Highly efficient, base-catalysed, intramolecular hydroamination of non-activated olefins

Article abstract of DOI:10.1016/j.tet.2007.11.066

The intramolecular hydroamination of a large variety of non-activated alkenes can be efficiently catalysed by small amounts of lithium bases, providing smoothly and in high yields the corresponding five- and six-membered ring heterocycles. Fused and bridged bicyclic amines, of varying ring sizes, can be readily prepared either by a sequential hydroamination process or by a tandem, double addition reaction.

Full text of DOI:10.1016/j.tet.2007.11.066

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 1077e1087
www.elsevier.com/locate/tet
Highly efficient, base-catalysed, intramolecular
hydroamination of non-activated olefins
Coralie Quinet, Pierre Jourdain, Christophe Hermans, Ali Atesy,
*
´
´
Isabelle Lucas, Istvan E. Marko
Universite´ catholique de Louvain, De´partement de Chimie, Place Louis Pasteur 1, B-1348 Louvain-la-Neuve, Belgium
Received 14 September 2007; received in revised form 16 November 2007; accepted 16 November 2007
Available online 22 November 2007
´
Dedicated fondly and with deep respect to Professor Csaba Szantay, at the occasion of his 80th Birthday
Abstract
The intramolecular hydroamination of a large variety of non-activated alkenes can be efficiently catalysed by small amounts of lithium bases,
providing smoothly and in high yields the corresponding five- and six-membered ring heterocycles. Fused and bridged bicyclic amines, of
varying ring sizes, can be readily prepared either by a sequential hydroamination process or by a tandem, double addition reaction.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
that much milder conditions are necessary for the addition
of amines to alkynes, dienes, norbornene and styrene deri-
vatives.6 However, it must be borne in mind that, in sharp
contrast to ethylene or 1-hexene, these olefins are activated
substrates.7
Addition reactions are powerful processes that fulfil a num-
ber of the important requirements beseeched by environmen-
tally benign transformations.1 Indeed, addition reactions are
100% atom-economical, in that both starting materials merge
into a single adduct, provide little or no by-products and can
typically be carried out either neat or in innocuous solvents.2
Among such processes, the hydroamination of terminal, non-
functionalised, alkenes occupies a cardinal position.3 From
an environmental and economical viewpoint, the addition of
an NeH unit onto a carbonecarbon double bond is an ideal
transformation, which affords the corresponding amine, in
a single step, from readily available starting materials.4
Unfortunately, despite an enormous amount of work, only
limited success has been achieved so far in the intermolecular
hydroamination of non-activated alkenes, which still requires
forcing conditions, including elevated temperatures (up to
180 ꢀC) and high pressures (up to 800 bars).5 It is noteworthy
Though essentially thermoneutral, the hydroamination reac-
tion suffers from the serious drawback of high activation
energy, mostly due to the electronic repulsions between the
lone pairs of the approaching nucleophile and the high-electron
density of the olefinic p-system.8 Henceforth, catalysts that
could efficiently lower this activation barrier would provide
an easy entry into the important class of nitrogen-bearing com-
pounds. This endeavour, which has been pursued by numerous
research groups worldwide, culminated in the discovery of
remarkably active and efficient catalytic systems.9e11 How-
ever, many of these unique catalysts suffer from a number of
shortcomings, such as extreme sensitivity towards moisture
or air, limited stability and tolerance towards nucleophilic
solvents, difficult and lengthy preparation, high cost and mod-
erate efficiency (turnover number or frequency).12
A few years ago, we have reported that small amounts of
n-BuLi-catalysed the intramolecular hydroamination13 of sev-
eral u-unsaturated amines, providing the corresponding pyrro-
lidines and piperidines in moderate to good yields (Fig. 1).14
* Corresponding author.
E-mail address: marko@chim.ucl.ac.be (I.E. Marko).
´
y
Present address: UCB-Pharma SA Chemical Research, Chemin du Foriest,
B-1420, Braine l’Alleud, Belgium.
0040-4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.11.066

1078
C. Quinet et al. / Tetrahedron 64 (2008) 1077e1087
R1
H
R1
In order to establish a truly efficient and broadly applicable
R
16 mol% n-BuLi
THF, r.t. or 50 °C
N
N
R
methodology for the assembly of a large variety of five- and
six-membered ring nitrogen heterocycles, it became crucial
to delineate and control the parameters responsible for the
cyclised versus isomerised products ratio and to define optimal
conditions for quantitative ring closure. In this article, we wish
to disclose a new protocol, based upon a deeper mechanistic
understanding of this unique base-catalysed hydroamination
reaction, and illustrate its wide applicability by the generation
of a large number of pyrrolidines and piperidines as well as by
the efficient preparation of a range of fused and bridged bicy-
clic nitrogen derivatives.
n
n
CH3
1
2
H
H
N
N
CH3
CH3
3 (85%)
4 (91%)
Bn
N
Et
Bn
N
N
CH3
CH3
5 (84%)
CH3
6 (99%)
7 (95%)
2. Results and discussion
At the onset of our work, the cyclisation of amine 815 was
followed by H NMR spectroscopy, in THF-d8. Much to our
R = H, Et, Bn; n = 1, 2; R1 = H, Me, c-C6H11
1
surprise, a rapid equilibrium was established between 8 and
the isomerised alkenes 10E and 10Z. Only traces of the cyc-
lised product 9 could be detected after 24 h (Fig. 3, entry 1).
Warming up the reaction mixture to 50 ꢀC led to an inc-
rease in adduct 9. It appears therefore that abstraction of H4
by the lithiated amide proceeds with a lower activation energy
than its addition at C5.16 Increasing the temperature provides
more energy to overcome this barrier and pyrrolidine 9, the
thermodynamic product, slowly accumulates (Fig. 3, entry
2). Using an even higher boiling solvent, such as THP (tetra-
hydropyran) led to a further improvement (Fig. 3, entry 3),
which unfortunately proved to be a ceiling. Indeed, performing
the cyclisation in toluene (110 ꢀC) afforded essentially the same
ratio of 9 and 10 as that obtained in hot THF (50 ꢀC), whilst
employing MeTHP (2-methyl tetrahydropyran, 110 ꢀC) pro-
vided only the isomerised alkenes 10E and 10Z (not shown in
Fig. 3). Several other solvents proved equally unsuitable.
Figure 1.
As can be seen, a number of primary and secondary amines
underwent smooth cyclisation under these conditions, with
secondary amines reacting faster and more efficiently than
primary ones, probably because of the higher nucleophilicity
of the corresponding lithiated amides. Moreover, whilst pyrro-
lidine formation occurred readily, delivering adducts 3e6 in
excellent yields, cyclisation to generate the analogous six-
membered ring heterocycles proved to be particularly difficult
and only piperidine 7 could be obtained in good yields. To
the best of our knowledge, only one example of a n-BuLi-
catalysed intramolecular hydroamination of a non-activated
alkene had been reported in the literature prior to our contribu-
tion by Suginome and co-workers.10h
Whilst these results open exciting new avenues for the con-
struction of a range of nitrogen heterocycles, it is important to
note that all these substrates benefit strongly from the Thorpee
Ingold effect and its absence leads to a significant erosion in
both the rate and yields of the hydroamination reaction (Fig. 2).
Indeed, treatment of 1-amino-4-pentene 8 with n-BuLi, in
THF at 50 ꢀC, provided pyrrolidine 9 in only 32% yield,
accompanied by the isomerised derivative 10 as the major
component (68%). The addition of one substituent to the chain
linking the amine to the terminal alkene is enough to invert the
ratio of cyclised versus isomerised product, though pyrrolidine
12 (65%) is never obtained quantitatively and is always
contaminated by the internal olefin 13 (35%).
2
H
NH2
16 mol%
NH2
16 mol%
N
3
5
4
H
n-BuLi
n-BuLi
6
CH3
9
10
8
Entry
Solvent
Temp.
10 / 9
Conv.
1
2
3
4
THF
THF
20 °C
50 °C
90 °C
110 °C
93 : 7
87%
68 : 32
>95%
THP
29 : 71
66 : 34
>99%
>99%
H
H
H
toluene
16 mol% n-BuLi
THF, 50 °C, 2h
N
N
N
H
H
+
110 °C
>99%
5
THP : Toluene (1:1)
<5 : >95
CH3
8
9 (32%)
10 (68%)
Figure 3.
H
H
H
N
16 mol% n-BuLi
THF, 50 °C, 2h
At this stage, two important observations were fortuitously
made that proved to be of paramount importance for devising
optimal reaction conditions. First of all, quantitative lithiation
of 8 can be smoothly realised by adding to this amine 1 equiv
of n-BuLi, in THF at 20 ꢀC. However, even under prolonged
N
N
H
H
+
CH3
11
12 (65%)
13 (35%)
Figure 2.

C. Quinet et al. / Tetrahedron 64 (2008) 1077e1087
1079
Table 1
n-BuLi-catalysed hydroamination of u-unsaturated amines
R
R
H
N
N
Li
H
H
H
Entry
1
Substrate
Product
Yielda (%)
86
Li
R
N
R
N
NH
NH2
14
15
8
9
NH
NH2
Figure 4.
