Palladium-catalyzed direct amination of allylic alcohols at room temperature

Article abstract of DOI:10.1055/s-0034-1379249

A palladium complex ligated with Xantphos has beenz identified as an efficient catalyst for the catalytic amination of allylic alcohols, which allows the direct amination of allylic alcohols with amines to proceed at room temperature in the absence of additives. The method is compatible with a variety of functional groups and can be used to prepare a wide range of linear allylic amines in good to excellent yields with high stereoselectivities.

Full text of DOI:10.1055/s-0034-1379249

LETTER
▌2781
letter
Palladium-Catalyzed Direct Amination of Allylic Alcohols at Room
Temperature
Direct Amination of Allylic Alcohols
Maorong Wang, Yinjun Xie, Jiawen Li, Hanmin Huang*
State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences,
Lanzhou 730000, P. R. of China
Fax +86(931)4968129; E-mail: hmhuang@licp.cas.cn
Received: 28.07.2014; Accepted after revision: 15.09.2014
Therefore, further development of an efficient catalytic
Abstract: A palladium complex ligated with Xantphos has been
system that could enable the direct amination of allylic al-
identified as an efficient catalyst for the catalytic amination of allyl-
cohols to be conducted in the absence of additives under
mild conditions would be highly desired. Herein we de-
ic alcohols, which allows the direct amination of allylic alcohols
with amines to proceed at room temperature in the absence of addi-
tives. The method is compatible with a variety of functional groups scribe an efficient palladium catalytic system for the di-
and can be used to prepare a wide range of linear allylic amines in
good to excellent yields with high stereoselectivities.
rect amination of allylic alcohols in the absence of
additives at room temperature, which provides an efficient
Key words: palladium, amination, allylic alcohols, room tempera-
ture, additive-free
protocol for the synthesis of allylic amines with high regio-
selectivity.
On the basis of our previous success on the synthesis of al-
lylamines by using Pd(Xantphos)(MeCN)2(OTf)2 as cata-
lyst,7 we initially chose 1-phenylprop-2-en-1-ol (1a) and
dibenzylamine (2a) as model substrates, Pd(Xant-
phos)(MeCN)2(OTf)2 as a catalyst precursor, and 2-PrOH
as solvent to attempt the amination reaction. After the re-
action mixture was stirred at room temperature for 12
hours, 85% yield of the desired product 3aa was isolated,
and only linear allylic amine was observed (Table 1, entry
1). Other cationic palladium complexes such as
Allylic amines are highly important compounds which
have intrigued chemists due to their unique usage and
wide existence in natural products, pharmaceuticals, and
other synthetics.1 Among many types of synthetic meth-
ods available for constructing the allylamine scaffold,2 the
transition-metal-catalyzed amination of allylic alcohols3–6
has proven to be one of the most efficient approach for the
synthesis of allylic amines, due to the high atom economy
(water was produced as the only by-product) and step
economy. As such, several catalytic protocols, such as
palladium-3–5 and platinum-catalyzed6 direct amination of
allylic alcohols have been successfully developed
(Scheme 1), however, most of them suffer from some dis-
advantages such as the use of Lewis acids or carboxylic
acids as additives to increase the leaving aptitude of the
hydroxyl group, the use of special ligands and high tem-
perature.3–6
Pd(Xantphos)(MeCN)2(BF4)2
and
Pd(Xant-
phos)(MeCN)2(TFA)2 could also catalyze this amination
reaction and gave 3aa in 82% and 85% yields, respective-
ly (Table 1, entries 2 and 3).
When neutral Pd(Xantphos)Cl2 was used as a catalyst, a
better result was gained (Table 1, entry 4). Other neutral
palladium complexes with different phosphine ligands
were also investigated. When Pd(DPEphos)Cl2 was cho-
a) previous work
A
OH
R2
A: Lewis acids or Brønsted acids
b) this work
OH
NR3
OH
R32NH
2
[Pd]
[Pd]
A
R1
R2
R1
R1
R2
R1
R2
NR3
R32NH
r.t.
2
[Pd]
Pd(Xantphos)Cl2
r.t.
R1
R2
R1
R2
R1
R2
additive-free, room temperature
Scheme 1 Palladium-catalyzed amination of allylic alcohols
SYNLETT 2014, 25, 2781–2786
Advanced online publication: 16.10.2014
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0034-1379249; Art ID: st-2014-w0635-l
© Georg Thieme Verlag Stuttgart · New York

