Ruthenium-catalyzed linear selective allylic aminations of monosubstituted allyl acetates

Article abstract of DOI:10.1016/j.tetlet.2008.06.002

The ruthenium-catalyzed highly linear selective allylic amination of monosubstituted allylic acetates with secondary amines was developed. The regioselectivity was controlled by the Ru₃(CO)₁₂/2-DPPBA catalyst, and a linear-type aminated product was obtained as a single regioisomer.

Full text of DOI:10.1016/j.tetlet.2008.06.002

Tetrahedron Letters 49 (2008) 4873–4875
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Tetrahedron Letters
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Ruthenium-catalyzed linear selective allylic aminations
of monosubstituted allyl acetates
*
*
Motoi Kawatsura , Fumio Ata, Takuya Hirakawa, Shuichi Hayase, Toshiyuki Itoh
Department of Chemistry and Biotechnology, Graduate School of Engineering, Tottori University, Koyama, Tottori 680-8552, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The ruthenium-catalyzed highly linear selective allylic amination of monosubstituted allylic acetates
with secondary amines was developed. The regioselectivity was controlled by the Ru3(CO)12/2-DPPBA
catalyst, and a linear-type aminated product was obtained as a single regioisomer.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 6 May 2008
Revised 30 May 2008
Accepted 2 June 2008
Available online 5 June 2008
Keywords:
Ruthenium
Catalyst
Allylic amination
Regioselectivity
The transition metal-catalyzed allylic amination of allyl sub-
strates is one of the most useful carbon–nitrogen bond forming
reactions, of which there are several examples known to date.1–3
However, control of the regiochemistry during the reaction of
monosubstituted allyl substrates, which forms both linear and
branched isomers, is still a challenging process. Generally, palla-
dium catalysts produces linear-type product as a major regioisom-
er, but ruthenium catalysts prefer to form branch-type product. To
the best of our knowledge, three research groups independently re-
ported the ruthenium-catalyzed allylic amination of monosubsti-
tuted allyl substrates.4–7 According to their reports, the
regioselectivity is highly dependent on the reaction conditions,
such as the ruthenium complexes, solvent or allyl substrates. It
has been recognized; however, that ruthenium catalysts generally
form a branch-type product in preference to a linear-type product.
There are only a few exceptional linear selective results, and these
can be explained by the ruthenium-catalyzed isomerization of
branched allylic amines into their linear isomers.4–6 On the other
hand, we recently reported the first example of the ruthenium-cat-
alyzed highly linear selective allylic alkylation of mono-substituted
allyl acetate with malonate anions.8 During the course of this
study, we found that the Ru3(CO)12/2-DPPBA [2-(diphenylphos-
phino)benzoic acid] catalyst system also produces the linear selec-
tive allylic amination of monosubstituted allyl acetate with several
amines.
According to our previous result of the allylic alkylation with
the malonate anion, we applied the ruthenium catalyst, which
was generated from Ru3(CO)12 and 2-DPPBA, to the allylic amina-
tion reaction of 1-phenyl-2-propenyl acetate (1a) with piperidine
(2a) (Scheme 1). Unfortunately, the desired amination reaction
did not occur at 60 °C in THF (Table 1, entry 2). To realize the in-
tended ruthenium-catalyzed allylic amination of 1a, we added sev-
eral bases to the reactions, which confirmed that the DBU is the
most suitable base to initiate the desired amination reaction (en-
tries 3–6). Typically, the reaction was carried out as follows:
3.3 mol % of Ru3(CO)12, 10 mol % 2-DPPBA, allyl acetate 1a, and
DBU (2.0 equiv) in THF were allowed to react with piperidine
(2a) at 60 °C for 12 h. The reaction smoothly proceeded under
these conditions, and the linear-type allylic amine 4a was obtained
N
cat. Ru3(CO)12
Ph
OAc
cat. L
3a
+
N
H
Ph
THF, 60 ºC
1a
Ph
N
2a
4a
PPh2
, PPh3, DPPE
L =
CO2H
* Corresponding authors. Tel./fax: +81 857 31 5179.
E-mail addresses: kawatsur@chem.tottori-u.ac.jp (M. Kawatsura), titoh@chem.
tottori-u.ac.jp (T. Itoh).