2
3
93b
73c
heating at reflux, the fully deprotonated amine never under-
went the hydroamination reaction. This observation strongly
suggested that no true carbanionic species was generated dur-
ing the transformation of 8 into 9.17 Moreover, addition of
a small amount (10e20 mol %) of an amine, such as diiso-
propyl amine, to the refluxing solution of lithiated 8 led to its
cyclisation into 9. Finally, treatment of 8 with either catalytic
quantities or with 1 equiv of LDA smoothly afforded adduct 9,
in essentially the same rate and yield. It therefore transpires
that the addition of the lithiated amide onto the carbonecarbon
double bond of 8 can occur only if the developing negative
charge on C6 of the terminal olefin in the transition state is
immediately neutralised by a proton provided by a coordinated,
proximal amine (Fig. 4).18,19
To form the proper aggregate in solution and to generate
enough of it to ensure a smooth reaction may not be a trivial
problem since such a construct should be highly solvent-
dependant.20 Screening several solvents and solvent mixtures
rapidly provided a solution in the form of a 1:1 mixture of
THP/toluene. Under these conditions, quantitative formation
of the desired adduct was eventually achieved for the first
time and the a-methyl pyrrolidine 9 could be isolated in an
excellent 86% yield (Fig. 3, entry 5). Having delineated suit-
able conditions for the efficient hydroamination of 1-amino-
4-pentene 8, attention was then turned towards exploring the
scope and limitations of this novel protocol. Some selected
results are collected in Table 1.
11
12
NH2
NH
16
17
N
H
Ph
Ph
N
Ph
Ph
4
5
79
19
18
N
H
N
79d
20
21
NH2
NH
6
7
8
63e
83
23
22
H
N
N
Ph
Ph
25
24
H
N
Ph
N
Ph
95f
27
NH
26
NH2
9
78e
28
29
a
As can be seen in Table 1, a variety of substituted pyrroli-
dines can be efficiently produced by the n-BuLi-catalysed
hydroamination reaction of the corresponding u-unsaturated
amines (entries 1e5). It is noteworthy that both primary and
secondary amine precursors can be employed, leading to the
desired adducts in excellent yields. In all cases, complete
conversion was observed. Interestingly, secondary amines
cyclise faster than primary ones. The power of the new proto-
col can be better appreciated when considering that attempted
ring closure of 11 under the ‘old’ conditions provided 12 in
only 65% yield. But perhaps, the most dramatic illustration
of the superiority of this new methodology can be seen in
the formation of the piperidine system (Table 1, entries 6, 7
and 9). Indeed, such a ring closure either proved impossible
to achieve under the ‘old’ conditions or proceeded in mediocre
yield. This cyclisation was effective only when the amine was
secondary and benefited from the ThorpeeIngold effect (Table
1, entry 8). However, adding 16 mol % of n-BuLi21 to a THP/
toluene (1:1) solution of amine 24 led to its quantitative conver-
sion into the six-membered ring heterocycle 25, which could be
isolated in a gratifying 83% yield (Table 1, entry 7). Even more
impressive is the base-catalysed cyclisation of 28, bearing
All yields are for pure, isolated compounds. Unless stated otherwise, all
the conversions are quantitative and the reactions are performed using
16 mol % n-BuLi (1.6 M in hexanes) in THP/toluene (1:1, 0.5 M solutions)
at 110 ꢀC (bath temperature).
b
dr¼1.4:1.
c
dr¼2.6:1.
d
dr¼5.7:1.
e
Conversion (%).
Performed in refluxing THF.
f
a primary amine and a highly hindered terminal alkene, afford-
ing adduct 29 in up to 78% conversion (Table 1, entry 9).
The synthetic utility of this method can be further illustrated
by the rapid assembly of the alkaloid (ꢁ)-dihydropinidine 31
from a readily available precursor, the primary amine 30 (Fig. 5).
Thus, treatment of 30 with n-BuLi, under the usual condi-
tions, for 48 h, delivered the desired natural product 31 in 85%
n-BuLi 1,6 M / hexane (16 mol%)
THP / toluene 1:1, 110 °C, 48h
N
H
H2N
30
100% conv., 85% yield, d.r.= 3:1
( )-dihydropinidine 31
Figure 5.

1080
C. Quinet et al. / Tetrahedron 64 (2008) 1077e1087
isolated yield, as a mixture of cis and trans isomers in a 3:1
diastereomeric ratio.
HN
16 mol% n-BuLi
dioxane, r.t., 3h
100% conv.
H2N
Me
Me
40
41
Whilst five- and six-membered monocyclic nitrogen deriva-
tives can now be readily manufactured from easily accessible
u-unsaturated amines, we wondered if bicyclic structures,
akin to the pyrrolizidine and indolizidine alkaloids,22 could
also be rapidly assembled using this novel hydroamination
protocol. Some selected results are collected in Table 2.
As can be seen from Table 2, substituted pyrrolidine 32 and
piperidine 34 underwent smooth cyclisation, in the presence of
catalytic quantities of n-BuLi, in THP/toluene, affording the
desired, fused bicyclic adducts 33 and 35 in excellent yields
and with high or even complete diastereocontrol (Table 2,
entries 1 and 2). Even more interesting were the cascade hy-
droaminations of amines 36 and 38, which upon exposure to
small amounts of n-BuLi, produced in high overall yield, the
substituted pyrrolizidine derivatives 37 and 39 (Table 2,
entries 3 and 4). Interestingly, in these two cases, only the
meso compound was formed with complete stereocontrol.
These double cyclisations open new vistas for the application
of our base-catalysed hydroamination reaction to the efficient
and concise synthesis of a variety of fused alkaloids and alka-
loid-like structures.
n-BuLi
THP / toluene, 90 °C
16 mol% n-BuLi
Me
N
Me
THP / toluene,
90 °C, 16h
80%
+
N
42
52 : 48
43
Figure 6.
in an almost 1:1 diastereomeric ratio. Interestingly, exposure
of 41 to the cyclisation conditions afforded 42 and 43 in similar
yields and diastereomeric ratios, thereby confirming the pas-
sage through 41 in the direct conversion of 40 into 42 and 43.
3. Conclusions
In summary, we have disclosed a novel, base-catalysed
intramolecular hydroamination reaction of non-activated
alkenes that offers an efficient access to a large variety of
substituted pyrrolidines and piperidines, as well as to a range
of fused and bridged bicyclic amine derivatives akin to the
pyrrolizidine and indolizidine alkaloid families, from readily
available simple u-unsaturated amines. Cascade hydroamina-
tion reactions also occur smoothly with excellent levels of
diastereocontrol. Ongoing efforts are now aimed at expanding
further the scope of this unique transformation and applying it
to the efficient synthesis of several relevant natural products.
To further probe the limits of our method, the assembly of
a bridged bicyclic amine, by a double intramolecular hydro-
amination reaction, was attempted (Fig. 6).
Thus, treatment of the primary amine 40 with n-BuLi in
dioxane, at room temperature for 3 h, afforded quantitatively
the substituted pyrrolidine 41. In stark contrast, repeating
this reaction in THP/toluene, at 90 ꢀC for 16 h, led to the
smooth formation of the bridged bicyclic adducts 42 and 43
4. Experimental
Table 2
Synthesis of fused bicyclic amines by n-BuLi-catalysed hydroamination
4.1. General information
Entry
Substrate
Product
Yielda (%)
All compounds (Acros, Aldrich and Fluka) were used as
received. THF, THP and dioxane were distilled under argon
from sodium benzophenone ketyl. All the primary amine sub-
strates were dried over Na/K amalgam and distilled (vacuum
transferred) immediately prior to use. Flash chromatography
was performed on silica gel 60 (40e63 mm) (ROCC).
NH
N
H
1
83b
32
33
NH
N
H
2
3
76c
1
1 H and 13C NMR spectra were recorded on a Varian Gemini-
34
35
2000 (working frequency 300 and 75 MHz, respectively),
on a Bruker AC-250 (working frequency 250 and
62.5 MHz, respectively), on a Brucker AC-300 Avance II
(working frequency 300 and 75 MHz, respectively) or on
a Brucker AM-500 (working frequency 500 and 125 MHz,
respectively) at ambient temperature in CDCl3 (Aldrich).
2 Mass spectra were recorded on a Finigan TSQ 7000.
3 All reactions were carried out under an atmosphere of ar-
gon in flame-dried apparatus with magnetic stirring, unless
otherwise indicated.
N
NH2
85b
H
36
37
N
NH2
Ph
4
84b
Ph
38
39
a
All yields are for pure, isolated compounds. Unless stated otherwise, all
the conversions are quantitative and the reactions are performed using
16 mol % n-BuLi (1.6 M in hexanes) in THP/toluene (1:1, 0.5 M solutions)
at 110 ꢀC (bath temperature).
4 The identity of every product was confirmed by comparison
with literature spectroscopic data. The structure determination
of new compounds was made with the help of 2D-COSY,
HMQC, HMBC, 2D-NOESY and NOEDIFF experiments.
b
A single diastereoisomer is obtained.
dr¼14:1.
c

C. Quinet et al. / Tetrahedron 64 (2008) 1077e1087
1081
All the amino-alkene substrates have been prepared accord-
ing to known procedures.
4.1.4. 1-Benzylamino-4-pentene (18)
10
9
11
7
4.1.1. 1-Amino-4-pentene (8)
8
NH6
5
4
6
1
NH2
2
3
5
4
1
2
3
1H NMR (300 MHz, CDCl3) dH (ppm): 7.40e7.15 (5H, m,
Ph), 5.81 (1H, ddt, J¼16.7, 10.0, 6.7 Hz, H-2), 5.07e4.88 (2H,
m, H-1), 3.78 (2H, s, H-7), 2.64 (2H, t, J¼7.2 Hz, H-5), 2.10
(2H, q (dt), J¼7.7 Hz, H-3), 1.60 (2H, quint (tt), J¼7.2 Hz,
H-4), 1.33 (1H, s, H-6). 13C NMR (75 MHz, CDCl3) dC (ppm):
140.4 (C-8), 138.3 (C-2), 128.2 and 127.9 (C-9 and C-10),
126.7 (C-11), 114.5 (C-1), 54.0 and 48.9 (C-5 and C-7), 31.6
and 29.3 (C-3 and C-4). MS (CI, 70 eV) m/z (relative intensity,
%): 190 (Mþ1, 100), 134 (12), 91 (10). IR (KBr) n (cmꢂ1):
3323 [w], 3064 [m], 3027 [m], 2963e2845 [s], 1641 [m], 1495
[m], 1453 [s], 1374 [m], 995 [m], 910 [s], 732 [s], 697 [s].
