Catalytic, enantioselective intramolecular hydroamination of primary amines tethered to Di- and trisubstituted alkenes

Article abstract of DOI:10.1021/jo202009q

The in situ preparation of chiral amido alkyl ate yttrium complexes from an array of chiral N-benzyl-like-substituted binaphthyldiamines is reported. These chiral heteroleptic complexes are shown to be efficient catalysts for the enantioselective intramolecular hydroamination of primary amines tethered to sterically demanding alkenes at high reaction temperatures. Fine tuning of their chiral environment allowed up to 77% ee to be reached for the cyclization of aminoalkenes bearing 1,2-dialkyl-substituted carbon-carbon double bonds. These chiral complexes also demonstrate the ability to promote the cyclization of amine-tethered trisubstituted alkenes in up to 55% ee, as the first report of the formation of enantioenriched quaternary centers by an hydroamination reaction.

Full text of DOI:10.1021/jo202009q

Article
pubs.acs.org/joc
Catalytic, Enantioselective Intramolecular Hydroamination of
Primary Amines Tethered to Di- and Trisubstituted Alkenes
Yulia Chapurina,†,§ Houssein Ibrahim,† Regis Guillot,‡ Emilie Kolodziej,†,‡ Jacqueline Collin,†,‡
́
Alexander Trifonov,§ Emmanuelle Schulz,*,†,‡ and Jerome Hannedouche*,†,‡
́
̂
†Equipe de Catalyse Molec
́ ́
ulaire, Universite Paris-Sud, ICMMO, UMR 8182, Orsay F-91405, France
§G.A. Razuvaev Institute of Organometallic Chemistry of Russian Academy of Sciences, Tropinia 49, 603600 Nizhny Novgorod
GSP-445, Russia
‡CNRS, Orsay F-91405, France
S
* Supporting Information
ABSTRACT: The in situ preparation of chiral amido alkyl ate yttrium complexes from an array of chiral N-benzyl-like-
substituted binaphthyldiamines is reported. These chiral heteroleptic complexes are shown to be efficient catalysts for the
enantioselective intramolecular hydroamination of primary amines tethered to sterically demanding alkenes at high reaction
temperatures. Fine tuning of their chiral environment allowed up to 77% ee to be reached for the cyclization of aminoalkenes
bearing 1,2-dialkyl-substituted carbon−carbon double bonds. These chiral complexes also demonstrate the ability to promote the
cyclization of amine-tethered trisubstituted alkenes in up to 55% ee, as the first report of the formation of enantioenriched
quaternary centers by an hydroamination reaction.
double bond.8 Some examples related to the hydroamination/
cyclization of aminoolefins possessing a styrenyl functionality
INTRODUCTION
The hydroamination reaction and its asymmetric version
■
(as more activated substrates) have been nevertheless
developed dramatically in the last twenty years as can be
successfully described in the presence of rare-earth-based
attested by the exponentially increasing number of reports
catalysts and interestingly with high selectivities in the presence
dealing with the progress of such methodologies in the
of asymmetric promoters.9 However, very little success is
described for the transformation of sterically encumbered
double bonds and more specifically for the transformation of
1,2-dialkyl-disubstituted olefins. To the best of our knowledge,
only the group of Marks described the efficiency of cyclo-
pentadienyl-based lanthanide catalysts to achieve this trans-
formation at high temperature for the synthesis of pyrrolidine
and piperidine derivatives.10 They also successfully reported the
enantioselective version of this transformation by using C1-
symmetric organolanthanide catalysts leading to the targeted
compounds with up to 68% ee.11,12 Furthermore, the group of
Molander was one of the first to achieve the intramolecular
hydroamination of 1,1-disubstituted olefins with unhindered
Sm- and Nd-based catalytic systems providing a variety of
heterocycles containing quaternary centers.13,14 Aminoolefins
possessing this 1,1-methyl-substituted pattern have then been
literature.1,2 These transformations indeed perfectly match the
concept of sustainable chemistry since they allow the formation
of new nitrogen−carbon bonds in an ideal atom efficiency and
economy, starting from non activated substrates. Numerous
proficient methodologies have thus been recently described
that imply either the activation of the unsaturated carbon−
carbon bond or the activation of the amine functionality
through a catalyzed process. A rough description of these
transformations involves a transition-metal catalysis in the
former case,3,4 whereas group IV metals5 and rare-earth
elements6 are engaged in the later one. Marks and his group
particularly pioneered this field, and demonstrated the ability of
cyclopentadienyl-based lanthanide complexes to promote the
intramolecular hydroamination of aminoolefins toward the
formation of valuable nitrogen-containing heterocycles.7 Nowa-
days, the scope of the transformation using rare-earth-based
catalysts includes the facile formation of pyrrolidine and
piperidine heterocycles in high yields and selectivities, starting
from primary or secondary aminoolefins, possessing a terminal
Received: October 5, 2011
Published: November 7, 2011
© 2011 American Chemical Society
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a
Table 1. AIH of Terminal Aminoalkenes 1a and 2a Promoted by Chiral Amido Alkyl Ate Yttrium catalysts
b
c
entry
subst.
prod.
(R)-H2Ln
t (h)
% conv.
% ee
1
1a
1b
(R)-H2L0
(R)-H2L1
(R)-H2L2
(R)-H2L3
(R)-H2L4
(R)-H2L5
(R)-H2L6
(R)-H2L7
(R)-H2L9
(R)-H2L0
(R)-H2L1
(R)-H2L2
(R)-H2L3
(R)-H2L4
(R)-H2L5
(R)-H2L6
(R)-H2L7
(R)-H2L9
1
>99
90
75
5
2
0.30
0.30
0.25
0.16
0.25
0.25
0.25
3
97
12
5
4
95
5
>99
>99
95
5
6
11
9
7
8
86
8
9
0.25
95
16
40
30
6
d
10
11
12
13
14
15
16
17
18
2a
2b
16
95
19
19
19
2
>99
90
87
15
20
20
26
23
30
87
2
88
4
>99
>99
98
4
19
a
b
c
Reactions performed in the presence of 6 mol % precatalyst, in C6D6, at rt. Measured by 1H NMR spectroscopy. Determined by HPLC analysis of
d
the product following derivatization (see Supporting Information). The reaction was run at 50 °C.
used occasionally as test substrates to evaluate and classify the
activity of new catalysts by several groups.15 As far as we know,
however, no report deals with the preparation of such
quaternary centers by asymmetric intramolecular hydroamina-
tion (AIH) until now.
obtained in 75% ee with a complete conversion after 1-h
reaction time at room temperature (Table 1, entry 1). This
result compared finely in terms both of activity and selectivity
with those of our previously described alkyl binaphthylamido
lanthanide-type catalysts.18
We report here in details our investigations on the efficiency
of the catalysts prepared from ligands (R)-H2Ln (n = 1−9)
(Figure 1) for the intramolecular hydroamination of mono-
We previously reported a new and reliable route to chiral
amido alkyl yttrium catalysts which proved to be highly efficient
for the enantioselective cyclization of several 1,2-disubstituted
aminoolefins.16 We now describe in further details our simple
methodology to prepare various chiral amido alkyl ate yttrium
complexes, the chirality arising from a binaphthylamido
backbone possessing different substituents on the nitrogen
atoms. The in situ prepared precatalysts have been tested for
their ability to promote the hydroamination/cyclization of
demanding aminoolefins, and new scalemic heterocycles could
be prepared through this procedure. Finally, these catalytic
systems were efficient enough to promote the cyclization of not
only 1,1-disubstituted- but also 1,1,2-trisubstituted olefins
toward the formation of enantioenriched pyrrolidines possess-
ing a new quaternary center.
RESULTS AND DISCUSSION
■
As we formerly described, the in situ preparation of the yttrium
catalyst proceeded easily by reaction between the ate precursor
complex [Li(THF)4][Y(CH2TMS)4]17 and one equivalent of
ligand (R)-H2Ln in C6D6 leading to the immediate formation of
a yellow solution. The first NMR analyses performed with N-
cyclopentyl-disubstituted ligand H2L0 indicated the expected
set of signals confirming the formation of an amido alkyl ate
complex, [(R)-L0][Y(CH2TMS)2Li(THF)4]. The ability of this
new species to promote AIH was demonstrated with the direct
use of the mixture for the cyclization of C-(1-allylcyclohexyl)-
methyl amine 1a, a test substrate bearing a terminal double
bond (Table 1). The expected pyrrolidine 1b was indeed
Figure 1. Chiral (R)-N-substituted binaphthyl diamine ligands.
substituted primary aminoolefins 1a and 2a (Table 1). The N-
benzyl-substituted ligand (R)-H2L1 allowed a rapid cyclization
of aminoolefin 1a, albeit pyrrolidine 1b was obtained in nearly
racemic form (Table 1, entry 2). Further modification of the
ligand with donating substituents at the ortho or para position
of the phenyl group (entries 3−5) or steric modification
(entries 6−9) did not enhance significantly the selectivity of the
corresponding catalysts, albeit good activity was maintained.
