Base-catalysed asymmetric hydroamination/cyclisation of aminoalkenes utilising a dimeric chiral diamidobinaphthyl dilithium salt

Article abstract of DOI:10.1039/b518360j

A dimeric proline derived diamidobinaphthyl dilithium salt represents the first example of a chiral main group metal based catalyst for asymmetric hydroamination/cyclisation reactions of aminoalkenes. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b518360j

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COMMUNICATION
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Base-catalysed asymmetric hydroamination/cyclisation of amino-
alkenes utilising a dimeric chiral diamidobinaphthyl dilithium salt{
Patricia Horrillo Mart´ınez, Kai C. Hultzsch* and Frank Hampel
Received (in Cambridge, UK) 3rd January 2006, Accepted 28th March 2006
First published as an Advance Article on the web 11th April 2006
DOI: 10.1039/b518360j
lithiation of (S,S,S)-2 in hexanes generated the dilithium salt
(S,S,S)-3 as a yellow–orange powder. (S,S,S)-3 possesses a dimeric
structure, as revealed by X-ray crystallographic analysis (Fig. 1).{
All four lithium atoms are situated in different coordination
environments. The terminal lithium atom Li2 is coordinated to two
amine nitrogen atoms of pyrrolidine donor groups (av. Li–N
A dimeric proline derived diamidobinaphthyl dilithium salt
represents the first example of a chiral main group metal based
catalyst for asymmetric hydroamination/cyclisation reactions of
aminoalkenes.
The high importance of nitrogen containing compounds in
biological systems and industrial relevant basic and fine chemicals
has sparked significant research efforts for their efficient synthesis.
Although many synthetic methods have been devised over the last
century, one of the simplest synthetic approaches, hydroamination,
has become only the focus of attention with the advent of
transition metal catalysts. The addition of amine N–H function-
alities to unsaturated carbon–carbon bonds generates amines in a
waste-free, highly atom-economical manner starting from simple
and inexpensive precursors.1
˚
2.10 A) and one amido nitrogen atom (Li2–N120 1.992(4) A). Li1
˚
˚
is stabilized by two amine (av. Li–N 2.19 A) and two amido
˚
nitrogen ligands. While Li1–N20 is rather short (1.975(4) A), Li1–
2
N10 is significantly elongated (2.264(4) A) due to a g binding
˚
14
˚
mode of the naphthyl amido moiety (Li1–C31 2.448(5) A).
The interior lithium atoms Li1a and Li2a are significantly
stabilized by p-interaction with the aromatic rings15 of the
diamidobinaphthyl ligands. Li1a is coordinated to three amido
˚
nitrogen atoms (Li–N 1.936(4)–2.104(4) A), with one amido
ligand, consisting of N20, C41 and C50, being bound in a g3 mode.
Li2a is bound only to two amido nitrogens and displays a
similar g3 coordination mode to N120, C141 and C150 as
Because of the chirality of many hydroamination products,
asymmetric hydroamination of alkenes (AHA) carried out with
chiral catalysts is an attractive, but highly challenging task.2 Recent
interest has focused on the development of chiral early1e,3 and
late1f,4 transition metal catalysts. Although alkali metals are
known hydroamination catalysts for more than fifty years,5 the
overall number of reports is limited.1a–c Many investigations have
focused on the hydroamination of activated alkenes, such as vinyl
arenes and 1,3-dienes.6 Most noteworthy, base catalysed hydro-
amination has been utilised in the industrial scale synthesis of (2)-
menthol.6b,7 The base catalysed hydroamination of non-activated
alkenes is significantly less developed,5b,c,8 and (non-asymmetric)
hydroamination/cyclisation of aminoalkenes utilising n-BuLi,9 or
b-diketiminato calcium complexes10 has been reported only
recently. Despite the high potential of the hydroamination
reaction, to the best of our knowledge no base catalysed
asymmetric hydroamination of non-activated alkenes using a
main group metal has been reported.11,12 In this communication
we present an asymmetric hydroamination catalyst system based
on a chiral diamidobinaphthyl dilithium salt.
observed for Li1a. Additionally, Li2a is stabilized by a g2
p
˚
interaction with C42 and C43 (av. Li–C 2.45 A).
Initial catalytic experiments revealed that (S,S,S)-3 is a suitable
catalyst for asymmetric hydroamination/cyclisation reactions of
various aminopentene derivatives (Table 1). For example, cyclisa-
tion of 5 proceeded using 5 mol% (S,S,S)-3 (= 20 mol% Li) within
42 h in 86% isolated yield and 68% ee at 22 uC (Table 1, entry 2).