1H NMR (300 MHz, CDCl3) dH (ppm): 5.81 (1H, ddt, J¼17.2,
10.5, 6.7 Hz, H-2), 5.00e4.83 (2H, m, H-1), 2.61 (2H, t,
J¼6.7 Hz, H-5), 2.08 (2H, q (dt), J¼7.2 Hz, H-3), 1.45 (2H, quint
(tt), J¼7.2 Hz, H-4), 1.00 (2H, s, H-6). 13C NMR (75 MHz,
CDCl3) dC (ppm): 138.2 (C-2), 114.5 (C-1), 41.6 (C-5), 32.8
and 31.1 (C-3 and C-4). MS (CI, 70 eV) m/z (relative intensity,
%): 86 (Mþ1, 100), 69 (90). IR (KBr) n (cmꢂ1): 3369 [w],
3292 [w], 3077 [m], 2976e2853 [s], 1641 [s], 1611 [w], 1449
[w], 1439 [w], 995 [m], 910 [s], 820 [s]. CAS: [22537-07-1].
ꢃ
HRMS (EIþ, Mþ ): (C13H19N) calcd: 190.1595; found:
4.1.2. 1-Amino-2-methyl-4-pentene (11)
190.1591. CAS: [489428-62-8].
7
NH2
5
4.1.5. 5-Benzylaminohexene (20)
1
2
3
6
4
11
10
12
8
1H NMR (300 MHz, CDCl3) dH (ppm): 5.78 (1H, ddt,
J¼16.7, 10.0, 6.7 Hz, H-2), 5.03e4.89 (2H, m, H-1), 2.52
(1H, dd, J¼12.0, 6.2 Hz, H-5a), 2.44 (1H, dd, J¼12.0,
6.2 Hz, H-5b), 2.33e2.10 (1H, m, H-3a), 1.90e1.77 (1H, m,
H-3b), 1.45 (1H, oct (qtt), J¼6.7 Hz, H-4), 0.99 (2H, s, H-
7), 0.86 (3H, d, J¼6.7 Hz, H-6). 13C NMR (75 MHz, CDCl3)
dC (ppm): 136.9 (C-2), 115.7 (C-1), 48.0 (C-5), 38.8 (C-3),
36.2 (C-4), 17.3 (C-6). MS (CI, 70 eV) m/z (relative intensity,
%): 100 (Mþ1, 100), 83 (30). IR (KBr) n (cmꢂ1): 3381 [w],
3296 [w], 3077 [m], 2958e2872 [s], 1640 [s], 1459 [m], 1440
[m], 1379 [w], 1261 [m], 995 [s], 911 [s], 803 [s], 733 [s].
CAS: [79116-24-8].
9
6
NH7
5
4
1
2
3
1H NMR (300 MHz, CDCl3) dH (ppm): 7.38e7.17 (5H, m,
Ph), 5.80 (1H, ddt, J¼17.2, 10.0, 6.7 Hz, H-2), 5.05e4.86 (2H,
m, H-1), 3.82 (1H, A part of AB, J¼12.9 Hz, H-8a), 3.73 (1H,
B part of AB, J¼12.9 Hz, H-8b), 2.70 (1H, sext (qt),
J¼6.2 Hz, H-5), 2.19e1.98 (2H, m, H-3), 1.65e1.19 (3H,
m, H-4 and H-7), 1.08 (3H, d, J¼12.9 Hz, H-6). 13C NMR
(75 MHz, CDCl3) dC (ppm): 140.7 (C-9), 138.6 (C-2), 128.2
and 128.0 (C-10 and C-11), 126.7 (C-12), 114.3 (C-1), 52.0
(C-5), 51.3 (C-8), 36.2 (C-4), 30.3 (C-3), 20.3 (C-6). MS (CI,
70 eV) m/z (relative intensity, %): 176 (Mþ1, 100), 174 (8),
120 (10), 91 (15). IR (KBr) n (cmꢂ1): 3311 [w], 3076 [m],
3064 [m], 3027 [m], 2999e2813 [s], 1640 [s], 1495 [s], 1453
[s], 1120 [s], 1028 [m], 994 [m], 911 [s], 733 [s], 698 [s].
CAS: [54436-58-7].
4.1.3. 5-Aminooctene (16)
8
6
9
NH2
5
7
1
2
3
4
4.1.6. 1-Amino-2,2-dimethyl-5-hexene (22)
1H NMR (300 MHz, CDCl3) dH (ppm): 5.81 (1H, ddt,
J¼17.0, 10.3, 6.7 Hz, H-2), 5.11e4.08 (2H, m, H-1), 2.77e
2.62 (1H, m, H-5), 2.24e1.96 (2H, m, H-3), 1.57e1.19 (6H,
m, H-4, 6 and 7), 1.13 (2H, br s, H-9), 0.90 (3H, t, J¼
6.8 Hz, H-8). 13C NMR (75 MHz, CDCl3) dC (ppm): 139.0
(C-2), 114.6 (C-1), 50.6 (C-5), 40.1 and 37.4 (C-4 and C-6),
30.7 (C-3), 19.4 (C-7), 14.4 (C-8). MS (APCI, 70 eV) m/z (rel-
ative intensity, %): 128 (Mþ1, 5), 126 (15), 111 (25), 69
(100). IR (film) n (cmꢂ1): 3335 [w], 3078 [w], 2957e2870 [s],
1641 [m], 1618 [m], 1572 [m], 1475 [s], 1306 [m], 995 [s],
717 [m]. HRMS (APCIþ, MHþ): (C8H18N) calcd: 128.1439;
found: 128.1436.
H
9
NH
1
6
2
3
8
5
4
7
1H NMR (300 MHz, CDCl3) dH (ppm): 5.80 (1H, ddt,
J¼16.8, 9.9, 6.6 Hz, H-2), 5.02e4.82 (2H, m, H-1), 2.38
(2H, s, H-6), 2.04e1.93 (2H, m, H-3), 1.33e1.25 (2H, m,
H-4), 0.95 (2H, br s, H-9), 0.82 (6H, s, H-7 and H-8). 13C
NMR (50 MHz, CDCl3) dC (ppm): 139.1 (C-2), 113.7 (C-1),
52.6 (C-6), 38.4 (C-4), 34.3 (C-5), 28.3 (C-3), 24.5 (C-7 and
ꢃ
C-8). MS (EI, 70 eV) m/z (relative intensity, %): 127 (Mþ ,

1082
C. Quinet et al. / Tetrahedron 64 (2008) 1077e1087
8), 112 (75), 95 (30), 70 (73), 55 (100). IR (film) n (cmꢂ1):
3394 [w], 3316 [w], 3078 [m], 2955e2852 [s], 1641 [m],
1473 [m], 1364 [m], 994 [m], 909 [s], 813 [m], 733 [w].
CAS: [141511-50-4].
m, H-4 and H-5), 0.98 (6H, s, H-7 and H-8). 13C NMR
(50 MHz, CDCl3) dC (ppm): 148.4 (C-2), 110.3 (C-1), 42.9
(C-6), 39.9 and 28.9 (C-4 and C-5), 36.3 (C-3), 26.8 (C-7 and
C-8). MS (EI, 70 eV) m/z (relative intensity, %): 128 (Mþ1, 20),
112 (61), 95 (64), 69 (59), 67 (58), 56 (100). IR (film) n (cmꢂ1):
3369 [w], 3292 [w], 3082 [m], 2960e2866 [s], 1640 [m], 1473
[m], 1414 [m], 1380 [m], 1363 [m], 1003 [m], 910 [s], 816 [m],
687 [w]. HRMS (EIþ, MHþ): (C8H18N) calcd: 128.1439;
found: 128.1436.
4.1.7. 1-Benzylamino-5-hexene (24)
11
10
9
12
8
7
1
NH
6
5
4.1.10. 6-Amino-nonene (30)
2
3
9
8
4
H
6 NH
10
1
7
1H NMR (300 MHz, CDCl3) dH (ppm): 7.36e7.20 (5H, m,
Ph), 5.80 (1H, ddt, J¼16.9, 10.3, 6.7 Hz, H-2), 5.05e4.88 (2H,
m, H-1), 3.78 (2H, s, H-8), 2.63 (2H, t, J¼6.9 Hz, H-6), 2.06
(2H, q (dt), J¼7.2 Hz, H-3), 1.60e1.37 (4H, m, H-4 and H-5),
1.29 (1H, br s, H-7). 13C NMR (75 MHz, CDCl3) dC (ppm):
140.5 (C-9), 138.5 (C-2), 128.1 and 127.8 (C-10 and C-11),
126.6 (C-12), 114.2 (C-1), 53.9 (C-8), 49.1 (C-6), 33.4 (C-3),
29.4 (C-5) and 26.5 (C-4). MS (EI, 70 eV) m/z (relative inten-
2
3
5
4
1H NMR (300 MHz, CDCl3) dH (ppm): 5.80 (1H, ddt,
J¼17.0, 10.3, 6.7 Hz, H-2), 5.05e4.87 (2H, m, H-1), 2.74e
2.62 (1H, m, H-6), 2.14e1.96 (2H, m, H-3), 1.56e1.18 (8H,
m, H-4, 5, 7 and 8), 1.14 (2H, br s, H-10), 0.90 (3H, t,
J¼6.9 Hz, H-9). 13C NMR (75 MHz, CDCl3) dC (ppm): 139.0
(C-2), 114.6 (C-1), 51.0 (C-6), 40.6 and 37.8 (C-5 and C-7), 34.1
(C-3), 25.7 (C-4), 19.5 (C-8), 14.4 (C-9). MS (CI, 70 eV) m/z
(relative intensity, %): 142 (Mþ1, 100), 98 (25), 83 (8), 72
(40), 69 (11). IR (film) n (cmꢂ1): 3372 [w], 3299 [w], 3078 [m],
2957e2871 [s], 1641 [s], 1617 [m], 1460 [s], 1379 [m], 993 [m],
909 [s], 808 [s], 742 [m]. HRMS (CIþ, MHþ): (C9H20N) calcd:
142.1596; found: 142.1594. E.A.: (C16H27NO3S, RNHþ3 PTSꢂ)
Calcd: C, 61.31; H, 8.68; N, 4.47; S, 10.23%. Found: C, 61.19;
H, 9.14; N, 4.33; S, 10.12%.