2782
M. Wang et al.
LETTER
Table 1 Optimization of the Reaction Conditionsa
could also be used to prepare the corresponding product
3aa in 90% yield (Table 2, entry 3). The sterically hin-
dered allylic alcohols 1d and 1e could also react with 2a
under the standard conditions, giving the corresponding
amination products 3da and 3ea with 51% and 38%
yields, respectively (Table 2, entries 4 and 5). The lower
yields of these amination products were possibly due to
the steric effect of the substituents, which restricted the
nucleophilic attack of amine to the η3-allylpalladium in-
OH
Bn
Bn
catalyst
N
+
HN
Bn
solvent, r.t., 12 h
Bn
2a
1a
3aa
Entry [Pd] (5 mol%)
Solvent
Yield (%)b
1
2
Pd(Xantphos)(MeCN)2(OTf)2
Pd(Xantphos)(MeCN)2(BF4)2
Pd(Xantphos)(MeCN)2(TFA)2
Pd(Xantphos)Cl2
Pd(DPEphos)Cl2
2-PrOH
2-PrOH
2-PrOH
2-PrOH
2-PrOH
2-PrOH
2-PrOH
2-PrOH
2-PrOH
MeOH
EtOH
85
82
85
91
89
0
Table 2 Allylic Amination of Allylic Alcohols with 2aa
3
OH
R3
Bn
Bn
Pd(Xantphos)Cl2
2-PrOH, r.t., 12 h
Bn
4
HN
+
R1
R3
R1
N
5
R2
R2
Bn
1
2a
3
6
Pd(DPPE)Cl2
Entry Substrate
Product
Yield (%)b
91
7
Pd(DPPP)Cl2
0
Bn
8
Pd(DPPF)Cl2
0
OH
Ph
N
1
Bn
9
Pd(PPh3)2Cl2
0
Ph
1a
10
11
12
13
14
15
Pd(Xantphos)Cl2
Pd(Xantphos)Cl2
Pd(Xantphos)Cl2
Pd(Xantphos)Cl2
Pd(Xantphos)Cl2
86
81
25
0
3aa
OH
Bn
N
CH2Cl2
MeCN
THF
Bn
2
78
3ba
1b
0
Bn
Bn
Bn
Ph
N
Ph
OH
Pd(Xantphos)Cl2
2-PrOH
trace
3c
90
51
Bn
t-BuOK (10 mol%)
1c
3aa
Ph
16
–
2-PrOH
0
OH
a Reaction conditions: 1a (0.4 mmol), 2a (0.6 mmol), [Pd] (0.02
mmol), solvent (1.5 mL), r.t., 12 h.
b Isolated yield.
N
4d
Ph
Bn
1d
3da
Ph
OH
sen as catalyst, the reaction could conduct well and gave
the amination product in 89% yield (Table 1, entry 5).
However, the reaction could not take place, when
Ph
N
5
38
Ph
Ph
Bn
1e
3ea
Pd(DPPE)Cl2,
Pd(DPPP)Cl2,
Pd(DPPF)Cl2
and
Bn
Pd(PPh3)2Cl2 were utilized as catalyst precursors (Table 1,
entries 6–9). After screening the catalysts,
Pd(Xantphos)Cl2 was chosen as the most effective cata-
lyst to examine the influence of solvents. As a result, the
reaction could also be promoted smoothly in MeOH and
EtOH (Table 1, entries 10 and 11), while the reaction
could not take place in acetonitrile and THF (Table 1, en-
tries 13 and 14). A control experiment indicated that the
reaction was inhibited when 10 mol% of t-BuOK was
added (Table 1, entry 15). The amination of allylic alcohol
could not take place in the absence of palladium catalyst
(Table 1, entry 16).
N
OH
6
7
8
83
34
Bn
1f
3fa
Bn
OH
N
Bn
1g
3ga
Bn
OH
n-Bu
N
89 (E/Z =
14:86)
n-Bu
Bn
1h
3ha
a Reaction conditions: Allylic alcohol 1 (0.4 mmol), dibenzylamine
(2a; 0.6 mmol) and Pd(Xantphos)Cl2 (0.02 mmol) in 2-PrOH under
nitrogen atmosphere at r.t. for 12 h, unless otherwise noted.
b Isolated yield.
With the optimized conditions in hand, the scopes of allyl-
ic alcohols were first investigated.7 When the 4-position
of the phenyl ring of 1-phenylprop-2-en-1-ol was substi-
tuted by a methyl group, 78% yield of amination product
3ba was obtained (Table 2, entry 2). Cinnamonic alcohol
c Reaction was carried out for 19 h.
d Amount of Pd(Xantphos)(MeCN)2(OTf)2 used was 0.02 mmol.
Synlett 2014, 25, 2781–2786
© Georg Thieme Verlag Stuttgart · New York