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Scheme 1. Evolution in Solution of in Situ Prepared Complexes
High conversions were indeed observed in all cases within less
than half an hour at room temperature. The cyclization of gem-
dialkyl aminohexene 2a which requires harsher conditions than
those for 1a was next examined. The catalyst prepared from
ligand (R)-H2L0 afforded the expected piperidine, but the
reaction had to be conducted at 50 °C to achieve a high
conversion (Table 1, entry 10). The use of the benzyl-like
substituents led to more active catalysts since the trans-
formation could be performed at room temperature and the N-
benzyl-substituted ligand (R)-H2L1 afforded total conversion in
piperidine 2b after one night at room temperature with 30% ee,
a better value than that obtained for product 1b (entry 11
versus entry 2 in Table 1). The use of different benzyl-like
ligands allowed the activity of the corresponding catalysts
(ligands (R)-H2L4−7, entries 14−17) to be increased without
enhancement of selectivity.
Comparison of the enantiomeric excesses reported in Table 1
with those given by catalysts prepared from N-cyclopentyl
ligand (R)-H2L0 either isolated18b or in situ prepared from
yttrium chloride and BuLi18a indicates that N-cyclopentyl
ligand (R)-H2L0 affords more enantioselective catalysts than
the benzyl-like ligands for the cyclization of monosubstituted
aminoolefins leading to five- or six-membered nitrogen
heterocycles.
yellow crystals suitable to perform X-ray analysis. In this case,
however, a different transformation occurred, and a new
tetraamido ate yttrium complex B could be characterized. As we
already described with similar ligands,19 this complex was
composed of a discrete lithium cation Li(THF)4+ and a discrete
complex anion {Y[(R)-C20H12N2(C14H14)]2}−.20 Involved in
the catalytic transformation of substrate 1a, this isolated species
showed, once more, a different behavior as a more
enantioselective catalyst (compared to that of its in situ
prepared precursor [20% ee for 1b]) but as a much less active
promoter (17 h reaction time). The thus observed different
catalytic efficiencies of the in situ generated complexes vs those
of the isolated complexes demonstrate their structural
dissimilarities.
As this first set of experiments demonstrated that the easily in
situ generated catalytic precursors proved to be highly active
species, the study was next extended to the cyclization of more
challenging substrates. Ligands bearing benzyl-like substituents
were considered as privileged structures for these trans-
formations since corresponding catalysts showed enhanced
activity compared to those prepared from the more sterically
encumbered ligand (R)-H2L0.
As demanding substrates, amines including 1,2-disubstituted
double bonds were first examined (Scheme 2 and Table 2). A
Attempts were drawn toward the characterization of the new
precatalytic species generated from in situ reaction between
[Li(THF)4][Y(CH2TMS)4] and the N-modified binaphthyldi-
amine ligands (R)-H2L0 and (R)-H2L1. As we previously
described,16 crystallization of the mixture using (R)-H2L0 in a
hexane/benzene solution afforded crystals of a new dimeric
heterobimetallic alkyl species {Li(THF)[μ-(R)-L0]Y[μ-
CH2SiMe2CH2-μ]2}2, A (Scheme 1) which was isolated in
70% yield. This complex, resulting from C−H bond activation,
was tested for its ability to promote the cyclization of substrate
1a and led to catalytic results different from those reported for
the in situ generated species. The dimeric complex proved
indeed to be more enantioselective since pyrrolidine 1b was
isolated with a high ee value of 80%, but a 2-h reaction at room
temperature was required to afford a complete conversion. A
similar isolation attempt was performed starting from ligand
(R)-H2L1, and this procedure led again to the recovery of
Scheme 2. AIH of 1,2-Disubstituted Aminoalkenes
first test was realized to transform 2-cyclohexyl aminohex-4-ene
3a in pyrrolidine 3b in the presence of a catalyst prepared from
(R)-H2L0. A complete conversion could not be achieved even
after three days reaction at 70 °C, and 3b was formed in only
12% ee (Table 2, entry 1). Nevertheless, the use of the N-
benzyl ligand (R)-H2L1 promoted the transformation of 3a into
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a
Table 2. AIH of 1,2-Disubstituted Aminoalkenes 3−5a Promoted by Chiral Amido Alkyl Ate Yttrium Catalysts
b
c,d
entry
subst.
prod.
(R)-H2Ln
t (h)
T (°C)
% conv.
% ee
(config.)
1
3a
3b
(R)-H2L0
(R)-H2L1
(R)-H2L2
(R)-H2L3
(R)-H2L4
(R)-H2L5
(R)-H2L6
(R)-H2L7
(R)-H2L8
(R)-H2L9
(R)-H2L1
(R)-H2L4
(R)-H2L6
(R)-H2L9
(R)-H2L1
(R)-H2L2
(R)-H2L3
74
19
70
70
58
83
50
87
93
79
87
97
12
49
35
53
55
47
47
47
nd
2
3
70
110
70
4
19
5
19
70
6
50
70
7
19
70
8
19
70
9
36
110
110
110
110
110
110
50
5
e
10
11
12
13
14
15
16
17
18
19
20
21
22
23
19
96 (50)
68
20
4a
5a
4b
5b
110
120
120
110
15
77
88
20
89
13
91
52
>99
38
76
36
70
40
e
19
70
>99 (80)
75
(S)
36
40
83
>99
40
77
(R)-H2L4
(R)-H2L5
(R)-H2L6
(R)-H2L8
(R)-H2L9
19
70
73
36
70
<5
51
36
70
30
48
110
70
15
nd
−10
70
33
a
b
c
1
Reactions run in C6D6 (40 − 70 °C), in C7D8 (110 °C). Measured by H NMR spectroscopy. Determined by HPLC analysis of the product
following derivatization (see Supporting Information). The negative sign indicates configuration opposite to that obtained in the other cases.
Isolated yield.
d
e
3b in a higher yield after one night at 70 °C with 49% ee (Table
2, entry 2). The use of ligands (R)-H2L3 and (R)-H2L4 with
para substituents on the phenyl rings allowed the reaction to be
performed in the same conditions with a slight increase in
enantiomeric excess values (entries 4 and 5). With the bulkier
ligands (R)-H2L2 and (R)-H2L5 with ortho substituents on the
phenyl ring, higher reaction temperatures or longer reaction
times were required for the formation of 3b without increasing
selectivity compared to those of the N-benzyl-substituted ligand
(entries 3 and 6). The replacement of phenyl by 1- or 2-
naphthyl groups (R)-H2L6 and (R)-H2L7 did not modify
activity or enantioselectivity (entries 7 and 8 versus entry 2).
The ligand (R)-H2L8 including a sulfur atom did not yield to an
active catalytic species even at high temperature (entry 9). The
best result in terms of enantioselectivity (68% ee) was reached
by using binaphthyldiamine modified by an anthrylmethyl
moiety (R)-H2L9, a high value taking into account that the
transformation was run at 110 °C and turned to completion
(entry 10). Some of these easily prepared catalyst solutions
were examined for the cyclization of 4a, a transformation
previously only described by the group of Marks.11 Delightfully,
the catalysts were active at 110 °C (entries 11−14), and (R)-
H2L9 led to the preparation of pyrrolidine 4b in 52% ee, the
highest value reported for this substrate to date (Table 2, entry
14). The more active gem-diphenyl-substituted substrate 5a
could be transformed at lower temperatures. N-benzyl-
substituted ligand (R)-H2L1 and ligands (R)-H2L3 and (R)-
H2L4 with para substituents on the phenyl ring led to high
enantioselectivities for this reaction (entries 15, 17−19). With
the bulkier ligands, lower selectivities and longer reaction times
were observed (entries 16, 20−23). The highest activity and
enantioselectivity (77% ee) were furnished by the ligand (R)-
H2L3 with p-methoxy substituents on the phenyl rings (entry
18).
The cyclization of aminoolefins with a phenyl substituent on
the double bond was studied as an efficient route toward
nitrogen heterocycles including aromatic rings (Scheme 2,
Table 3). Several ligands have been tested for the cyclization of
Table 3. AIH of 1,2-Disubstituted Aminoalkenes 6a and 7a
a
Promoted by Chiral Amido Alkyl Ate Yttrium Catalysts
b
c,d
entry subst. prod. (R)-H2Ln t(h) T (°C)
% conv.
