Ir-catalyzed asymmetric allylic amination using chiral diaminophosphine oxides

Article abstract of DOI:10.1016/j.tetlet.2006.10.003

An Ir-catalyzed asymmetric allylic amination using chiral diaminophosphine oxide is described. Asymmetric allylic amination of terminal allylic carbonates proceeded in the presence of 2 mol % of Ir catalyst, 2 mol % of chiral diaminophosphine oxide, 5 mol % of NaPF₆, and BSA, affording the chiral branched allylic amines in up to 95% ee.

Full text of DOI:10.1016/j.tetlet.2006.10.003

Tetrahedron Letters 47 (2006) 8737–8740
Ir-catalyzed asymmetric allylic amination using chiral
diaminophosphine oxides
Tetsuhiro Nemoto, Tatsurou Sakamoto, Takayoshi Matsumoto and Yasumasa Hamada*
Graduate School of Pharmaceutical Sciences, Chiba University, Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
Received 15 September 2006; revised 29 September 2006; accepted 2 October 2006
Available online 20 October 2006
Abstract—An Ir-catalyzed asymmetric allylic amination using chiral diaminophosphine oxide is described. Asymmetric allylic ami-
nation of terminal allylic carbonates proceeded in the presence of 2 mol % of Ir catalyst, 2 mol % of chiral diaminophosphine oxide,
5 mol % of NaPF6, and BSA, affording the chiral branched allylic amines in up to 95% ee.
Ó 2006 Elsevier Ltd. All rights reserved.
Considerable effort has been directed toward the cata-
lytic asymmetric synthesis of a-chiral amines, due to
the ubiquity of the chiral amine unit in biologically
OTMS
TMS
N
CH3
(BSA)
HN
HN
active compounds. Among the various approaches
N
N
H
O
reported to date,1
a
transition metal-catalyzed
P
P
N
N
OTMS
asymmetric allylic amination reaction is one of the most
powerful methods for the synthesis of chiral allylic
amines.2 Several reactions of this type using Pd,3 Ir,4
or other transition metal catalysts5 have been reported.
We recently reported Pd-catalyzed asymmetric allylic
alkylation6 and amination7 using aspartic acid-derived
P-chirogenic diaminophosphine oxides: DIAPHOXs.8,9
Detailed mechanistic studies on this catalyst system6b
revealed that chiral diaminophosphine oxide 1a is
activated by N,O-bis(trimethylsilyl)acetamide (BSA)-
induced tautomerization to afford trivalent phosphorus
compound 2a, which functions as the actual ligand
(Scheme 1). Phosphites and phosphoroamidites are
effective ligands in Ir-catalyzed allylic substitution reac-
tions of terminal allylic electrophiles to give branched
products.10,11 The diamidophosphite structure of 2a
led us to hypothesize that the present ligand system
could be extended to Ir-catalyzed asymmetric allylic
substitution reactions. We describe herein an Ir-cata-
lyzed asymmetric allylic amination using chiral diamino-
phosphine oxides.
H
H
O
TMS
N
CH3
1a
2a
H
Scheme 1. BSA-induced tautomerization of 1a to 2a.
We first examined asymmetric allylic amination of
cinnamyl carbonate 3a with benzylamine (Table 1). No
reaction occurred when 1 mol % of chloro(1,5-cyclo-
octadiene)iridium(I) dimer ([Ir(cod)Cl]2) and 4 mol %
of (S,RP)-1a (Ir:1a = 1:2) were used in CH2Cl2 at room
temperature (entry 1). In contrast, when 1 mol % of
[Ir(cod)Cl]2 and 2 mol % of (S,RP)-1a (Ir:1a = 1:1) were
used, branched product 4a was obtained in 63% ee, even
though the yield was only 10% (entry 2). In this reaction,
the formation of linear products 4a0 was not observed in
1H NMR analysis of the crude sample. Encouraged by
this result, we investigated the effect of various additives.
Both the reactivity and enantioselectivity were dramati-
cally affected by the counter anion of sodium salts
(entries 2–5), and the best reactivity was obtained when
hexafluorophosphate salt was used. Although there was
a slight decrease in the enantiomeric excess (59% ee),
branched product 4a was obtained in 99% yield using
5 mol % of NaPF6 (entry 7).12 We next attempted to
improve the enantioselectivity by tuning the structure
of the chiral diaminophosphine oxide (Table 2 and
Fig. 1). Detailed investigations into the ligand structure
Keywords: Asymmetric allylic amination; Asymmetric catalysis; Di-
aminophosphine oxide; Iridium.
*
Corresponding author. Tel./fax: +81 43 290 2987; e-mail: hamada@
p.chiba-u.ac.jp
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.10.003

