Gold-catalyzed direct amination of allylic alcohols

Article abstract of DOI:10.1055/s-2007-973865

An efficient and direct synthesis of allylic amines from allylic alcohols was developed by utilization of gold complexes as catalysts under mild reaction conditions. AuCl₃ proved to be a better catalyst than a cationic gold(I) complex of AuCl(PPh₃)/AgOTf. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-973865

964
LETTER
Gold-Catalyzed Direct Amination of Allylic Alcohols
G
old-Catalyze
h
d Direct
A
m
e
ination of
A
n
llylic
A
lcoh
g
ols hai Guo, Feijie Song, Yuanhong Liu*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Lu, Shanghai 200032, P. R. of China
E-mail: yhliu@mail.sioc.ac.cn
Received 14 December 2006
processes20 and zirconium-mediated allylic alcohol for-
mation reactions,21,22 we found that gold could efficiently
catalyze nucleophilic substitutions of allylic alcohols.
Herein, we would like to report gold-catalyzed23,24 direct
amination of allylic alcohols, which offers a straightfor-
ward route to substituted allylic amines.
Abstract: An efficient and direct synthesis of allylic amines from
allylic alcohols was developed by utilization of gold complexes as
catalysts under mild reaction conditions. AuCl3 proved to be a better
catalyst than a cationic gold(I) complex of AuCl(PPh3)/AgOTf.
Key words: gold catalysis, allylic alcohols, amination, nucleo-
philic substitution, synthetic methods
We began our investigation with the reaction of 1,3-
diphenylprop-2-en-1-ol (1a) and p-toluenesulfonamide
(Scheme 1). Treatment of a mixture of 1a and two equiv-
alents of TsNH2 with 2 mol% AuCl3 in anhydrous MeCN
afforded the corresponding allyl sulfonamide 2a smoothly
in 87% isolated yield after stirring 30 minutes at room
temperature. Reducing the amount of TsNH2 to one
equivalent resulted in a lower yield (67%) of 2a after three
hours. It is worth noting that no other additive was needed
for this reaction. The cationic gold(I) complex
AuCl(PPh3)/AgOTf also showed good catalytic activity in
THF to afford 76% of 2a, however, a prolonged reaction
time (12 h) was required.
Transition-metal-catalyzed carbon–carbon bond or car-
bon–heteroatom bond-formation reactions which can pro-
vide a significant amplification of molecular complexity
from simple building blocks occupy an important place in
organic synthesis.1 In this regard, metal-catalyzed nucleo-
philic substitution of allylic substrates represents a power-
ful method for producing useful synthetic intermediates
which have been widely applied in natural product synthe-
sis.2 Most of the studies focused on the Pd-catalyzed
allylation using allylic carboxylates,3 carbonates,4
phosphates,5 halides6 and related compounds7 as sub-
strates. However, there have been only limited reports on
the allylic transformation utilization of allylic alcohols di-
rectly.8–18 This is apparently due to the poor leaving abili-
ty of the hydroxy group compared to the groups
mentioned above. From both an economical and an envi-
ronmental point of view, conversion of allylic alcohols di-
rectly into allylation products is highly desirable. Several
successful approaches for metal-catalyzed (mainly Pd) di-
rect substitution of allylic alcohols have been developed.
In most cases, additives such as Ti(Oi-Pr)4,9 Et3B,10
Ph3B,11 SnCl2,12 As2O3,13 CO214 etc. were employed for in
situ activation of the OH group. In a recent work reported
by Ozawa and Yoshifuji,15 h3-allyl palladium complexes
bearing unique phosphorus ligands, diphosphinidenecy-
clobutenes, have been demonstrated to catalyze the direct
allylation in the absence of activating agents. More re-
cently, InCl316 and Brønsted acid such as p-toluenesulfon-
ic acid monohydrate17 have emerged as useful catalysts
for nucleophilic substitution of allylic alcohols. Neverthe-
less, the search of highly efficient catalysts for direct
cleavage of the C–O bond in allylic alcohols still remains
as a challenging objective.18 On the other hand, it was re-
ported that Au(III) salts and Au(I) complexes displayed
considerable catalytic activity under moderate condi-
tions.19 In the course of our studies on gold-catalyzed
OH
NHTs
Ph
catalyst
+
TsNH2
2 equiv
solvent, r.t.
Ph
Ph
Ph
1a
2a
catalyst
yield (%) of 2a
2% AuCl3, MeCN, 30 min
5% (PPh3)AuCl/AgOTf, THF, 12 h
87
76
Scheme 1 Gold-catalyzed direct substitution of 1a with TsNH2
Table 1 AuCl3-Catalyzed Amination of 1a with Various Amines26
NHR
2 mol% AuCl3
1a
RNH2
+
Ph
Ph
in MeCN
2
Entry RNH2
Temp
(°C)
Time
(h)
Product Yield
(%)a
1
2
3
4
5
p-FC6H4NH2
50
50
50
r.t.
50
24
3
2b
2c