% ee
1
6a
6b
(R)-H2L1
(R)-H2L3
(R)-H2L6
(R)-H2L9
(R)-H2L1
(R)-H2L2
(R)-H2L3
(R)-H2L4
(R)-H2L5
(R)-H2L6
(R)-H2L8
(R)-H2L9
19
19
19
36
24
19
7
70
70
70
70
50
70
40
70
70
70
70
91
90
93
<5
38
<5
20
2
3
4
70
e
5
7a
7b
>99 (83)
53
<5
6
>99
99
7
55
8
2
>99
>99
95
55
9
19
8
−11
26
10
11
12
19
92
27
19
70
b
90
−19
a
Reactions run in C6D6 (40−70 °C). Measured by 1H NMR
spectroscopy. Determined by HPLC analysis of the product following
derivatization (see Supporting Information). The negative sign
c
d
indicates opposite configuration to that obtained in the other cases.
e
Isolated yield.
gem-dimethyl aminoolefin 6a, and reactions could be performed
at 70 °C with moderate enantioselectivities (entries 1−4). The
highest enantiomeric excess value for 6b (38%) was recorded
with ligand (R)-H2L3 with p-methoxy substituent on the phenyl
ring (entry 2). This cyclization has been performed by several
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groups with chiral zirconium catalysts,5d yttrium bis thiolato
catalysts,9a and scandium or lutetium binaphtholato complex-
es8c with better enantioselectivities. The cyclization of gem-
diphenyl substrate 7a has been examined with all ligands of the
series. The best results in terms of enantioselectivity (53−55%
ee) were furnished by ligands (R)-H2L1 and (R)-H2L3−4 as
observed for the formation of 5b (Table 3, entries 5−12).
Since the cyclizations of aminoolefins including gem-diphenyl
groups are in most cases faster than those of substrates with
gem-dimethyl groups (compare the cyclizations of 5a and 4a
and those of 7a and 6a), we focused on substrates with gem-
diphenyl substituents in the β-position from the nitrogen for
studying the hydroamination of highly hindered aminoolefins.
The N-benzyl-substituted binaphthyl amine (R)-H2L1 was
selected as test ligand due to its efficiency and its easy
availability. The synthesis of a pyrrolidine starting from the
1,2,2-trialkyl-substituted aminoalkene 8a was first examined
(Scheme 3). Satisfyingly, the targeted compound 8b could be
prepared, but an enhanced quantity of catalyst (12 mol %) was
essential in this case, and the temperature of the reaction was
raised up to 110 °C. Pyrrolidine 8b bearing a isopropyl group
was obtained with 50% conversion after 120 h and 33% ee. To
the best of our knowledge, this result is the first report of a
successful hydroamination reaction leading to this pyrrolidine
bearing an isopropyl substituent in the α-position of the
nitrogen atom21 and thus the highest enantioselectivity so far.
(Table 4). To evaluate the feasibility of such transformations
we first tested the cyclization of substrate 9a with a methyl
substituent on the internal carbon of the double bond into the
achiral pyrrolidine 9b using a catalyst prepared from racemic N-
benzyl-substituted ligand H2L1.15 We were pleased to find that
the hydroamination reaction occurred in very mild conditions,
at room temperature and within a short reaction time in spite of
the encumbered double bond of 9a (Table 4, entry 1). The
hydroamination of the similar substrate 10a with a phenyl
substituent on the terminal carbon of the double bond could be
performed with a variety of ligands at different temperatures
(entries 2−8). Pyrrolidine 10b was obtained at 70 °C with
satisfying enantiomeric excesses with ligands (R)-H2L1, (R)-
H2L3 and (R)-H2L6. The best enantioselectivities were
observed with ligands (R)-H2L3 and (R)-H2L6 (55% ee, entries
4 and 6) but the reaction was faster with N-benzyl-substituted
ligands H2L1 and H2L3 (entries 2 and 4). Reaction could be
performed at 110 °C with bulkier ligands (even anthrylmethyl-
substituted (R)-H2L9) but with low values of enantiomeric
excesses for pyrrolidine 10b (entries 3, 5, 7, and 8). Ligand (R)-
H2L1 was thus selected for testing the hydroamination of
substrate 11a with a trialkyl-substituted inactivated double
bond. To our delight the formation of pyrrolidine 11b was
observed at 110 °C within prolonged reaction time but with a
good enantioselectivity (55% ee, entry 9). As far as we know,
enantioselective hydroamination with the formation of a
quaternary center was never reported, and the amido alkyl
ate yttrium species described here were able to catalyze the
formation of two such compounds.
Scheme 3. Formation of New Heterocycles by AIH of 1,2,2-
Trisubstituted Aminoalkene 8a
CONCLUSION
■
We presented here a simple in situ synthesis of chiral amido
alkyl ate yttrium complexes by stoichiometric combination of a
well-known and room temperature stable yttrium precursor
[Li(THF)4][Y(CH2SiMe3)4] with a variety of chiral N-benzyl
type-substituted binaphthylamine ligands. These complexes
were active as catalysts for the room temperature cyclization of
monosubstituted aminoalkenes leading to 1b and 2b as
respectively a five- and a six-membered N-heterocycle, with
low ee’s (up to 30%). These new chiral amido alkyl ate
complexes afforded a better efficiency for the asymmetric
A last challenge was to perform the hydroamination of
trisubstituted olefins with an internal substituent on the double
bond for the enantioselective formation of quaternary centers
a
Table 4. AIH of Trisubstituted Aminoalkenes 9−11a toward the Formation of Quaternary Centers
b
c
entry
subst.
prod.
(R)-H2Ln
t (h)
T (°C)
% conv.
% ee
(config.)
1
2
3
4
5
6
7
8
9
9a
9b
(±)-H2L1
(R)-H2L1
(R)-H2L2
(R)-H2L3
(R)-H2L5
(R)-H2L6
(R)-H2L8
(R)-H2L9
(R)-H2L1
1
19
25
70
90
−
49
11
55
8
d
10a
10b
97 (66)
(S)
48
110
70
98
99
96
98
50
98
50
19
19
110
70
36
55
15
5
48
110
110
110
36
e
11a
11b
120
55
a
b
c
1
Reactions run in C6D6 (25−70 °C), in C7D8 (110 °C). Measured by H NMR spectroscopy. Determined by HPLC analysis of the product
d
e
following derivatization (see Supporting Information). Isolated yield. Reaction performed with 12 mol % cat.
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in THF (15 mL) was added dropwise at −20 °C and the reaction
mixture was allowed to warm up to room temperature overnight. It
was hydrolyzed with water (30 mL), and the aqueous phase was
extracted with ether (3 × 30 mL). The combined organic layers were
dried (MgSO4), filtered, and concentrated. The crude product was not
isolated but used in the following step without any purification. It was
solubilized in ether (15 mL) and added dropwise to a suspension of
LiAlH4 (2 g, 56 mmol) in ether (50 mL) at 0 °C. The reaction mixture
was allowed to warm up to room temperature for 3 h and then
hydrolyzed with water until the formation of white hydroxide
aluminum salts. The solid was separated from the mixture by filtration.
The organic layer was dried (MgSO4), filtered, and concentrated. The
residue was distilled (225 °C, 0.1 mbar) to afford a colorless liquid
(5.0 g, 43%). IR νmax (cm−1) 3378, 3054, 3022, 2933, 2891, 1595,
1577, 1493, 1444, 1429, 1155, 1032, 969; 1H NMR (250 MHz,
CDCl3) δH (ppm) 7.35−7.12 (m, 15H), 6.42 (d, J = 15.8 Hz, 1H),
5.82−5.77 (m, 1H), 3.36 (s, 2H), 3.10 (d, J = 17.6 Hz, 2H), 0.93 (br s,
2H); 13C NMR (62.5 MHz, CDCl3) δC (ppm) 146.4, 137.7, 132.9,
128.6, 128.4, 128.3, 127.2, 126.7, 126.3, 126.2, 52.1, 48.9, 40.5; HRMS
(ESI) m/z calcd for C23H24N [M + H]+ 314.1903. Found 314.1902.
Synthesis of 4-Methyl-2,2,5-triphenyl-pent-4-en-1-amine
10a. trans-α-Methyl-cinnamaldehyde (10 g, 9.5 mL, 68 mmol) was
solubilized in ether (15 mL) and added dropwise to a suspension of
LiAlH4 (5.2 g, 137 mmol) in ether (50 mL) at 0 °C. The reaction
mixture was allowed to warm up to room temperature for 3 h and then
hydrolyzed with water until the formation of white hydroxide
aluminum salts. The solid was separated from the mixture by filtration.
