Palladacycle-catalyzed tandem allylic amination/allylation protocol for one-pot synthesis of 2-allylanilines from allylic alcohols

Article abstract of DOI:10.1002/adsc.201100424

An efficient methodology involving the predominant formation of C-C bonds is described for the first direct synthesis of 2-allylanilines from allylic alcohols via a one-pot tandem allylic amination/ allylation protocol catalyzed by a palladacycle under mild conditions without the requirement for additional activators.

Full text of DOI:10.1002/adsc.201100424

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DOI: 10.1002/adsc.201100424
Palladacycle-Catalyzed Tandem Allylic Amination/Allylation
Protocol for One-Pot Synthesis of 2-Allylanilines from Allylic
Alcohols
Ke Chen,a Yongxin Li,a Sumod A. Pullarkat,a,* and Pak-Hing Leunga,*
a
Division of Chemistry and Biological Chemistry, School of Physical & Mathematical Sciences, Nanyang Technological
University, Singapore 637371, Singapore
Fax : (+65)-6316-6984; phone: (+65)-6316-8906; e-mail: sumod@ntu.edu.sg or pakhing@ntu.edu.sg
Received: May 24, 2011; Revised: September 9, 2011; Published online: January 12, 2012
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201100424.
Abstract: An efficient methodology involving the
predominant formation of C C bonds is described
drawbacks of harsh reaction conditions, low yield or
limited substrate scope.[19] A few recent reports have
also appeared of microwave-assisted and heteropoly
acid (HPA)-catalyzed processes but these have dem-
ꢀ
for the first direct synthesis of 2-allylanilines from
allylic alcohols via a one-pot tandem allylic amina-
tion/allylation protocol catalyzed by a palladacycle
under mild conditions without the requirement for
additional activators.
onstrated limited substrate scope or low yields.[20]
A
one-pot procedure which combines the efficient allylic
amination of allylic alcohols and the subsequent ally-
lation of the N-allylaniline products which can be con-
ducted under mild conditions to provide a direct
access to 2-allylanilines with good regioselectivity and
high yield is therefore desirable. This attractive syn-
thetic methodology will avoid the formation of chemi-
cal waste in multistep synthesis and is atom economi-
cal.
Keywords: 2-allylanilines; allylation; allylic amina-
ꢀ
tion; C C bond formation; palladacycles
A “green” direct catalytic substitution of allylic alco-
Palladacycles have attracted much attention in the
hols with the inherent dual advantages of avoiding homogeneous catalysis of reactions such as cross-cou-
the formation of stoichiometric amounts of unwanted pling,[21] allylic amination,[22] allylic rearrangement[23]
chemical waste (in the synthesis of activated sub- and so on. We have previously explored the use of
strates and during amination) as well as the formation palladacycles for the asymmetric Claisen rearrange-
of water as the sole co-product has recently attracted ment reaction[24] and also investigated their potential
ꢀ
much attention from both environmental and eco- in C N bond formation scenarios such as hydroami-
nomical points of view.[1,2] However, due to the inert- nation.[25] We have also recently reported their effica-
[26]
ꢀ
ness of the hydroxy moiety in such scenarios, direct cy in C P bond formation reactions.
We report
substitutions of allylic alcohols typically require high here the catalytic properties of a simple cationic pal-
temperatures,[3] neat conditions,[4] or considerable ladacycle (Figure 1) which is readily derived from the
amounts of activators.[5–14] To date, there are several well known dimeric complex {[Pd[Me2NCH2C6H4]
ACHTUNGTRENNUNG(m-
reports on the transition metal-catalyzed allylic ami- Cl)}2.[27] This cationic complex is chemically stable
nation of allylic alcohols or allylic alcohol derivatives and is soluble in most organic solvents. Furthermore,
with arylamines leading to the predominant genera-
ꢀ
tion of N-allylanilines via C N bond forma-
tion.[1c,10b,15–17] Subsequent conversion of the N-allyl-
ACHTUNGTRENNUNGanilines themselves into 2-allylanilines is attractive
since the products obtained are starting materials for
the preperation of bicyclic nitrogen-containing hetero-
cycles through the cyclization of the nitrogen onto the
double bond.[18] However, the synthesis of 2-allylani-
lines via thermal, protic acid-promoted and charge-ac-
celerated rearrangments reported to date all have Figure 1. Structure of the palladacycle.