The L-proline derived axial chiral tetraamines 2 were prepared
in two steps through coupling of BOC-L-proline and racemic
diaminobinaphthyl (rac-DABN) followed by LiAlH4 reduction
(Scheme 1). The diastereomeric BOC-L-proline substituted diami-
nobinaphthyls (R,S,S)-1 and (S,S,S)-1 could be seperated via
column chromatography or preparative HPLC.13 Subsequent
Institut fu¨r Organische Chemie, Friedrich-Alexander Universita¨t
Erlangen-Nu¨rnberg, Henkestr. 42, D-91054, Erlangen, Germany.
E-mail: hultzsch@chemie.uni-erlangen.de; Fax: +49-9131-8526865;
Tel: +49-9131-8526866
{ Electronic supplementary information (ESI) available: Experimental
procedures and characterising data for all compounds. See DOI: 10.1039/
b518360j
Scheme 1 Reagents and conditions: i, ClCO2Et, Et3N, THF, 215 uC, 1 h;
ii, rac-DABN, THF, 215 uC, 1 h, then 25 uC overnight; iii, chromato-
graphic diastereomer separation; iv, LiAlH4, Et2O, 0 uC, then 7 h reflux; v,
2 equiv. n-BuLi, hexanes/benzene, 0 uC, then 1 h at 25 uC.
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Chem. Commun., 2006, 2221–2223 | 2221

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requiring elevated temperatures (80 uC) and resulted in a slight
erosion in enantioselectivity.
The close proximity of at least two lithium atoms seems to be
essential for catalyst performance, because simple lithium amides,
such as LiN(SiMe3)2, required significant higher reaction tem-
peratures (Table 1, entry 6). A catalyst system comprising of
LiN(SiMe3)2 and (–)-sparteine12b resulted in improved rate of
cyclisation (Table 1, entry 7),16 but no enantiomeric excess in the
pyrrolidine product was observed. Also, the chiral mono(lithium)
amide (S)-417 was inferior in reactivity and selectivity (Table 1,
entries 5 and 10).
Cyclisation of sterically more demanding aminoalkenes 7 and 9
proceeded significantly faster thanks to the increased gem-dialkyl
effect.18 While diphenyl-substituted 7 was cyclised in only 31% ee
using (S,S,S)-3 at 22 uC, substrate 9 showed the highest selectivity of
75% ee. The 1,2-disubstituted aminoalkene 11 was cyclised very
rapidlywithin5minat22uCduetotheactivatingeffectoftheelectron-
withdrawing phenyl-substituent, though enantioselectivity was low.
The first cyclisation of aminodialkene 13 proceeded also rapidly
at 22 uC within 2 h, yielding the allyl-substituted pyrrolidines
14a and 14b in good enantioselectivity (72% ee for the
minor diastereomer 14b), but only low diastereoselectivity. The
minor diastereomer 14b, presumably the isomer with a cisoid
Fig. 1 Molecular structure of (S,S,S)-3 with thermal ellipsoids at 30%
˚
probability level. Selected bond lengths(A)anddihedral angles (u):Li1–N10
2.264(4), Li1–N16 2.204(4), Li1–N20 1.975(4), Li1–N26 2.174(4), Li1–C31
2.448(5), Li1a–N10 1.936(4), Li1a–N20 2.104(4), Li1a–N110 2.070(4),
Li1a–C41 2.253(4), Li1a–C50 2.489(4), Li2–N116 2.112(4), Li2–N120
1.992(4), Li2–N126 2.097(4), Li2a–N110 1.974(4), Li2a–N120 2.031(4),
Li2a–C42 2.466(5), Li2a–C43 2.437(5), Li2a–C141 2.263(5), Li2a–C150
2.537(5); C31–C40–C50–C41 76.6(3), C131–C140–C150–C141 84.8(3).
Even at 2.5 mol% catalyst loading the reaction gave 93% yield (by
NMR spectroscopy) in 67% ee after 45 h. Addition of THF
(Table 1, entry 4) significantly reduced catalytic performance
Table 1 Hydroamination/cyclisation reactions utilising lithium amide catalystsa
Entry Substrate
Product
Cat.
[cat.]/[subst.]b T/uC t/h
Yieldc (%) eed (%) (config.)