The organic layer was dried (MgSO4), filtered, and concentrated to
afford a colorless liquid (10 g, 67 mmol, 99%). (E)-2-Methyl-3-
phenylprop-2-en-1-ol (10 g, 67 mmol) was solubilized in Et2O (15
mL) and added dropwise to a suspension of PBr3 (8.2 mL, 87 mmol)
in ethanol (30 mL) at 0 °C. The reaction mixture was allowed to warm
up to room temperature overnight and then hydrolyzed with water and
NH4Cl saturated. The aqueous phase was extracted with ether (3 × 30
mL). The organic layer was dried (MgSO4), filtered, and concentrated
to afford a colorless liquid (11.2 g, 53 mmol, 79%). To a solution of
diisopropylamine (5.9 mL, 42 mmol) in THF (30 mL), n-BuLi (1.6 M
in hexanes, 28 mL, 45 mmol) was added dropwise at −20 °C, and the
reaction mixture was stirred at −20 °C for 2 h. A solution of
diphenylacetonitrile (6.7 g, 35 mmol) in THF (15 mL) was added
dropwise at −20 °C, and the reaction mixture was stirred for 3
additional hours. A solution of (E)-(3-bromo-2-methylprop-1-en-1-
yl)benzene (11.2 g, 53 mmol) in THF (15 mL) was added dropwise at
−20 °C, and the reaction mixture was allowed to warm up to room
temperature overnight. It was hydrolyzed with water (30 mL), and the
aqueous phase was extracted with ether (3 × 30 mL). The combined
organic layers were dried (MgSO4), filtered, and concentrated in
vacuo. The crude product was purified by flash chromatography on
silica gel (cyclohexane/ethyl acetate 75/25) to give a white crystalline
solid. It was solubilized in ether (15 mL) and added dropwise to a
suspension of LiAlH4 (2.0 g, 52 mmol) in ether (50 mL) at 0 °C. The
reaction mixture was allowed to warm up to room temperature for 3 h
and then hydrolyzed with water until the formation of white hydroxide
aluminum salts. The solid was separated from the mixture by filtration.
The organic layer was dried (MgSO4), filtered, and concentrated. The
residue was distillated (250 °C, 0.2 mbar) to afford a colorless liquid
(6.6 g, 20 mmol, 57%). IR νmax (cm−1) 3083, 3054, 3022, 2922, 2857,
1948, 1806, 1598, 1493, 1443; 1H NMR (250 MHz, CDCl3) δH
(ppm) 7.33−7.10 (m, 15H), 6.17 (s, 1H), 3.47 (s, 2H), 3.08 (s, 2H)
1.23 (s, 3H), 0.87 (br s, 2H); 13C NMR (62.5 MHz, CDCl3) δC (ppm)
147.1, 136.1, 129.9, 129.0, 128.6, 128.15, 128.1, 126.2, 126.1, 52.3,
47.95, 47.1, 20.2; HRMS (ESI) m/z calcd for C24H26N [M + H]+
328.2060. Found 328.2043.
intramolecular hydroamination of more challenging substrates.
Indeed, the demanding cyclization of primary amines tethered
to 1,2-disubstituted alkenes was efficiently performed at high
temperatures with yttrium complexes bearing binaphthylamine
ligands substituted on nitrogen atoms by benzyl-like groups.
Among the series of tested ligands, the N-anthrylmethyl-
binaphthylamine ligand (R)-H2L9 afforded the most enantio-
selective catalyst at 110 °C for the hydroamination/cyclization
of gem-dialkyl aminoalkenes 3a and 4a including a 1,2-dialkyl-
substituted double bond. For the reaction of other phenyl-
containing substrates 5a−7a, the best asymmetric inductions
were reached by using complexes prepared from N-para-
substituted benzyl ligands (R)-H2L3 or (R)-H2L4. An
enantiomeric excess value of 77% was indeed disclosed as the
highest value reported so far for the asymmetric intramolecular
hydroamination of amine-tethered 1,2-disubstituted alkenes.
We also unveiled here the first examples of catalytic asymmetric
hydroamination of aminoalkenes bearing trisubstituted double
bonds. Quaternary centers were so generated from the
cyclization of amines tethered to 1,1,2-trisubstituted alkenes
under harsher reaction conditions than the cyclization of the
corresponding disubstituted alkenes, and with enantioselectiv-
ities of up to 55%.
These results demonstrate that these easily accessible
heteroleptic binaphthylamido alkyl ate yttrium complexes
containing N-benzyl-like substituents have the ability to
catalytically induce the enantioselective intramolecular hydro-
amination of very sterically demanding substrates in a stable
and stereodefined environment even under harsh reaction
conditions. Studies are currently ongoing to further improve
the reactivity, enantioselectivity, and substrate scope of these
new complexes in the catalytic hydroamination reaction of
challenging substrates.
EXPERIMENTAL SECTION
■
All manipulations were carried out under an argon atmosphere by
using standard Schlenk or glovebox techniques. THF was distilled
from sodium benzophenone ketyl, degassed by freeze−pump−thaw
method, and stored over activated 4 Å molecular sieves. Benzene-d6,
toluene-d8, and diethyl ether were dried with sodium benzophenone
ketyl, transferred under vacuum, and stored over activated 4 Å
molecular sieves. Toluene was dried over CaH2 powder and distilled
prior to use. n-BuLi (1.6 M in hexanes) was purchased and used as
received. LiCH2SiMe3 (1 M in pentane), (R)-(+)-1,1′-binaphthyl-2,2′-
diamine, and crotyl chloride and cinnamyl bromide were purchased
and used without any further purification. Solid LiCH2SiMe3 was
obtained by cold recrystallization of a 1 M pentane solution of
19
22
LiCH2SiMe3. Ligands (R)-H2L0 and (R)-H2L1 were prepared
according to reported procedures. Substrates 1a,19 2a,23 6a,8c 8a, and
9a15f were prepared as reported. Substrates 3a,19 4a,24 and 5a25 were
prepared following a reported procedure using crotyl chloride
(trans:cis = 85:15) instead of crotyl bromide. All substrates were
dried overnight on 4 Å molecular sieves with a few drops of benzene-
d6 or toluene-d8 prior to use. Chemical shifts for H and 13C spectra
1
were referenced internally according to the residual solvent resonances
and reported relative to tetramethylsilane. Infrared spectra were
recorded on a FT-IR spectrometer as Nujol mulls or as KBr disks and
are reported in cm−1. Optical rotations are reported as follows: [α]D (c
in g per 100 mL in solvent).
Synthesis of 4-Methyl-2,2-diphenyl-hex-4-en-1-amine 11a.
Tiglic aldehyde (5 g, 59 mmol) was solubilized in ether (15 mL) and
added dropwise to a suspension of LiAlH4 (4.5 g, 118 mmol) in ether
(50 mL) at 0 °C. The reaction mixture was allowed to warm up to
room temperature for 3 h and then hydrolyzed with water until the
formation of white hydroxide aluminum salts. The solid was separated
from the mixture by filtration. The organic layer was dried (MgSO4),
Synthesis of 2,2,5-Triphenyl-pent-4-enylamine 7a. To a
solution of diisopropylamine (6.2 mL, 44 mmol) in THF (30 mL)
was added n-BuLi (1.6 M in hexanes, 30 mL, 48 mmol) dropwise at
−20 °C, and the reaction mixture was stirred at −20 °C for 2 h. A
solution of diphenylacetonitrile (7.2 g, 37 mmol) in THF (15 mL) was
added dropwise at −20 °C, and the reaction mixture was stirred for 3
additional hours. A solution of (E)-cinnamylbromide (8.6 g, 44 mmol)
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filtered, and concentrated to afford a colorless liquid (4.5 g, 52 mmol).