2-DPPBA
Scheme 1.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.06.002

4874
M. Kawatsura et al. / Tetrahedron Letters 49 (2008) 4873–4875
Table 1
Table 2
Ruthenium-catalyzed allylic amination of 1a with 2aa
Ru3(CO)12/2-DPPBA catalyzed allylic amination of 1a with amines 2b–ma
Entry
L
Base
Yieldb (%)
3a:4ac,d
Entry Amine 2
Solvent
Temp. (°C) Yieldb (%) 3:4c,d
1
2
3
4
5
6
7e
8
9
—
—
—
0
0
0
0
37
95
48
0
—
—
—
—
2:>98
2:>98
2:>98
—
1
2
3
4
5
6
7
8
9
10
11
12
13
Morpholine (2b)
THF
THF
Dioxane 100
Dioxane 100
60
60
85
0
2:>98
—
2-DPPBA
2-DPPBA
2-DPPBA
2-DPPBA
2-DPPBA
2-DPPBA
PPh3
Et2NH (2c)
Et2NH (2c)
Bu2NH (2d)
Et3N
DABCO
K2CO3
DBU
DBU
DBU
DBU
73
72
79
90
75
0
2:>98
2:>98
2:>98
2:>98
2:>98
—
Heptamethyleneimine (2e) Dioxane 100
BuNHMe (2f)
CyNHMe (2g)
iPr2NH (2h)
Dioxane 100
Dioxane 100
Dioxane 100
Dioxane 100
Dioxane 100
Dioxane 100
Dioxane 100
Dioxane 100
DPPE
76
5:95
Cy2NH (2i)
0
—
MeNHTs (2j)
PhNHMe (2k)
p-AnNHMe (2l)
BuNH2 (2m)
70
37
50
<5
2:>98e
2:>98
2:>98
ND
a
Reaction conditions: 1a (0.33 mmol), 2a (0.50 mmol), Ru3(CO)12 (3.3 mol %), L
(10 mol % for 2-DPPBA and DPPE, 20 mol % for PPh3), base (0.66 mmol), THF
(0.7 mL), 60 °C, 12 h.
b
Isolated yield after purification by column chromatography.
c
a
The ratio was determined by 400 MHz 1H NMR analysis of crude materials.
Reaction conditions: 1a (1.0 mmol), 2b–m (2.0 mmol), Ru3(CO)12 (1.7 mol %), 2-
d
The ratio of E/Z isomers of 4a was determined to be 95:5 by 400 MHz 1H NMR
DPPBA (5 mol %), DBU (2.0 mmol) solvent (0.2 mL), 12 h.
b
analysis of crude materials.
Isolated yield after purification by column chromatography.
The reaction was stopped for 0.5 h, and the conversion of 1a was determined to
The ratio of 3/4 was determined by 400 MHz 1H NMR analysis of crude
e
c
be 61%.
materials.
d
The ratio of E/Z isomers of 4 was determined to be >95:5 by 400 MHz 1H NMR
analysis of crude materials unless otherwise noted.
e
The ratio of E/Z isomers of 4j was determined to be 60:40 by 400 MHz 1H NMR
as a single regioisomer. We also confirmed that the use of 2-DPPBA
is important for attaining this highly linear selective allylic amina-
tion in high yield (95%). For example, the reaction using PPh3 re-
sulted in no reaction (entry 7). Another phosphine ligand, DPPE,
catalyzed the amination reaction, but the yield was lower (76%)
and a detectable amount of the branch-type product was also
formed (entry 8). As we mentioned above, it is well known that
many palladium catalysts perform the linear selective allylic ami-
nation. However, some palladium catalysts form detectable
amount of branch-type product.9 On the other hand, the
Ru3(CO)12/2-DPPBA catalyst exhibited the perfect linear selectivity
and gave 4a as a single regioisomer.
analysis of crude materials.
