Regioselective Construction of α,α-Disubstituted Allylic Amines by the Ruthenium-Catalyzed Allylic Amination of Tertiary Allylic Acetates

Article abstract of DOI:10.1021/acs.orglett.6b03672

The ruthenium-catalyzed regioselective allylic amination of tertiary allylic acetates with several types of amines has been accomplished. The reaction was effectively catalyzed by CpRuCl₂/5,5′-dimethyl-2,2′-bipyridine or its related ruthenium catalyst systems, and α,α-disubstituted allylic amines were formed as a single regioisomer in moderate to high yields.

Full text of DOI:10.1021/acs.orglett.6b03672

Letter
pubs.acs.org/OrgLett
Regioselective Construction of α,α-Disubstituted Allylic Amines by
the Ruthenium-Catalyzed Allylic Amination of Tertiary Allylic
Acetates
Shota Mizuno, Shou Terasaki, Toru Shinozawa, and Motoi Kawatsura*
Department of Chemistry, College of Humanities & Sciences, Nihon University, Sakurajosui, Setagaya-ku, Tokyo 156-8550, Japan
S
* Supporting Information
ABSTRACT: The ruthenium-catalyzed regioselective allylic ami-
nation of tertiary allylic acetates with several types of amines has
been accomplished. The reaction was effectively catalyzed by
Cp*RuCl2/5,5′-dimethyl-2,2′-bipyridine or its related ruthenium
catalyst systems, and α,α-disubstituted allylic amines were formed as
a single regioisomer in moderate to high yields.
With the standard reaction conditions (Table 1, entry 12) in
he transition-metal-catalyzed allylic amination of allylic
Tcompounds is one of the most useful reactions to hand, we investigated the reaction of 1a with several aliphatic
amines 2b−p. As shown in Table 2, most of the reactions
smoothly proceeded, and we succeeded in obtaining the desired
α,α-disubstituted allylic amines in good to high yields without
forming a regioisomer. For example, cyclic aliphatic amines
2b−j provided the intended products in the range of 79−90%
yield (entries 1−9). We further examined the reaction with
acyclic aliphatic secondary amines (2k−n) (entries 10−13).
Unfortunately, the reactions with diethylamine (2k) or N-
methylcyclohexylamine (2n) resulted in a low yield even at 40
°C (entries 10 and 13) because the formation of 2-phenyl-1,3-
butadiene due to the undesirable elimination reaction of 1a,15
but N-methylbenzylamine (2l) and N-methylbutylamine (2m)
gave the corresponding allylic amines in good yields (entries 11
and 12). We also examined and confirmed that the reactions
with aliphatic primary amines, such as 2o and 2p, afforded the
desired α,α-disubstituted allylic amines 3ao and 3ap in 93% and
82% yields, respectively (entries 14 and 15).
We next examined the reaction of 1a with aniline (2q), but
again our optimized reaction conditions provided the diene,
which was formed from 1a as the major product and did not
give any trace amount of the intended product 3aq (Table 3,
entry 1). Based on this initial observation, we reinvestigated the
suitable catalyst conditions for the reaction with an aromatic
amine 2q. To our delight, although the exact role is not clear,10
we found that the addition of a tertiary amine is effective to
allow the intended regioselective allylic amination reaction to
occur. For example, when NEt3 (2 equiv) was added to the
reaction system, the desired reaction proceeded, and allylic
amine 3aq was formed in 71% yield (entry 2). We further
examined the reaction by other tertiary amines and then
confirmed that the highest yield (84%) was attained by adding
EtNiPr2 (entries 3−5).16 We also examined the reaction with
construct allylic amines, and several transition-metal catalysts
have been employed for such reactions.1 However, the
reactions of tertiary allylic compounds with amines, which
provide α,α-disubstituted allylic amines, are still difficult
reaction processes compared to the reaction of secondary or
primary allylic compounds. To the best of our knowledge, there
are only a limited number of examples of the regioselective
allylic amination of tertiary allylic compounds; some
palladium,2 iridium,3 iron,4 and rhodium5 catalysts are known
as effective catalysts to realize such reactions. On the other
hand, ruthenium is also known to catalyze the allylic amination
reaction of allylic compounds with amines,6−11 but there is still
no example of the reaction of tertiary allylic compounds. Based
on this background, during the course of our research on the
several types of ruthenium-catalyzed allylic substitutions,10,12
we examined the reaction of tertiary allylic acetates, which are
easy to prepare, with several amines and succeeded in obtaining
α,α-disubstituted allylic amines.
We first examined the reaction of tertiary allylic acetate 1a
with morpholine (2a) using several ruthenium catalysts (RuCl3,
[RuCl2(p-cymene)]2, Ru3(CO)12, Cp*RuCl2, etc.)13 and
solvents and then confirmed that the reaction by Cp*RuCl2
(3 mol %) in CH3CN provided the intended α,α-disubstituted
allylic amines (3aa) in 75% NMR yield as a single regioisomer
(Table 1, entries 1−3). We next examined the reaction in the
presence of 2,2′-bpy (2,2′-bipyridine, L1) as a ligand at 60 °C
and succeeded in increasing the yield of 3aa to 86% (entries 4−
8). These results suggest that the Ru(II) species, which was
formed from Ru(III) precatalyst in the presence of 2,2′-bpy and
CH3CN, played an active catalyst for the desired allylic
amination reactions.8a,14 To attain a higher yield of 3aa, we
