Easy routes towards chiral lithium binaphthylamido catalysts for the asymmetric hydroamination of amino-1,3-dienes and aminoalkenes

Article abstract of DOI:10.1002/ejoc.201001596

The preparation of chiral lithium salts of N,N′-disubstituted binaphthyldiamines and their use as catalysts for asymmetric hydroamination/cyclisation of amino-1,3-dienes and aminoalkenes are reported. Several straightforward methods involving the combinat

Full text of DOI:10.1002/ejoc.201001596

FULL PAPER
DOI: 10.1002/ejoc.201001596
Easy Routes towards Chiral Lithium Binaphthylamido Catalysts for the
Asymmetric Hydroamination of Amino-1,3-dienes and Aminoalkenes
Julia Deschamp,[a] Jacqueline Collin,[a,b] Jérôme Hannedouche,*[a,b] and
Emmanuelle Schulz*[a,b]
Keywords: Asymmetric catalysis / Hydroamination / Lithium / Amino-1,3-dienes / Nitrogen heterocycles
The preparation of chiral lithium salts of N,NЈ-disubstituted
binaphthyldiamines and their use as catalysts for asymmetric
hydroamination/cyclisation of amino-1,3-dienes and amino-
alkenes are reported. Several straightforward methods in-
volving the combination of ligand with solutions of methyl-
or [(trimethylsilyl)methyl]lithium (LiCH2TMS) by ex situ or in
situ preparation have been investigated. The use of
LiCH2TMS in an in situ procedure was revealed as the
easiest for carrying out reactions with reliable results by fine-
tuning the quantity of base. Screening of a variety of ligands
led to the selection of binaphthyldiamines modified by
benzyl, pyridyl or naphthyl groups for the cyclisation of con-
jugated aminodienes in pyrrolidine or piperidine with the
highest stereo- and enantioselectivities described to date (up
to 61 and 72% ee, respectively). Primary and secondary
aminoalkenes are efficiently cyclised at room temperature,
but with poor enantioselectivities.
brings the opportunity to control the regio- and stereoselec-
tivities of the transformation by the appropriate metal–
chiral ligand(s) synergy. Recent years have witnessed the
emergence of manifold chiral catalytic systems based on
late-transition metals,[2] group IV metals,[3] rare-earth ele-
ments[4] and alkali metals,[5] for the regio- and enantioselec-
tive hydroamination of unactivated olefins either in an in-
ter- or in an intramolecular fashion.[6] Despite major break-
throughs in this area, some advances in terms of activity,
enantioselectivity and substrate scope are still needed to
bring this attractive alternative up to the requirements of a
truly efficient and low-environmental-impact methodology.
In this context, we have recently reported the use of sim-
ple diaminobinaphthyl dilithium salts as efficient and easily
accessible lithium-based (pre)catalysts for asymmetric intra-
molecular hydroamination (AIH) of amino-1,3-dienes with
outstanding activities, high diastereoselectivities and mod-
erate enantiomeric excess (ee) values.[5d] Although the era
of alkali-metal-catalysed hydroamination reaction origi-
nated in the early 1950s, only limited studies were devoted
to the hydroamination of truly unactivated alkenes under
harsh conditions of pressure and temperature.[7,8] Most of
the reports focused on the alkali-metal-catalysed hydro-
amination of vinylarenes[9,10] and 1,3-dienes[11,12] as activated
alkene surrogates under gentler reaction conditions. It was
only in 2006 that the potential of an asymmetric variant of
a base-catalysed hydroamination reaction was demon-
strated.[5a] In this seminal work by Hultzsch et al., a well-
defined, dimeric, chiral, diamidobinaphthyl dilithium salt
was elegantly exploited as an efficient chiral (pre)catalyst
for the 5-exo cyclisation of primary amines tethered to un-
activated alkenes. Pyrrolidines were quantitatively accessed
Introduction
Amines constitute a key scaffold of a variety of natural
and synthetic organic molecules with diverse applications,
such as pharmaceuticals, fine and bulk chemicals, and cata-
lysts. The quest for the development of sustainable, more
efficient and selective processes for their syntheses has never
been as high as in recent years and will undoubtedly in-
crease exponentially in the near future. Amongst the pleth-
ora of synthetic routes, the direct addition of an amine onto
an unactivated carbon–carbon double bond, the so-called
hydroamination reaction,[1] represents a very promising re-
search field towards the development of an economical and
environmentally benign synthetic method. Indeed, this reac-
tion offers a waste-free process with 100% atom efficiency
from relatively inexpensive and ubiquitous olefins and
amines. Nevertheless, this seemingly simple transformation
suffers from a high activation barrier caused by an un-
favourable interaction between the nitrogen lone pair of the
amine and the electron-rich double bond of the incoming
olefin. Moreover, the negative reaction entropy impedes the
use of higher reaction temperatures. Catalysis may yet af-
ford a general answer to this intricate problem by lowering
the reaction barrier. In addition, a metal-catalysed process
[a] Université Paris-Sud, Equipe de Catalyse Moléculaire,
ICMMO, UMR 8182,
91405 Orsay, France
Fax: +33-1-69154680
E-mail: jerome.hannedouche@u-psud.fr
emmanuelle.schulz@u-psud.fr
[b] CNRS,
91405 Orsay, France
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001596.
Eur. J. Org. Chem. 2011, 3329–3338
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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J. Hannedouche, E. Schulz et al.
FULL PAPER
under mild conditions with ee values up to 75%.[5a] One ducted in the presence of a catalytic amount of MeLi (in
year later, the group of Tomioka reported that the combina- diethyl ether, 0.2 equiv.) added to the substrate in solution
tion of butyllithium, diisopropylamine and a chiral bis(ox- in benzene. Interestingly, the transformation was consider-
azoline) ligand was a competent in situ generated catalyst ably slower, and complete conversion took 4 h. The dia-
for the synthesis of enantioenriched N-methylisoquinoline stereomeric ratio was reversed with the formation of the (Z)
and -isoindoline up to 91% ee by lithium-catalysed AIH.[5b] diastereomer as the major species [(E)/(Z) = 20:80] and a
To the best of our knowledge, these two reports were, at non-negligible amount of the pyrrolidine containing a ter-
the time, the sole contributions to the field of alkali-metal- minal olefin was detected by NMR spectroscopy. Hence,
catalysed asymmetric hydroamination.
the ligand-accelerating effect is significant for this transfor-
Herein, we unveil a more complete study of our work on mation.
the hydroamination/cyclisation of amino-1,3-dienes cata-
lysed by chiral dilithium diamides[5d] and disclose an exten-
sion of this methodology to AIH of primary amines
tethered to unactivated alkenes.
Results and Discussion
Scheme 1. Asymmetric hydroamination of amino-1,3-dienes.