2d
2e
2f
79
92
84
92
29
p-ClC6H4NH2
p-IC6H4NH2
3
p-NO2C6H4NH2
p-MeC6H4NH2
0.5
24
SYNLETT 2007, No. 6, pp 0964–0968
Advanced online publication: 26.03.2007
0
3.
0
4.
2
0
0
7
a Isolated yield.
DOI: 10.1055/s-2007-973865; Art ID: W25406ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Gold-Catalyzed Direct Amination of Allylic Alcohols
965
In order to test the scope of nucleophiles, we examined the um-mediated alkyne–aldehyde coupling reaction,22 also
substitution reactions of 1a with a variety of amines under reacted with TsNH2 smoothly to generate 2j and 2k in
the optimized reaction conditions. The results are summa- 66% and 80% yields, respectively, in high regio- and ste-
rized in Table 1. Treatment of 1a with p-FC6H4NH2 re- reoselectivity (entries 5, 6). However, in these cases, at
sulted in the formation of allyl amine 2b in 79% yield least 4 equivalents of the amine nucleophile were required
(Table 1, entry 1). Other halide functionalities, such as for achieving a clean transformation. The E-configuration
chloro or iodo, on the aromatic ring of the amine were also of C=C bond in these products was determined by 1H–1H
well tolerated during the reaction, affording the corre- NOESY NMR spectral analysis. The reaction also pro-
sponding products 2c and 2d in 92% and 84% yields, re- ceeded well with cyclic allylic alcohol 1h, furnishing 2l in
spectively (entries 2 and 3).
84% yield (entry 7). A phenyl-substituted tertiary alcohol
1i gave 2m in 89% yield as a single regioisomer (entry 8).
This result indicated that the sulfonamide selectively at-
tacked the less hindered terminus of allylic moiety. Simi-
larly, an alkyl-substituted tertiary alcohol 1j afforded 2n
in 75% yield with high regioselectivity (entry 9). The use
of alcohols 1l–o resulted in the formation of a mixture of
two regioisomers in 58–76% yields (entries 11–14). The
two regioisomers in products 2p and 2r could be easily
separated by column chromatography. It should be noted
that while the current catalyst is quite effective for some
secondary and tertiary allylic alcohols, the substrate of
non-1-en-3-ol which may form less stable carbon cations
and the primary alcohols such as 2-propen-1-ol and (2E)-
3-phenyl-2-propen-1-ol do not react with amine at all un-
der similar reaction conditions. Although the mechanism
of the reaction presented here is not clear yet, a plausible
reaction pathway is considered as follows: The initial
cleavage of a C–O bond in allylic alcohol, which is prob-
ably induced by the coordination of OH group to AuCl3,
affords an allylic cation intermediate. Subsequent nucleo-
philic attack of an amine give the desired allyl amines.
The similar reaction mechanism was also suggested by
other related studies.25
The most reactive substrate was p-NO2C6H4NH2 contain-
ing a strong electron-withdrawing group on the aromatic
ring, which provided substitution product 2e in 92% yield
within 30 minutes (entry 4). In contrast to this result, elec-
tron-donating group (Me) on the aromatic ring resulted in
a lower yield (29%) of 2f, even after stirring at 50 °C for
24 hours (entry 5). This result suggested that a facile co-
ordination of electron-rich amine to the metal center
might occur, which tended to inhibition of the catalysis.
The present method could be applied successfully to var-
ious types of cyclic and acyclic allylic alcohols to provide
the allylic amines in 58–96% yields (Table 2). The reac-
tion of 1-phenylbut-2-en-1-ol (1b) with TsNH2 afforded
the corresponding amide 2g in 90% yields with high regi-
oselectivity (Table 2, entry 1), in which the new C–N
bond was formed selectively at the C-3 position of the
starting material. Interestingly, its regioisomer 1c gave
rise to the same product in slightly lower yield of 82% (en-
try 2). These experimental results suggested that the same
allylic cation was generated as the reactive intermediate
for both allylic alcohols. When 1,5-diphenylpenta-1,4-
dien-3-ol (1e) was employed, a stereodefined (2E,4E)-
2,4-pentadienyl aryl amine product 2i was selectively
formed in 96% yield (entry 4). The trisubstituted olefins
1f and 1g, which were easily prepared through a zirconi-
Table 2 AuCl3-Catalyzed Direct Amination of Allylic Alcohol 1b–o
Entry Allylic alcohol
RNH2
Time (h) Product
Yield (%)a
90
OH
NHTs
1
TsNH2
TsNH2
1
1
Ph
Ph
1b
2g
2g
OH
2
3
82
85
Ph
1c
p-NO2C6H4
OH
HN
p-NO2C6H4NH2
p-NO2C6H4NH2
1
Ph
Bu
Ph
Bu
1d
2h
p-NO2C6H4
OH
HN
4
5
0.25
96
Ph
Ph
Ph
Ph
1e
2i
NHTs
OH
0.25
66b,c
nPr
Ph
nPr
Ph
TsNH2
nPr
nPr
1f
2j
Synlett 2007, No. 6, 964–968 © Thieme Stuttgart · New York