LETTER
Direct Amination of Allylic Alcohols
2783
termediates. The amination of simple allylic alcohols with the present conditions, only 34% yield of product 3ga was
alkyl groups could also be promoted by Pd(Xantphos)Cl2 obtained when 2-methylprop-2-en-1-ol (1g) was used as
and generate the corresponding allylamines in good to ex- coupling partner.
cellent yields (Table 2, entries 6 and 8). However, under
Table 3 Allylic Amination of 1-Phenylprop-2-en-1-ol (1a) with Aminesa
OH
R2
R1
Pd(Xantphos)Cl2
2-PrOH, r.t., 12 h
R1
N
HN
+
R2
1a
2
3
Entry
Amine
Product
Yield (%)
N
N
H
1
76
2b
3ab
3ac
OH
N
H
N
2
3
93
88
OH
2c
MeO
N
H
N
N
N
OMe
2d
3ad
3ae
3af
Cl
Cl
N
H
4b
89
27
Cl
Cl
2e
N
H
5
Br
Br
2f
N
H
N
6
94
2g
3ag
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 2781–2786

2784
M. Wang et al.
LETTER
Table 3 Allylic Amination of 1-Phenylprop-2-en-1-ol (1a) with Aminesa (continued)
OH
R2
R1
Pd(Xantphos)Cl2
2-PrOH, r.t., 12 h
R1
N
HN
+
R2
1a
2
3
Entry
Amine
Product
Yield (%)
O
N
N
H
O
7
61
2h
3ah
N
H
N
8
85
N
N
2i
3ai
3aj
N
N
O
O
NH
N
9
69
95
2j
Ph
Ph
Ph
Ph
N
HN
10b
2k
3ak
3al
NH2
N
H
11
12
75
72
2l
OMe
NH2
N
H
MeO
2m
3am
a Reaction conditions: 1-phenylprop-2-en-1-ol (1a; 0.4 mmol), amine 2 (0.6 mmol) and Pd(Xantphos)Cl2 (0.02 mmol) in 2-PrOH under nitrogen
atmosphere at r.t. for 12 h, isolated yield, unless otherwise noted.
b Amount of Pd(Xantphos)(MeCN)2(OTf)2 used was 0.02 mmol.
In order to further expand the substrate scope, different expedient synthesis of complex allylic amines. Other typ-
amines were then introduced to the palladium-catalyzed ical amines such as bis(naphthalen-1-ylmethyl)amine, N-
reaction system. As shown in Table 3, a wide range of benzyl-1-(furan-2-yl)methanamine and N-benzyl-1-(pyri-
dibenzylamines were transformed to the corresponding din-3-yl)methanamine were also compatible with this re-
linear allylic amines with high regioselectivity and stere- action, and generated the corresponding products in good
oselectivity efficiently. For example, dibenzylamines sub- to excellent yields (Table 3, 3ag, 3ah and 3ai). To our de-
stituted with electron-donating or electron-withdrawing light, this new protocol could be applied for the rapid syn-
groups, such as hydroxyl, methoxy, chloro and bromo, at thesis of cinnarizine (3ak) in 95% yield, which is a
the phenyl ring furnished the amination products in good commercial antihistamine pharmaceutical. Primary aro-
yields (Table 3, 3ab, 3ac, 3ad and 3ae). It is worth noting matic amines could also be used as nucleophiles, giving
that the tolerance of the hydroxyl group and the halogens the corresponding secondary allylamines in good yields
on the aromatic ring in this transformation offers an op- (3al and 3am). However, heteroaromatic amines (such as
portunity for subsequent cross-coupling, which facilitates imidazole and pyrazole) as well as amines with large ste-
Synlett 2014, 25, 2781–2786
© Georg Thieme Verlag Stuttgart · New York