Hydroamination/Cyclisation of Amino-1,3-dienes
We describe herein our attempts to optimise the prepara-
tion of chiral lithium amides as efficient asymmetric cata-
lysts to promote the AIH of primary amino-1,3-dienes.
Hepta-4,6-dienylamine (1a) and octa-5,7-dienylamine (1b)
were used as test substrates to afford the corresponding un-
saturated pyrrolidine 2a and piperidine 2b as potentially
valuable synthons for the preparation of biologically active
molecules (Scheme 1). Binaphthylamine-based ligands were
chosen as asymmetric scaffolds, since, when associated with
rare-earth precatalysts, they allowed the preparation of
highly enantioenriched N-containing heterocycles from pri-
mary or secondary aminoalkenes.[4j–4n,13] Delightfully, a
catalyst preparation arising from dropwise addition of
2 equiv. of a solution of MeLi in diethyl ether to a solution
Figure 1. Chiral (R)-N-substituted binaphthyldiamine ligands.
Moreover, the structure of the base influenced the course
of (R)-H2L1 (Figure 1) in THF and subsequent solvent of the transformation. The use of nBuLi lowered the dia-
evaporation, afforded an active species for the enantioselec- stereomeric ratio and more importantly afforded a nearly
tive cyclisation of 1a in deuterated benzene. 2-Propenylpyr- racemic (Z) compound (Table 1, entry 9). Although LiCH2-
rolidine 2a was indeed formed with complete conversion SiMe3 as a solution in pentane (2 equiv.) led to a satisfyin-
within a very short time; the major (E) diastereomer gly efficient catalyst (Table 1, Entry 10), it surprisingly com-
[(E)/(Z) = 84:16] was isolated with 51% ee (Table 1, en- pletely lost its activity when it was exactly weighed from
try 1). With the aim of optimising these values, the amount an isolated powder and dissolved in diethyl ether (Table 1,
of base was increased up to 6 equiv. (Table 1, Entries 2 and Entries 10 and 11). From this screening study, the best con-
3), allowing a slight increase in the ee values accompanied, ditions for the catalyst preparation imply the use of a solu-
however, with a decrease of the (E)/(Z) ratio. On the other tion of both MeLi (4 equiv.) and ligand in diethyl ether.
hand, the use of diethyl ether as a solvent for the prepara- This methodology was chosen as a standard for the contin-
tion of the catalyst did improve both the activity and selec- uation of the study (Method A).
tivity of the transformation. The best conditions were
The effect of the catalytic ratio on the course of the reac-
achieved with 4 equiv. of MeLi to give the most rapid reac- tion was then studied (Table 2), indicating that the stoichio-
tion and the synthesis of the major (E) diastereomer of 2a metric reaction also occurred smoothly and led to the target
[(E)/(Z) = 92:8] in 51% ee (Table 1, Entries 4–6). Interest- products with similar selectivities as those reported for the
ingly, the minor diastereomer was also synthesised under catalyst used in a 10 mol-% ratio (Table 2, Entries 1 and
those conditions with 50% ee. Very similar results were ob- 2).[14] Decreasing the catalyst amount to 5 mol-% required
tained with a solution of MeLi in diethoxymethane a longer reaction time to reach complete conversion and led
(Table 1, Entry 7). Furthermore, the precatalytic mixture to poorer stereo- and enantiodifferentiation. It was possible
obtained from MeLi in diethyl ether proved to be stable as to run the reaction with a catalyst ratio of 2 mol-%, but
a powder stored under anaerobic conditions and after stor- similarly the trends in terms of activity and selectivity were
age led to the same values (Table 1, Entry 8). It is important not positive (Table 2, Entries 3 and 4). The use of 10 mol-
to note that the transformation could also be run in the % catalyst was thus chosen as the best compromise for short
absence of a ligand. A blank experiment was thus con- reaction times and optimised selectivities.
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Chiral Lithium Binaphthylamido Catalysts
Table 1. Effect of the method of catalyst preparation[a] from (R)-H2L1 on the asymmetric hydroamination reaction of 1a.[b]
Entry
Alkyllithium reagent
Solvent
Equiv.
Time
[h]
Conversion[c]
[%]
Ratio[d]
(E)/(Z)
ee(E)[d] [%]
ee(Z)[d] [%]
(config.[e])
(config.[e])
1
2
3
4
5
MeLi[f]
MeLi[f]
MeLi[f]
MeLi[f]
MeLi[f]
MeLi[f]
MeLi[g]
MeLi[f]
nBuLi[i]
THF
THF
THF
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
2
4
6
2
4
6
4
4
3
2
2
0.33
0.33
0.50
0.25
0.17
0.25
0.17
0.17
0.25
0.50
1
Ͼ95
Ͼ95
Ͼ95
Ͼ95
Ͼ95
Ͼ95
Ͼ95
Ͼ95
Ͼ95
Ͼ95
0
84:16
77:23
72:28
92:8
92:8
85:15
92:8
92:8
85:15
93:7
–
51 (S)
52 (S)
57 (S)
49 (S)
51 (S)
50 (S)
47 (S)
51 (S)
58 (S)
49 (S)
–
3
0
4
47 (S)
50 (S)
6 (S)
47 (S)
58 (S)
6
6
7
8[h]
9
[j]
10
11
LiCH2SiMe3
LiCH2SiMe3
40 (S)
–
[k]
[a] Catalyst preparation was performed by dropwise addition of a solution of the corresponding alkyllithium reagent to a solution of
(R)-H2L1 in solvent (c = 0.02–0.03 m) at room temp., followed by stirring for 10 min and concentration in vacuo. [b] Reactions were
carried out in C6D6 at room temp. under argon with 10 mol-% of catalyst. [c] The configuration was determined by 1H NMR spectroscopy.
[d] Determined by HPLC analysis of the product following derivatisation with 2-benzoyl chloride. [e] See the Supporting Information for
details. [f] MeLi in diethyl ether (1.6 m). [g] MeLi in diethoxymethane (3 m). [h] Catalyst powder used after 4 d of storage at room temp.
under argon. [i] nBuLi in hexanes (1.6 m). [j] LiCH2SiMe3 in pentane (1 m). [k] LiCH2SiMe3 as an isolated powder.