1
2
3
4
5
6
7
(S,S,S)-3
(S,S,S)-3
(S,S,S)-3
(S,S,S)-3?4THF
(S)-4
LiN(SiMe3)2
7.5
5
2.5
5
10
10
22
22
22
9
42
45
96
64 (S)
68 (S)
67 (S)
53 (S)
2
96 (86)
93
66
56
98
80 407
120 333
90
90
38
22
—
0
LiN(SiMe3)2/(–)-sparteine 10
98
8
9
10
(S,S,S)-3
(S,S,S)-3?4THF
(S)-4
5
5
10
22
80
0.8 97
31 (S)
24 (S)
—
27
70
0
120 140
11
12
13
(S,S,S)-3
(S,S,S)-3
(S,S,S)-3?4THF
2.5
22
20
60
1.1 91
75 (S)
74 (S)
69 (S)
5e
5
2
91
98 (82)
64
14
15
a
(S,S,S)-3
(S,S,S)-3
5
5
22
22
0.08 98
17
2
98 (79)
64, 72f
b
c
Reaction conditions: C6D6, Ar atm. Calculated for a dimeric species for (S,S,S)-3 and (S,S,S)-3?4THF containing 4 Li atoms each. NMR
d
yield relative to ferrocene internal standard. Values given in parentheses are isolated yields from preparative scale reactions. Enantiomeric
excess was determined by 19F NMR of the Mosher amides. Reaction in toluene. dr(14a:14b) = 1.2:1.
e
f
2222 | Chem. Commun., 2006, 2221–2223
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Scheme 2 Bicyclisation of 14b.
arrangement of the two methyl substituents,19 underwent slow
bicyclisation at 22 uC (70% conv. of 14b in 6 d) to give 2,4,6-
dimethyl-1-azabicyclo[2.2.1]heptane (15) with 8:1 exo,exo:endo,exo
diastereoselectivity (Scheme 2). The major diastereomer 14a with a
transoid arrangement of the two methyl substituents remained
unaffected under these conditions.
Lithium amides are well known to form higher aggregates.20
Although the molecularity of (S,S,S)-3 under catalytic conditions
is not known,21 it seems obvious, though still speculative, that a
dimeric structure similar to that observed in the solid state is
pivotal for the catalytic process described herein. Preliminary
experiments indicate a relative minor influence of catalyst loading
or added THF on enantiomeric excess (Table 1, entries 1–4), while
the effect on catalytic activity is more pronounced. With respect to
the importance of the nuclearity of (S,S,S)-3 for its catalytic
activity it is also important to note that lithiation of (R,S,S)-2 did
not generate a well defined species, based on the broad and
featureless NMR spectra, and no catalytic activity was observed.22
Further investigations are currently aimed at extending the
scope of the catalyst to intermolecular hydroamination reactions.
More detailed mechanistic and kinetic investigations are required
in order to elucidate the catalytically active species and understand
the factors which are responsible for the increased catalytic activity
and enantioselectivity in the dimeric dilithium amide complex
(S,S,S)-3 relative to simple lithium amides, such as (S)-4.
Generous financial support by the Deutsche Forschungs-
gemeinschaft (DFG) and the Dr Otto Ro¨hm Geda¨chtnisstiftung
is gratefully acknowledged. K. C. H. is a DFG Emmy Noether
fellow (2001–2006) and thanks Professor John A. Gladysz for his
continual support.
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from enantiopure (R)-diaminobinaphthyl.
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Notes and references
{ Crystallographic data for (S,S,S)-3?C6H6: C70H78Li4N8, Mr = 1059.16,
crystal size 0.15 6 0.10 6 0.10 mm, monoclinic, space group P21, a =
˚
9.7704(1), b = 17.6269(3), c = 16.8330(2) A, b = 93.335(1)u, V = 2894.10(7)
A , Z = 2, Dc = 1.215 g cm23, F(000) = 1132, Mo-Ka radiation (l =
3
˚
0.71073 A), T = 173(2) K, m = 0.070 mm21, 13208 independent reflections
˚
were measured on a Nonius KappaCCD system, R1 (I > 2s(I)) = 0.0542,
wR2 (all data) = 0.1438. The absolute configuration could not be
determined (abs. struct. param. 0.30(16)), but the relative configuration
was assigned based on the known (S) configuration of the BOC-L-proline
ligand precursor. CCDC 297865. For crystallographic data in CIF or other
electronic format see DOI: 10.1039/b518360j
16 Chelating diamines, such as TMEDA are known to accelerate lithium
catalysed hydroaminations, see ref. 8.
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7
21 The Li NMR spectrum showed only a single resonance for (S,S,S)-3
(C6D6, 60 uC).
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22 No reaction was observed in the attempted cyclisation of 5 (90 h,
110 uC). The spectral features of this compound suggest an oligomeric
structure, rather than a dimeric species similar to (S,S,S)-3.
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Chem. Commun., 2006, 2221–2223 | 2223