8738
T. Nemoto et al. / Tetrahedron Letters 47 (2006) 8737–8740
Table 1. The effect of additive
[Ir(cod)Cl] (1 mol %)
2
NHBn
(
S,RP)-1a (Ir/1a = 1/ x)
BnNH (3 equiv), additive
OCOOMe
NHBn
2
BSA (3 equiv)
3a
(
S
)-4a
4a'
CH Cl (0.4 M), rt
2
2
(4a : 4a' = > 99 : 1)
Entry
x
Additive (mol %)
Time (h)
Yielda (%)
eeb (% ee)
1
2
3
4
5
6
7
8
2
1
1
1
1
1
1
1
—
—
22
22
22
22
7
7
7
12
No reaction
—
63
60
66
21
58
59
58
10
16
70
93
86
99
95
NaI (10)
NaBF4 (10)
NaBARF (10)c
NaPF6 (10)
NaPF6 (5)
NaPF6 (2)
a Isolated yield of 4a.
b Determined by HPLC analysis.
c BARF: tetrakis(3,5-bis-trifluoromethyl-phenyl)borate.
indicated that introduction of substituents onto the
aromatic rings attached to the nitrogen atoms tended
to improve the enantioselectivity. The best result was
obtained using chiral diaminophosphine oxide (S,RP)-
1h, which possessed a t-Bu substituent on the para-posi-
tion of the aromatic rings, and the enantiomeric excess
of 4a increased to 92% ee when the reaction was per-
formed at ꢀ20 °C (entry 11). On the other hand, when
the reaction was performed using (S,RP)-1i, a diamino-
phosphine oxide without a nitrogen atom on the side-
arm, there was no significant change in the
enantioselectivity compared with that obtained using
1a (entry 9). This result indicates that this series of di-
aminophosphine oxides coordinates to the Ir metal in
a monodentate manner through the phosphorus atom.
Having developed efficient conditions,13 we examined
the scope and limitation of different substrates (Table
3). When 2 mol % of Ir catalyst, 2 mol % of (S,RP)-1h,
and 5 mol % of NaPF6 were used, asymmetric allylic
amination of 3a with primary amines and an a-branched
primary amine proceeded at ꢀ20 °C to provide the
corresponding branched allylic amines in good yield
and in high enantioselectivity (entries 1–3). In contrast,
there was a decreased enantioselectivity when morpho-
line was used as a nucleophile. When 2 mol % of the
catalyst was used, asymmetric allylic amination 3a
proceeded at room temperature to give the correspond-
ing product with 65% ee (entry 4).14 Asymmetric allylic
amination of various terminal allylic carbonates was
also examined using benzylamine as the nucleophile.
Aromatic substituents with electron-donating and elec-
tron-withdrawing functionalities were tolerant to this
reaction, giving the products with good to high enantio-
selectivities (entries 5–12). Terminal allylic carbonates
with a naphthyl substituent (entries 13 and 14) or a het-
eroaromatic substituent (entry 15) were also applicable
to this reaction, affording the corresponding product
with good enantioselectivity. In addition, asymmetric
allylic amination of 5, a substrate with an alkyl substitu-
ent, was examined using 2 mol % of the catalyst, giving
the corresponding product 6 in 74% yield with 68% ee,
Table 2. Optimization of the structure of (S,RP)-DIAPHOX using
asymmetric allylic amination of 3a with benzylaminea
Entry
(S,RP)-
DIAPHOX
Tempb
(°C)
Time
(h)
Yieldc
(%)
eed
(% ee)
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
rt
rt
rt
rt
rt
rt
rt
rt
rt
4
ꢀ20
7
19
19
19
19
19
19
19
19
24
48
99
71
26
55
10
51
25
93
99
98
96
59
45
47
65
73
60
68
86
58
91
92
1g
1h
1i
10
11
1h
1h
a Reaction conditions: [Ir(cod)Cl]2 (1 mol %), (S,RP)-DIAPHOX
(2 mol %), NaPF6 (5 mol %), BSA (3 equiv), benzylamine (3 equiv),
CH2Cl2 (0.4 M).
b rt: room temperature.
c Isolated yield of 4a.
d Determined by HPLC analysis.
X
X
1a: X = H, Y = H, R = phenyl
Y
H
1b: X = H, Y = H, R = 1-naphthyl
1c: X = H, Y = H, R = 2-naphthyl
1d: X = H, Y = H, R = 4-biphenyl
Y
N
H
O
1i
HN
1e: X = CF , Y = H, R = phenyl
3
N
P
H
O
1f: X = OMe, Y = H, R = phenyl
1g: X = OMe, Y = OMe, R = phenyl
1h: X = t-Bu, Y = H, R = phenyl
N
P
H
N
Ph
R
Figure 1. Chiral diaminophosphine oxides: (S,RP)-DIAPHOXs.

