Intermolecular hydroamination between nonactivated alkenes and aniline catalyzed by lanthanide salts in ionic solvents

Article abstract of DOI:10.1021/ol9012074

An efficient methodology for intermolecular hydroamination of unactivated alkenes and anilines catalyzed by lanthanide salts was developed. The Markovnikov products were obtained in moderate to good yields.

Full text of DOI:10.1021/ol9012074

ORGANIC
LETTERS
2009
Vol. 11, No. 17
3791-3793
Intermolecular Hydroamination between
Nonactivated Alkenes and Aniline
Catalyzed by Lanthanide Salts in Ionic
Solvents
Peng Yin and Teck-Peng Loh*
DiVision of Chemistry and Biological Chemistry, School of Physical and Mathematical
Sciences, Nanyang Technological UniVersity, Singapore 637371
teckpeng@ntu.edu.sg
Received May 27, 2009
ABSTRACT
An efficient methodology for intermolecular hydroamination of unactivated alkenes and anilines catalyzed by lanthanide salts was developed.
The Markovnikov products were obtained in moderate to good yields.
The catalytic hydroamination of alkenes has attracted
tremendous attention because it provides efficient and
direct entry to synthetically useful amines.1 Accordingly,
much effort has been focused on the development of new
catalytic methods for the hydroamination of alkenes. Much
progress in this area has been accomplished, especially
in the intramolecular and intermolecular hydroamination
of activated alkenes or/and activated amines.2 However,
the catalytic intermolecular hydroamination of nonacti-
vated alkenes with unactivated amines is still a challenging
task.3 A few exceptions include the intermolecular hy-
droamination of 1-pentene with propylamine reported by
Marks and co-workers4 and hydroamination of unactivated
olefins with aniline reported by Bergman5a and Doye.5b
Brunet has reported a successful intermolecular hydroami-
nation of unactivated alkenes with aniline catalyzed by
PtBr2 in n-Bu4PBr in the presence of strong acid.3e,f
Despite significant progress in the development of intermo-
lecular hydroamination reactions, addition of more basic
amines such as aniline to nonactivated alkenes using cheaper
metal complexes under milder reaction conditions continues
to pose significant challenges to synthetic chemists.6 In this
paper, we report an efficient method for the catalytic
intermolecular hydroamination of nonactivated alkenes and
aniline using Pr(OTf)3 as catalyst (eq 1).
(1) For selected reviews, see: (a) Doye, S. Sci. Synth. 2009, 40a, 241–
304. (b) Muller, T. E.; Hultzsch, K. C.; Yus, M.; Foubelo, F.; Tada, M.
Chem. ReV. 2008, 108, 3795–3892. (c) Brunet, J.-J.; Chu, N.-C.; Rodriguez-
Zubiri, M. Eur. J. Inorg. Chem. 2007, 4711–4722. (d) Hultzsch, K. C. AdV.
Synth. Catal. 2005, 347, 367–391. (e) Alonso, F.; Beletskaya Irina, P.; Yus,
M. Chem. ReV. 2004, 104, 3079–3160. (f) Pohlki, F.; Doye, S. Chem. Soc.
ReV. 2003, 32, 104–114. (g) Seayad, J.; Tillack, A.; Hartung, C. G.; Beller,
M. AdV. Synth. Catal. 2002, 344, 795–813. (h) Muller, T. E.; Beller, M.
Chem. ReV. 1998, 98, 675–703.
(2) For selected examples, see: (a) Hesp, K. D.; Stradiotto, M. Org.
Lett. 2009, 11, 1449–1452. (b) Tsuhako, A.; Oikawa, D.; Sakai, K.;
Okamoto, S. Tetrahedron Lett. 2008, 49, 6529–6532. (c) Liu, Z.; Hartwig,
J. F. J. Am. Chem. Soc. 2008, 130, 1570–1571. (d) Cho, J.; Hollis, T. K.;
Helgert Theodore, R.; Valente Edward, J. Chem. Commun. 2008, 5001–
5003. (e) Carney, J. M.; Donoghue, P. J.; Wuest, W. M.; Wiest, O.; Helquist,
P. Org. Lett. 2008, 10, 3903–3906. (f) Komeyama, K.; Morimoto, T.;
Takaki, K. Angew. Chem., Int. Ed. 2006, 45, 2938–2941. (g) Michuax, J.;
Terrasson, V.; Marque, S.; Wehbe, J.; Prim, D.; Campagne, J.-M. Eur. J.
Org. Chem. 2007, 2601–2603. (h) Huang, J.-M.; Wong, C.-M.; Xu, F.-X.;
Loh, T.-P. Tetrahedron Lett. 2007, 48, 3375–3377. (i) Qin, H.; Yamagiwa,
N.; Matsunaga, S.; Shibasaki, M. Chem.-Asian J. 2007, 2, 150–154. (j) Qin,
H.; Yamagiwa, N.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2006,
128, 1611–1614. (k) Taylor, J. G.; Whittall, N.; Hii, K. K. Org. Lett. 2006,
8, 3561–3564. (l) Zhang, J.; Yang, C.-G.; He, C. J. Am. Chem. Soc. 2006,
128, 1798–1799. (m) Liu, X.-Y.; Li, C.-H.; Che, C.-M. Org. Lett. 2006, 8,
2707–2710. (n) Bender, C. F.; Widenhoefer, R. A. Org. Lett. 2006, 8, 5303–
5305. (o) Brouwer, C.; He, C. Angew. Chem., Int. Ed. 2006, 45, 1744–
1747. (p) Karshtedt, D.; Bell, A. T.; Tilley, T. D. J. Am. Chem. Soc. 2005,
127, 12640–12646.
Initially, we screened the hydroamination of 4-phenyl-1-
butene and aniline using a catalytic amount of Pr(OTf)3 (2
10.1021/ol9012074 CCC: $40.75
Published on Web 08/05/2009
 2009 American Chemical Society