Adv. Synth. Catal. 2012, 354, 83 – 87
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Ke Chen et al.
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Table 1. Optimization of the reaction conditions.
Entry[a]
Solvent
Temperature [oC]
Time [h]
Yield[b] [%]
Product ratio[c]
1
2
3
4
5
6
7
8
9
DCE
70
70
70
70
70
40
50
60
70
12
12
12
12
12
12
12
12
6
94
–
–
0:91:9
–
–
tolueue
dioxane
DMF
CH3CN
DCE
DCE
DCE
DCE
–
–
16
17
45
50
85
100:0:0
100:0:0
80:20:0
70:30:0
15:80:5
[a]
Unless otherwise indicated, all reactions were performed using substrate (0.5 mmol), amine (0.75 mmol), catalyst
(5 mol%).
Isolated yield of 3aa+4aa+5aa.
Product ratio of 3aa:4aa:5aa.
[b]
[c]
the distinct electronic directing influence originating amine substrate on the palladium centre. The elec-
from the strong p-accepting aromatic carbon and the tronic character of the arylamines seems to greatly in-
s-donating nitrogen donor are well established.[28] fluence the regioselectivity, while the reactivity to-
Such electronic properties would allow electronically wards allylic amination seems relatively unaffected.
different substrates to interact simultaneously with As shown in Table 2 , electron-donating groups at the
the palladium centre for coupling or addition reac- para position of anilines enhanced both reactivity and
tions. We herein present the application of this palla- selectivity in favour of the C-allylated products
dacycle as an efficient catalyst for the one-pot tandem (Table 2, entries 1–3), while the presence of a elec-
allylic amination/allylation protocol for the synthesis tron-withdrawing group such as nitro or carboxylate
of 2-allylanilines from allylic alcohols.
favoured the N-allylated products (Table 2, en-
Initially the catalyst was evaluated using 1,3-di- tries 12–14) and no C-allylated product was observed
phenyl-2-propen-1-ol (1a) and toluidine (2a) (Table 1, in such instances. This trend however seems to be dis-
entry 1) and 2-allylaniline was found to be the major rupted when a very strong electron-withdrawing
product of the reaction contrary to the usual predomi- group like trifluoromethyl (Table 2, entry 6) is in-
nance of the N-allylated product in similar catalytic volved. This observation can be attributed to the fact
scenarios. It needs to be noted that the allylic amina- that the lone pair of the amino group in this aniline
tion occurs without the need for any external activa- substrates is not able to interact with the Pd centre as
tor and even more significantly the subsequent allyla- compared to aniline substrates with weaker electron-
tion can occur at the relatively low temperature of withdrawing groups. The trend reversal also occurs in
708C. Encouraged by these results, we proceeded to the presence of a potentially coordinating group such
optimize the conditions and an evaluation of solvents as cyano (Table 2, entry 7) which competes with the
showed that the non-coordinating solvent DCE pro- amino group for coordination on the palladium.
vided the best results (Table 1, entry 1). It was also es-
When halogens (F, Cl) were introduced (with their
tablished that 708C was indeed the optimum tempera- electron-donation ability by conjugation and electron-
ture with lower temperatures giving poor yields withdrawing potential by induction) at the para posi-
(Table 1, entries 6–8). It is noteworthy that similar re- tion of aniline, the C-allylation products were still
activity and prꢀoduct selectivity were observed when preferred (Table 2, entries 4, 5, 10, 11). For para
TfOꢀ and ClO4 were used as counterions.
mono-substituted arylamines, monoallylation products
With the optimum conditions established, we pro- in which allylation occurred at the ortho position
ceeded to screen various arylamines and good to high were observed as the major product and the diallyla-
yields were achieved in all cases (Table 2). A key tion products in which substitution occurred simulta-
point in the catalyst design is that it allows the simul- neously at both the ortho positions were the minor
taneous interaction of the allylic alcohol and the ones. To avoid such an undesired diallylation, 2,4-di-
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Palladacycle-Catalyzed Tandem Allylic Amination/Allylation Protocol for One-Pot Synthesis of 2-Allylanilines
Table 2. Palladacycle-catalyzed tandem allylic amination/allylation reaction.