Table 2. Effect of the catalyst ratio[a] on the asymmetric hydro-
A similar trend was obtained for the use of the pyridyl-
derived ligand (R)-H2L3. The stepwise preparation of the
amide salt by using diethyl ether as the solvent (Table 3,
Entry 5) afforded, after 2 h of reaction time, the (Z) product
as the main compound with 26% ee, and a configuration
reversed relative to that obtained with ligand (R)-H2L1 as
the precursor. Interestingly, the in situ preparation (Table 3,
Entry 6) gave a more active and enantioselective catalyst,
and the (Z) isomer could be isolated in up to 65% ee (R),
which was the highest value obtained for this series. Modi-
fied binaphthyldiamine ligand (R)-H2L4, with naphthyl
groups on the nitrogen atoms, behaved analogously to li-
gand (R)-H2L1 as the catalyst precursor and, in particular,
Method B allowed the formation of a selective catalyst that
promoted the formation of the (E) isomer as the main prod-
uct with up to 55% ee (S) (Table 3, Entries 7 and 8). Finally,
two binaphthyldiamine ligands substituted with bulky alkyl
groups on the nitrogen atoms were prepared, but they af-
forded less active and stereoselective catalysts (Table 3, En-
tries 9–12). Both isomers of product 2a were formed in a
nearly equimolar mixture, and the enantioselectivities were
notably diminished compared with those obtained by the
catalysts containing benzyl-like substituents. The highest
values were obtained by using ligand (R)-H2L5, with cy-
clopentyl substituents, and reached only 43% ee (S) for the
(E) isomer and 32% ee (S) for the (Z) isomer (Table 3, En-
try 9).
amination reaction of 1a.[b]
Entry Catalyst ratio Time Ratio[c]
ee(E)[c]
ee(Z)[c] [%]
[%]
[h] (E)/(Z) [%](config.[d]
)
(config.[d]
)
1
2
3
4
100
10
5
0.33
0.17
92:8
92:8
52 (S)
51 (S)
48 (S)
46 (S)
56 (S)
50 (S)
42 (S)
29 (S)
0.40 88:12
84:16
2
3
[a] Catalyst preparation was performed by dropwise addition of a
solution of MeLi in diethyl ether (1.6 m, 4 equiv.) to a solution of
(R)-H2L1 in Et2O (c = 0.02–0.03 m) at room temp., followed by
stirring for 10 min and concentration in vacuo. [b] Reactions were
carried out in C6D6 at room temp. under argon and went into com-
pletion (conversion Ͼ95%, as measured by 1H NMR spec-
troscopy). [c] Determined by HPLC analysis of the product follow-
ing derivatisation with 2-benzoyl chloride. [d] See the Supporting
Information for details.
With the aim of optimising and facilitating catalyst prep-
aration, another procedure was developed (see Method B
in Table 3) for which the addition of MeLi in diethyl ether
as a base was directly performed in a solution of the consid-
ered ligand in deuterated benzene. The resulting mixture
was briefly stirred at room temperature before the substrate
was added directly without any previous removal of the sol-
vent. Both catalyst preparation procedures were then com-
pared for the transformation of the two aminodienes 1a and
1b and in the presence of structurally different ligands
(Table 3). Satisfyingly, in situ Method B, applied to the syn-
thesis of the amide ligand arising from (R)-H2L1, afforded
product 2a with the same results as those obtained by ap-
plying stepwise Method A (compare Entries 1 and 2 in
Table 3). Thus, simplified Method B demonstrated its prac-
ticability and was also applied for the synthesis of different
catalysts from various ligands. The use of the bulkier ligand
(R)-H2L2 allowed the preparation of less active catalysts
(Table 3, Entries 3 and 4), which furthermore showed a re-
verse selectivity for the favoured formation of the (Z) dia-
These catalysts were then evaluated for the intramolecu-
lar hydroamination of substrate 1b, leading to the forma-
tion of piperidine 2b. As expected for the formation of six-
membered heterocycles, the reaction proved to be trickier
and had to be conducted at 50 °C to afford good conver-
sions in reasonable reaction times. Satisfyingly, benzyl-
modified ligand (R)-H2L1 afforded an active catalyst that
provided the expected compound 2b in high yield after 21 h
of reaction time and a high (E)/(Z) selectivity in favour of
stereomer for 2a. Both procedures afforded, however, cata- the (E) isomer. This catalyst gave the (E) isomer with up to
lysts that were poorly enantioselective.
72% ee (S) and the (Z) compound with up to 55% ee (S);
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FULL PAPER
Table 3. Asymmetric hydroamination of amino-1,3-dienes 1a and 1b[a] catalysed by the 1:4 (R)-H2L/MeLi precatalyst system prepared
according to Method A[b] or Method B.[c]
Entry
Substrate
Product
(R)-H2L
Method
Time
[h]
Conversion[d]
[%]
Ratio[e]
(E)/(Z)
ee(E)[e] [%]
ee(Z)[e] [%]
(config.[f])
(config.[f])
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
(R)-H2L1
(R)-H2L1
(R)-H2L2
(R)-H2L2
(R)-H2L3
(R)-H2L3
(R)-H2L4
(R)-H2L4
(R)-H2L5
(R)-H2L5
(R)-H2L6
(R)-H2L6
(R)-H2L1
(R)-H2L1
(R)-H2L2
(R)-H2L2
(R)-H2L4
(R)-H2L4
(R)-H2L5
(R)-H2L5
(R)-H2L6
(R)-H2L6
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
0.17
0.17
3
1
2
0.5
0.25
0.25
2
1
2
Ͼ95 (68)[g]
Ͼ95
92:8
92:8
51 (S)
52 (S)
9 (S)
10 (S)
2
50 (S)
53 (S)
2
Ͼ95
25:75
28:72
22:78
15:85
75:25
91:9
47:53
41:59
55:45
58:42
89:11
91:9
80:20
51:49
86:14
91:9
66:34
61:39
86:14
85:15
Ͼ95[h]
89
6
26 (R)
65 (R)
8 (S)
36 (S)
32 (R)
23 (R)
10 (R)
8 (R)
55 (S)
51 (S)
23 (R)
8 (R)
15 (S)
57 (S)
9 (S)
2
Ͼ95[h]
Ͼ95
8
49 (S)
55 (S)
43 (S)
37 (S)
30 (S)
35 (S)
72 (S)
71 (S)
9 (S)
13 (S)
67 (S)
62 (S)
56 (S)
56 (S)
51 (S)
45 (S)
Ͼ95[h]
Ͼ95
Ͼ95[h]
Ͼ95
1
Ͼ95[h]
Ͼ95 (62)[g]
Ͼ95
21
17
46
42
4
Ͼ95
Ͼ95[h]
92
4
Ͼ95
27
20
27
22
Ͼ95
Ͼ95[h]
Ͼ95
5
Ͼ95[h]
11 (R)
[a] Reactions were carried out in C6D6 at room temp. (1a) or 50 °C (1b) with 10 mol-% of precatalyst. [b] Method A: catalyst preparation
was performed by dropwise addition of 4 equiv. of a solution of MeLi in diethyl ether (1.6 m) to a solution of the ligand (R)-H2L in
diethyl ether (c = 0.025 m) at room temp., followed by stirring for 10 min and concentration in vacuo. [c] Method B: catalyst preparation
was performed by dropwise addition of 4 equiv. of a solution of MeLi in diethyl ether (1.6 m) to a solution of the ligand (R)-H2L in
C6D6 (c = 0.025 m) at room temp. After stirring for 10 min, the substrates were directly added to this catalyst solution. [d] Measured by
1H NMR spectroscopy. [e] Determined by HPLC analysis of the product following derivatisation with 2-benzoyl chloride. [f] See the
Supporting Information for details. [g] Isolated yield of 2a·HCl and 2b·HCl. [h] 10% of the product containing a terminal double bond
1
was detected by H NMR spectroscopy.
