Asymmetric intermolecular hydroamination of unactivated alkenes with simple amines

Article abstract of DOI:10.1002/anie.201004570

A hard nut to crack: The asymmetric intermolecular Markovnikov addition of simple amines to unactivated alkenes can be achieved utilizing binaphtholate rare-earth-metal catalysts with up to 61% ee and 73% de in the case where R ² contains a stereogenic center.

Full text of DOI:10.1002/anie.201004570

Communications
DOI: 10.1002/anie.201004570
Asymmetric Hydroamination
Asymmetric Intermolecular Hydroamination of Unactivated Alkenes
with Simple Amines**
Alexander L. Reznichenko, Hiep N. Nguyen, and Kai C. Hultzsch*
In memory of Herbert Schumann (1935–2010)
The development of efficient methods for the synthesis of
nitrogen-containing compounds remains an important goal in
contemporary catalysis research because of the central role of
this class of compounds in biological systems and pharma-
reactions of styrene[6b] and 1,3-cyclohexadiene[14] indicated
the potential applicability of these systems in asymmetric
intermolecular hydroaminations. As the lanthanum catalyst
showed rather low selectivity[14] we decided to utilize the
generally more selective yttrium and lutetium catalysts in our
study. For the initial catalyst screening we chose the reaction
of 1-heptene with benzylamine.
ceutical applications.[1] The addition of an amine N H bond
À
to a carbon–carbon multiple bond, so-called hydroamina-
tion,[2] is a reaction with great synthetic potential, as it not
only reduces the formation of waste owing to its atom
economy, but it utilizes also very simple starting materials.
The development of novel catalyst systems for hydroamina-
tion has seen significant progress in the last two decades,[2,3]
but the intermolecular hydroamination of unactivated
alkenes with simple amines remains very challenging.[4]
Therefore, it is not too surprising that asymmetric hydro-
amination reactions[5] have been studied predominantly in
intramolecular reactions.[6,7] Intermolecular reactions have
been reported only sporadically and all of these studies were
limited to the reaction between aniline derivatives and
activated alkenes, such as vinyl arenes,[8] 1,3-dienes,[9] and
strained bicyclic alkenes.[10] The first enantioselective gold-
catalyzed addition of cyclic ureas to unactivated alkenes in up
to 78% ee was reported recently by Widenhoefer and co-
workers.[11] Herein we report the stereoselective addition of
simple amines to unactivated alkenes utilizing chiral rare-
earth-metal-based catalysts.
Indeed, the addition of benzylamine to 1-heptene can be
observed at 1508C in the presence of 5 mol% of the
binaphtholate complexes 1–4 (Table 1). As expected,[4a,b] the
reaction proceeds with high Markovnikov selectivity. The
reactions achieve high conversions and no other by-products
were observed besides the hydroamination product.[15]
The triphenylsilyl-substituted binaphtholate yttrium com-
plex (R)-1-Y achieved the highest enantioselectivity, 58% ee
(Table 1, entry 1).[16] A 15-fold excess of alkene was used in
order to accelerate the reaction. Lower alkene/amine ratios
led to longer reaction times and lower conversion (Table 1,
entry 3), while a greater excess of alkene led to a slight
acceleration of the reaction (Table 1, entry 4). The enantio-
meric excess was only slightly influenced by the alkene/amine
ratio. The R-configured binaphtholate catalysts formed the
hydroamination product with R configuration,[17] which is the
opposite selectivity of that observed for intramolecular
hydroaminations of aminoalkenes with these catalysts.[6b]
The sterically more shielded tri(xylyl)silyl-substituted
binaphtholate complex (R)-2-Y and the novel tert-butyldi-
phenylsilyl- and cyclohexyldiphenylsilyl-substituted binaph-
tholate complexes (R)-3-Y and (R)-4-Y, respectively, achieve
slightly lower selectivities of 44–47% ee, with (R)-3-Y dis-
playing the lowest activity. The smaller ionic radius of
lutetium in (R)-1-Lu results in lower selectivity as well,
while the activity remains comparable to that of the yttrium
complex (Table 1, entry 6). Therefore, further investigations
with a broader range of substrates were conducted predom-
inantly with 1-Y (Table 2).