R
R'
N
1.7 mol% Ru3(CO)12
5 mol% 2-DPPBA
Ph
R
R'
N
3b-m (branch)
+
OAc
Ph
H
DBU, dioxane
R
1b
2a-m
Ph
N
R'
4b-m (linear)
Based on the initial results, we examined the allylic amination
of 1a with several amines (Scheme 2). The reaction with morpho-
line (2b) gave the same result as that with 2a (Table 2, entry 1), but
the reaction with diethylamine (2c) did not occur at 60 °C in THF
(entry 2). We then reinvestigated the reaction conditions, and
found that the desired linear selective reaction proceeded at
100 °C in dioxane (entry 3). The reaction with other secondary al-
kyl amines 2d–g also gave linear-type allylic amines as the major
regioisomer (entries 4–7). However, this catalytic reaction is very
sensitive to the steric factor of the amines, and the reaction with
2h and 2i did not form any aminated products (entries 8 and 9).
The reaction with N-methylaniline (2k) and 4-methoxy-N-methy-
laniline (2l) also gave a linear-type product selectively, but the
reactions were slightly slow (entries 11 and 12). Unfortunately,
only a trace amount of the aminated product was formed in the
reaction with the primary amines 2m (entry 13).10,11 Furthermore,
we demonstrated the Ru3(CO)12/2-DPPBA-catalyzed allylic amina-
tion of cinnamyl acetate (1b), which is a regioisomer of 1a, with
several amines (Scheme 3). As we expected, the acetate 1b exhib-
ited a similar reactivity with the same linear selectivity as obtained
for the reaction of 1a. For example, the reaction of 1b with second-
ary alkyl amines 2a–g proceeded with excellent regioselectivity in
Scheme 3.
moderate to good yield (Table 3, entries 1–7), but the reaction with
sterically hindered amines 2h and 2j did not produce any aminated
products (entries 8 and 9). Again, the reaction with 2j–l gave
linear-type products as a single regioisomer (entries 10–12), but
that with a primary amine did not form desired aminated product
(entry 13).10,11 These results suggest that both the reaction of
Table 3
Ru3(CO)12/2-DPPBA catalyzed allylic amination of 1b with amines 3a–ma
Entry
Amine 2
Temp. (°C)
Yieldb (%)
3:4c,d
1
2
3
4
5
6
7
8
9
10
11
12
13
Piperidine (2a)
Morpholine (2b)
Et2NH (2c)
60
60
95
90
68
87
84
74
84
0
2:>98
2:>98
2:>98
2:>98
2:>98
2:>98
2:>98
—
100
100
100
100
100
100
100
100
100
100
100
Bu2NH (2d)
Heptamethyleneimine (2e)
BuNHMe (2f)
CyNHMe (2g)
iPr2NH (2h)
Cy2NH (2i)
MeNHTs (2j)
PhNHMe (2k)
p-AnNHMe (2l)
BuNH2 (2m)
0
—
62
37
67
<5
2:>98e
2:>98
2:>98
ND
R
R'
N
a
1.7 mol% Ru3(CO)12
5 mol% 2-DPPBA
Reaction conditions: 1b (1.0 mmol), 2a–m (2.0 mmol), Ru3(CO)12 (1.7 mol %), 2-
Ph
OAc
R
R'
DPPBA (5 mol %), DBU (2.0 mmol) dioxane (0.2 mL), 12 h.
N
3b-m (branch)
+
b
Isolated yield after purification by column chromatography.
H
DBU, solvent
Ph
c
R
The ratio of 3/4 was determined by 400 MHz 1H NMR analysis of crude
1a
2b-m
Ph
N
materials.
d
The ratio of E/Z isomers of 4 was determined to be >95:5 by 400 MHz 1H NMR
R'
analysis of crude materials unless otherwise noted.
4b-m (linear)
e
The ratio of E/Z isomers of 4j was determined to be 60:40 by 400 MHz 1H NMR
analysis of crude materials.
Scheme 2.

M. Kawatsura et al. / Tetrahedron Letters 49 (2008) 4873–4875
4875
(>98%).13,14 This result is in good agreement with the catalytic
reactions, and also supports the fact that the Ru3(CO)12/2-DPPBA
catalyst selectively forms linear-type allylic amines.
3.3 mol% Ru3(CO)12
10 mol% 2-DPPBA
N
+
3a
Ph
N
DBU, THF, 60 ºC
Ph
In conclusion, we demonstrated the Ru3(CO)12/2-DPPBA-cata-
lyzed linear selective allylic amination of monosubstituted allylic
acetates with secondary amines. The regioselectivity was highly
controlled by the Ru3(CO)12/2-DPPBA catalyst, and a linear-type
aminated product was obtained.