these were the highest values reported for compound 2b. to make a difference, the in situ amide preparation led to
The in situ procedure yielded an even more active catalyst far more active catalysts. Method B, as a straightforward in
possessing similar selectivities (Table 3, Entries 13 and 14). situ methodology, allowed the rapid preparation of active
In accordance with the results obtained for the previous and selective catalysts for the cyclisation of aminodienes.
transformation, the use of the analogous mesityl-substi- Corresponding N-heterocycles could be isolated in good
tuted ligand (R)-H2L2 was detrimental to both the activity yields and with the highest enantioselectivities reported to
and the selectivities (Table 3, Entries 15 and 16). Ligand date for such substrates.
(R)-H2L4, with naphthyl groups, gave rise to the most active
To obtain more insight into the structure of the obtained
catalysts of the series, since complete conversions were pre-catalysts, attempts were devoted to the preparation of
reached in 4 h when using both preparation methods crystals suitable for X-ray analysis. This turned out to be
(Table 3, Entries 17 and 18). Enantioselectivities, however, successful by the use of racemic ligand H2L1 mixed together
did not reach those obtained with precursor (R)-H2L1. In with 2 equiv. of MeLi, as we previously reported.[5d] The
this case again, the use of the ligands with alkyl groups, catalytic activity of this isolated species was evaluated for
(R)-H2L5 and (R)-H2L6, led to active catalysts that were the transformation of substrate 1a at room temperature, but
both less stereo- and enantioselective (Table 3, Entries 19– the use of 10 mol-% of catalyst did not show any activity,
22). As already described for the transformation of amino- even after prolonged reaction times. The catalyst synthesis
diene 1a, a blank reaction was conducted with substrate 1b procedure was thus slightly modified, and ligand (Ϯ)-H2L1
in C6D6 in the presence of 20 mol-% of a solution of MeLi was treated with 4 equiv. of MeLi in diethyl ether and
in diethyl ether. The reaction went to completion at 50 °C, stirred for 10 min. This procedure also led to the isolation
but the mixture had to be stirred for more than 2 d and of crystals suitable for X-ray analysis, giving rise to exactly
afforded product 2b in an (E)/(Z) ratio of 78:22, providing the same structure as that prepared with 2 equiv. of MeLi.
additionally a non-negligible amount of a product contain- The resulting crystals were further used to promote the
ing a terminal double bond (20%). Again in this case, the cyclisation of 1a (10 mol-%), which, interestingly, rapidly
preparation of chiral amide derivatives led to an important occurred within 15 min to yield the expected heterocycle 2a
rate enhancement for hydroamination/cyclisation.
with the same diastereoselectivity as that observed when
It should be noted, that for each ligand and considering using the corresponding (R)-H2L1 ligand as the precursor
both substrates 1a and 1b, when it was technically possible [(E)/(Z) = 92:8]. Finally, we proved that the same efficiency
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Chiral Lithium Binaphthylamido Catalysts
(i.e., both activity and selectivity) could be restored to the conversion of substrate 1a in 53% ee (S) for the main (E)
crystals issued from the precise stoichiometric preparation isomer of 2a; the (E)/(Z) selectivity, however, reached only
[1:2 (Ϯ)-H2L1/MeLi mixture] by adding a small amount of 80:20 (Table 4, Entry 3). Decreasing the quantity of LiCH2-
MeLi (one drop) to the reaction mixture. These experiments SiMe3 to 2.5 equiv., as a slight excess of base only, gave rise
clearly indicated that a small excess of base was essential to the preparation of the most active (10 min to comple-
for the reaction to be successful, but this had to be precisely tion) and selective catalyst [(E)/(Z) = 92:8] for the prepara-
controlled to avoid the competitive racemic transformation, tion of the (E) isomer of product 2a in up to 50% ee (S)
although we demonstrated that the latter was far more slug- (Table 4, Entry 4). The use of LiCH2SiMe3 as a base with-
gish. Accordingly, the use of a solution of MeLi is not al- out a ligand was also investigated as a potential catalyst,
ways straightforward, and we looked for other bases that and analogously to MeLi, this base promoted a transforma-
could allow the fine-tuning of a simpler protocol and the tion, albeit at a slower rate and with a reversed selectivity,
precise control of the amount of base. LiCH2SiMe3 as a leading to the (Z) compound, as the major isomer (Table 4,
solution in pentane afforded interesting results for the Entry 5). The new procedure involving the use of 2.5 equiv.
transformation of 1a associated with (R)-H2L1 as the ligand of LiCH2SiMe3 as an isolated powder with the appropriate
(see Table 1, Entry 10). This base can be stored as a powder ligand dissolved in C6D6 (Method C) was thus chosen as
under an inert gas after removal of the solvent, and a pre- the easiest methodology, leading to very reproducible re-
cise amount can thus be weighed. A 1:2 mixture of (R)- sults, for preparing a chiral catalyst for the intramolecular
H2L1/LiCH2SiMe3 was thus prepared and stirred in diethyl hydroamination of aminodienes. This procedure was thus
ether for 10 min, before the solvent was removed. The applied to the transformation of both substrates 1a and 1b
transformation of 1a was then attempted in C6D6 with in the presence of different binaphthyldiamine chiral li-
10 mol-% of this complex, but no reaction occurred (see gands. The results are gathered in Table 5. The catalyst pre-
Table 1 Entry 11 and Table 4, Entry 1). According to the pared with the bulky ligand (R)-H2L2, with mesityl substit-
observations made by using MeLi as the base, an analogous uents on the nitrogen groups, allowed the cyclisation of 1a
catalyst was prepared, but 4 equiv. of LiCH2SiMe3 as a with the major isomer of product 2a as the (Z) isomer [(E)/
powder was added in the procedure instead of the exact (Z) = 30:70] in nearly racemic form (Table 5, Entry 2), a
stoichiometry (Table 4, Entry 2). The activity was restored, very similar result to that obtained when employing MeLi
and results similar to those obtained with MeLi as base as the base (Table 3, Entry 4). The absence of enantioselec-
were observed, except that the (Z) compound was isolated tion and the reversal in stereoselectivity in this case could
in its nearly racemic form (Table 3 Entries 1 and 2 and be explained by competitive cyclisation with LiCH2SiMe3
Table 4, Entry 2).
