67 (3gb)
64 (3gd)
71 (3hd)
88 (3he)
78 (3ia)
90 (3id)
35 (3ja)
22 (3jd)
80
86
94
88
86
86
90
93
90
94
94
12
85
90
87
90
90
86
86
81
86
24
4
nd
0
2
6
3
b
[Ru-1]
DBU
DBU
DBU
DBU
37
78
<2
71
75
80
31
16
−
54
65
81
85
0
4
RuCl2(cod)
Ru3(CO)12
RuCl3
5
<2
<2
<2
<2
<2
<2
<2
<2
<2
6
2a
2c
2d
2c
2d
2d
2d
2d
2b
2d
2b
2d
2d
2e
2a
2d
2a
2d
7
c
RuCl3
DBU
8
d
c
10
RuCl3
DBU
9
de
,
c
f
11
12
13
14
15
RuCl3
DBU
90 (85)
17
10
11
12
de
,
RuCl3
DABCO
Et3N
de
,
RuCl3
18
0
de
,
c
RuCl3
DMAP
Cs2CO3
<2
nd
12
13
de
,
RuCl3
23
14
15
16
17
18
19
20
21
22
23
a
The yields were determined by 1H NMR of crude materials using an
1f
b
c
internal standard (trioxane). [Ru-1] = [RuCl2(p-cymene)]2. 1 equiv
of DBU was used. Reactions were conducted at 40 °C. 10 mol % of
L was used. Isolated yield in parentheses.
1g
1g
1h
1h
1i
d
e
f
Although we succeeded in realizing that reactions of 1a−i
with six-membered aliphatic amines provided enantioenriched
allylic amines in both good yields and high ee values, we also
realized that the reaction with pyrrolidine (2g) gave a poor
result (Table 3, entry 1). To improve these poor results, we
reinvestigated the catalyst conditions for the reaction with 2f.
During the reaction of 1a with 2g, we observed the formation
of the deacetylated allylic alcohol from 1a; therefore we
changed the leaving group of the allyl substrate from acetate to
methyl carbonate 1a′ or tert-butyl carbonate 1a″. Changing of
the leaving group improved the reaction results, and 1a″
produced the desired aminated product 3af in good yields
(entries 3−5); the best result (82% yield with 80% ee) was
attained when the reaction was conducted using 20 mol % of
the pybox ligand (4 equiv to Ru) at 60 °C (entry 5). All the
other reactions of 1e″, 1f″, or 1g″ with 2f also gave
enantiomerically enriched allylic amines with good enantiose-
lectivities (81−84% ee) (entries 6−8).
We further examined the reaction of 1a with other amines,
such as azepane (2h) or acyclic amine 2i (Table 4), but again
our optimized conditions gave allylic amines in low yields and
low enantiomeric excesses (entries 1 and 4). However, we
succeeded in determining the suitable reaction conditions for
the reaction with 2h or 2i, and acceptable results (93% yield
with 82% ee for 2h, and 92% yield with 82% ee for 2i) were
obtained by increasing the amount of amines and DBU to 3
equiv and changing the solvents from THF to acetone (entries
3 and 5). We also demonstrated the reaction of other allylic
1i
1j
1j
a
Reaction conditions: 1a−j (1.0 mmol), 2a−f (2.0 mmol), DBU (2.0
mmol), 5 mol % of RuCl3, and 10 mol % of (S,S)-ip-pybox in THF at
b
c
40 °C for 24 h. Isolated yield. 20 mol % of L was used.
acetates (1b−d and 1i) with 2i and could obtain enantiomeri-
cally enriched allylic amines with good enantiomeric excesses
(entries 6−9). The details of the reaction mechanism of the
RuCl3/(S,S)-ip-pybox catalyzed enantioselective reaction, in-
cluding the key intermediate, active ruthenium species, or the
role of DBU, have not yet been clarified, but we believe that the
reaction proceeds through (S,S)-ip-pybox ligated π-allyl and/or
σ-allylruthenium complexes, and epimerization had occurred in
those ruthenium intermediates to afford the enantiomerically
enriched allylic amines.
In conclusion, we demonstrated the RuCl3/(S,S)-ip-pybox
catalyzed allylic amination of racemic 1-arylallyl esters with
amines (mainly aliphatic secondary amines)19 and succeeded in
obtaining enantiomerically enriched allylic amines with a high
enantioselectivity with perfect regioselectivity. Further studies,
such as the reaction of other allylic esters,20 reaction with
aromatic amines, or study of the mechanistic details, are
currently in progress in our group.
B
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Letter
a
Notes
Table 3. Reaction with Pyrrolidine (2g)
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was partially supported by Individual Research
Expense of College of Humanities and Sciences at Nihon
University for 2013.
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ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and spectral data for the products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: kawatsur@chs.nihon-u.ac.jp.
*E-mail: titoh@chem.tottori-u.ac.jp.
C
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(19) Reactions of cinnamyl acetate or cinnamyl chloride with
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D
dx.doi.org/10.1021/ol5002768 | Org. Lett. XXXX, XXX, XXX−XXX