The (E)-2-methylbut-2-en-1-ol (4.5 g, 52 mmol) was solubilized in
Et2O (15 mL) and added dropwise to a suspension of PBr3 (6.4 mL,
68 mmol) in ethanol (30 mL) at 0 °C. The reaction mixture was
allowed to warm up to room temperature overnight and then was
hydrolyzed with water and saturated NH4Cl. The aqueous phase was
extracted with ether (3 × 30 mL). The organic layer was dried
(MgSO4), filtered, and concentrated to afford a colorless liquid (5.9 g,
39 mmol). To a solution of diisopropylamine (4.3 mL, 31 mmol) in
THF (30 mL) was added dropwise at −20 °C n-BuLi (1.6 M in
hexanes, 21 mL, 34 mmol), and the reaction mixture was stirred at
−20 °C for 2 h. A solution of diphenylacetonitrile (5.0 g, 26 mmol) in
THF (15 mL) was added dropwise at −20 °C, and the reaction
mixture was stirred for 3 additional hours. A solution of (E)-1-bromo-
2-methylbut-2-ene (5.9 g, 39 mmol) in THF (15 mL) was added
dropwise at −20 °C, and the reaction mixture was allowed to warm up
to room temperature overnight. It was hydrolyzed with water (30 mL),
and the aqueous phase was extracted with ether (3 × 30 mL). The
combined organic layers were dried (MgSO4), filtered, and
concentrated in vacuo. The crude product was purified by flash
chromatography on silica gel (cyclohexane/ethyl acetate, 75/25) to
give a white crystalline solid. It was solubilized in ether (15 mL) and
added dropwise to a suspension of LiAlH4 (1.5 g, 39 mmol) in ether
(50 mL) at 0 °C. The reaction mixture was allowed to warm up to
room temperature for 3 h and then hydrolyzed with water until the
formation of white hydroxide aluminum salts. The solid was separated
from the mixture by filtration. The organic layer was dried (MgSO4),
filtered, and concentrated. The residue was distillated (250 °C, 0.3
mbar) to afford a colorless liquid (4.1 g, 15 mmol, 59%). IR νmax
(cm−1) 3086, 3022, 2919, 2858, 1947, 1804, 1598, 1495, 1444, 1380;
1H NMR (250 MHz, CDCl3) δH (ppm) 7.32−7.18 (m, 10H), 5.29−
(R)-N2,N2′-Bis(4-methoxybenzyl)-1,1′-binaphthyl-2,2′-dia-
mine H2L3. Purification by flash chromatography (pentanes/ethyl
acetate, 70/30) to give a pale-white solid (0.800 g, 88%); mp 125 °C;
[α]25D +59.2 (c = 1.1, CHCl3); IR νmax (cm−1) 3411, 3050, 2929, 2833,
2366, 1615, 1596, 1504, 1424, 1337, 1300, 1246, 1173, 1150, 1101,
1
1033; H NMR (250 MHz, CDCl3) δH (ppm) 7.91−7.83 (m, 4H),
7.28 (d, J = 7.7 Hz, 6H), 7.18 (d, J = 7.7 Hz, 6H), 6.83 (d, J = 8.3 Hz,
4H), 4.38 (s, 6H), 3.79 (s, 6H); 13C NMR (62.5 MHz, CDCl3) δC
(ppm) 158.7, 144.4, 133.9, 131.8, 129.7, 128.3, 128.1, 127.8, 126.8,
124.0, 122.1, 114.4, 113.9, 112.1, 55.3, 47.2; Anal. Calcd for
C36H32N2O2: C, 82.41; H, 6.15; N, 5.34; O, 6.10. Found: C, 82.32;
H, 6.11; N, 5.37; O, 6.19.
(R)-N2,N2′-Bis(4-chlorobenzyl)-1,1′-binaphthyl-2,2′-diamine
H2L4. Purification by flash chromatography (pentanes/ethyl acetate,
70/30) to give a pale-white solid (0.850 g, 93%). mp 118 °C; [α]25
D
+9.5 (c = 1.1, CHCl3); IR νmax (cm−1) 3420, 3054, 2920, 1616, 1597,
1
1510, 1504, 1422, 1336, 1291, 1150, 1090, 810; H NMR (250 MHz,
CDCl3) δH (ppm) 7.95−7.87 (m, 4H), 7.37−7.14 (m, 16H), 4.46 (br
s, 4H), 4.37 (br s, 2H); 13C NMR (62.5 MHz, CDCl3) δC (ppm)
144.0, 138.5, 133.9, 132.8, 129.9, 128.8, 128.4, 128.3, 128.0, 127.0,
124.0, 122.4, 114.2, 112.3, 47.1; Anal. Calcd for C34H26N2Cl2: C,
76.55; H, 4.91; N, 5.25. Found: C, 76.08; H, 4.89; N, 5.23.
(R)-N2,N2′-Bis(2,4,6-trimethylbenzyl)-1,1′-binaphthyl-2,2′-di-
amine H2L5. Purification by flash chromatography (hexanes/ethyl
acetate, 95/5) to give a slightly yellow solid (0.453 g, 46%); mp 110
°C; [α]25 +30.9 (c = 1.1, CHCl3); IR νmax (cm−1) 3403, 2914, 1618,
D
1
1510, 1477, 1421, 1346, 1294, 1149, 1021, 850, 806; H NMR (360
MHz, CDCl3) δH (ppm) 7.73 (d, J = 8.6 Hz, 2H), 7.60 (d, J = 7.9 Hz,
2H), 7.23 (d, J = 8.6 Hz, 2H), 7.05−6.97 (m, 4H), 6.87 (d, J = 8.3 Hz,
2H), 6.56 (s, 4H), 4.17 (d, J = 11.2 Hz, 2H), 4.05 (d, J = 11.2 Hz, 2H),
3.30 (br s, 2H), 2.03 (s, 6H), 1.95 (s, 12H); 13C NMR (90 MHz,
CDCl3) δC (ppm) 145.4, 137.6, 137.0, 134.0, 131.9, 129.9, 129.0,
128.2, 128.1, 126.7, 124.0, 122.1, 114.7, 112.7, 43.6, 21.0, 19.3; HRMS
(ESI) m/z Calcd for C40H41N2 [M + H]+ 549.3270. Found 549.3273.
(R)-N2,N2′-Bis(naphthalen-1-ylmethyl)-1,1′-binaphthyl-2,2′-
diamine H2L6. Purification by flash chromatography (pentanes/ethyl
acetate, 90/10) to give a pale-white solid (0.75 g, 73%); mp 134 °C;
[α]25D 3.85 (c = 1.1, CHCl3); IR νma1x (cm−1) 1738, 1615, 1508, 1424,
1337, 1304, 1246, 1150, 1005, 855; H NMR (250 MHz, DMSO) δH
(ppm) 8.01 (d, J = 8.0 Hz, 2H), 7.90 (d, J = 8.0 Hz, 2H), 7.81−7.73
(m, 6H), 7.53−7.41 (s, 6H), 7.28−7.13 (m, 8H), 6.9 (d, J = 8.1 Hz,
2H), 4.90−4.86 (s, 6H). Due to poor solubility, further character-
ization data could not be obtained.
5.24 (m, 1H), 3.43 (s, 2H), 2.96 (s, 2H), 1.58 (d, J = 6.4 Hz, 3H), 1.01
(s, 3H), 0.83 (br s, 2H); 13C NMR (62.5 MHz, CDCl3) δC (ppm)
147.06, 132.5, 128.2, 127.7, 125.7, 123.5, 51.3, 47.5, 45.7, 17.25, 13.5;
HRMS (ESI) m/z calcd for C19H24N [M + H]+ 266.1903. Found
266.1893.
General Procedure for the Synthesis of Ligands (R)-H2L2 to
(R)-H2L9. To a solution of (R)-(+)-1,1′-binaphthyl-2,2′-diamine
(0.500 g, 1.8 × 10−3 mol) in dry toluene (5 mL) at ambient
temperature and under argon were successively added activated 4 Å
molecular sieves and the corresponding aldehyde (3.9 × 10−3 mol).
The reaction mixture was next heated at 110 °C for 2−5 days. After
cooling down to room temperature, the reaction mixture was filtered,
and the solid residue was washed several times with dry toluene. The
colored filtrate was concentrated under reduced pressure to afford the
crude bis-imine product as an oily residue. To a stirred suspension of
lithium aluminum hydride (0.205 g, 5.4 × 10−3 mol) in diethyl ether
(20 mL) at 0 °C and under argon was dropwise added a suspension of
the crude bis-imine product in diethyl ether (20 mL). The reaction
mixture was next allowed to warm up to ambient temperature and
stirred overnight at the same temperature. Distilled water was added to
the reaction mixture at 0 °C until the excess of hydride was
neutralized. A gas evolution and the formation of a white precipitate
were observed. The latter was filtered off through a paper filter and the
filtrate was washed three times with a saturated aqueous solution of
sodium chloride. The combined organic layers were dried over
anhydrous magnesium sulfate, filtered, and concentrated in vacuo to
give a slightly colored solid.
(R)-N2,N2′-Bis(naphthalen-2-ylmethyl)-1,1′-binaphthyl-2,2′-
diamine H2L7. Purification by flash chromatography (pentanes/ethyl
acetate, 70/30) to give a pale-white solid (0.600 g, 62%); mp 225 °C;
[α]25 6.6 (c = 1.1, CHCl3); IR νmax (cm−1) 3413, 3050, 2346, 1616,
D
1508, 1423, 1337, 1323, 1301, 1239, 1213, 1149, 1125, 1021; 1H NMR
(250 MHz, CDCl3) δH (ppm) 7.82−7.61 (m, 12H), 7.41−7.15 (m,
14H), 4.55 (s, 4H), 4.49 (s, 2H); 13C NMR (62.5 MHz, CDCl3) δC
(ppm) 144.4, 137.5, 134.1, 133.5, 132.8, 129.9, 128.4, 128.0, 127.9,
127.8, 127.0, 126.2, 125.7, 125.4, 125.3, 124.1, 122.3, 114.5, 112.3,
47.9; Anal. Calcd for C42H32N2: C, 89.33; H, 5.71; N, 4.96. Found: C,
89.21; H, 5.79; N, 4.93.