ꢃ
sity, %): 189 (Mþ , 9), 120 (24), 91 (100). IR (film) n (cmꢂ1):
3310 [w], 3063 [m], 3027 [m], 2928e2822 [s], 1640 [m], 1495
[m], 1454 [s], 1367 [m], 1120 [m], 910 [s], 732 [s], 697 [s].
CAS: [145126-90-5].
4.1.8. 1-Benzylamino-2,2-dimethyl-5-hexene (26)
13
12
11
14
10
4.1.11. 2-(But-3-enyl)pyrrolidine (32)
9
1
NH
6
2
3
8
1
9
H
N
5
2
4
3
8
7
7
1H NMR (300 MHz, CDCl3) dH (ppm): 7.35e7.30 (5H, m,
Ph), 5.81 (1H, ddt, J¼17.0, 10.3, 6.6 Hz, H-2), 5.02e4.86 (2H,
m, H-1), 3.79 (2H, s, H-10), 2.36 (2H, s, H-6), 2.20e1.90 (2H,
m, H-3), 1.40e1.28 (3H, m, H-4 and H-9), 0.89 (6H, s, H-7 and
H-8). 13C NMR (75 MHz, CDCl3) dC (ppm): 140.9 (C-11),
139.5 (C-2), 128.0 and 127.8 (C-12 and C-13), 126.5 (C-14),
113.6 (C-1), 59.6 (C-6), 54.6 (C-10), 39.2 (C-4), 33.8 (C-5),
28.3 (C-3), 25.4 (C-7 and C-8). MS (EI, 70 eV) m/z (relative
4
5
6
1H NMR (300 MHz, CDCl3) dH (ppm): 5.80 (1H, ddt,
J¼17.0, 10.3, 6.7 Hz, H-2), 5.05e4.85 (2H, m, H-1), 3.03e
2.86 (2H, m, H-5 and H-8a), 2.85e2.73 (1H, m, H-8b), 2.20e
1.99 (2H, m, H-3), 1.92e1.78 (1H, m, H-6a), 1.77e1.59 (3H,
m, H-7 and H-9), 1.58e1.39 (2H, m, H-4), 1.29e1.13 (1H, m,
H-6b). 13C NMR (75 MHz, CDCl3) dC (ppm): 138.9 (C-2), 114.5
(C-1), 58.9 (C-5), 46.7 (C-8), 35.9 (C-4), 31.9 (C-3 and C-6), 25.5
(C-7). MS (APCI, 70 eV) m/z (relative intensity, %): 126 (Mþ1,
5), 109 (22), 70 (100). IR (film) n (cmꢂ1): 3418 [w], 3074 [w],
2957e2868 [s], 1639 [m], 1620 [m], 1537 [m], 1396e1362 [s],
995 [m], 906 [s], 812 [m], 737 [w]. CAS: [95092-07-2].
ꢃ
intensity, %): 217 (Mþ , 14), 120 (87), 91 (100), 55 (9). IR
(film) n (cmꢂ1): 3064 [m], 3027 [m], 2955e2808 [s], 1640 [m],
1495e1454 [s], 1363 [m], 1118 [s], 908 [s], 735 [s], 698 [s].
E.A.: (C15H23N) Calcd: C, 82.89; H, 10.67; N, 6.44%. Found:
C, 82.77; H, 10.69; N, 6.43%.
4.1.12. 2-(But-3-enyl)piperidine (34)
4.1.9. 1-Amino-4,4-dimethyl-5-hexene (28)
1
H
9
10
2
H
1
NH
6
5
9
3
N
2
3
7
8
4
5
4
6
8
7
1H NMR (300 MHz, CDCl3) dH (ppm): 5.76 (1H, ddd,
J¼18.2, 10.1, 0.9 Hz, H-2), 4.96e4.84 (2H, m, H-1), 2.64
(2H, t, J¼6.0 Hz, H-6), 1.49 (2H, br s, H-9), 1.42e1.22 (4H,
1H NMR(300 MHz, CDCl3) dH (ppm): 5.80(1H, ddt, J¼17.0,
10.3, 6.7 Hz, H-2), 5.07e4.87 (2H, m, H-1), 3.10e2.97 (1H, m,
H-9a), 2.61 (1H, td, J¼11.7, 2.7 Hz, H-9b), 2.44 (1H, dtd,

C. Quinet et al. / Tetrahedron 64 (2008) 1077e1087
1083
ꢃ
J¼13.2, 6.5, 2.5 Hz, H-5), 2.15e2.01 (2H, m, H-3), 1.81e1.70
(1H, m) and 1.69e1.52 (2H, m) (H-6a, 7a and 8a), 1.51e1.22
(5H, m, H-4, 7b, 8b and 10), 1.13e0.96 (1H, m, H-6b). 13C NMR
(75 MHz, CDCl3) dC (ppm):138.9 (C-2), 114.6 (C-1), 56.5(C-5),
47.4 (C-9), 35.9 (C-4), 33.1 (C-6), 30.4 (C-3), 26.8 and 25.0 (C-7
and C-8). MS (APCI, 70 eV) m/z (relative intensity, %): 140
(Mþ1, 75), 123 (5), 84 (100), 81 (75). IR (film) n (cmꢂ1): 3281
[w], 3076 [w], 2927e2852 [s], 1639 [m], 1441 [m], 1327 [m],
1120e997 [m], 906 [s], 798 [m]. CAS: [78867-47-1].
%): 139 (Mþ , 1), 124 (2), 98 (13), 83 (12), 57 (47). IR (film) n
(cmꢂ1): 3389 [w], 3313 [w], 3075 [m], 3003 [m], 2950e2870
[s], 1639 [m], 1464 [m], 1440 [m], 1415 [m], 1379 [m], 1323
[m], 1066 [m], 997 [m], 912 [s], 815 [m]. CAS: [39074-87-8].
4.2. Typical experimental procedure of the
hydroamination reaction with n-BuLi
To a stirred solution of aminoolefin (1 equiv), dissolved in
a 1:1 mixture of tetrahydropyran and toluene (0.5 M) in
a Schlenk tube maintained under an argon atmosphere, was
added n-BuLi (1.6 M/hexanes, 16 mol %) at room tempera-
ture. The solution was stirred while heating at 110 ꢀC (oil
bath temperature).
4.1.13. 5-Amino-nona-1,8-diene (36)
9
7
8
6
10
NH2
5
After cooling to room temperature, diethyl ether, water and
a 1 M aqueous solution of HCl were added sequentially. The
solvents were removed in vacuo and the residual solid was par-
titioned between diethyl ether and water containing 300 mg of
KOH. The layers were separated and the aqueous phase was
extracted with diethyl ether. The pooled organic extracts
were washed with water and then with a saturated aqueous so-
lution of NaCl, dried over MgSO4, filtered and the solvent was
removed carefully in vacuo (at 0 ꢀC for secondary amines).
1
4
2
3
1H NMR (300 MHz, CDCl3) dH (ppm): 5.83 (2H, ddt,
J¼17.2, 10.1, 6.7 Hz, H-2 and H-8), 5.35 (2H, dd, J¼17.2,
1.4 Hz, H-1a and H-9a), 4.96 (2H, dd, J¼10.1, 1.4 Hz, H-1b
and H-9b), 2.78e2.71 (1H, m, H-5), 2.19e2.02 (4H, m, H-3
and H-7), 1.57e1.40 (4H, m, H-4 and H-6). 13C NMR
(75 MHz, CDCl3) dC (ppm): 139.2 (C-2 and C-8), 115.0 (C-1
and C-9), 50.9 (C-5), 37.9 (C-4 and C-6), 31.1 (C-3 and
C-7). MS (CI) m/z (relative intensity, %): 140.0 (Mþ1, 10),
85.7 (14). IR (film) n (cmꢂ1): 3357 [w], 3076 [s], 3009 [s],
1640 [m], 1635 [w], 1362 [m], 994 [m]. CAS: [245450-12-8].
4.2.1. Synthesis of 2-methylpyrrolidine (9)
6
H
NH2
N
5
4
n-BuLi 1,6 M / hexane (16mol%)
4.1.14. 5-Amino-5-phenylnona-1,8-diene (38)
1
2
THP / Toluene 1:1, 110 °C, 5d.
3
9
8
7
8
9
6
12
10
13
14
NH2
Isolated yield: 86%. 1H NMR (300 MHz, CDCl3) dH (ppm):
3.13e2.95 (2H, m) and 2.87e2.73 (1H, m) (H-2 and H-5),
1.93e1.62 (4H, m, H-3 and H-4), 1.28e1.16 (1H, m, H-6),
1.14 (3H, d, J¼6.0 Hz, H-1). 13C NMR (75 MHz, CDCl3) dC
(ppm): 54.5 (C-2), 46.7 (C-5), 33.7 and 25.7 (C-3 and C-4),
21.2 (C-1). MS (EI, 70 eV) m/z (relative intensity, %): 85
5
11
2
3
1
4
1H NMR (300 MHz, CDCl3) dH (ppm): 7.44e7.16 (5H, m,
Ph), 5.73 (2H, ddt, J¼17.2, 10.1, 6.7 Hz, H-2 and H-8), 4.95e
4.83 (4H, m, H-1 and H-9), 2.08e1.73 (8H, m, H-3, 4, 6 and
7). 13C NMR (75 MHz, CDCl3) dC (ppm): 146.5 (C-11), 138.8
(C-2 and C-8), 128.1, 128.0, 126.0 and 125.9 (C-12 and C-13),
125.7 (C-14), 114.2 (C-1 and C-9), 57.7 (C-5), 43.3 (C-4 and
C-6),28.2(C-3andC-7). MS(ESI, 70 eV)m/z(relativeintensity,
%): 216 (Mþ1, 29), 143 (5), 129 (7), 91 (4). IR (film) n (cmꢂ1):
3370 [w], 3078 [s], 3061 [m], 2927 [s], 1638 [m], 1600 [w],
1493 [w], 1446 [m], 1413 [w], 1025 [m]. HRMS (ESIþ,
MHþþNa): (C15H22NNa) calcd: 216.1752; found: 216.1757.