Catalyst systems based on rare-earth-metal complexes
exhibit high catalytic activity, in particular in intramolecular
hydroaminations,[2,3f] whereas intermolecular hydroamina-
tions are significantly more difficult to achieve as a result of
the unfavorable competition between weakly coordinating
alkenes and strongly coordinating amines.[4a,b,6b,12] We have
previously reported on efficient biphenolate and binaphtho-
late rare-earth-metal catalysts,[6b,13] which can catalyze the
intramolecular hydroamination of aminoalkenes with high
activity and up to 95% ee. Preliminary studies with a
corresponding binaphtholate lanthanum complex for the
[*] A. L. Reznichenko, H. N. Nguyen, Prof. Dr. K. C. Hultzsch
Department of Chemistry and Chemical Biology
Rutgers, The State University of New Jersey
610 Taylor Road, Piscataway, NJ 08854-8087 (USA)
Fax: (+1)732-445-5312
E-mail: hultzsch@rci.rutgers.edu
Homepage: http://chem.rutgers.edu/~hultzsch/
[**] This work was supported by the National Science Foundation
through an NSF CAREER Award (CHE 0956021).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201004570.
8984
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Table 1: Catalyst screening for the intermolecular hydroamination of 1-
Analogous to 1-heptene, linear and branched 1-alkenes
heptene with benzylamine.[a]
are converted into their respective N-benzylalkan-2-amines
with good turnover. However, branching in the allylic
position, for example in vinylcyclohexane (Table 2, entry 8)
leads to significantly diminished reactivity. The highest
reactivity was observed for 4-phenyl-1-butene, for which a
lower alkene/amine ratio of 10:1 was possible. All reactions
with 1-Y provide similar selectivities in the range of 51–
61% ee. Reactions with cyclopentanamine proceed with
comparable enantioselectivity, but diminished activity
(Table 2, entries 9–11). Similar observations were made for
para-methoxybenzylamine, in which the reduced reactivity
can be attributed to a possible deactivation of the catalyst by
the methoxy group.
The reaction of 1-heptene with the enantiomerically pure
(R)-1-phenylethanamine using (S)-1-Y produces the hydro-
amination product in 54% yield (75% conversion) and a
diastereomeric excess of 73%, while the reaction of the
apparent mismatching catalyst (R)-1-Y led only to traces of
the hydroamination product even at elevated reaction
temperatures and longer reaction time (Scheme 1).
Entry
Cat.
t [h]
Conv. [%][b]
(yield [%][c])
ee [%][d]
(config.)
1
2
3
4
5
6
7
8
9
(R)-1-Y
(R)-1-Y
(R)-1-Y[f]
(R)-1-Y[g]
(S)-1-Y[h]
(R)-1-Lu
(R)-2-Y
(R)-3-Y
(R)-4-Y
36
48
48
18
18
30
24
48
17
90 (65)
– (78)[e]
85 (57)
95 (68)
95
95 (62)
90 (61)
85 (59)
90
58 (R)
58 (R)
57 (R)
54 (R)
55 (S)
40 (R)
44 (R)
46 (R)
47 (R)
[a] General reaction conditions: 3.0 mmol 1-heptene, 0.2 mmol benzyl-
amine (alkene/amine 15:1), 10 mmol cat. (0.1 mL of a 0.1m cat. solution
in [D6]benzene or [D8]toluene). [b] The conversion of the amine was
determined by 1H NMR spectroscopic analysis. [c] Yield of isolated
product after column chromatography. [d] Determined by 19F NMR
spectroscopy of the Mosher amide after removal of the benzyl group.
[e] Preparative-scale reaction using 12.0 mmol 1-heptene, 1.0 mmol
benzylamine (alkene/amine 12:1). [f] Alkene/amine 7:1. [g] 8 mol%
cat., alkene/amine 50:1. [h] 4 mol% cat., 1708C.