mol %) at 160 °C in a sealed tube under various conditions
for 36 h. The results are summarized in Table 1. The reaction
Table 2. Effects of Different Catalysts
Table 1. Hydroamination between 4-Phenyl-1-butene and
Aniline under Different Conditionsa
ratio
(3aa:3aa’)b
entry
catalyst
yield (%)a
1
2
3
4
5
6
7
8
9
La(OTf)3·H2O
Ce(OTf)3·H2O
Pr(OTf)3
Gd(OTf)3
Dy(OTf)3
DyCl3
Er(OTf)3
Lu(OTf)3
TfOH
60
48
75
76
77
70
78
80
10
98:2
94:6
95:5
94:6
96:4
94:6
96:4
95:5
entry
solvent
DMF
iodine
yield (%)b ratio (3aa:3aa’)c
1
2
6 mol %
6 mol %
0
0
0
0
toluene
3d
4d
5d
6
[Omim]Cl
[Omim]BF4
n-Bu4PBr
n-Bu4PBr
n-Bu4PI
22
69
71
75
64
97:3
91:9
93:7
95:5
91:9e
a Combined yield. b Ratio of the two isomers as determined by 1H NMR
analysis.
6 mol %
7d
8
n-Bu4PI
n-Bu4PI
6 mol %
6 mol %
9
a All reactions were performed with aniline (1 equiv), Pr(OTf)3 (2 mol
%), solvent (0.3 equiv), I2 (indicated above), and 4-phenyl-1-butene (2 equiv)
in sealed tube at 160 °C (oil temperature) for 36 h. b Combined yield. c Ratio
(Table 2, entries 5 and 6). Luterium triflate was the best
catalyst, affording the desired product in 80% yield with the
Markovnikov product as the major product (95:5, Table 2,
entry 8). It is important to note that reaction carried out in
the presence of TfOH resulted in only 10% yield of the
product (Table 2, entry 9).
of the two isomers as determined by H NMR analysis. d No iodine was
1
added. e No Pr(OTf)3 was added.
in n-Bu4PBr without iodine afforded the product in low yield
(22%, Table 1, entry 5). The addition of a catalytic amount
of iodine increased the yield of the product (Table 1, entries
6 and 8). The best yield (75%) was obtained when the
reaction was carried out in n-Bu4PI in the presence of a
catalytic amount of I2 at 160 °C (Table 1, entry 8). No
product was observed when the reaction was performed in
toluene, DMF, [Omim]Cl, or [Omim]BF4 (Table 1, entries
1-4). It is important to note that, contrary to the reaction
conditions reported by Brunet,3e,f our method does not require
the use of strong acids.
Next, we investigated the catalytic activity of various rare
earth metals using our optimized conditions. The results are
summarized in Table 2. In all cases, the desired product was
obtained in moderate to excellent yields. Dysprosium triflate
exhibited better catalytic activity than dysprosium trichloride
Furthermore, since there are no notable differences for the
catalytic abilities of these lanthanide triflates, reactions with
various alkenes were investigated using cheap Pr(OTf)3 as
catalyst. The results are summarized in Table 3. Cyclopen-
tene, cyclohexene, and cycloheptene gave the desired
products in good yields (Table 3, entries 2-4). In the case
of terminal olefins, Markovnikov addition products were
obtained as the major products (Table 3, entries 6-8). For
allylbenzene, the Markovnikov product was obtained as a
single isomer (Table 3, entry 8).
Noticeably, the reaction of 4-phenyl-1-butene with p-
anisidine afforded the desired Markovnikov product (3ba)
in moderate yield (32%) and 3% yield of the compound 3ba′
using praseodymium triflate as catalyst (eq 2). Other
nitrogen-containing compounds, such as o-anisidine, mor-
pholine, benzylamine, and diethylamine, did not afford any
of the desired products.
(3) (a) Beller, M.; Breindl, C.; Eichberger, M.; Hartung, C. G.; Seayad,
J.; Thiel, O. R.; Tillack, A.; Trauthwein, H. Synlett 2002, 1579–1594. (b)
Zhao, J.; Marks, T. J. Organometallics 2006, 25, 4763–4772. (c) Khedkar,
V.; Tillack, A.; Benisch, C.; Melder, J.-P.; Beller, M. J. Mol. Catal. A:
Chem. 2005, 241, 175–183. (d) Rodriguez-Zubiri, M.; Anguille, S.; Brunet,
J.-J. J. Mol. Catal. A: Chem. 2007, 271, 145–150. (e) Brunet, J.-J.; Cadena,
M.; Chu, N. C.; Diallo, O.; Jacob, K.; Mothes, E. Organometallics 2004,
23, 1264–1268. (f) Brunet, J.-J.; Chu, N. C.; Diallo, O. Organometallics
2005, 24, 3104–3110.
(4) (a) Li, Y.; Marks, T. J. Organometallics 1996, 15, 3770–3772. (b)
Ryu, J.-S.; Li, G. Y.; Marks, T. J. J. Am. Chem. Soc. 2003, 125, 12584–
12605.
(5) (a) Anderson, L. L.; Arnold, J.; Bergman, R. G. J. Am. Chem. Soc.
2005, 127, 14542–14543. (b) Marcsekova, K.; Doye, S. Synthesis 2007,
145–154.
(6) McBee, J. L.; Bell, A. T.; Tilley, T. D. J. Am. Chem. Soc. 2008,
130, 16562–16571.
3792
Org. Lett., Vol. 11, No. 17, 2009

