Synthesis of α-Tertiary Amines by the Ruthenium-catalyzed Regioselective Allylic Amination of Tertiary Allylic Esters

Article abstract of DOI:10.1246/cl.200107

We demonstrated a ruthenium-catalyzed regioselective allylic amination of tertiary allylic esters with various amines using [Cp*Ru(CH₃CN)₃][PF₆]/5,5¤-dimethyl-2,2¤-bipyridine (5,5¤-diMe-2,2¤-bpy) and related ruthenium catalytic systems, and successfully obtained a diverse range of α-tertiary amines as single regioisomers. The present ruthenium catalytic system was effective for reactions with various types of amines.

Full text of DOI:10.1246/cl.200107

Received: February 11, 2020 | Accepted: March 11, 2020 | Web Released: March 17, 2020
CL-200107
Synthesis of α-Tertiary Amines by the Ruthenium-catalyzed Regioselective Allylic Amination
of Tertiary Allylic Esters
Shota Mizuno,1 Hiroaki Tsuji,1 Yasuhiro Uozumi,*2,3 and Motoi Kawatsura*1
1Department of Chemistry, College of Humanities & Sciences, Nihon University, Sakurajosui, Setagaya-ku, Tokyo 156-8550, Japan
2Institute for Molecular Science (IMS), Myodaiji, Okazaki 444-8787, Japan
3SOKENDAI (The Graduate University for Advanced Studies), Myodaiji, Okazaki 444-8787, Japan
E-mail: uo@ims.ac.jp (Y. Uozumi), kawatsur@chs.nihon-u.ac.jp (M. Kawatsura)
a) Previous stud y
We demonstrated
allylic amination of tertiary allylic esters with various amines
using [Cp*Ru(CH3CN)3][PF6]/5,5¤-dimethyl-2,2¤-bipyridine
a ruthenium-catalyzed regioselective
Me NR1R2
R
cat. [Pd, Rh, Ir, Fe]
Me LG
R
HNR1R2
amines
+
α,α-disubstituted
(5,5¤-diMe-2,2¤-bpy) and related ruthenium catalytic systems,
and successfully obtained a diverse range of α-tertiary amines
as single regioisomers. The present ruthenium catalytic system
was effective for reactions with various types of amines.
tertiary
allylic amines
allylic compounds
3 mol% Cp*RuCl2
Me NR1R2
R
Me OAc
R
HNR1R2
3 mol% 5,5'-diMe-2,2'-bpy
+
CH3CN, 60 °C, 19 h
tertiary
allylic acetates
Me
Me
Keywords: Ruthenium
| Amination | α-Tertiary amines
N
N
5,5'-diMe-2,2'-bpy
b) This work
Transition-metal-catalyzed allylic amination of allylic com-
pounds is one of the most useful reactions to synthesize allylic
amines,1 and several types of reactions in this category have been
reported. However, the reactions of tertiary allylic compounds
with amines, which provide α,α-disubstituted allylic amines,
are more difficult as compared to the reactions of primary or
secondary allylic compounds. Pd,2 Rh,3 Ir,4 and Fe5 catalysts are
known to be effective for the allylic amination of tertiary allylic
compounds, and we have previously reported a ruthenium-
catalyzed reaction6 (Scheme 1a). Although the intended reac-
tions of tertiary allylic compounds were carried out in those
studies, there was a limitation in that at least one substituent on
the allylic compound had to be a methyl group.7 On the other
hand, α-tertiary amines are useful organic components in the
fields of pharmaceutical chemistry and materials science.8
However, allylic amination of tertiary allylic compounds bearing
an ethyl group or a methoxymethyl group generally does not
proceed, or produces linear products.2i Therefore, it is important
to establish a method that provides access to α-tertiary amines
possessing other alkyl or aryl groups instead of a methyl group,
by the transition-metal-catalyzed reaction of tertiary allylic com-
pounds. Against this background, we attempted the ruthenium-
catalyzed regioselective allylic amination of tertiary allylic esters
and succeeded in obtaining α-tertiary amines (Scheme 1b).