966
S. Guo et al.
LETTER
Table 2 AuCl3-Catalyzed Direct Amination of Allylic Alcohol 1b–o (continued)
Entry Allylic alcohol RNH2 Time (h) Product
Yield (%)a
80b,c
OH
nPr
NHTs
nPr
6
7
TsNH2
TsNH2
2
Ph
Ph
Ph
Ph
1g
OH
2k
NHTs
1
1
1
84d
89
1h
2l
Ph
Bu
Ph
Bu
OH
8
9
TsNH2
TsNH2
NHTs
1i
1j
2m
OH
75
NHTs
2n
Ph
Ph
OH
10
11
p-NO2C6H4NH2
p-NO2C6H4NH2
1
86
p-NO2C6H4
N
H
1k
2o
OH
p-NO2C6H4
p-NO2C6H4
72d,e
HN
24
+
Ph
N
H
Ph
Ph
1l
2p, 1:1
NHTs
NHTs
OH
76b,e,f
nPr
nPr
nPr
12
TsNH2
2
+
nPr
(minor)
nPr
(major)
nPr
1m
2q, 1:9
p-NO2C6H4
p-NO2C6H4
OH
HN
HN
13
14
p-NO2C6H4NH2
1.5
+
58e
Ph
Ph
Ph
(minor)
1n
(major)
2r, 1:1.2
NHTs
NHTs
Bu
OH
TsNH2
1
+
64d,e,g
Bu
(minor)
(major)
1o
2s, 1.9:1
a Isolated yield. Unless noted, all the reactions were carried out at r.t. using 2 equiv of nucleophile and 2 mol% of AuCl3.
b 4 Equiv of TsNH2 were used.
c The E-configuration of C=C bond in the product was determined by NOESY spectroscopy.
d The reaction was carried out at 50 °C.
e Combined yield.
f The E-configuration of C=C bond in the major isomer was determined by NOESY spectroscopy. Only one alkene isomer of minor isomer was
obtained, the geometry of C=C bond in minor isomer was not defined.
g Two regioisomers were obtained; however, the geometry of C=C bond in these isomers could not be defined due to the overlapping of the
signals of vinylic protons in 1H NMR.
Synlett 2007, No. 6, 964–968 © Thieme Stuttgart · New York

LETTER
Gold-Catalyzed Direct Amination of Allylic Alcohols
967
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Acknowledgment
We thank the National Natural Science Foundation of China (Grant
No.20402019, 20121202, 20423001), the Major State Basic Rese-
arch Development Program (Grant No. 2006CB806105), and Chi-
nese Academy of Science for financial support.
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LETTER
layer chromatography (3 h). The solvent was removed in
vacuo and the residue was purified by flash chromatography
on silica gel (PE–EtOAc = 30:1) afforded product 2c in 92%
isolated yield.
(25) (a) Terrasson, V.; Marque, S.; Georgy, M.; Campagne, J.;
Prima, D. Adv. Synth. Catal. 2006, 348, 2063. (b) Liu, J.;
Muth, E.; Flörke, U.; Henkel, G.; Merz, K.; Sauvageau, J.;
Schwake, E.; Dyker, G. Adv. Synth. Catal. 2006, 348, 456.
(26) Typical Procedure for AuCl3-Catalyzed Direct
Amination of Allylic Alcohols
N-(E)-(4-Chlorophenyl)-(1,3-diphenylallyl)amine (2c): 1H
NMR (CDCl3, TMS): d = 4.12 (br s, 1 H), 5.02 (d, J = 5.7
Hz, 1 H), 6.35 (dd, J = 6.0, 15.9 Hz, 1 H), 6.50–6.61 (m, 3
H), 7.04–7.09 (m, 2 H), 7.19–7.41 (m, 10 H). 13C NMR
(CDCl3, TMS): d = 60.65, 114.64, 122.23, 126.48, 127.13,
127.67, 127.77, 128.56, 128.87, 128.93, 130.12, 131.25,
136.40, 141.53, 145.66. HRMS (EI): m/z calcd for
C21H18ClN: 319.1128; found: 319.1121.
A solution of AuCl3 in MeCN (0.05 M) was prepared. Under
N2 atmosphere, 1,3-diphenylprop-2-en-1-ol (1a, 0.11 g, 0.5
mmol) and p-ClC6H4NH2 (0.13 g, 1 mmol) were added to a
25 mL round-bottomed flask containing a stirring bar, and
then 5 mL MeCN was added. To the mixture, 0.2 mL AuCl3
(0.01 mmol) was added. The resulting solution was stirred at
50 °C until the reaction was completed as monitored by thin-
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