(Table 4, Entry 5). The pyridine-substituted ligand (R)-
H2L3 also gave pyrrolidine 2a with a good selectivity for
isomer (Z) [(E)/(Z) = 24:76] and 61% ee (Table 5, Entry 3).
These values are very similar to those obtained by
Method B using MeLi, albeit with small differences in the
rate of the reaction and enantioselectivity for the minor
stereoisomer (E) (Table 3, Entry 6). The enantioselectivity
slightly increased when using LiCH2SiMe3, whereas the rate
of the reaction decreased. The catalyst prepared from li-
gand (R)-H2L4, with naphthyl groups on the nitrogen
atoms, afforded pyrrolidine 2a with the same (E)/(Z) ratio
and the same ee value for isomer (E) (51%) as those given
by (R)-H2L1 (Table 5, Entries 1 and 4). The similar behav-
iour of these two ligands had already been observed in reac-
tions run with catalysts prepared according to Method B.
Remarkably, for both ligands, the replacement of MeLi by
LiCH2SiMe3 in the procedure led to a decrease in the ee
value of isomer (Z) (compare Table 3, Entries 2 and 8 with
Table 5, Entries 1 and 4). The lithium amide catalysts pre-
pared from (R)-H2L5 or (R)-H2L6 and LiCH2SiMe3 led to
product 2a with or without low stereoselectivities and low
values for the ee of both isomers (Table 5, Entries 5 and 6),
as similarly observed when MeLi was employed as the base
(Table 3, Entries 9–12). The cyclisation of substrate 1b was
Table 4. Use of LiCH2TMS as a base[a] for the asymmetric hydro-
amination reaction of 1a.[b]
Entry Solvent Equiv. Time Ratio[c] ee(E)[c] [%] ee(Z)[c] [%]
of base
[h] (E)/(Z) (config.[d]
)
(config.[d]
)
1
2
3
Et2O
Et2O
C6D6
C6D6
2
4
4
1
–
–
–
6
0.25 90:10
0.25 80:20
0.16
1
47 (S)
53 (S)
50 (S)
–
5
14 (S)
–
4
2.5
92:8
33:67
5[e]
C6D6 5 mol-%
[a] Catalyst preparation was performed by the addition of LiCH2-
SiMe3 as an isolated powder to a solution of (R)-H2L1 in solvent
(c = 0.02–0.03 m) at room temp., followed by stirring for 10 min
and concentration in vacuo (for Et2O solution) or direct use (for
C6D6 solution). [b] Reactions were carried out in C6D6 at room
temp. under argon with 10 mol-% of catalyst and went to comple-
1
tion (conversion Ͼ95%, measured by H NMR spectroscopy). [c]
Determined by HPLC analysis of the product following derivatis-
ation with 2-benzoyl chloride. [d] See the Supporting Information
for details. [e] Reaction run without ligand, and 24% of a product
containing a terminal double bond was detected by 1H NMR spec-
troscopy.
A simplified procedure was further developed by directly further investigated by using catalysts prepared from dif-
using the reaction solvent (i.e., C6D6) for the preparation ferent ligands according to Method C. Interestingly, ligand
of the catalyst, thus avoiding the intermediary evaporation (R)-H2L1 led to the preparation of piperidine 2b within 18 h
step. This procedure afforded an active species, since the with high stereoselectivity for isomer (E) [(E)/(Z) = 90:10]
expected product was isolated after 15 min with complete and 72 and 58% ee for isomers (E) and (Z), respectively
Eur. J. Org. Chem. 2011, 3329–3338
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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3333

J. Hannedouche, E. Schulz et al.
FULL PAPER
Table 5. Asymmetric hydroamination of amino-1,3-dienes 1a and 1b[a] catalysed by the 1:2.5 (R)-H2L/LiCH2SiMe3 precatalyst system[b]
(Method C).
Entry
Substrate
Product
(R)-H2L
Time
[h]
Conversion[c]
[%]
Ratio[d]
(E)/(Z)
ee(E)[d] [%]
ee(Z)[d] [%]
(config.[e])
(config.[e])
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1a
1b
1b
1b
2a
2a
2a
2a
2a
2a
2b
2b
2b
(R)-H2L1
(R)-H2L2
(R)-H2L3
(R)-H2L4
(R)-H2L5
(R)-H2L6
(R)-H2L1
(R)-H2L4
(R)-H2L5
0.25
1
3
0.25
2
1
18
4
19
Ͼ95
Ͼ95
Ͼ95
Ͼ95
Ͼ95
Ͼ95
Ͼ95
Ͼ95
Ͼ95
92:8
30:70
24:76
92:8
51:49
58:42
90:10
90:10
64:36
50 (S)
6
14 (S)
1
18 (S)
51 (S)
35 (S)
20 (S)
72 (S)
73 (S)
51 (S)
61 (R)
13 (S)
18 (R)
9 (R)
58 (S)
42 (S)
2
[a] Reactions were carried out in solution in C6D6 at room temp. (1a) or 50 °C (1b) with 10 mol-% of precatalyst. [b] Catalyst preparation
was performed by the addition of 2.5 equiv. of LiCH2SiMe3 as an isolated powder to a solution of (R)-H2L in C6D6 (c = 0.02–0.03 m)
1
at room temp. After stirring for 10 min, substrates were directly added to this catalyst solution. [c] Measured by H NMR spectroscopy.
[d] Determined by HPLC analysis of the product following derivatisation with 2-benzoyl chloride. [e] See the Supporting Information for
details.
(Table 5, Entry 7). Thus, the use of LiCH2SiMe3 resulted in scribed above for such reactions (Scheme 2). Catalysts pre-
the same ee value of isomer (E) and a slightly higher value pared according to Methods A, B and C were first com-
for isomer (Z) than when Method B employing MeLi was pared for the cyclisation of two substrates. We focused on
used (Table 3, Entry 14). These enantioselectivities are the aminoalkene 1c, which was used as a test substrate in our
best reported to date for this piperidine.[15] A comparison former studies, and 1d, which usually cyclised with a high
of catalysts prepared from benzyl- and naphthyl-substituted rate due to a strong Thorpe–Ingold effect. Ligands (R)-
binaphthyldiamines (R)-H2L1 and (R)-H2L4 revealed an in- H2L1, which led to the most enantioselective lithium-cata-
creased reaction rate with the latter with the same stereo- lysed cyclisation of aminodienes 1a–b, and (R)-H2L5, which
and enantioselectivities for isomer (E) (Table 5, Entries 7 led to the most enantioselective rare-earth-catalyzed cyclisa-
and 8) as observed with Method B (Table 3, Entries 14 and tions of aminoalkenes 1c and 1d, were selected as the most
18). Indeed, with a catalyst prepared from (R)-H2L4 and promising ligands for preparing the catalysts.[13b] The re-
LiCH2SiMe3, transformation of 1b in piperidine 2b was sults are gathered in Table 6.
achieved with a ratio of (E)/(Z) = 90:10 and 73% ee for
isomer (E). Catalysts resulting from ligand (R)-H2L5, either
according to Method C (Table 5, Entry 9) or according to
Method B (Table 3, Entry 20), led to similar results with
lower reaction rates.