(R)-N2,N2′-Bis(benzothiophen-2-ylmethyl)-1,1′-binaphthyl-
2,2′-diamine H2L8. Purification by flash chromatography (pentanes/
ethyl acetate, 80/20) to give a pale-white solid (0.67 g, 64%); mp 101
°C; [α]25 92.6 (c = 1.1, CHCl3); IR νmax (cm−1) 1618, 1595, 1424,
D
1
1295, 1019, 1019, 742; H NMR (250 MHz, CDCl3) δH (ppm) 7.88
(R)-N2,N2′-Bis(2-methoxybenzyl)-1,1′-binaphthyl-2,2′-dia-
mine H2L2. Purification by flash chromatography (pentanes/ethyl
acetate, 95/5) to give a pale-white solid (0.750 g, 79%); mp 142 °C;
[α]D25 +65.7 (c = 1.1, CHCl3); IR νmax (cm−1) 3405, 3047, 2932, 2897,
2834, 1616, 1596, 1509, 1488, 1459, 1424, 1302, 1243, 1125, 1197,
(d, J = 7.8 Hz, 2H), 7.81 (d, J = 7.8 Hz, 2H), 7.68 (d, J = 7.8 Hz, 2H),
7.59 (d, J = 7.7 Hz, 2H,), 7.33−7.17 (m, 10H), 7.09−7.07 (m, 4H),
4.61 (s, 4H), 4.41 (s, 2H); 13C NMR (62.5 MHz, CDCl3) δC (ppm)
145.2, 143.8, 139.9, 139.5, 134.0, 130.0, 128.3, 128.2, 127.1, 124.3,
124.2, 124.0, 123.3, 122.6, 122.5, 120.8, 114.3, 112.6, 43.8; HRMS
(ESI) m/z Calcd for C38H29N2S2 [M + H]+ 577.1767. Found
577.1754.
1
1028; H NMR (250 MHz, CDCl3) δH (ppm) 7.80 (d, J = 7.8 Hz,
2H), 7.72 (d, J = 7.8 Hz, 2H,), 7.25−7.23 (m, 2H), 7.14−7.03 (m,
8H), 6.85 (d, J = 8.3 Hz, 2H), 6.73−6.63 (m, 4H), 4.34 (s, 6H), 3.41
(s, 6H); 13C NMR (62.5 MHz, CDCl3) δC (ppm) 157.3, 144.9, 134.2,
129.5, 128.4, 128.1, 127.8, 127.7, 126.6, 124.2, 121.9, 120.2, 114.7,
112.7, 110.0, 54.8, 43.5; Anal. Calcd for C36H32N2O2: C, 82.41; H,
6.15; N, 5.34; O, 6.10. Found: C, 82.31; H, 6.27; N, 5.16; O, 5.97.
Synthesis of Ligand (R)-N2,N2′-Bis(anthracen-9-ylmethyl)-
1,1′-binaphthyl-2,2′-diamine H2L9. To a solution of (R)-
(+)-1,1′-binaphthyl-2,2′-diamine (0.500 g, 1.8 × 10−3 mol) in xylene
(5 mL) was added anthracene-9-carbaldehyde (1.0 g, 5.1 × 10−3 mol)
at ambient temperature and under argon. The homogeneous reaction
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mixture was equipped with a Dean−Stark apparatus and next heated at
169 °C for 6 days. After cooling down to room temperature, the
reaction mixture was filtered, and the red-orange solid residue was
washed several times with dry xylene and dried under reduced
pressure. The dried red/orange solid residue was portionwise added to
a stirred suspension of lithium aluminum hydride (0.500 g, 13.2 ×
10−3 mol) in THF (50 mL) at 0 °C under argon . The reaction
mixture was next allowed to warm up to ambient temperature and
stirred overnight at the same temperature. The solvent was
concentrated in vacuo, and dried diethyl ether was added (50 mL).
Distilled water was added to the reaction mixture at 0 °C until the
excess of hydride was neutralized. The target product was obtained as
a yellow suspension in ether. This phase was recovered, and DCM was
added to give rise to a yellow solution. The combined organic layers
were dried over anhydrous magnesium sulfate, filtered, and
concentrated in vacuo to give a slightly colored solid. Purification by
flash chromatography (chloroform) gave a pale-yellow solid (1 g,
monitored by comparative integration of the signal relative to the
olefinic protons of the substrate and the signal relative to the protons
of the product. After the appropriate time, the reaction was quenched
by addition of a small amount of CH2Cl2.
NMR-Scale Asymmetric Intramolecular Hydroamination/
Cyclization of 1a Catalyzed by Isolated Complexes A and B.
In a glovebox, crystals of complexes A or B (0.042 × 10−3 mol) were
dissolved in C6D6 (2 mL), and a 670 μL-aliquot of the corresponding
homogeneous solution was taken off by a micropipet and transferred
to a vial containing 1a (0.23 × 10−3 mol). The reaction mixture was
then introduced into a screw-tap NMR tube. The conversion of the
reaction was monitored by comparative integration of the signal
relative to the olefinic protons of the substrate and the signal relative
to the protons of the product. After the appropriate time, the reaction
was quenched by addition of a small amount of CH2Cl2.
Procedures for Preparative-Scale Asymmetric Intramolecu-
lar Hydroamination/Cyclization: C-(1-But-2-enyl-cyclohexyl)-
methylamine 3a to 3b. In the glovebox, (R)-H2L9 (28 mg, 0.042
× 10−3 mol) was added to a solution of [Li(THF)4][Y(CH2SiMe3)4]
(31 mg, 0.042 × 10−3 mol) in toluene (2 mL). The precatalyst (201
μmol) in toluene and 3a (115.5 mg, 0.69 mmol) were loaded into a
storage tube equipped with a magnetic stir bar and J. Young valve. The
valve was then closed and the clear solution stirred for 36 h at 110 °C.
The reaction was stopped with dichloromethane, and the residue was
distilled (70 °C, 0.4 mbar) to afford a colorless liquid (50 mg, 50%).
55%). mp 263 °C; [α]25 +78.5 (c = 0.4, CHCl3); IR νmax (cm−1)
D
1
3054, 2361, 2342, 1617, 1509, 1472, 1420, 1291, 810, 728; H NMR
(250 MHz, CDCl3) δH (ppm) 8.29 (s, 2H), 7.88 (dd, J = 4.0 Hz, J =
9.2 Hz, 8H), 7.81 (d, J = 8.7 Hz, 2H), 7.69−7.66 (m, 2H), 7.51 (d, J =
9.2 Hz), 7.35−7.29 (m, 6H), 7.19−7.09 (m, 8H), 5.18 (dd, J = 8.2 Hz,
J = 11.7 Hz, 2H), 4.99 (dd, J = 4.7 Hz, J = 10.5 Hz, 2H), 3.92−3.84
(m, 2H); 13C NMR (62.5 MHz, CDCl3) δC (ppm) 146.1, 134.1, 131.5,
130.6, 130.0, 129.4, 129.0, 128.5, 128.4, 128.3, 127.8, 127.0, 126.3,
125.1, 124.3, 124.1, 122.5, 115.6, 42.6; HRMS (ESI) m/z Calcd for
C50H37N2 [M+H]+ 664.2904. Found 664.2823.
[α]25 +10.0 (c = 1.1, CHCl3) for ee = 68%; IR νmax (cm−1) 2926,
D
2854, 1623, 1450; 1H NMR (300 MHz, CDCl3) δH (ppm) 2.97−2.87
(m, 1H), 2.76 (d, J = 10.8 Hz, 1H), 2.61 (d, J = 10.8 Hz, 1H), 1.78−
1.70 (m, 2H), 1.50−1.20 (m, 11H), 1.19−1.08 (m, 1H), 1.02−0.95
(m, 1H), 0.89 (t, J = 8.0 Hz, 3H); 13C NMR (90 MHz, CDCl3) δC
(ppm) 60.8, 45.2, 38.7, 37.2, 29.9, 26.4, 24.1, 23.9, 11.9; HRMS (ESI)
m/z Calcd for C11H21N [M+] 167.1669. Found: 167.1671.