ꢃ
(Mþ , 19), 84 (18), 70 (100), 57 (45), 56 (22). IR (film) n
(cmꢂ1): 3396 [m], 2959e2870 [s], 1630 [m], 1530 [m], 1452e
1410 [s], 1348 [m], 1198 [w], 814 [w], 729 [w]. CAS: [765e
38-8].
4.2.2. Synthesis of 2,4-dimethylpyrrolidine (12)
7
H
NH2
N
5
n-BuLi 1,6 M / hexane (16mol%)
1
4.1.15. 1-Amino-2,2-diallylpropane (40)
2
THP / Toluene 1:1, 110 °C, 20h
4
3
12
6
6
5
4
3
10
11
8
H2N
7
1
Isolated yield: 93% (cis as major product, dr¼58:42). H
NMR (500 MHz, CDCl3) dH (ppm): trans: 3.26e3.13 (2H,
m, H-2 and H-5a), 2.39 (1H, dd, J¼10.6, 7.6 Hz, H-5b),
2.27e2.13 (1H, m, H-4), 1.48 (2H, t, J¼7.3 Hz, H-3), 1.15
(3H, d, J¼6.3 Hz, H-1), 1.00 (3H, d, J¼6.8 Hz, H-6). Cis:
3.26e3.13 (1H, m, H-2), 3.04 (1H, dd, J¼10.6, 7.9 Hz, H-5a),
2.56 (1H, dd, J¼10.6, 7.0 Hz, H-5b), 2.27e2.13 (1H, m, H-4),
2.13e2.03 (1H, m, H-3a), 1.17 (3H, d, J¼6.3 Hz, H-1), 1.03
9
2
1
1H NMR (300 MHz, CDCl3) dH (ppm): 5.89e5.73 (2H, m,
H-2 and H-7), 5.11e4.97 (4H, m, H-1 and H-8), 2.48 (2H, s, H-5),
2.00 (4H, d, J¼7.7 Hz, H-3 and H-6), 1.05 (2H, br s, H-10), 0.85
(3H, s, H-9). 13C NMR (50 MHz, CDCl3) dC (ppm): 134.7 (C-2
and C-7), 117.1 (C-1 and C-8), 50.0 (C-5), 41.7 (C-3 and C-6),
36.7 (C-4), 22.2 (C-9). MS (EI, 70 eV) m/z (relative intensity,

1084
C. Quinet et al. / Tetrahedron 64 (2008) 1077e1087
(3H, d, J¼6.6 Hz, H-6), 0.91e0.81 (1H, m, H-3b). 13C NMR
(125 MHz, CDCl3) dC (ppm): 55.1 (C-5trans), 54.1 (C-5cis),
55.1 (C-2cis), 53.6 (C-2trans), 43.4 (C-3cis), 41.9 (C-3trans), 34.7
and 33.4 (C-4), 21.6 and 21.5 (C-1), 19.6 and 19.3 (C-6). MS
4.2.5. Synthesis of 1-benzyl-2,5-dimethylpyrrolidine (21)
10
9
11
7
Ph
8
6
5
NH
N
n-BuLi 1,6 M / hexane (16mol%)
ꢃ
(EI, 70 eV) m/z (relative intensity, %): 99 (Mþ , 5), 84 (100),
1
2
THP / Toluene 1:1, 110 °C, 10h
4
57 (47). IR (film) n (cmꢂ1): 3341 [w], 2957e2872 [s], 1624
[w], 1533 [w], 1456 [m], 1379 [m], 1128 [w], 1082 [w], 837
[w], 775 [w]. CAS: [40465-44-9] cis-(2R,4S ); [73604-50-9]
trans-(S,S ).
3
20
21
1
Isolated yield: 79% (cis as major product, dr¼85:15). H
NMR (500 MHz, CDCl3) dH (ppm): cis: 7.41e7.20 (5H, m,
Ph), 3.76 (2H, s, H-7), 2.64e2.48 (2H, m, H-2 and H-5),
1.87e1.70 (2H, m, H-3a and H-4a), 1.46e1.31 (2H, m, H-3b
and H-4b), 1.07 (6H, d, J¼6.1 Hz, H-1 and H-6). Trans:
7.41e7.20 (5H, m, Ph), 3.85 (1H, d, J¼13.8 Hz, H-7a), 3.52
(1H, d, J¼13.8 Hz, H-7b), 3.07e2.98 (2H, m, H-2 and H-5),
2.07e1.96 (2H, m, H-3a and H-4a), 1.46e1.31 (2H, m, H-3b
and H-4b), 0.98 (6H, d, J¼6.3 Hz, H-1 and H-6). 13C NMR
(125 MHz, CDCl3) dC (ppm): cis: 139.4 (C-8), 129.5 and
128.1 (C-9 and C-10), 126.8 (C-11), 59.6 (C-7), 55.2 (C-2 and
C-5), 31.5 (C-3 and C-4), 20.8 (C-1 and C-6). Trans: 140.9
(C-8), 128.7 and 128.2 (C-9 and C-10), 126.6 (C-11), 55.1
(C-2 and C-5), 51.9(C-7), 31.1(C-3 and C-4), 17.3(C-1and C-6).
MS (CI, 70 eV) m/z (relative intensity, %): 190 (Mþ1, 8), 91
(100). IR (KBr) n (cmꢂ1): 3062 [w], 3026 [w], 2960e2868
[s], 1494 [m], 1453 [m], 1372 [m], 1207 [w], 730 [m], 697 [s].
4.2.3. Synthesis of 2-methyl-5-propylpyrrolidine (17)
8
7
9
2
H
NH
H
N
6
n-BuLi 1,6 M / hexane (16mol%)
1
5
4
THP / Toluene 1:1, 110 °C, 3h
3
16
17
Isolated yield: 73% (trans as major product, dr¼72:28). 1H
NMR (500 MHz, CDCl3) dH (ppm): trans: 3.25 (1H, sext (qt),
J¼6.5 Hz, H-2), 3.14 (1H, quint (tt), J¼6.6 Hz, H-5), 2.07e
1.87 (2H, m) and 1.53e1.18 (6H, m) (H-3, 4, 6 and 7), 1.10
(3H, d, J¼6.3 Hz, H-1), 0.90 (3H, t, J¼6.9 Hz, H-8). Cis: 3.06
(1H, sext (qt), J¼6.8 Hz, H-2), 2.96 (1H, quint (tt), J¼6.5 Hz,
H-5), 1.86e1.77 (2H, m) and 1.53e1.18 (6H, m) (H-3, 4, 6
and 7), 1.15 (3H, d, J¼6.2 Hz, H-1), 0.90 (3H, t, J¼6.9 Hz,
H-8). 13C NMR (125 MHz, CDCl3) dC (ppm): trans: 58.0 (C-5),
53.4 (C-2), 39.7, 34.7, 33.0 and 20.7 (C-3, 4, 6 and 7), 22.2
(C-1), 14.4 (C-8). Cis: 59.7 (C-5), 54.7 (C-2), 39.2, 33.4, 32.1
and 20.8 (C-3, 4, 6 and 7), 21.5 (C-1), 14.5 (C-8). MS (EI,
ꢃ
HRMS (EIþ, Mþ ): (C13H19N) calcd: 189.1517; found:
189.1512. CAS: [4209e68-1] cis-(S,R), [4209-71-6] and
[119008-53-6] trans-(R,R), [153481-73-3] trans-(S,S ).
4.2.6. Synthesis of 1-benzyl-2-methylpiperidine (25)
10
9
11
ꢃ
70 eV) m/z (relative intensity, %): 127 (Mþ , 1), 112 (1), 86
Ph
NH
7
(9), 84 (100), 72 (31), 70 (10), 67 (9). IR (film) n (cmꢂ1):
3393 [m], 2957e2870 [s], 1628 [w], 1458 and 1400 [m], 1375
[w], 1132 [w], 1097, 808 [w], 735[w]. CAS: [90886-40-1].