A comparison of the three methods did not reveal strong
differences in stereo- and enantiodifferentiation for the
cyclisation of 1,3-aminodienes in pyrrolidine 2a or piperid-
ine 2b. Method C is a straightforward, in situ methodology
that allows better tuning of the quantity of base and the
simplest protocol for the preparation of the catalyst. The
screening of different N-substituted binaphthyldiamines led
to the selection of (R)-H2L1 and (R)-H2L4, with benzyl and
Scheme 2. Asymmetric hydroamination of aminoalkenes with chi-
ral lithium amide derivatives.
naphthyl groups, respectively, as ligands that provided the
highest stereo- and enantioselectivities. For the synthesis of
both products 2a and 2b, they allowed the selective forma-
tion of (E) isomers, with the highest enantioselectivity val-
ues. Noteworthy is the ability of ligand (R)-H2L3 to pro-
mote the cyclisation of 1a with a reversed stereoselectivity,
leading preferentially to the (Z) isomer with a high ee value
of 61%.
Substrate 1c could be cyclised with low ee values with
catalysts prepared from (R)-H2L1, according to the three
above-mentioned procedures (Table 6, Entries 1–3). Decep-
tively, the use of ligand (R)-H2L5 did not result in an im-
provement in enantioselectivities regardless of the method-
ology employed for the catalyst preparation (Table 6, En-
tries 4–6). Notably, the highest reaction rates were observed
with catalysts prepared with both ligands according to
Method C. Pyrrolidine 2c was thus obtained at room tem-
Hydroamination/Cyclisation of Aminoalkenes
Since only rare examples of asymmetric hydroamination/ perature within 2 h (Table 6, Entries 3 and 6). Conversely, a
cyclisation of aminoalkenes promoted by lithium base cata- blank experiment conducted with 10 mol-% LiCH2TMS as
lysts have been reported,[5a–5c] our next goal was to study the catalyst allowed the cyclisation of 1c, but the reaction
the efficiency of the diaminobinaphthyllithium salts de- was considerably slower, indicating that this transformation
3334
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 3329–3338

Chiral Lithium Binaphthylamido Catalysts
Table 6. Asymmetric hydroamination of aminoalkenes 1c–d[a] cata- in situ preparation of catalyst with LiCH2SiMe3, is the most
lysed by the 1:4 (R)-H2L/MeLi precatalyst system (Methods A[b] or
efficient for the cyclisation of aminoalkenes 1c and 1d and
B[c]) or 1:2.5 (R)-H2L/LiCH2TMS precatalyst system
is thus employed for the following studies. Since ligand (R)-
(Method C).[d]
H2L5, as the sterically most hindered ligand on the nitrogen
Entry
Ligand
Substrate Method Time Conv. ee(2)
atoms, led to interesting results in terms of enantio-
selectivity, at least for substrate 1d, two analogous ligands
with cyclohexyl and isopropyl substituents, respectively,
(R)-H2L7 and (R)-H2L8, were tested in these transforma-
tions. The corresponding chiral lithium amide derivatives
were prepared according to Method C and were used to
promote cyclisation of both substrates (Table 6, Entries 7,
8, 15 and 16). The reactions were, in all cases, completed
in longer reaction times than those with ligand (R)-H2L5.
Pleasingly, however, the use of these ligands afforded 2-
methyl-4,4-diphenylpyrrolidine with up to 55% ee (Table 6,
Entry 16).
Hydroamination of more demanding substrates 1e–i cat-
alysed by lithium amides prepared with LiCH2SiMe3, ac-
cording to Method C, were next examined. These results
are reported in Table 7. For aminoalkene 1e substituted by
a gem-dimethyl group, cyclisation could be achieved at
room temperature, and pyrrolidine 2e was obtained, albeit
with a low ee value, using ligand (R)-H2L1 (Table 7, En-
try 1). The same transformation was run in the presence of
ligand (R)-H2L5, but the enantioselectivity was not im-
proved, and the reaction times were longer than those with
(R)-H2L1 (Table 7, Entry 2). Noticeable is the absence of
conversion into pyrrolidine 2e in a blank experiment with
20 mol-% LiCH2TMS in the absence of ligand. The trans-
formation of 1,2-disubstituted aminoalkene 1f was very fast
with both catalysts prepared from ligands (R)-H2L1 and
(R)-H2L5, but the product was obtained as a racemic form
(Table 7, Entries 3 and 4). Interestingly, secondary amino-
alkene 1g could be transformed into pyrrolidine 2g with
catalysts prepared from ligands (R)-H2L1 and (R)-H2L5
with LiCH2SiMe3, either at room temperature or 50 °C
[h]
[%][e] [%][f,g]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
(R)-H2L1
(R)-H2L1
(R)-H2L1
(R)-H2L5
(R)-H2L5
(R)-H2L5
(R)-H2L7
(R)-H2L8
(R)-H2L1
(R)-H2L1
(R)-H2L1
(R)-H2L5
(R)-H2L5
(R)-H2L5
(R)-H2L7
(R)-H2L8
1c
1c
1c
1c
1c
1c
1c
1c
1d
1d
1d
1d
1d
1d
1d
1d
A
B
C
A
B
C
C
C
A
B
C
A
B
C
C
C
4
17
2
Ͼ95
Ͼ95
Ͼ95
Ͼ95
Ͼ95
Ͼ95
92
90
92
Ͼ95
90
Ͼ95
Ͼ95
90
12
10
7
10
11
9
Ͻ5
11
9
20[h]
19
2
8
4
4
17
19
20
19
2
24
4
5
18
58
51
56
48
55
87
75
[a] Reactions were carried out in C6D6 at room temp. with 10 mol-
% of precatalyst. [b] Method A: catalyst preparation was performed
by dropwise addition of 4 equiv. of a solution of MeLi in diethyl
ether (1.6 m) to a solution of the ligand (R)-H2L in diethyl ether
(c = 0.025 m) at room temp., followed by stirring for 10 min and
concentration in vacuo. [c] Method B: catalyst preparation was per-
formed by dropwise addition of 4 equiv. of a solution of MeLi in
diethyl ether (1.6 m) to a solution of the ligand (R)-H2L in C6D6
(c = 0.025 m) at room temp. After stirring for 10 min, substrates
were directly added to this catalyst solution. [d] Method C: catalyst
preparation was performed by addition of 2.5 equiv. of LiCH2S-
iMe3 as isolated powder to a solution of (R)-H2L in C6D6 (c =
0.02–0.03 m) at room temp. After stirring for 10 min, substrates
were directly added to this catalyst solution. [e] Measured by 1H
NMR spectroscopy. [f] Determined by HPLC analysis of the prod-
uct following derivatisation with 2-benzoyl chloride. [g] See the
Supporting Information for details. [h] Reaction was performed at
50 °C.