4a
3a
Scheme 4.
Table 4
Acknowledgements
Ruthenium-catalyzed isomerization of 3a to 4aa
This work was partially supported by a Grant-in-Aid for Scien-
tific Research from the Ministry of Education, Culture, Sports, Sci-
ence and Technology, Japan.
Entry
Time (h)
3a:4ab
1
2
3
4
12
24
53
89
97:3
83:17
58:42
51:49
References and notes
a
Reaction conditions: 3a (1.0 mmol), DBU (2.0 mmol), THF (0.2 mL).
b
The ratio was determined by 400 MHz 1H NMR analysis of crude materials.
1. (a) Jørgensen, K. A. In Modern Amination Methods; Ricci, A., Ed.; Wiley-VCH:
Weinheim, 2000. Chapter 1, pp 1–35; (b) Johannsen, M.; Jørgensen, K. A. Chem.
Rev. 1998, 98, 1689–1708.
2. Selected examples of transition metal catalyzed allylic aminations of allylic
esters: for [Pd]: (a) Dubovyk, I.; Watson, I. D. G.; Yudin, A. K. J. Am. Chem. Soc
2007, 129, 14172–14173; (b) Johns, A. M.; Liu, Z.; Hartwig, J. F. Angew. Chem.,
Int. Ed 2007, 46, 7259–7261; (c) Faller, J. W.; Wilt, J. C. Org. Lett. 2005, 7, 633–
636 and references cited therein; For [Ir]: (d) Takeuchi, R.; Ue, Naoki; Tanabe,
K.; Yamashita, K.; Shiga, N. J. Am. Chem. Soc. 2001, 123, 9525–9534; (e) Ohmura,
T.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 15164–15165; (f) Leitner, A.;
Shekhar, S.; Pouy, M. J.; Hartwig, J. F. J. Am. Chem. Soc. 2005, 127, 15506–15514;
(g) Polet, D.; Alexakis, A.; Tissot-Croset, K.; Corminboeuf, C.; Ditrich, K. Chem.
Eur. J. 2006, 12, 3596–3609; (h) Weihofen, R.; Tverskoy, O.; Helmchen, G.
Angew. Chem., Int. Ed. 2006, 45, 5546–5549 and references cited therein; For
[Rh]: (i) Evans, P. A.; Robinson, J. E.; Nelson, J. D. J. Am. Chem. Soc. 1999, 121,
6761–6762; (j) Evans, P. A.; Robinson, J. E.; Nelson, J. D. J. Am. Chem. Soc. 1999,
121, 12214.
3. Examples of ruthenium-catalyzed allylic aminations of allylic esters: (a)
Morisaki, Y.; Kondo, T.; Mitsudo, T. Organometallics 1999, 18, 4742–4746; (b)
Matsushima, Y.; Onitsuka, K.; Kondo, T.; Mitsudo, T.; Takahashi, S. J. Am. Chem.
Soc. 2001, 123, 10405–10406; (c) Matsushima, Y.; Onitsuka, K.; Takahashi, S.
Organometallics 2004, 23, 3763–3765.
4. (a) Kondo, T.; Ono, H.; Satake, N.; Mitsudo, T.; Watanabe, Y. Organometallics
1995, 14, 1945–1953; (b) Kondo, T.; Mitsudo, T. Curr. Org. Chem. 2002, 6, 1163–
1179.
5. (a) Mbaye, M. D.; Demerseman, B.; Renaud, J.-L.; Toupet, L.; Bruneau, C. Angew.
Chem., Int. Ed. 2003, 42, 5066–5068; (b) Mbaye, M. D.; Demerseman, B.;
Renaud, J.-L.; Bruneau, C. J. Organomet. Chem 2005, 690, 2149–2158; (c) Renaud,
J.-L.; Demerseman, B.; Mbaye, M. D.; Bruneau, C. Curr. Org. Chem. 2006, 10,
115–133.
6. Fernández, I.; Hematschweiler, R.; Pregosin, P. S.; Albinati, A.; Rizzato, S.
Organometallics 2006, 25, 323–330.
7. Recently, regio- and enantio-selective allylic etherfication of mono-substituted
allyl compounds was reported, see: Onitsuka, K.; Okuda, H.; Sasai, H. Angew.