8
n-BuLi 1,6 M / hexane (16mol%)
1
N
6
5
2
3
THP / Toluene 1:1, 110 °C, 112h
4
24
25
Isolated yield: 83%. 1H NMR (500 MHz, CDCl3) dH (ppm):
7.40e7.18 (5H, m, Ph), 4.00 (1H, d, J¼13.2 Hz, H-7a), 3.19
(1H, d, J¼13.5 Hz, H-7b), 2.30 (1H, dt, J¼12.0, 3.7 Hz,
H-6a), 2.35e2.21 (1H, m, H-2), 1.94 (1H, dt, J¼11.5, 3.4 Hz,
H-6b), 1.70e1.57 (2H, m) and 1.57e1.20 (4H, m) (H-3, 4 and 5),
1.17 (3H, d, J¼6.2 Hz, H-1). 13C NMR (50 MHz, CDCl3) dC
(ppm): 140.0 (C-8), 129.2 and 128.2 (C-9 and C-10), 126.8
(C-11), 58.8 (C-7), 56.6 (C-2), 52.4 (C-6), 35.0, 26.3 and 24.2
(C-3, 4 and 5), 19.6 (C-1). MS (EI, 70 eV) m/z (relative intensity,
4.2.4. Synthesis of 1-benzyl-2-methylpyrrolidine (19)
9
8
10
6
Ph
7
NH
5
4
N
n-BuLi 1,6 M / hexane (16mol%)
1
2
THP / Toluene 1:1, 110 °C, 1h
3
18
19
ꢃ
Isolated yield: 79%. 1H NMR (300 MHz, CDCl3) dH (ppm):
7.35e7.15 (5H, m, Ph), 4.01 (1H, d, J¼12.9 Hz, H-6a), 3.12
(1H, d, J¼12.9 Hz, H-6b), 2.95e2.83 (1H, m, H-5a), 2.37 (1H,
sext (qt), J¼7.7 Hz, H-2), 2.08 (1H, q (dt), J¼9.1 Hz, H-5b),
2.00e1.84 (1H, m), 1.80e1.53 (2H, m) and 1.52e1.35 (1H,
m) (H-3 and H-4), 1.17 (3H, d, J¼5.7 Hz, H-1). 13C NMR
(75 MHz, CDCl3) dC (ppm): 139.3 (C-7), 128.9 and 128.0
(C-8 and C-9), 126.6 (C-10), 59.5 (C-6), 58.3 and 54.0 (C-2
and C-5), 32.7 and 21.4 (C-3 and C-4), 19.1 (C-1). MS (CI,
70 eV) m/z (relative intensity, %): 176 (Mþ1, 69), 160 (100),
91 (49). IR (KBr) n (cmꢂ1): 3063 [w], 3028 [w], 2963 [s],
2869 [m], 2786 [m], 1495 [m], 1454 [m], 1374 [m], 1140 [w],
%): 189 (Mþ , 17), 174 (100), 91 (70). IR (film) n (cmꢂ1): 3085
[w], 3063 [m], 3027 [m], 2963e2788 [s], 1494 [m], 1452 [s],
1373 [s], 1329 [m], 1133 [m], 1116 [s], 1066 [s], 730 [s], 697
[s]. CAS: [777-38-8].
4.2.7. Synthesis of 1-benzyl-2,5,5-trimethylpiperidine (27)
12
11
13
Ph
NH
9
10
1
n-BuLi 1,6 M / hexane (16mol%)
N
6
2
8
THF, 50 °C, 22h
3
5
4
26
27
7
ꢃ
736 [m], 697 [s]. HRMS (EIþ, Mþ ): (C12H17N) calcd:
Isolated yield: >95%. 1H NMR (500 MHz, CDCl3) dH
(ppm): 7.38e7.17 (5H, m, Ph), 3.99 (1H, d, J¼13.8 Hz, H-9a),
175.136100; found: 175.136060. CAS: [774-91-4].

C. Quinet et al. / Tetrahedron 64 (2008) 1077e1087
1085
3.08 (1H, d, J¼13.5 Hz, H-9b), 2.30 (1H, dd, J¼11.1, 2.1 Hz,
H-6a), 2.28e2.16 (1H, m, H-2), 1.68 (1H, d, J¼11.4 Hz,
H-6b), 1.62e1.28 (2H, m) and 1.22e1.13 (2H, m) (H-3 and
H-4), 1.12 (3H, d, J¼6.3 Hz, H-1), 0.94 (3H, s) and 0.79
(3H, s) (H-7 and H-8). 13C NMR (50 MHz, CDCl3) dC
(ppm): 140.4 (C-10), 128.2 and 127.7 (C-11 and C-12),
126.1 (C-13), 63.6 (C-9), 58.1 (C-6), 56.3 (C-2), 36.8 and
31.4 (C-3 and C-4), 30.6 (C-5), 28.6, 25.0 and 18.4 (C-1, 7
77 (61), 70 (26), 69 (100), 67 (35), 65 (20), 55 (67), 53 (22),
51 (18). IR (film) n (cmꢂ1): 3391 [s], 2957e2866 [s], 1649e
1560 [s], 1456e1381 [m], 1356[m], 1090 [w], 1036 [w], 800
[w], 702 [w]. CAS: [19451-50-4] cis-(S,S ).
4.2.10. Synthesis of 3-methyl-octahydro-indolizidine (35)
1
2
H
N
3
4
ꢃ
and 8). MS (EI, 70 eV) m/z (relative intensity, %): 217 (Mþ ,
9
N
n-BuLi 1,6 M/ hexane (16mol%)
18), 202 (100), 91 (68). IR (film) n (cmꢂ1): 3086 [m], 3063
[m], 3027 [s], 2957e2822 [s], 1494 [s], 1453 [s], 1370 [s],
1332 [s], 1148 [s], 1124 [s], 1067 [s], 741 [s], 728 [s], 697 [s].
E.A.: (C15H23N) Calcd: C, 82.89; H, 10.67; N, 6.44%. Found:
C, 82.20; H, 10.55; N, 6.14%.
8
THP / Toluene 1:1, 110 °C, 2h
H
5
6
7
34
35
1
Isolated yield: 76% (cis as major product, dr¼93:7). H
NMR (500 MHz, CDCl3) dH (ppm): cis: 3.14 (1H, br d,
J¼10.7 Hz, H-5), 2.16e2.04 (1H, m, H-2), 1.93e1.61 (7H,
m), 1.59e1.46 (1H, m) and 1.41e1.13 (4H, m) (H-3, 4, 6,
7, 8 and 9), 1.11 (3H, d, J¼6.1 Hz, H-1). Trans: 2.92 (1H,
br d, J¼11.6 Hz, H-5), 2.16e2.04 (1H, m, H-2), 1.93e1.61
(7H, m), 1.59e1.46 (1H, m) and 1.41e1.13 (4H, m) (H-3, 4,
6, 7, 8 and 9), 0.97 (3H, d, J¼5.1 Hz, H-1). 13C NMR
(125 MHz, CDCl3) dC (ppm): 65.7 (C-5), 60.6 (C-2), 51.3
(C-9), 31.3 (C-3), 30.4 (C-6), 29.1 (C-4), 25.5 and 24.5 (C-7
and C-8), 18.4 (C-1). MS (EI, 70 eV) m/z (relative intensity,
4.2.8. Synthesis of 2-methyl-6-propylpiperidine (31)
9
8
10
H
H
NH
1
6 N
2
7
n-BuLi 1,6 M / hexane (16mol%)
THP / Toluene 1:1, 110 °C, 48h
3
5
4
30
31
1
Isolated yield: 85% (cis as major product, dr¼75:25). H
NMR (500 MHz, CDCl3) dH (ppm): cis: 2.67e2.57 (1H, m,
H-2), 2.55e2.44 (1H, m, H-6), 1.80e1.72 (1H, m), 1.70e
1.52 (2H, m), 1.50e1.18 (5H, m) and 1.04e0.96 (2H, m)
(H-3, 4, 5, 7 and 8), 1.07 (3H, d, J¼6.2 Hz, H-1), 0.94e0.82
(3H, m, H-9). Trans: 3.12e3.02 (1H, m, H-2), 2.95e2.87 (1H,
m, H-6), 1.80e1.72 (1H, m), 1.70e1.52 (2H, m), 1.50e1.18
(5H, m) and 1.04e0.96 (2H, m) (H-3, 4, 5, 7 and 8), 1.09 (3H,
d, J¼6.6 Hz, H-1), 0.94e0.82 (3H, m, H-9). 13C NMR
(125 MHz, CDCl3) dC (ppm): cis: 57.0 (C-6), 52.7 (C-2),
39.9, 34.6, 32.5, 25.1 and 19.3 (C-3, 4, 5, 7 and 8), 23.3
(C-1), 14.5 (C-9). Trans: 50.7 (C-6), 46.1 (C-2), 40.6, 38.4,
32.3, 26.1 and 19.5 (C-3, 4, 5, 7 and 8), 22.9 (C-1), 14.3 (C-9).
MS (APCI, 70 eV) m/z (relative intensity, %): 142 (Mþ1, 48),
83 (48), 69 (100). IR (film) n (cmꢂ1): 3337 [w], 2955e2856
[s], 1653e1570 [w], 1460e1439 [m], 1377 [m], 1308 [w],
1126 [w], 795 [w], 748 [w], 721 [w]. CAS: [65337-42-0]
cis-(2S,6R), [65266-41-3] cis-(2R,6S ).
ꢃ
%): 139 (Mþ , 11), 138 (30), 136 (20), 124 (100), 96 (17),
84 (68), 82 (28), 80 (14), 69 (35), 67 (16), 55 (43). IR (film)
n (cmꢂ1): 3398 [w], 2957e2856 [s], 2787e2714 [w], 1664
[m], 1441e1373 [m], 1200e1067 [m], 806 [w], 739 [w].
CAS: [68344-43-4] trans-(8S,3R), [68344-39-8] cis-(S,S ).