was not competing with the asymmetric cyclisation. The di- (Table 7, Entries 5–8), although the products were nearly
meric chiral diaminobinaphthyl dilithium salt reported by racemic. This cyclisation could not be performed by a cata-
Hultzsch et al. was far more enantioselective, since 2c was lytic amount of LiCH2SiMe3 in the absence of ligand. The
isolated under these conditions with 75% ee.[5a] The hydro- more demanding 1,2-disubstituted aminoalkene 1h, which
amination of substrate 1d catalysed by lithium amide pre- has been cyclised only at elevated temperature with rare-
pared from (R)-H2L1 by any of the three methods afforded earth-based catalysts,[4m,16] could not be transformed into
pyrrolidine 2d with small ee values (Table 6, Entries 9–11). the corresponding pyrrolidine 2h at 50 °C by using the cata-
The binaphthyldiamine with cyclopentyl groups on the ni- lyst prepared from benzyl-substituted binaphthyldiamine
trogen atoms, (R)-H2L5, afforded more enantioselective cat- (R)-H2L1 (Table 7, Entry 9). Under similar conditions, ami-
alysts regardless of the base used. Pyrrolidine 2d was ob- noalkene 1i was not cyclised to the corresponding piper-
tained with 51–58% ee (Table 6, Entries 12–14), and the idine, but transformed into a product resulting from the
shortest reaction time was again observed for the catalyst isomerisation of the double bond (Table 7, Entry 10). The
prepared in situ by using LiCH2SiMe3 as the base (Table 6, chiral lithium amide prepared from N,NЈ-dibenzylbinaph-
Entry 14). In this case, the chiral lithium amide prepared thyldiamine [(R)-H2L1] and LiCH2SiMe3 was thus revealed
from (R)-H2L5 afforded pyrrolidine 2d with an improved ee as a very efficient catalyst for the transformation of primary
than that reported in the literature, which was obtained un- or secondary aminoalkenes, despite not being active for the
der comparable conditions.[5a] An analogous blank experi- most demanding olefins, such as amino-tethered 1,2-di-
ment was run with 1d (LiCH2SiMe3 in catalytic amount in alkyl-substituted alkenes, or for the preparation of piper-
the absence of ligand), leading to similar results as those idines. Whereas this catalyst afforded the highest enantio-
observed for the cyclisation of 1c. A ligand-accelerating ef- selectivity for the hydroamination/cyclisation of amino-1,3-
fect is thus clearly observed for the hydroamination of dienes, it conversely proved to be poorly enantioselective
aminoalkenes 1c and 1d. The simple Method C, involving for the transformation of aminoalkenes. Ligand (R)-H2L5,
Eur. J. Org. Chem. 2011, 3329–3338
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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3335

J. Hannedouche, E. Schulz et al.
FULL PAPER
substituted by cyclopentyl groups on the nitrogen atoms, atom. The role of the chiral lithium ligand could be to acti-
gave promising ee values (up to 58% ee) for pyr- vate the double bond in a stereodefined environment.
rolidine 2d, which contained a gem-diphenyl group.
Table 7. Asymmetric hydroamination of aminoalkenes 1e–i[a] when
Experimental Section
using Method C as the procedure for catalyst preparation.[b]
General Procedure for NMR-Scale Asymmetric Intramolecular Hy-
droamination of Amino-1,3-Dienes 1a and 1b and Aminoalkenes 1c–
i by Method C: A solution of LiCH2SiMe3 (20 mg, 0.20ϫ10–3 mol)
in [D6]benzene (0.6 mL) was added dropwise to a solution of the
appropriate ligand (R)-H2L (0.08ϫ10–3 mol) in [D6]benzene
(1.8 mL) in an argon-filled Schlenk tube at room temperature. The
homogeneous yellow reaction solution was then stirred at ambient
temperature for 15 min. In an argon-filled glovebox, an aliquot
(600 μL) of the homogeneous reaction mixture was removed by a
micropipette and transferred to a vial containing the corresponding
substrate (0.20ϫ10–3 mol). The reaction mixture was then intro-
duced into a screw-cap or a J-Young NMR tube. After the appro-
priate time, the reaction was quenched by the addition of a small
amount of dichloromethane.
Entry
Ligand
Substrate
Time
[h]
Conv.
[%][c]
ee(2)
[%][d,e]
1
2
3
4
5
6
7
8
9
(R)-H2L1
(R)-H2L5
(R)-H2L1
(R)-H2L5
(R)-H2L1
(R)-H2L1
(R)-H2L5
(R)-H2L5
(R)-H2L1
(R)-H2L1
1e
1e
1f
44
60
92
4
7
2
0
5
9
5
2
Ͼ95
Ͼ95
Ͼ95
Ͼ95
Ͼ95
Ͼ95
Ͼ95
0
0.33
0.33
16
1f
1g
1g
1g
1g
1h
1i
2[f]
24
2[f]
19[f]
19[f]
[g]
10
–
[a] Reactions were carried out in C6D6 at room temp. or 50 °C with
10 mol-% of the precatalyst. [b] Catalyst preparation was per-
formed by the addition of 2.5 equiv. of LiCH2SiMe3 as an isolated
powder to a solution of (R)-H2L in C6D6 (c = 0.02–0.03 m) at room
temp. After stirring for 10 min, substrates were directly added to
Procedure for Asymmetric Intramolecular Hydroamination of 1a to
2a by Method A: Table 3, Entry 1. A 1.6 m solution of MeLi
(200 μL, 0.32ϫ10–3 mol) in diethyl ether was added dropwise to a
solution of (R)-N,NЈ-bis(benzyl)-1,1Ј-binaphthyl-2,2Ј-diamine (R)-
H2L1 (37 mg, 0.08ϫ10–3 mol) in diethyl ether (5 mL) in an argon-
filled Schlenk tube equipped with an O-ring tap (J. Young) at room
temperature. The homogeneous yellow reaction solution was then
stirred at ambient temperature for 10 min and concentrated in
vacuo. In an argon-filled glovebox, the corresponding residue was
dissolved in [D6]benzene (2 mL), and the mixture was removed by
a micropipette and transferred to a vial containing the substrate 1a
(88 mg, 0.80ϫ10–3 mol). The reaction mixture was then introduced
into a Schlenk tube equipped with an O-ring tap (J. Young). After
15 min, the reaction was quenched by the addition of a small
amount of dichloromethane, and the mixture was distilled under
reduced pressure. A solution of hydrogen chloride in methanol
1
this catalyst solution. [c] Measured by H NMR spectroscopy. [d]
Determined by HPLC analysis of the product following derivatis-
ation with 2-benzoyl chloride. [e] See the Supporting Information
for details. [f] Reaction was performed at 50 °C. [g] A total conver-
sion was observed in the product that resulted in isomerisation of
the double bond.