LETTER
Direct Amination of Allylic Alcohols
2785
rically hindering groups (such as i-Pr2NH and dicyclohex- with a broad range of allylic alcohols and amines was in-
ylamine) were not suitable for the present reaction.
vestigated, affording the corresponding allylamines in
good to excellent yields with high stereoselectivities.
Moreover, this method could be utilized to synthesize the
antihistamine pharmaceutical cinnarizine.
To gain insight into the mechanism, some control experi-
ments were carried out. When using 1a or 1c as starting
material, the same linear product 3aa was observed. This
result suggested that the amination may proceed via a
Tsuji–Trost-type reaction mechanism.8 Furthermore, a
stoichiometric reaction of 1a with Pd(Xantphos)Cl2 was
conducted under the standard conditions. After 30 min-
utes, a η3-allylpalladium complex was clearly detected by
HRMS (ESI) analysis (Scheme 2). This result indicated
that a η3-allylpalladium species might be the intermediate
of this process.
Acknowledgment
This research was supported by the Chinese Academy of Sciences
and the National Natural Science Foundation of China (21222203,
21172226 and 21133011).
Supporting Information for this article is available online
at
http://www.thieme-connect.com/products/ejournals/journal/
10.1055/s-00000083.SunogIpimrfiantoSuIpg
n
fonirtat
ori
References and Notes
OH
2-PrOH
O
+
Pd(Xantphos)Cl2
(1) (a) Towse, G. J. Laryngol. Otol. 1980, 94, 1009. (b) Shupak,
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Chem. Rev. 1998, 98, 1689.
Ph
Ph2P
Ph
PPh2
r.t., 30 min
Pd
1a
Cl
A
calcd. m/z for [A-Cl]: 801.1679
found: m/z = 801.1686
(2) For selected reviews on the synthesis of allylic amines, see:
(a) Cheik, R. B.; Chaabouni, R.; Laurent, A.; Mison, P.;
Nafti, A. Synthesis 1983, 685. (b) Overman, L. E.;
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Scheme 2 Stoichiometric reaction between 1a and catalyst
On the basis of the results and previous reports,8,9 a tenta-
tive mechanism of palladium-catalyzed amination of al-
lylic alcohol has been exemplified in Scheme 3. Initially,
an active Pd(0) species together with a catalytic amount of
acid are generated when the Pd(II) precatalyst is reduced
by 2-PrOH.6c Subsequent oxidative addition of allylic al-
cohol 1 to the Pd(0) species would take place via cleavage
of the C–O bond facilitated by the acid, giving the key
η3-allylpalladium species A. Finally, the electrophilic
Pd(II) species A is attacked by amine 2 to deliver the final
product and regenerate the active catalyst species.
In summary, we have identified that Pd(Xantphos)Cl2 is
an efficient catalyst for the direct amination of allylic al-
cohols. The reaction was promoted smoothly at room tem-
perature in the absence of additives. The substrate scope
(4) For palladium-catalyzed amination of allylic alcohol with
additive, see: (a) Yang, S.-C.; Hung, C.-W. J. Org. Chem.
1999, 64, 5000. (b) Kimura, M.; Futamata, M.; Shibata, K.;
Tamaru, Y. Chem. Commun. 2003, 234. (c) Qin, H.;
PdX2
2-PrOH
HX
X–
HX
OH
acetone
+OH2
Pd(0)
HX
+
NR2
Ph
Ph
Ph
1
3
X–
Pd
H2O
R2NH
Ph
ligand was omitted for clarity
A
2
Scheme 3 Proposed mechanism of allylic amination
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 2781–2786