4.2.11. Synthesis of cis-hexahydro-3,5-dimethyl-1H-
pyrrolizidine (37)
n-BuLi 1,6 M / hexane (16mol%)
NH2
N
THP / Toluene 1:1, 110 °C, 20h
36
37
9
7
8
O
14
10
6
O2N
NO2
13
12
NO2
H
2
N
1
5
H
4
11
3
4.2.9. Synthesis of cis-hexahydro-3-methyl-1H-pyrrolizidine
(33)
Isolated yield: 88%. 1H NMR (500 MHz, CDCl3) dH (ppm):
9.07 (2H, s, H-12), 4.68 (1H, sext (ttd), J¼7.8 Hz, H-5), 3.41
(2H, qdd, J¼7.3, 6.8, 3.8 Hz, H-2 and H-8), 2.43 (2H, dddd,
J¼10.8, 6.8, 4.2, 2.7 Hz, H-4a and H-6a), 2.25 (2H, dddd,
J¼12.2, 7.7, 6.6, 4.4 Hz, H-3a and H-7a), 2.07 (2H, dddd, J¼
12.0, 9.9, 3.5, 2.8 Hz, H-3b and H-7b), 1.77 (2H, dddd,
J¼11.2, 9.8, 9.4, 4.5 Hz, H-4b and H-6b), 1.55 (6H, d, J¼
6.7 Hz, H-1 and H-9). 13C NMR (125 MHz, CDCl3) dC
(ppm): 155.8 (C-14), 138.4 (C-13), 134.7 (C-11), 126.3
(C-12), 68.9 (C-5), 65.3 (C-2 and C-8), 34.0 (C-3 and C-7), 30.7
(C-4 and C-6), 16.8 (C-1 and C-9). MS (EI, 70 eV) m/z (relative
1
2
H
N
3
8
7
N
n-BuLi 1,6 M / hexane (16mol%)
THP / Toluene 1:1, 110 °C, 2h
4
H
5
6
32
33
Isolated yield: 83%. 1H NMR (500 MHz, CDCl3) dH (ppm):
3.61 (1H, quint (dddd), J¼7.0 Hz, H-5), 2.98e2.91 (1H, m,
H-2), 2.68e2.57 (2H, m, H-8), 2.06e1.98 (1H, m), 1.97e1.80
(4H, m) and 1.54e1.32 (3H, m) (H-3, 4, 6 and 7), 1.13 (3H,
d, J¼6.2 Hz, H-1). 13C NMR (125 MHz, CDCl3) dC (ppm):
65.0 (C-5), 62.3 (C-2), 53.5 (C-8), 35.8 (C-3), 33.1 (C-6),
32.4 (C-4), 25.9 (C-7), 21.2 (C-1). MS (EI, 70 eV) m/z (rela-
ꢃ
intensity, %): 139 (Mþ , 20), 138 (15), 124 (100), 121 (9), 111
(42), 110 (13). IR (film) n (cmꢂ1): 3428 [m], 3078 [s], 2977 [m],
2873 [m], 1561 [w], 1346 [m], 1112 [m]. CAS: [138615-28-8],
[56160-71-5] for the free amine 31.
ꢃ
tive intensity, %): 125 (Mþ , 6), 124 (53), 110 (17), 108 (43),
105 (15), 97 (36), 96 (24), 91 (16), 83 (28), 82 (56), 80 (57),

1086
C. Quinet et al. / Tetrahedron 64 (2008) 1077e1087
4.2.12. Synthesis of cis-hexahydrodro-3,5-dimethyl-7a-
phenyl-1H-pyrrolizidine (39)
H-2 and H-6), 2.21 (2H, s, H-7), 1.41 (2H, dd, J¼11.0,
7.2 Hz, H-3a and H-5a), 1.18 (3H, s, H-9), 1.11 (6H, d,
J¼6.7 Hz, H-1 and H-8), 1.45e1.35 (2H, m, H-3b and
H-5b). 43: 3.34e3.08 (2H, m, H-2 and H-6), 2.45 (1H, dd,
J¼9.6, 2.4 Hz, H-7a), 2.23e2.16 (1H, m, H-7b), 1.59 (1H,
ddd, J¼10.1, 10.1, 3.4 Hz) and 1.39e1.30 (1H, m) (H-3a
and H-5a), 1.20 (3H, s, H-9), 1.17 (3H, d, J¼7.2 Hz) and 1.09
(3H, d, J¼7.2 Hz) (H-1 and H-8), 1.01e0.93 (1H, m) and 0.60
(1H, ddd, J¼11.5, 6.2, 2.4 Hz) (H-3b and H-5b).13C NMR
(75 MHz, CDCl3) dC (ppm): 42: 62.2 (C-2 and C-6), 57.3
(C-7), 46.7 (C-4), 45.3 (C-3 and C-5), 22.9 (C-1 and C-8),
17.1 (C-9). 43: 62.9 and 59.7 (C-2 and C-6), 50.7 (C-7), 48.3
(C-4), 47.4 and 43.9 (C-3 and C-5), 22.7 (C-1), 17.7 and 17.6
(C-8 and C-9). MS (CI, 70 eV) m/z (relative intensity, %): 140
(Mþ1, 60), 98 (23), 95 (8), 55 (100). IR (film) n (cmꢂ1):
2960e2864 [s], 1457 [m], 1375 [m], 1046 [m]. CAS:
[700378-37-6] (R,S ); [700378-28-5] (S,S ).
9
7
8
6
11
n-BuLi 1,6 M / hexane (16mol%)
NH2
12
13
N
5
THP / Toluene 1:1, 110 °C, 20h
10
2
1
4
3
38
39
Isolated yield: 84%. 1H NMR (300 MHz, CDCl3) dH (ppm):
7.50e7.16 (5H, m, Ph), 2.51e2.48 (2H, m, H-2 and H-8),
2.24e1.54 (8H, m, H-3, 4, 6 and 7), 1.36 (6H, d, J¼6.6 Hz, H-1
and H-9). 13C NMR (75 MHz, CDCl3) dC (ppm): 127.5 and
125.9 (C-11 and C-12), 125.1 (C-13), 68.6 (C-5), 53.1 (C-2 and
C-8), 35.2 (C-4 and C-6), 30.6 (C-3 and C-7), 22.1 (C-1 and C-9).
MS (ESI, 70 eV) m/z (relative intensity, %): 216.17 (MþþH, 95),
214.19 (73), 199.15 (7), 155.11 (10), 143.08 (14), 129.06 (21). IR
(film) n (cmꢂ1): 3038 [w], 2962e2848 [s], 1675e1538 [m],
1438e1360 [m], 1224e1120 [m], 778 [w], 732 [w].
4.2.13. Synthesis of 4-allyl-2,4-dimethylpyrrolidine (41)
Acknowledgements
10
HN
10
HN
6
6
5
5
8
8
7
7
4
4
´
Financial support for this work by the Universite catholique
2
2
3
3
9
9
de Louvain, the Fond National de la Recherche Scientifique
(to A.A.) and Merck Sharp and Dohme (unrestricted Grant
to I.E.M.) is gratefully acknowledged.
41A
41B
1
1
1
Isolated yield: 95% (41A as major product, dr¼60:40). H
NMR (300 MHz, CDCl3) dH (ppm): 41A: 5.88e5.72 (1H, m,
H-7), 5.06e5.01 (2H, m, H-8), 3.30e3.13 (1H, m, H-2), 2.84
(1H, A part of AB, J¼11.0 Hz, H-5a), 2.56 (1H, B part of AB,
J¼11.0 Hz, H-5b), 2.21 (1H, br s, H-10), 2.11 (2H, d,
J¼7.7 Hz, H-6), 1.62 (1H, dd, J¼12.5, 6.8 Hz, H-3a), 1.15
(3H, d, J¼6.2 Hz, H-1), 1.14e1.08 (1H, m, H-3b), 1.02 (3H,
s, H-9). 41B: 5.88e5.72 (1H, m, H-7), 5.06e5.01 (2H, m,
H-8), 3.30e3.13 (1H, m, H-2), 2.70 (1H, A part of AB,
J¼11.0 Hz, H-5a), 2.67 (1H, B part of AB, J¼11.0 Hz, H-5b),
2.21 (1H, br s, H-10), 2.10 (2H, d, J¼7.7 Hz, H-6), 1.83 (1H,
dd, J¼12.9, 7.2 Hz, H-3a), 1.16 (3H, d, J¼6.2 Hz, H-1), 1.05
(3H, s, H-9), 1.03e0.97 (1H, m, H-3b). 13C NMR (75 MHz,
CDCl3) dC (ppm): 135.7 and 135.6 (C-735A and C-735B), 116.9
(C-835A and C-835B), 59.4 and 59.2 (C-535A and C-535B), 54.5
and 54.1 (C-235A and C-235B), 47.9, 47.5, 46.4 and 45.3
(C-335A, C-335B, C-635A and C-635B), 43.1 (C-435A and C-435B),
26.8 and 25.9 (C-135A and C-135B), 21.8 and 21.4 (C-935A and
References and notes
1. Haggin, J. Chem. Eng. News 1993, 23 (May 31).
2. (a) Trost, B. M. Science 1991, 254, 1471; (b) Sheldon, R. A. Ind. Environ.
Chem. 1992, 99; (c) Sheldon, R. A. J. Chem. Technol. Biotechnol. 1997,
68, 381; (d) Sheldon, R. A. Nature 1999, 399, 33; (e) Trost, B. M. Acc.
Chem. Res. 2002, 35, 695.
3. See for example: (a) Gasc, M. B.; Lattes, A.; Perie, J. J. Tetrahedron 1983,
39, 703; (b) Roundhill, D. M. Chem. Rev. 1992, 92, 1; (c) Taube, R.
Applied Homogeneous Catalysis with Organometallic Compounds;
Cornils, B., Herrmann, W. A., Eds.; Wiley-VCH: Weinheim, 1996; Vol.
1, p 507; (d) Muller, T. E.; Beller, M. Chem. Rev. 1998, 98, 675; (e) Togni,
¨
A.; Grutzmacher, H. Catalytic Heterofunctionalization; Wiley-VCH:
Weinheim, 2001; p 91.
4. The direct addition of an amine to an olefin is clearly the most economical
and environmentally friendly access to substituted amines. Indeed, though
substituted amines can be prepared industrially from alcohols, the alcohols
themselves are typically obtained from the corresponding alkenes, hence
adding one more step to the process. Moreover, the classic synthesis of
amines by nucleophilic substitution generates large quantities of salts,
which have to be disposed of in a suitable and ecologically benign manner.
5. These conditions are required, for example, for the addition of ammonia
onto ethylene, catalysed by alkali metals: Howk, B. W.; Little, E. L.;
Scott, S. L.; Whitman, G. M. J. Am. Chem. Soc. 1954, 76, 1899.