Chem., Int. Ed. 2008, 47, 1455–1457.
8. (a) Kawatsura, M.; Ata, F.; Wada, S.; Hayase, S.; Uno, H.; Itoh, T. Chem. Commun.
2007, 298–300; (b) Kawatsura, M.; Ata, F.; Hayase, S.; Itoh, T. Chem. Commun.
2007, 4283–4285.
9. For examples, see: (a) Felpin, F.-X.; Landais, Y. J. Org. Chem. 2005, 70, 6441–
6446; (b) Hierso, J.-C.; Fihri, A.; Amardeli, R.; Meunier, P.; Doucet, H.; Santelli,
M. Tetrahedron 2005, 61, 9759–9766; (c) Ooe, M.; Murata, M.; Takahama, A.;
Mizugaki, T.; Ebitani, K.; Kaneda, K. Chem. Lett. 2003, 32, 692–693; (d)
Feuerstein, M.; Laurenti, D.; Doucet, H.; Santelli, M. Tetrahedron Lett. 2001, 42,
2313–2315.
10. We confirmed that large amount of undesired 3-phenyl-1-propene (>50%) was
formed.
11. Zhang, S.-W.; Mitsudo, T.; Kondo, T.; Watanabe, Y. J. Organomet. Chem 1993,
450, 197–207.
Ph
+
Ph
N
+ 3a
60 ºC, THF
N
H
2a
Ru(II)(L)(CO)2
6 h
4a
5
100% conversion
90% isolated yield
(3a : 4a = 2 : >98)
(L = 2-DPPBA)
Scheme 5.
monosubstituted allyl acetates 1a and 1b proceeds through the
same
-allylruthenium intermediate.12
We next studied the reaction pathway of this linear selective
allylic amination by the Ru3(CO)12/2-DPPBA catalyst. As men-
tioned, the ruthenium-catalyzed isomerization of branched allylic
p
amines into their linear isomers is a known process in p-allylruthe-
nium chemistry.4–6 Based on this previous observation, we exam-
ined the isomerization of the branch-type allylic amine 3a into
the linear-type allylic amine 4a using the Ru3(CO)12/2-DPPBA cat-
alyst. Allylic amine 3a was treated with Ru3(CO)12 (3.3 mol %), 2-
DPPBA (10 mol %) and DBU (2.0 equiv) in THF at 60 °C. The ratio
of 3a and 4a was measured by the 1H NMR spectrum of the crude
materials. As shown in Scheme 4 and Table 4, a trace amount of the
linear-type allylic amine 4a was produced in 12 h (entry 1), and the
amount of 4a slowly increased (entries 2 and 3). However, the ratio
of 3a to 4a was 51:49 after 89 h, and the reaction had almost
stopped (entry 4). This result revealed that our ruthenium catalyst
systems also catalyze the isomerization reaction from 3a to 4a, but
it was slow.
We earlier reported the linear selective nucleophilic attack by
malonate anion on the
was generated from either the regioisomeric allyl acetates 1a or
1b using the Ru3(CO)12/2-DPPBA catalyst. Based on this previous
study, we anticipated that nitrogen nucleophiles also selectively
p
-allylruthenium intermediate 5,8a which
12. Phenyl group is necessary for this regioselectivity because the linear
selectivities in the reaction of methyl group substituted allyl acetate (3-
acetoxy-1-butene) with piperidine were 52% (60 °C, 12 h) and 51% (100 °C,
24 h).
attack the sterically less hindered
produce the linear-type aminated product. To prove this hypothe-
sis, we next examined the stoichiometric reaction of -allylruthe-
p-allyl terminus and directly
p
13. We also examined the same reaction for 1 h, then confirmed the 70%
conversion of the ruthenium complex 5 and the ratio of 3a/4a to be 2/>98 by
1H NMR analysis of crude materials.
14. The reaction of ruthenium complex 5 with primary amine 2m resulted in no
reaction, and recovered the complex 5.
nium complex 5 with 2a (Scheme 5). The complex 5 was treated
with 2a at 60 °C for 6 h, and we then confirmed by the 1H NMR
spectrum the 100% conversion (90% isolated yield after silica gel
column chromatography) and almost perfect linear selectivity