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M. Wang et al.
LETTER
Yamagiwa, M.; Matsunaga, S.; Shibasaki, M. Angew. Chem.
Int. Ed. 2007, 46, 409. (d) Nishikata, T.; Lipshutz, B. H.
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Bhanage, B. M. Catal. Sci. Technol. 2012, 2, 835.
After the mixture was concentrated under reduced pressure,
the residue was purified by flash column chromatography on
silica gel and eluted with EtOAc–PE (1:100 to 1:1) to afford
the desired product 3.
Selected spectral data:
Compound 3aa: 1H NMR (400 MHz, CDCl3): δ = 7.07–
7.31 (m, 15 H), 6.41 (d, J = 16.0 Hz, 1 H), 6.17–6.24 (m, 1
H), 3.53 (s, 4 H), 3.12 (d, J = 5.6 Hz, 2 H). 13C NMR (100
MHz, CDCl3): δ = 138.6, 136.1, 131.4, 127.7, 127.5, 127.2,
126.7, 126.2, 125.8, 125.2, 56.9, 54.7. HRMS (ESI): m/z [M
+ H] calcd for C23H24N: 314.1903; found: 314.1909.
Compound 3ad: 1H NMR (400 MHz, CDCl3): δ = 7.56 (d,
J = 6.8 Hz, 1 H), 7.13–7.42 (m, 11 H), 6.94–6.97 (m, 1 H),
6.80 (d, J = 7.6 Hz, 1 H), 6.52 (d, J = 16.0 Hz, 1 H), 6.29–
6.36 (m, 1 H), 3.76 (s, 3 H), 3.66–3.68 (m, 4 H), 3.25 (d, J =
6.4 Hz, 2 H). 13C NMR (100 MHz, CDCl3): δ = 157.7, 140.0,
137.4, 132.3, 129.9, 128.9, 128.6, 128.3, 127.9, 127.8,
127.4, 126.9, 126.4, 120.6, 110.3, 58.4, 56.3, 55.4, 51.5.
HRMS (ESI): m/z [M + H] calcd for C24H26N: 344.2009;
found: 344.2004.
(5) For palladium-catalyzed amination of allylic alcohol without
additive at high temperature, see: (a) Defieber, C.; Ariger,
M. A.; Moriel, P.; Carreira, E. M. Angew. Chem. Int. Ed.
2007, 46, 3139. (b) Mora, G.; Deschamps, B.; van Zutphen,
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Qu, J. Org. Lett. 2010, 12, 2726. (d) Ghosh, R.; Sarkar, A.
J. Org. Chem. 2011, 76, 8508.
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Miyamoto, Y.; Ipposhi, J.; Ohshima, T.; Mashima, K. Org.
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Angew. Chem. Int. Ed. 2012, 51, 150. (d) Ohshima, T.;
Mashima, K. J. Synth. Org. Chem., Jpn. 2012, 70, 1145.
(7) General Procedure for Amination of Allylic Alcohols:
Allylic alcohols 1 (0.4 mmol), Pd(Xantphos)Cl2 (0.02 mmol,
5 mol%), amines 2 (0.6 mmol) and 2-PrOH (1.5 mL) were
added to a 25-mL flame-dried Young-type tube under a
nitrogen atmosphere. The mixture was stirred at r.t. for 12 h.
(8) (a) Tsuji, J.; Takahashi, H.; Morikawa, M. Tetrahedron Lett.
1965, 4387. (b) Trost, B. M.; Fullerton, T. J. J. Am. Chem.
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Reagents and Catalysts; Wiley: New York, 2000.
(e) Godleski, S. A. In Comprehensive Organic Synthesis;
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York, 1991, 585.
(9) Xie, Y.; Hu, J.; Wang, Y.; Xia, C.; Huang, H. J. Am. Chem.
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Synlett 2014, 25, 2781–2786
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