Entry[a]
Anilines
Yield[b] of 3 [%]
Yield[b] of 4 [%]
1
2
3
4
5
6
7
8
4-Me, 2a
–
–
–
–
–
–
–
–
–
–
–
96
95
85
85
86
89
85
88
83
90
95
93
90
88
–
4-OMe, 2b
4-OPh, 2c
4-F, 2d
4-Cl, 2e
4-CF3, 2f
4-CN, 2g
2,4-di-Me, 2h
2,4-di-OMe, 2i
2,4-di-F, 2j
2,4-di-Cl, 2k
4-NO2, 2l
4-CO2Me, 2m
4-CO2H, 2n
9
10
11
12
13
14
–
–
[a]
Unless otherwise indicated, all reactions were performed at 708C using allylic alcohol (0.5 mmol), amine (0.75 mmol),
catalyst (5 mol%) in 1,2-dichloroethane (3 mL) for 12 h.
Isolated yield.
[b]
Table 3. Palladacycle-catalyzed tandem allylic amination/allylation reaction of various alcohols.
Entry[a]
1[c]
Alcohol
Anilines
Yield[b] of 4 [%]
Yield[b] of 6 [%]
1b
1b
2a
2b
80
75
92
–
–
2[c]
3[c]
4
1b
1c
1d
1e
1f
2h
2h
2h
2h
2h
–
78
75
72
–
5
6
7[c,d]
70
[a]
Unless otherwise indicated, all reactions were performed at 708C using allylic alcohol (0.5 mmol), amine (0.75 mmol),
catalyst (5 mol%) in 1,2-dichloroethane (3 mL) for 12 h.
Isolated yield.
Reactions were performed at 908C.
For 24 h.
[b]
[c]
[d]
Adv. Synth. Catal. 2012, 354, 83 – 87
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Ke Chen et al.
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Scheme 1. Proposed reaction pathway for the palladium-catalyzed tandem allylic amination/allylation reaction.
ACHTUNGTRENNUNGsubstituted arylamines were also screened as reactants dichloroethene (3 mL). The resultant reaction mixture was
stirred at 708C for 12 h. On completion, the reaction mix-
ture was concentrated under reduced pressure and the resul-
tant residue was directly purified by flash column chroma-
tography on silica gel (EtOAc/n-hexane: 1/50!1/15) to give
2-allylaniline 4aa in 85% yield.
and the results showed that only the corresponding
monoallylation products were formed and higher
yields were obtained as expected (Table 2, entries 8–
11).
Various aromatic amines were employed under op-
timized conditions providing the 2-allylanilines in
good to high yields (70–95%) (Table 2). Reactions in-
volving relatively less activated allylic alcohol sub-
strates 1b, 1d and 1f needed higher temperature
(908C) in order to obtain good yields. Excellent regio-
selectivities were observed when substituted anilines
were employed in the tandem one-pot allylic amina-
tion/allylation of other allylic alcohols 1b–f (Table 3)
with 4 or 6 being formed as the major products. This
reaction favours the less sterically hindered products.
To obtain insights into the reaction mechanism, a
closely monitored experiment was conducted with 1a/
1b in the presence of catalyst (5 mol%) (Scheme 1).
The results indicated the gradual formation of the N-
allylated product 3ah/3bh along with the formation of
an intermediate di(1,3-diphenyl-2-propenyl) ether 7a/
di(1-methyl-3-phenyl-2-propenyl) ether 7b at the
early stage of the reaction. These results revealed that
the formation of 3ah/3bh may proceed via two path-
ways as shown in Scheme 1: namely, a direct allylic
amination with 1a/1b and an allylation via the inter-
mediate 7a/7b. Subsequently, 3ah/3bh underwent the
allylation reaction to give the 2-allylaniline 4ah/4bh.
In summary, we have developed a one-pot pallada-
cycle-catalyzed tandem allylic amination/allylation of
allylic alcohols that provides direct access to hithero
unaccessible 2-allylanilines in high yields and under
mild conditions with water being the only by-product
and without any activator. We have also proposed a
reaction pathway for this catalyzed tandem reaction
protocol.
Acknowledgements
We thank Nanyang Technological University for support of
this research and a Ph.D. scholarship to K.C.
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