We first carried out the reaction of tertiary allylic acetate 1a
to contain ethyl and phenyl groups with morpholine (2a) in the
presence of Cp*RuCl2 (5 mol %)/5,5¤-diMe-2,2¤-bpy (5 mol %)
in acetonitrile at 60 °C for 19 h, which were effective conditions
for the reaction of a methyl group-bearing tertiary allylic acetate
with an amine (Table 1, Entry 1).6 However, the reaction
resulted in low conversion (<5%) to α-tertiary amine 3a. Based
on this initial result, we anticipated that it is necessary to use
other ruthenium precatalysts for the intended reaction.
R
NR1R2
lykla OCO2Me
Ph
lyra OAc
Ph
cat. [Ru/L]
or
+
HNR1R2
Ph
tertiary
allylic esters
Scheme 1. Synthesis of α,α-disubstituted allylic amines by
allylic amination.
Table 1. Optimization of ruthenium-catalyzed allylic amina-
tion of tertiary allylic estersa
O
5 mol% [Ru]
5 mol% 5,5'-diMe-2,2'-bpy
Et
Ph
X = OAc: 1a
X
Et
Ph
N
+
HN
O
solv., 60 ˚C, time
2a
3a
OCO2Me 1b
OBoc: 1c
time yieldb
entry sub
[Ru]
solv.
(h)
(%)
1
2
3
1a
1a
1a
Cp*RuCl2
Cp*Ru(allyl)Cl2
Cp*Ru(cod)Cl
CH3CN 19
CH3CN 19
CH3CN 19
3c
15
14
20
12
<2c
16
41
38
44
48
66
50
4
1a [Cp*Ru(CH3CN)3][PF6] CH3CN 19
5
1a [Cp*Ru(CH3CN)3][PF6] DMF
19
19
19
6
7
1a [Cp*Ru(CH3CN)3][PF6]
1a [Cp*Ru(CH3CN)3][PF6]
THF
DCE
8
9
1a [Cp*Ru(CH3CN)3][PF6] toluene 19
1a [Cp*Ru(CH3CN)3][PF6] xylene 19
10
11
12
13
1a [Cp*Ru(CH3CN)3][PF6] toluene 48
1a [Cp*Ru(CH3CN)3][PF6] toluene 72
1b [Cp*Ru(CH3CN)3][PF6] toluene 72
1c [Cp*Ru(CH3CN)3][PF6] toluene 72
aReaction conditions: 1 (0.3 mmol), 2a (0.6 mmol), 5 mol % of
[Ru], and 5 mol % of 5,5¤-diMe-2,2¤-bpy in solvent (1.0 mL).
bIsolated yield. Determined by H NMR of crude materials.
Accordingly, we performed the reaction of 1a with 2a using
a ruthenium precatalyst such as RuCl3, [RuCl2(p-cymene)]2, or
Ru3(CO)12, but these attempts were unsuccessful.9,10 On the other
hand, we confirmed that the Cp*-ligated ruthenium precatalyst
with 5,5¤-diMe-2,2¤-bpy afforded the intended aminated product
3a, although the yield was low (Entries 2-4). To enhance the
c
1
formation of 3a, we next attempted the reaction with
[Cp*Ru(CH3CN)3][PF6]/5,5¤-diMe-2,2¤-bpy in several solvents
Chem. Lett. 2020, 49, 645–647 | doi:10.1246/cl.200107
© 2020 The Chemical Society of Japan | 645

Table 2. Ruthenium-catalyzed allylic amination of tertiary
allylic carbonates with aminesa
Table 3. Ruthenium-catalyzed allylic amination of α,α-diaryl