Initial kinetic studies suggest that the reaction is first
order with respect to amine, alkene, and catalyst concen-
tration (see the Supporting Information). These preliminary
Table 2: Asymmetric intermolecular hydroamination of 1-alkenes with a primary amine.[a]
Entry
1
Alkene
Amine
Product
Cat.
Alkene/amine
14:1
t [h]
Conv. [%][b]
(yield [%][c])
ee [%]
(config.)
(R)-1-Y
72
90 (70)
61 (R)[d]
2
3
(S)-1-Y
13:1
15:1
72
60
90 (54)
95 (59)
61 (S)[d]
50 (R)[d]
(R)-4-Y[e]
4
5
(R)-1-Y
(R)-1-Lu
15:1
15:1
40
44
97 (72)
95 (70)
57 (R)[d]
44 (R)[d]
6
7
(S)-1-Y
15:1
10:1
19
11
95 (59)
51 (S)[d]
(S)-1-Y[e]
100 (72)
56 (S)[d, g]
8
rac-1[f]
12:1
96
25
–
9
10
(S)-1-Y[e]
(R)-4-Y[e]
15:1
15:1
60
27
95 (61)
95 (68)
61[g]
56[g]
11
(S)-1-Y[e]
9:1
39
90 (68)
54[g]
12
13
14
(S)-1-Y
(R)-3-Y
(R)-4-Y
10:1
10:1
10:1
48
72
48
85 (67)
75 (61)
80
56 (S)[g]
54 (R)[g]
44 (R)[g]
[a] General reaction conditions: 1.8–3.0 mmol 1-alkene (9- to 15-fold excess), 0.2 mmol amine, 10 mmol cat. (0.1 mL of a 0.1m cat. solution in
[D6]benzene or [D8]toluene). [b] The conversion of amine was determined by 1H NMR spectroscopic analysis. [c] Yield of isolated product after column
chromatography. [d] Determined by 19F NMR spectroscopy of the Mosher amide after removal of the benzyl group by hydrogenation. [e] 4 mol% cat.
[f] 8 mol% cat., 1708C. [g] Determined by 1H NMR spectroscopy of the salt of O-acetyl mandelic acid.
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5 mol%). The NMR tube was then sealed, removed from the
glovebox, and placed into a thermostatted oil bath. Flame-sealed
NMR tubes were used for more volatile substrates, such as 1-hexene
or 1-pentene. The progress of the reaction was monitored by 1H NMR
spectroscopy. After completion of the reaction, the mixture was
concentrated in vacuo and purified by column chromatography on a
3 cm thick pad of silica or alumina.
Received: July 26, 2010
Published online: October 11, 2010
Scheme 1. Stereoselective addition of (R)-1-phenylethanamine to 1-
heptene using (S)-1-Y and (R)-1-Y.
Keywords: alkenes · amines · enantioselectivity ·
intermolecular hydroamination · rare-earth metals
.
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Scheme 2. Stereoselective synthesis of 2-aminoalkanes (using the
example of 2-aminooctane) by means of the asymmetric hydroamina-
tion of 1-alkenes.
It is important to note that the binaphtholate catalysts, in
contrast to chiral lanthanocenes,[18] seem to be configuration-
ally stable even under the very harsh reaction conditions
(150–1708C). Improvements in the catalyst design (in partic-
ular with respect to reactivity and selectivity) will certainly
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catalysts to probe the scope and limitations of this trans-
formation.
Experimental Section
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Chemie
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and the volatility of the products. A larger 1.0 mmol scale
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entry 2).
1
[16] The enantiomeric excess was determined by H NMR spectros-
copy of the salt of the O-acetyl mandelic acid, as well as by
19F NMR spectroscopy of the corresponding Mosher amide after
removal of the benzyl group.
[17] The absolute configuration was assigned by comparison of the
19F NMR spectroscopic data of the Mosher amide of the
deprotected primary amine with the data of analogous com-
pounds reported in the literature. See the Supporting Informa-
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