In Situ Preparation of Yttrium Complex by Reaction
between [Li(THF)4][Y(CH2SiMe3)4] and (R)-H2L0. In a glovebox,
to a solution of [Li(THF)4][Y(CH2SiMe3)4] (31 mg, 0.042 × 10−3
mol) in C6D6 (2 mL) was portionwise added (R)-H2L0 (18 mg, 0.042
× 10−3 mol). As the ligand was slowly added, the clear, slightly yellow
reaction mixture turned to a deeper yellow/orange-colored solution.
The homogeneous reaction solution was then allowed to stir 10 min at
ambient temperature and transferred to a screw-tap NMR tube for
2,2-Diphenyl-hex-4-enylamine 5a to 5b. In the glovebox, (R)-
H2L3 (22 mg, 0.042 × 10−3 mol) was added to a solution of
[Li(THF)4][Y(CH2SiMe3)4] (31 mg, 0.042 × 10−3 mol) in toluene (2
mL). The precatalyst (134 μmol in toluene) and 5a (116.5 mg; 0.46
mmol) were loaded into a storage tube equipped with a magnetic stir
bar and J. Young valve. The valve was then closed and the clear
solution stirred for 19 h at 70 °C. The reaction mixture was stopped
with dichloromethane and the residue was distilled (240 °C, 0.4 mbar)
1
analysis. H NMR (250 MHz, C6D6) δH (ppm) 7.72 (br s, 2H), 7.51
(br s, 2H), 7.42−7.39 (m, 2H), 6.89 (br s, 6H), 4.29 (br s, 2H), 3.33
(s, 16H), 2.51 (br s, 2H), 2.28 (br s, 2H), 1.60 (br s, 12H), 1.31 (s,
16H), 0.27 (s, 18H), 0.00 (s, TMS), − 0.96 (br s, 4H); 13C NMR
(62.5 MHz, C6D6) δC (ppm) 133.1, 131.7, 129.1, 127.9, 122.2, 119.4,
119.3, 68.5, 59.3, 36.0, 35.9, 25.8, 25.0, 24.3, 4.8, 0.4.
to afford a colorless liquid (94 mg, 80%). [α]25 +2.58 (c = 1.1,
D
CHCl3) for ee =75%; IR νmax (cm−1) 2918, 2877, 2710, 2553, 1601,
1493, 1456, 1380; 1H NMR (300 MHz, CDCl3) δH (ppm) 7.34−7.09
(m, 10H), 3.67 (d, J = 11.1 Hz, 1H), 3.40 (d, J = 11.1 Hz, 1H), 3.17−
3.08 (m, 1H), 2.73 (dd, J = 7.5 Hz, J = 14.2 Hz, 1H), 1.99 (dd, J = 9.1
Hz, J = 12.7 Hz, 1H), 1.73 (br s, 1H), 1.56−1.41 (m, 2H), 0.91 (t, J =
7.1 Hz, 3H); 13C NMR (90 MHz, CDCl3) δC (ppm) 148.0, 147.2,
128.6, 128.5, 127.3, 127.2, 126.2, 59.7, 57.9, 57.0, 45.2, 30.4; HRMS
(ESI) m/z Calcd for C18H22N [M+H+] 252.1747. Found: 252.1746.
2,2,5-Triphenyl-pent-4-enylamine 7a to 7b. In the glovebox,
(R)-H2L1 (20 mg, 0.042 × 10−3 mol) was added to a solution of
[Li(THF)4][Y(CH2SiMe3)4] (31 mg, 0.042·10−3 mol) in toluene (2
mL). The precatalyst (134 μmol) in toluene and 7a (151.5 mg; 0.46
mmol) were loaded into a storage tube equipped with a magnetic stir
bar and J. Young valve. The valve was then closed and the clear
solution stirred for 24 h at 50 °C. The reaction mixture was stopped
with dichloromethane, and the residue was distilled (250 °C, 0.3
General Procedure for NMR-Scale Asymmetric Intramolec-
ular Hydroamination/Cyclization of 1a−7a and 9a−10a. In a
glovebox, to a solution of [Li(THF)4][Y(CH2SiMe3)4] (31 mg, 0.042
× 10−3 mol) in C6D6 or C7D8 (2 mL) was portionwise added the
corresponding ligand (R)-H2Ln (0.042 × 10−3 mol) as a solid. As the
ligand was slowly added, the clear, slightly yellow reaction mixture
turned to a deeper yellow/orange-colored solution. The homogeneous
reaction solution was then allowed to stir 10 min at ambient
temperature, and a 670 μL-aliquot of the mixture was taken off by a
micropipet and transferred to a vial containing the substrate (0.23 ×
10−3 mol). The reaction mixture was then introduced into a screw-tap
NMR tube or a J. Young-tap NMR tube and placed in an oil bath
heated at the required temperature. The conversion of the reaction
was monitored by comparative integration of the signal relative to the
olefinic protons of the substrate and the signal relative to the protons
of the product. After the appropriate time, the reaction was quenched
by addition of a small amount of CH2Cl2.
General Procedure for NMR-Scale Asymmetric Intramolec-
ular Hydroamination/Cyclization of 8a and 11a. In a glovebox,
to a solution of [Li(THF)4][Y(CH2SiMe3)4] (31 mg, 0.042 × 10−3
mol) in C7D8 (2 mL) was portionwise added the corresponding ligand
(R)-H2L1 (0.042 × 10−3 mol) as a solid. As the ligand was slowly
added, the clear, slightly yellow reaction mixture turned to a deeper
yellow/orange-colored solution. The homogeneous reaction solution
was then allowed to stir 10 min at ambient temperature and 1340 μL-
aliquot of the mixture was taken off by a micropipet and transferred to
a vial containing the substrate (0.23 × 10−3 mol). The reaction mixture
was then introduced into a J. Young tap NMR tube and placed in an
oil bath heated at 110 °C. The conversion of the reaction was
mbar) to afford a colorless liquid (120 mg, 83%). [α]25 +16.6 (c =
D
1.1, CHCl3) for ee = 53%; IR νmax (cm−1) 3084, 3025, 2923, 2868,
1
1947, 1736, 1599, 1493, 1446, 1261, 1217, 1093, 1029, 753, 700; H
NMR (300 MHz, CDCl3) δH (ppm) δ 7.24−7.18 (m, 15H), 3.74 (d, J
= 11.1 Hz, 1H), 3.61−3.48 (m, 1H), 3.52 (d, J = 11.1 Hz, 1H), 2.91
(dd, J = 6.9 Hz, J = 13.0 Hz, 1H), 2.78−2.70 (m, 2H), 2.21 (dd, J = 9.4
Hz, J = 12.8 Hz, 1H), 1.65 (br s, 1H); 13C NMR (90 MHz, CDCl3) δC
(ppm) 147.9, 147.0, 140.1, 129.3, 128.6, 128.5, 128.2, 127.3, 127.1,
126.3, 126.2, 59.3, 57.9, 57.1, 45.1, 43.8; 11.8; HRMS (ESI) m/z Calcd
for C23H23N [M+]: 313.1903. Found: 313.1896.
2-Benzyl-2-methyl-4,4-diphenylpyrrolidine 10a to 10b. In
the glovebox, (R)-H2L1 (20 mg, 0.042 × 10−3 mol) was added to a
solution of [Li(THF)4][Y(CH2SiMe3)4] (31 mg, 0.042 × 10−3 mol) in
10170
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The Journal of Organic Chemistry
Article
Scheme 4. Derivatization Procedure for the Determination of Enantiomeric Excess Values
toluene (2 mL). The precatalyst (67 μmol) in toluene and 10a (75.3
mg; 0.23 mmol) were loaded into a storage tube equipped with a
magnetic stir bar and J. Young valve. The valve was then closed and
the clear solution stirred for 19 h at 70 °C. The reaction mixture was
stopped with dichloromethane, and the residue was distilled (250 °C,
J = 12.4 Hz, 1H), 1.93−2.05 (m, 2H), 1.19 (s, 3H), 1.00 (t, J = 7.6 Hz
3H); 13C NMR (62.5 MHz, CDCl3) δC (ppm) 146.3, 145.3, 139.3,
129.5, 128.7, 126.9, 126.7, 126.6, 126.2, 65.8, 60.4, 51.9, 49.4, 31.8,
29.9, 24.9; HRMS (ESI) m/z Calcd for C26H28NO [M + H+]:
370.2152. Found: 370.2165.
Retention Times of Derivatized Products. Retention times
were compared to racemic standard samples prepared by hydro-
amination reaction with the racemic ligand H2L1 (prepared from a
similar procedure as (R)-H2L1), followed by a derivatization reaction
as mentioned above (Table 5).