allylic acetates with aminesa
5 mol% [Cp*Ru(CH3CN)3][PF6]
5 mol% 5,5'-diMe-2,2'-bpy
5 mol% [Cp*Ru(CH3CN)3][PF6]
5 mol% 5,5'-diMe-2,2'-bpy
R
NR1R2
Ar
Ph
X
Ar NR1R2
Ph
R
OCO2Me
HNR1R2
HNR1R2
+
+
CH3CN, 80 ˚C, 19 h
toluene, 60 ˚C, 72 h
Ph
Ph
3m–v
X = OCO2Me: 1i
OAc: 1j–p
2a,e,g,h
2a–g
3a–l
1b–h
yieldb
(%)
entry
R
HNR1R2
product
yieldb
(%)
entry
Ar
HNR1R2
product
1
2
3
4
5
6
7
8
9
Et (1b)
Et (1b)
Et (1b)
Et (1b)
Et (1b)
Et (1b)
Et (1b)
nBu (1d)
iPr (1e)
morpholine (2a)
piperidine (2b)
pyrrolidine (2c)
HNBnMe (2d)
H2NBn (2e)
H2NiPr (2f)
H2NPh (2g)
morpholine (2a)
morpholine (2a)
3a
3b
3c
3d
3e
3f
3g
3h
3i
66
41
35
43
58
43
55
54
<2c
32
1c
2c
3
4
5
6
7
8
9
Ph (1i)
Ph (1j)
Ph (1j)
Ph (1j)
Ph (1j)
morpholine (2a)
morpholine (2a)
morpholine (2a)
HNEt2 (2h)
H2NBn (2e)
H2NPh (2g)
H2NBn (2e)
H2NBn (2e)
H2NBn (2e)
H2NBn (2e)
H2NBn (2e)
H2NBn (2e)
3m
3m
3m
3n
3o
3p
3q
3r
3s
3t
3u
3v
62
69
79
69
84
51
76
59
75
83
46
61
Ph (1j)
2-naphthyl (1k)
2-MeC6H4 (1l)
4-MeC6H4 (1m)
4-ClC6H4 (1n)
4-CF3C6H4 (1o)
4-PhC6H4 (1p)
10
11
12
MeOCH2 (1f) morpholine (2a)
Bn(1g)
CF3 (1h)
3j
3k
3l
10
11
12
morpholine (2a)
morpholine (2a)
38
<2c
aReaction conditions: 1b-h (0.3 mmol), 2a-g (0.6 mmol),
5 mol % of [Cp*Ru(CH3CN)3][PF6], and 5 mol % of 5,5¤-
diMe-2,2¤-bpy in toluene (1.0 mL) at 60 °C for 72 h. Isolated
aReaction conditions: 1i-p (0.3 mmol), 2a, 2e, 2g, and, 2h
(0.6 mmol), 5 mol % of [Cp*Ru(CH3CN)3][PF6], and 5 mol %
of 5,5¤-diMe-2,2¤-bpy in toluene (1.0 mL) at 80 °C for 19 h.
b
c
1
yield. Determined by H NMR of crude materials.
bIsolated yield. Toluene was used instead of CH3CN.
c
such as DMF, THF, DCE, toluene, and xylene (Entries 5-9); 3a
was obtained in 41% yield (88% conversion of 1a) when toluene
was used (Entry 8). We also observed 100% conversion of 1a
when the reaction time was increased to 72 h, but the yield of
3a increased only slightly (48% yield) (Entries 10 and 11). We
further examined the reaction by changing the leaving group of
the tertiary allylic compounds from acetate to methyl or tert-butyl
carbonate (1b and 1c, respectively) and obtained 3a in 66% yield
as a single regioisomer when using 1b (Entries 12 and 13). Then,
we established the optimal conditions as follows: reaction of 1b
with 2a using [Cp*Ru(CH3CN)3][PF6]/5,5¤-diMe-2,2¤-bpy in
toluene at 60 °C for 72 h. Furthermore, we confirmed that
1,3-diene was formed as a byproduct from 1b in 32% yield.