Conclusions
Substituted chiral binaphthyldiamine-based ligands were
thus used as precursors for the formation of the corre-
sponding lithium amide salts to promote the hydroamin- (1.25 m; 2 mL) was added dropwise to the colourless solution. The
mixture was stirred at room temperature for 1 h and was then con-
ation/cyclisation of amino-1,3-dienes and aminoalkenes ef-
ficiently. Various catalyst preparation procedures were in-
vestigated, which allowed the fine-tuning of a straightfor-
ward protocol, resulting in an easy procedure for the forma-
tion of active catalysts for both substrates types. In particu-
lar, stereodefined 2-propenylpyrrolidine 2a or -piperidine 2b
were prepared within short reaction times and with a level
of enantioselection that competed well with the rare exam-
ples described in the literature.[15] Although aminoalkenes
centrated in vacuo to afford 2a·HCl as a pale yellow solid (80 mg,
68%). [α]2D5 = +84.0 (c = 0.70, CH OH). IR (neat): ν = 3407, 3050,
˜
3
2917, 2740, 2558, 2480, 1632, 1587, 1451, 1422, 1310, 1069, 1021,
1
969 cm–1. H NMR (360 MHz, D2O): δ = 6.05 (dq, J = 15.2 and
6.6 Hz, 1 H, H2Ј), 5.63 (ddd, J = 15.2 and 8.2 and 1.6 Hz, 1 H,
H1Ј), 4.12 (q, J = 8 Hz, 1 H, H2), 3.38–3.34 (m, 2 H, H5), 2.44–
2.08 (m, 3 H, H3 and 2H4), 1.80–1.77 (m, 1 H, H3), 1.78 (dd, J =
6.6 and 1.6 Hz, 3 H, CH3) ppm. 13C NMR (62.5 MHz; D2O): δ =
134.3, 124.4, 62.1, 44.6, 29.9, 23.2, 17.1 ppm. MS (ESI): m/z (%) =
could be rapidly cyclised with this system, the correspond- 112 (100) [M]+. HRMS: calcd. for C7H14N [M]+ 112.1121; found
112.1126.
ing products were obtained in only low to moderate
enantioselectivities.
Procedure for Asymmetric Intramolecular Hydroamination of 1b to
We have previously reported the description of the lith-
2b by Method A: Table 3, Entry 13. A 1.6 m solution of MeLi
ium amide complex arising from the use of ligand (Ϯ)-H2L1 (200 μL, 0.32ϫ10–3 mol) in diethyl ether was added dropwise to a
solution of (R)-H2L1(37 mg, 0.08ϫ10–3 mol) in diethyl ether
in the presence of 2 equiv. of base (MeLi), obtained by X-
ray analysis.[5d] It was characterised as a monomeric species
(5 mL) in an argon-filled Schlenk tube equipped with an O-ring tap
(J. Young) at room temperature. The homogeneous yellow reaction
and showed no activity as a catalyst precursor for intramo-
solution was then stirred at ambient temperature for 10 min and
lecular hydroamination. We have demonstrated herein that,
concentrated in vacuo. In an argon-filled glovebox, the correspond-
in all cases, a slight excess of base (relative to the ligand)
ing residue was dissolved in [D6]benzene (2 mL), and the mixture
was necessary to conduct the catalytic transformation.
was removed by a micropipette and transferred to a vial containing
Mechanistic investigations are needed to propose some in-
termediates in the catalytic cycle, but we assume that the
excess of base induces the deprotonation of a small amount
the substrate 1b (100 mg, 0.80ϫ10–3 mol). The reaction mixture
was then introduced into a Schlenk tube equipped with an O-ring
tap (J. Young) and was heated at 50 °C. After 20 h, the reaction
of substrate to increase the nucleophilicity of the nitrogen was quenched by the addition of a small amount of dichlorometh-
3336
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Eur. J. Org. Chem. 2011, 3329–3338

Chiral Lithium Binaphthylamido Catalysts
[4]
For a selection of chiral rare-earth-based catalytic systems, see:
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ane, and the mixture was distilled under reduced pressure. A solu-
tion of hydrogen chloride in methanol (1.25 m, 2 mL) was added
dropwise to the colourless solution. The mixture was stirred at
room temperature for 1 h and was then concentrated in vacuo to
afford 2b·HCl as a pale yellow solid (80 mg, 62%). [α]2D5 = +114.0
(c = 1.05, CH OH). IR (neat): ν = 3405, 3199, 2933, 2582, 2527,
˜
3
2416, 1676, 1588, 1455, 1434, 1379, 1312, 1269, 1077, 1021,
1
967 cm–1. H NMR (360 MHz, D2O): δ = 5.92 (dq, J = 15.5 and
6.9 Hz, 1 H , H2Ј), 5.48 (ddd, J = 15.5 and 7.9 and 1.4 Hz, 1 H,
H1Ј), 3.62 (m, 1 H, H2), 3.35 (d, J = 12 Hz, 1 H, H6b), 2.97 (dd, J
= 12 Hz, 1 H, H6a), 1.93–1.82 (m, 3 H, H3b, H4b and H5b), 1.68 (d,
J = 6.8 Hz, 3 H, CH3), 1.58–1.52 (m, 3 H, H3a, H4a and H5a) ppm.
13C NMR (62.5 MHz, D2O): δ = 134.2, 127.2, 59.3, 45.4, 29.8, 22.7,
22.6, 18.3 ppm. MS (ESI): m/z (%) = 126 (100) [M]+. HRMS: calcd.
for C8H16N [M]+ 126.1277; found 126.1278.
Supporting Information (see footnote on the first page of this arti-
cle): Complete experimental procedures, full characterisation and
ee determinations.
Acknowledgments
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We thank the Centre National de la Recherche Scientifique
(CNRS), the Ministère de l’Education Nationale de l’Enseignement
Supérieur et de la Recherche (MENESR) and the Agence Nation-
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Received: November 26, 2010
Published Online: May 9, 2011
3338
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Eur. J. Org. Chem. 2011, 3329–3338