with the yield of 27% (eq 4). Therefore, the reaction does
not proceed simply via an acid-catalyzed mechanism.5
Table 3. Intermolecular Hydroamination of Aniline with
Various Alkenesa
In summary, the catalytic system of Pr(OTf)3/n-Bu4PI/I2
has been shown to have excellent catalytic activity for the
hydroamination of nonactivated alkenes with aniline. This
protocol offers several advantages including using simple
and cheap catalyst, being atom-economical, and giving
products in high yields. Therefore, this new technology offers
an attractive strategy for the synthesis of synthetically and
pharmaceutically useful amines. The detailed study of the
mechanism and further work to explore new catalysts that
tolerate a variety of functional groups under very mild
reaction conditions are in progress. Further extensions of this
methodology are also in progress.
a All reactions were performed with aniline (1 equiv), Pr(OTf)3 (2 mol
%), I2 (6 mol %), n-Bu4PI (0.3 equiv), and alkenes (2 equiv) in sealed tube
at 160 °C (oil temperature) for 36 h. b Isolated yield. c Up to 5% yield of
other isomers were also observed. d Reation time was 48 h. e A single isomer
was obtained.
Acknowledgment. We gratefully acknowledge the Nan-
yang Technological University and Singapore Ministry of
Education Academic Research Fund Tier 2 (No. T206B1221
and T207B1220RS) for the funding of this research.
To know more about the mechanism of the reaction, the
following reaction (eq 3) was carried out in the presence of
trapping reagents. The addition of three catalytic equivalents
of NEt3 or three catalytic equivalents of 2,6-di-tert-butylpy-
ridine could not completely inhibit hydroamination, giving
both the two products in the yield of 40% and 60%,
respectively. Surprisingly, the reaction of 4-phenyl-1-butene
with N-methylaniline gave the same product as with aniline
Supporting Information Available: Additional experi-
ment procedures and spectrum data for reactions products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL9012074
Org. Lett., Vol. 11, No. 17, 2009
3793