6. In these cases, release of internal strain energy or enhanced stabilising of
the generated carbanion is responsible for the ease of amine addition. See
for example: (a) Wegler, R.; Pieper, G. Chem. Ber. 1950, 83, 1; (b)
Asahara, T.; Seno, M.; Tanabe, S.; Den, N. Bull. Chem. Soc. Jpn. 1969,
42, 1966; (c) Imai, N.; Narita, T.; Tsuruta, T. Tetrahedron Lett. 1971,
38, 3517; (d) Narita, T.; Yamaguchi, T.; Tsuruta, T. Bull. Chem. Soc.
Jpn. 1973, 46, 3825; (e) Fujita, T.; Suga, K.; Watanabe, S. Aust. J.
Chem. 1974, 27, 531; (f) Hartung, C. G.; Breindl, C.; Tillack, A.; Beller,
M. Tetrahedron 2000, 56, 5157 and references cited therein.
ꢃ
C-935B). MS (EI, 70 eV) m/z (relative intensity, %): 139 (Mþ ,
9), 124 (28), 96 (43), 83 (7), 57 (100). IR (film) n (cmꢂ1):
3293 [w], 3076 [m], 2957e2899 [s], 1639 [m], 1533 [w],
1456 [m], 1415 [m], 1378 [m], 1097 [m], 996 [m], 912 [s].
CAS: [899832-60-1] 41A-(S,S ); [899832-59-8] 41B-(2S,4R);
[700378-27-4] 41B-(2R,4S ).
4.2.14. Synthesis of 2,4,6-trimethyl-1-aza-bicyclo[2.2.2]-
heptane (42e43)
7
7
9
9
3
3
5
5
4
4
N
N
1
1
8
6
8
6
2
2
42
43
7. For example, the addition of ammonia to propene to form propylamine
requires temperatures around 250 ꢀC and pressures in the range of
800e1000 bars (yield: 29%). (a) Schlott, R. J.; Falk, J. C.; Narducy,
1
Isolated yield: 80% (42 as major product, dr¼52:48). H
NMR (300 MHz, CDCl3) dH (ppm): 42: 2.82e2.69 (2H, m,

C. Quinet et al. / Tetrahedron 64 (2008) 1077e1087
1087
K. W. J. Org. Chem. 1972, 26, 4243; (b) Lehmkuhl, H.; Reinehr, D.
J. Organomet. Chem. 1973, 55, 215.
13. It is quite clear that intramolecular hydroamination reactions proceeded
with a lower activation energy than their intermolecular counterparts.
However, the u-amino-alkene substrates cannot be considered as activated
olefins, as described in Ref. 6.
8. Thermodynamic data for the addition of ammonia on ethylene: DGs
¼
ꢂ14.7 kJ molꢂ1, DHs¼ꢂ52.7 kJ molꢂ1, DSs¼ꢂ127.3 J molꢂ1 Kꢂ1and
for the addition of ethylamine on ethylene: DGs¼ꢂ33.4 kJ molꢂ1
,
14. Ates, A.; Quinet, C. Eur. J. Org. Chem. 2003, 1623.
DHs¼ꢂ78.7 kJ molꢂ1, DSs¼ꢂ152.2 J molꢂ1 Kꢂ1. Data obtained from:
Steinborn, D.; Taube, R. Z. Chem. 1986, 26, 349.
15. Amine 8 has been specifically selected for this purpose, since it is a sub-
strate that gives only poor yields of the corresponding pyrrolidine under
the previously described conditions.
9. For general references on hydroamination, see: (a) Seayad, J.; Tillack, A.;
Hartung, C. G.; Beller, M. Adv. Synth. Catal. 2002, 344, 795; (b) Pohlki, F.;
Doye, S. Chem. Soc. Rev. 2003, 32, 104; (c) Hartwig, J. F. Pure Appl. Chem.
2004, 76, 507; (d) Hong, S.; Marks, T. J. Acc. Chem. Res. 2004, 37, 673.
10. For alkali and alkaline earth metal-catalysed hydroamination of non-acti-
vated alkenes, see: (a) Clossom, R. D.; Napolitano, J. P.; Ecke, G. G.;
Kolka, A. J. Org. Chem. 1957, 22, 646; (b) Radzan, R. K. J. Chem.
Soc., Chem. Commun. 1969, 770; (c) See Ref. 6c; (d) Schott, R. J.;
Falk, J. C.; Narducy, K. W. J. Org. Chem. 1972, 37, 4243; (e) See
Ref. 7b; (f) Pez, G. P.; Galle, J. E. Pure Appl. Chem. 1985, 57, 1917;
(g) Steinborn, D.; Thies, B.; Wagner, I.; Taube, R. Z. Chem. 1989, 29,
333; (h) Fujita, H.; Tokuda, M.; Nitta, M.; Suginome, H. Tetrahedron
Lett. 1992, 33, 6359; (i) van Otterlo, W. A. L.; Pathak, R.; de Koning,
C. B.; Fernandes, M. A. Tetrahedron Lett. 2004, 45, 9561; (j) Khedkar,
V.; Tillack, A.; Benisch, C.; Melder, J.-P.; Beller, M. J. Mol. Catal. A
2005, 241, 175; (k) Lebeuf, R.; Robert, F.; Landais, Y. Org. Lett. 2005,
7, 4557; (l) Crimmins, M. R.; Casely, I. J.; Hill, M. S. J. Am. Chem.
Soc. 2005, 127, 2042; (m) Lebeuf, R.; Robert, F.; Schenk, K.; Landais,
Y. Org. Lett. 2006, 8, 4755; (n) Martinez, P. H.; Hultzsch, K. C.; Hampel,
F. Chem. Commun. 2006, 2221.
16. This proton abstraction could be an inter- or an intramolecular process.
Since it occurs at about the same rate, regardless of the ring size of
putative intramolecular transition states, we favour the intermolecular
pathway, taking place through the mixed amine-lithiated amide dimer.
17. The difference in basicity between the anion of a primary amine and the
corresponding carbanion averages around 20 pKa units, henceforth
precluding the formation of a discrete carbanionic intermediate in our hy-
droamination reactions. For an excellent pKa scale, see: Bordwell, F. C.
Acc. Chem. Res. 1988, 21, 456; See also: <http://www.chem.wisc.
edu/areas/reich/pkatable/>. For a splendid article discussing the various
mechanistic possibilities involved in the hydroamination ring closing
´
step, see: Gagne, M. R.; Stern, C. L.; Marks, T. J. J. Am. Chem. Soc.
1992, 114, 275.
18. (a) Laube, T.; Dunitz, J. D.; Seebach, D. Helv. Chim. Acta 1985, 68, 1373;
(b) Seebach, D. Angew. Chem., Int. Ed. Engl. 1988, 27, 1624; (c) Williard,
P. G.; Salvino, J. M. J. Org. Chem. 1993, 58, 1.
19. The role played by the lithium cation is of paramount importance. By co-
ordinating to the alkene p-system, it withdraws electron density from the
olefin, hence facilitating the addition of the amine. Moreover, its coordi-
nation to the amine acidifies the hydrogen atoms attached on the nitrogen,
easing the transfer of one of them to the developing carbanion. Finally,
partial donation of the electron density gathered by lithium from the
amine nitrogen and the CeC double bond to the amide nitrogen, increases
its nucleophilicity, speeding up its addition on the alkene.
11. For selected references on lanthanides and actinides-catalysed hydroami-
nations, see: (a) Kim, Y. K.; Livinghouse, T. Angew. Chem., Int. Ed. 2002,
41, 3645; (b) Ryu, J.-S.; Li, G. Y.; Marks, T. J. J. Am. Chem. Soc. 2003,
125, 12584; (c) Roesky, P. W.; Muller, T. E. Angew. Chem., Int. Ed. 2003,
¨
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42, 2708; (d) Motta, A.; Lanza, G.; Fragala, I. L.; Marks, T. J. Organome-
tallics 2004, 23, 4097; (e) Gribkov, D. V.; Hultzsch, K. C. Chem. Commun.
2004, 730; (f) Hultzsch, K. C.; Hampel, F.; Wagner, T. Organometallics
2004, 23, 2601; (g) Kim, Y. K.; Livinghouse, T. Org. Lett. 2005, 7,
20. This is clearly evidenced by the various aggregation forms of lithiated am-
ides in solvents of different polarity or coordinating abilities. For an excel-
lent review, see: Collum, D. B.; McNeil, A. J.; Ramirez, A. Angew. Chem.,
Int. Ed. 2007, 46, 3002 and references cited therein.
`
1737; Motta, A.; Fragala, I. L.; Marks, T. J. Organometallics 2006, 25,
5533; (h) Gribkov, D. V.; Hultzsch, K. C.; Hampel, F. J. Am. Chem.
Soc. 2006, 128, 3748; (i) Rastatter, M.; Zulys, A.; Roesky, P. W. Chem.
Commun. 2006, 874; (j) Riegert, D.; Collin, J.; Meddour, A.; Schultz,
E.; Trifonov, A. J. Org. Chem. 2006, 71, 2514; (k) Lee, A. V.; Schafer,
L. L. Eur. J. Inorg. Chem. 2007, 2243.
21. Since it is sold as a 1.6 M solution, using 16 mol % of n-BuLi is particu-
larly convenient. However, in many cases, we have observed that lower
amounts of n-BuLi are enough to bring the hydroamination to full conver-
sion. For example, the double cyclisation of 40 to 42 and 43 proceeded in
identical yields and diastereomeric ratios if 16, 10 or 5 mol % n-BuLi
were employed.
¨
12. For example, most of the lanthanide-based catalysts can only be prepared
using a glove-box or special Schlenck techniques. They are also exqui-
sitely sensitive towards the slightest trace of oxygen and lose most of their
activity in nucleophilic solvents.
´
22. (a) Bonjoch, J.; Sole, D. Chem. Rev. 2000, 100, 3455; (b) Daly, J. W.
J. Med. Chem. 2003, 46, 445; (c) Zezula, J.; Hudlicky, T. Synlett 2005,
388; (d) Kibayashi, C. Chem. Pharm. Bull. 2005, 53, 1375.