then attempted the reaction with other ligands (L2−7) (entries
9−14) and revealed that the highest yield (97% NMR yield,
91% isolated yield) was obtained when 5,5′-dimethyl-2,2′-
bipyridine (L5) was used instead of L1 (entry 12).
Received: December 9, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03672
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Organic Letters
Letter
Table 1. Ruthenium-Catalyzed Allylic Amination of 1a with
Morpholine (2a)
Table 2. Ruthenium-Catalyzed Allylic Amination of 1a with
Aliphatic Amines
a
a
b
entry
L
solvent
temp (°C)
yield (%)
1
THF
40
40
40
60
60
40
60
80
60
60
60
60
60
60
6
2
toluene
CH3CN
THF
8
3
75
14
12
81
86
77
74
87
95
4
L1
L1
L1
L1
L1
L2
L3
L4
L5
L6
L7
5
toluene
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
6
7
8
9
10
11
12
13
14
c
97 (91)
57
82
a
Reaction conditions: 1a (0.3 mmol), 2a (0.6 mmol), Cp*RuCl2
(0.009 mmol), and L (0.009 mmol) in solvent (1.0 mL) at the
b
indicated temperature for 19 h. Yields are determined by 1H NMR of
c
crude materials using an internal standard (phenanthrene). Isolated
yield is shown in parentheses.
other aniline analogues, such as 4-methoxyaniline (2r), 4-
trifluoromethylaniline (2s), or 1-naphthylamine (2t), in the
presence of EtNiPr2. As we expected, the reaction with 2r
afforded a good result, but the reactions with 2s and 2t resulted
in moderate yields because a diene was formed as a byproduct
(entries 7 and 8). Unfortunately, the present ruthenium catalyst
system was not effective for the reaction with N-methylaniline
(2u), and the reaction did not produce any allylic amines (entry
10).
We further demonstrated the reaction of several tertiary
allylic acetates 1b−g with several amines, such as the cyclic
secondary aliphatic amine 2a, acyclic secondary aliphatic amine
2m, aliphatic primary amine 2o, or primary aromatic amines 2q,
and the results are summarized in Scheme 1. For the reactions
with morpholine (2a), we observed a decreased yield for the
reactions of 1c−e, which possessed the p-methoxy group, p-
methyl group, or o-methyl group on the phenyl group due to
the formation of dienes. However, the reactions of 1b and 1f
provided the desired products 3ba and 3fa in 90% and 83%
yields, respectively. These results indicate that the steric
hindrance at the ortho position of the aryl group inhibits the
desired allylic amination reaction, and electron-donating groups
on the phenyl group also decreased the yields of allylic amines
due to the formation of dienes. Unfortunately, the reaction of
a
Reaction conditions: 1a (0.3 mmol), 2b−p (0.6 mmol), Cp*RuCl2
(0.009 mmol), and L5 (0.009 mmol) in CH3CN (1.0 mL) at 60 °C for
19 h. Isolated yields after chromatography are shown. Reaction was
conducted at 40 °C.
b
c
1g, which has an alkyl group instead of an aryl group, with 2a
using the optimized ruthenium catalysts exhibited a low
conversion (<10%) of 1g, but when the ligand was changed
from L5 to 4,7-dichloro-1,10-phenanthroline (L7), we
succeeded in obtaining the intended allylic amine 3ga in 88%
yield.
The reactions of 1b−g with N-methylbutylamine (2m) were
also examined, and they confirmed that the reaction of 1c−e
again resulted in a low yield, but 1b and 1f afforded the α,α-
disubstituted allylic amines 3bm and 3fm in good yield,
respectively. Furthermore, although the yield was moderate, we
could obtain 3gm in 40% yield when L7 was used. The
reactions of 1b−g with benzylamine (2o) also gave a similar
result, and we obtained the corresponding products in the
range of 32−80% isolated yields. We further investigated the
reactions of 1b−g with aniline (2q) and succeeded in obtaining
B
DOI: 10.1021/acs.orglett.6b03672
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
systems effectively catalyzed the intended regioselective allylic
amination with several types of aliphatic amines and primary
aromatic amines and succeeded in obtaining the desired α,α-
disubstituted allylic amines in moderate to high yields. Further
investigation of the ruthenium-catalyzed regio- and enantiose-
lective allylic substitutions of tertiary allylic acetates with several
types of nucleophiles, which include amides, is currently
underway by our group.
Table 3. Reaction of 1a with Anilines 2q−u
b
entry
2
additive
yield (%)
1
2
3
4
5
6
7
8
PhNH2 (2q)
0
PhNH2 (2q)
Et3N
71 (3aq)
84 (3aq)
63 (3aq)
43 (3aq)
70 (3ar)
49 (3as)
44 (3at)
66 (3at)
0
PhNH2 (2q)
EtNiPr2
DABCO
DBU
ASSOCIATED CONTENT
* Supporting Information
■
PhNH2 (2q)
S
PhNH2 (2q)
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b03672.
4-MeOC6H4NH2 (2r)
4-CF3C6H4NH2 (2s)
1-naphthylamine (2t)
1-naphthylamine (2t)
PhNHMe (2u)
EtNiPr2
EtNiPr2
EtNiPr2
EtNiPr2
EtNiPr2
c
9
Experimental procedures and spectral data for the
products (PDF)
10
a
Reaction conditions: 1a (0.3 mmol), 2q−u (0.6 mmol), additive (0.6
mmol), Cp*RuCl2 (0.009 mmol), and L5 (0.009 mmol) in CH3CN
(1.0 mL) at 60 °C for 19 h. Isolated yields after chromatography are
AUTHOR INFORMATION
b
■
c
Corresponding Author
*E-mail: kawatsur@chs.nihon-u.ac.jp.
ORCID
shown. Reaction was conducted at 40 °C.
Scheme 1. Ruthenium-Catalyzed Allylic Amination of
a,b
Several Allylic Acetates 1b−g with Amines 2a,m,o,q
Motoi Kawatsura: 0000-0002-8341-6866
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by the Individual Research Expense
of College of Humanities and Sciences at Nihon University.
■
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