With the standard conditions (Table 1, Entry 12) in hand,
we next investigated the reaction of allylic carbonates 1b-h
with several amines 2a-g (Table 2). The reactions with cyclic
aliphatic amines 2b and 2c provided the desired amination
products 3b and 3c in moderate yields, while the reactions with
acyclic aliphatic secondary amines 2d gave the desired α,α-
disubstituted allylic amine in 43% yield (Entries 2-4). The
reactions of 1b with aliphatic and aromatic primary amines, such
as benzylamine (2e), isopropylamine (2f), and aniline (2g),
afforded the desired allylic amines 3e, 3f, and 3g in 58%, 43%,
and 55% yields, respectively (Entries 5-7). We next carried out
the reaction of other alkyl group-substituted allylic carbonates
1d-h with 2a (Entries 8-12). The reaction of n-butyl group
substituted allylic carbonate 1d also proceeded to furnish allylic
amine 3h (Entry 8). Unfortunately, 1e, which had an iso-propyl
group, did not give the desired aminated product 3i but produced
only a 1,3-diene (Entry 9).11 This was probably because 1e
underwent elimination more rapidly than amination due to the
increased steric hindrance as compared to that observed with the
ethyl group.12 Accordingly, the reactions of substrates including
a methylene carbon at the α-position with morpholine were also
attempted: 1f and 1g afforded the α,α-disubstituted allylic amines
in 32% and 38% yields, respectively (Entries 10 and 11). On the
other hand, allylic carbonate 1h with strong electron-withdraw-
ing groups not gave 3l (Entry 12).13
We next carried out the reaction of allylic carbonate 1i
bearing two aryl groups; since the reaction proceeded smoothly
in the presence of the [Cp*Ru(CH3CN)3][PF6]/5,5¤-diMe-2,2¤-
bpy catalyst, we changed the reaction time from 72 h to 19 h
(Table 3, Entry 1). Screening of the reaction conditions revealed
that the use of allylic acetate 1j, with acetonitrile instead of
toluene, led to an increase in the yield (Entries 2 and 3). Having
established the optimal reaction conditions, we next investigated
the scope of the allylic amination of 1j with other amines
(Entries 4-6). The reaction with aliphatic secondary or primary
amines such as 2h and 2e produced the desired products 3n and
3o in 69% and 84% yields, respectively (Entries 4 and 5). On the
other hand, aniline (2g) reacted with 1j to give the desired
product 3p in only moderate yield (Entry 6). Furthermore, the
reactions of other aromatic group-substituted carbonates with
benzylamine (2e) proceeded to afford the corresponding prod-
ucts in good yields (Entries 7-12). The reactions of 1k bearing a
2-naphthyl group and 1l bearing methyl groups at the ortho-
position of the aromatic rings proceeded to give the desired
aminated products in 76% and 59% yields, respectively (Entries
7 and 8). Both electron-donating (1m) and electron-withdrawing
(1n-p) substituents at the para-position of the phenyl rings were
well tolerated, and the corresponding amination products were
obtained in 46%-83% yields (Entries 9-12).
The details of the mechanism underlying the ruthenium-
catalyzed amination are still not clear. However, the active
catalyst is proposed to be a Cp*Ru(2,2¤-bipyridine)(CH3CN)14,15
complex on the basis of the ruthenium catalyst system
646 | Chem. Lett. 2020, 49, 645–647 | doi:10.1246/cl.200107
© 2020 The Chemical Society of Japan

8
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([Cp*Ru(CH3CN)3][PF6]/2,2¤-bipyridine) and the known coor-
dination chemistry of ruthenium.16 Generally, π-allylruthenium,
σ-allylruthenium, and σ-enylruthenium17 complexes are possible
reaction intermediates in ruthenium-catalyzed allylic amination.
Further investigations into the mechanistic details as well as the
reaction of ruthenium complexes and other types of substrates
will be the subject of a future study.
In conclusion, we have demonstrated that the ruthenium-
catalyzed allylic amination of allylic esters provides a variety of
α-tertiary allylic amines. Although the detailed reaction mecha-
nism is still unclear, we have proposed the possible intermedi-
ates of the ruthenium catalysts that would be involved in the
formation of allyl or enylruthenium complexes. Investigation of
the ruthenium-catalyzed enantioselective allylic amination of
tertiary allylic esters with nitrogen nucleophiles and detailed
mechanistic studies are underway in our laboratory.
9
Supporting Information is available on https://doi.org/
10.1246/cl.200107.
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Chem. Lett. 2020, 49, 645–647 | doi:10.1246/cl.200107
© 2020 The Chemical Society of Japan | 647