T. Nemoto et al. / Tetrahedron Letters 47 (2006) 8737–8740
8739
Table 3. The substrate scope
[Ir(cod)Cl] (1 mol %)
2
(
S,RP)-1h (2 mol %)
1
2
1
2
NR R
BSA (3 equiv), HNR R (3 equiv)
NaPF (5 mol %)
6
R
OCOOMe
R
CH Cl (0.4 M), –20 °C
4a–o
3a–l
2
2
Entry
Substrate
Amine
Product Time (h)
Yielda (%)
Ratiob (branched/linear)
eec (% ee)
1
2
3
4d
5
6
7
8
9e
10
11
12
13e
14e
15
3a: R = phenyl
3a: R = phenyl
3a: R = phenyl
3a: R = phenyl
3b: R = 4-methoxyphenyl
3c: R = 4-fluorophenyl
3d: R = 4-chlorophenyl
3e: R = 4-(trifluoromethyl)-phenyl
3f: R = 3-methoxyphenyl
3g: R = 3-fluorophenyl
3h: R = 2-methoxyphenyl
3i: R = 2-fluorophenyl
3j: R = 1-naphthyl
Benzylamine
Frufurylamine
Isopropylamine
Morpholine
Benzylamine
Benzylamine
Benzylamine
Benzylamine
Benzylamine
Benzylamine
Benzylamine
Benzylamine
Benzylamine
Benzylamine
Benzylamine
4a
4b
4c
4d
4e
4f
48
48
60
24
24
36
48
96
60
48
48
36
60
60
36
96
95
98
96
99
99
99
90
97
92
97
99
98
97
94
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
92 (S)
94
92
65
91
92
94
94
88
95
93
88
87
87
88
4g
4h
4i
4j
4k
4l
4m
4n
4o
3k: R = 2-naphthyl
3l: R = 2-furanyl
a Isolated yield of the branched product.
b Determined by 1H NMR analysis of the crude sample.
c Determined by HPLC analysis.
d Reaction was performed at room temperature.
e Reactions were performed at ꢀ5 °C.
[Ir(cod)Cl] (1 mol %)
HN
Ph
Ph
Ph
N
N
Ph
Ph
2
Ph
OCOOMe
(
S,R )-1h (2 mol %)
P
Ph
Ph
BSA (3 equiv)
5
NaPF (5 mol %)
6
7 (8%)
6
+
CH Cl (0.4 M)
74%, 68% ee
2
2
benzylamine (3 eq)
–20 °C, 60 h
Ph
8 (5%)
Scheme 2. Asymmetric allylic amination of 5.
accompanied by 8% of linear–linear product 7 and 5%
of branched–linear product 8 (Scheme 2).
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2006.10.003.
In conclusion, we achieved the Ir-catalyzed asymmetric
allylic amination using chiral diaminophosphine oxides,
which was dramatically accelerated by the addition of
NaPF6. Using the Ir–DIAPHOX–NaPF6 catalyst sys-
tem, the reactions proceeded with excellent branched/
linear selectivity, affording the corresponding branched
allylic amines in up to 95% ee. Studies of application
to other nucleophiles, as well as mechanistic investiga-
tions into the catalyst system are in progress.
References and notes
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unknown, we speculate that, at the present stage, a
cationic iridium complex might be formed by the anion
exchange between hexafluorophosphate ion and a coordi-
nated species around the Ir metal, resulting in the
increased reactivity. Investigation of the mechanism is
ongoing.
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13. General procedure for the Ir-catalyzed asymmetric allylic
amination (Table 3, entry 1): To a stirred mixture of
[Ir(cod)Cl]2 (1.43 mg, 0.00213 mmol), (S,RP)-1h (2.15 mg,
0.00426 mmol), NaPF6 (1.79 mg, 0.0107 mmol), and 3a
(41.0 mg, 0.213 mmol) in CH2Cl2 at room temperature
was added BSA (152 lL, 0.639 mmol), and the solution
was stirred for 5 min at the same temperature. After the
reaction mixture was cooled down to ꢀ20 °C, benzylamine
(70 lL, 0.639 mmol) was added and the resulting mixture
was stirred for 48 h. The reaction mixture was concen-
trated under reduced pressure, and the obtained residue
was purified by flash column chromatography (SiO2,
hexane/ethyl acetate: 20/1) to give (S)-4a as yellow oil
(46.6 mg, 96%, 92% ee). The enantiomeric excess was
determined by HPLC analysis (DAICEL CHIRALCEL
OD-H, 2-propanol/hexane/diethylamine 0.25/99.74/0.01,
flow rate 0.5 mL/min, tR 15.1 min [(R)-isomer] and
17.4 min [(S)-isomer], detection at 254 nm).
7. Nemoto, T.; Masuda, T.; Akimoto, Y.; Fukuyama, T.;
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8. For other examples of transition-metal catalysis using
diaminophosphine oxides, see: (a) Ackermann, L.; Born,
R. Angew. Chem., Int. Ed. 2005, 44, 2444–2447; (b)
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9. For other examples of transition metal-catalyzed asym-
metric reactions using chiral phosphine oxides, see: (a)
Jiang, X.-B.; Minnaard, A. J.; Hessen, B.; Feringa, B. L.;
Duchateau, A. L. L.; Andrien, J. G. O.; Boogers, J. A. F.;
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14. There was no improvement in the enantioselectivity when
the reaction was performed at a lower temperature.