0.4 mbar) to afford a colorless liquid (50 mg, 66%). [α]25 +2.3 (c =
D
1.1, CHCl3) for ee = 49%; IR νmax (cm−1) 3058, 3025, 2963, 2923,
1948, 1805, 1598, 1493, 1446; 1H NMR (360 MHz, CDCl3) δH
(ppm) 7.47−7.12 (m, 15H), 3.75 (d, J = 11.7 Hz, 1H), 3.63 (d, J =
11.7 Hz, 1H), 2.77−2.63 (m, 3H), 2.50 (d, J = 12.3 Hz, 1H), 1.75 (br
s, 1H), 1.08 (s, 3H); 13C NMR (90 MHz, CDCl3) δC (ppm) 148.0,
147.6, 138.7, 130.5, 128.4, 128.0, 127.0, 126.2, 125.9, 62.5, 57.5, 57.0,
50.6, 49.0; HRMS (ESI) m/z Calcd for C24H25N [M + H+]: 328.2060.
Found: 328.2065.
Table 5. HPLC Retention Times
retention time
Determination of the Enantiomeric Excess Values. The
enantiomeric excess values were determined by HPLC analysis of
the derivatized product using a (S,S)-Whelk-O1 column (EtOH/
hexane 25/75; 0.9 mL·min−1, λ 254 nm (1c, 2c, 3c−5c, 7c) or iPrOH/
hexane 25/75; 0.7 mL.min−1, λ 254 nm (6c, 8c, 10c, 11c): Typical
procedure of derivatization: To a solution of the corresponding
cyclized product (1 equiv.) in CH2Cl2 (4 mL) was added
dimethylaminopyridine (0.2 equiv), triethylamine (2 equiv) and 1-
naphtoyl chloride (1.8 equiv) (for 1b, 2b, 3b, 4b) or 2-benzoyl
chloride (1.8 equiv) (for 5b−8b, 10b−11b) at ambient temperature.
After stirring for 2 h, a saturated aqueous solution of ammonium
chloride (4 mL) was poured into the reaction mixture, and the layers
were separated. The aqueous layer was extracted with CH2Cl2 (3 × 5
mL). The combined organic layers were then washed with a saturated
aqueous solution of ammonium chloride (5 mL), dried over
anhydrous magnesium sulfate, filtered, and concentrated in vacuo.
The crude product was purified by preparative TLC plate (silica gel)
(EtOAc/pentane, 25/75) (Scheme 4).
entry
cmpd
t1 (major) min
t2 (minor) min
1
2
1c
6.8
6.4
18.7
16.9
18.1
15.5
5.9
2c
3
3c
6.6
4
4c
6.5
5
5c
6.7
6
6c
17.6
6.6
46.4
7.5
7
7c
8
8c
16.3
42.0
52.7
32.2
28.0
23.7
9
10c
11c
11
Determination of the Absolute Configuration for 5b and
10b. The absolute (S) configuration of compound 5b was attributed
following a reported procedure.26 5b was derivatized with (R)-Mosher
1
chloride and corresponding diastereomers could be visualized by H
NMR spectroscopy. The ratio between both diastereomers corre-
sponded to the HPLC-measured ee value (75%) and the major isomer
was attributed the (S) configuration by comparison. 10b was
derivatized with (R)-Mosher chloride and the corresponding
diastereomers (R,S)-10b and (R,R)-10b could be visualized by 1H
NMR spectroscopy. The ratio between both diastereomers corre-
sponded to the HPLC-measured ee value (49%). The major isomer I
(Figure S1, SI) was recrystallized in methanol at room temperature
and characterized by X-ray structure and was attributed the (S)
configuration.
1-Benzoyl-4,4-diphenyl-2(propan-2-yl)pyrrolidine 8c: IR
νmax (cm−1) 665, 700, 754, 1074, 1301, 1402, 1487, 1519, 1645,
1
2922; H NMR (250 MHz, CDCl3) δH (ppm) 7.50−7.07 (m, 15H),
4.10 (d, J = 5.8 Hz, 1H), 3.88 (s, 1H), 2.85 (d, J = 7.3 Hz, 1H), 2.45−
2.42 (m, 1H), 1.70−1.66 (m, 1H), 1.56 (s, 1H), 1.53 (s, 3H), 1.51 (s,
3H); 13C NMR (62.5 MHz, CDCl3) δC (ppm) 26.4, 31.4, 36.6, 37.6,
47.0, 53.5, 56.1, 126.4, 126.7, 126.8, 127.5, 128.4, 128.5, 128.7, 129.0,
131.5, 146.9; HRMS (ESI) m/z Calcd for C26H28NO [M + H+]:
370.2152. Found: 370.2135.
1-Benzoyl-2-ethyl-2-methyl-4,4-diphenylpyrrolidine 11c: IR
1
νmax (cm−1) 550, 640, 765, 933, 1150, 1420, 2963, 3061; H NMR
ASSOCIATED CONTENT
* Supporting Information
(250 MHz, CDCl3) δH (ppm) 7.08−7.48 (m, 15H), 4.31 (d, J = 12.4
Hz, 1H), 3.73 (d, J = 12.4 Hz, 1H), 2.93 (d, J = 12.4 Hz, 1H), 2.52 (d,
■
S
10171
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The Journal of Organic Chemistry
Article
HPLC chromatogram of 3c−8c and 10c−11c; 1H NMR
Marks, T. J. J. Am. Chem. Soc. 1992, 114, 275−294. (d) Gagne, M. R.;
́
Brard, L.; Conticello, V. P.; Giardello, M. A.; Stern, C. L.; Marks, T. J.
Organometallics 1992, 11, 2003−2005.
1
spectra of (R)-H2L6; H and 13C NMR spectra of (R)-H2L2−5
,
(R)-H2L7−9, and 10a, 11a, 10b, and 11c, 8c; ORTEP diagram
of I and B. This material is available free of charge via the
Internet at http://pubs.acs.org.
(8) Intermolecular hydroamination promoted by rare earth metals-
based catalysts has been rarely described. (a) Li, Y.; Marks, T. J.
Organometallics 1996, 15, 3770−3772. (b) Ryu, J. −S.; Li, G. Y.;
Marks, T. J. J. Am. Chem. Soc. 2003, 125, 12584−12605. (c) Gribkov,
D. V.; Hultzsch, K. C.; Hampel, F. J. Am. Chem. Soc. 2006, 128, 3748−
AUTHOR INFORMATION
Corresponding Author
*E-mail: emmanuelle.schulz@u-psud.fr. E-mail: jerome.
hannedouche@u-psud.fr; Fax: (+33)169154680.
■
3759.
The first intermolecular asymmetric hydroamination of
unactivated alkenes with simple amines using rare earth metals-based
catalysts was only recently reported: (d) Reznichenko, A. L.; Nguyen,
H. N.; Hultzsch, K. C. Angew. Chem., Int. Ed. 2010, 49, 8984−8987.
(9) (a) Kim, J. Y.; Livinghouse, T. Org. Lett. 2005, 7, 1737−1739.
(b) See ref 7c. (c) See ref 8c. (d) An example of group IV metals-
catalyzed cyclization albeit with low ee: Reznichenko, A. L.; Hultzsch,
K. C. Organometallics 2010, 29, 24−27.
(10) Ryu, J.-S.; Marks, T. J.; McDonald, F. E. Org. Lett. 2001, 3,
3091−3094.
(11) Ryu, J.-S.; Marks, T. J.; McDonald, F. E. J. Org. Chem. 2004, 69,
1038−1052.
(12) An example of group IV metals-catalyzed cyclization of primary
amines tethered to 1,2-disubstituted alkenes in racemic version:
Leitch, D. C.; Payne, P. R.; Dunbar, C. R.; Schafer, L. L. J. Am. Chem.
Soc. 2009, 131, 18246−18247.
(13) (a) Molander, G. A.; Dowdy, E. D. J. Org. Chem. 1998, 63,
8983−8988. (b) Molander, G. A.; Dowdy, E. D. J. Org. Chem. 1999,
64, 6515−6517.
(14) Hegedus and his group reported as soon as 1978 the synthesis
of 2,2-dimethyl-2,3-dihydro-1H-indole by intramolecular hydroamina-
tion promoted by stoichiometric quantities of Pd. Hegedus, L. S.;
Allen, G. F.; Bozell, J. J.; Waterman, E. L. J. Am. Chem. Soc. 1978, 100,
5800−5807.
ACKNOWLEDGMENTS
■
We thank for financial support CNRS, MENSR, ANR (Grant
07 367), GDRI (“Homogeneous Catalysis for Sustainable
Development”), and French Embassy at Moscow. CNRS and
Russian Academy of Sciences are acknowledged for GDRI
support. A.T. thanks the Russian Foundation for Basic Research
(Grant 08-03-92501).
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