First intramolecular enantioselective iridium-catalysed allylic animations

Article abstract of DOI:10.1039/b400023d

Enantioselective indium-catalysed intramolecular allylic aminations, using phosphinooxazolines or phosphorus amidites as ligands, provided ee values of >90%, at a catalyst loading of <0.5 mol-%, and displayed a marked preference for intra- over corresponding intermolecular reactions.

Full text of DOI:10.1039/b400023d

First intramolecular enantioselective iridium-catalysed allylic aminations
Carolin Welter, Oliver Koch, Gunter Lipowsky and Günter Helmchen*
Organisch-Chemisches Institut der Ruprechts-Karls-Universität Heidelberg, Im Neuenheimer Feld 270,
D-69120 Heidelberg, Germany. E-mail: g.helmchen@urz.uni-heidelberg.de; Fax: +49 6221 544205;
Tel: +49 6221 548401
Received (in Cambridge, UK) 8th January 2004, Accepted 16th February 2004
First published as an Advance Article on the web 5th March 2004
Enantioselective iridium-catalysed intramolecular allylic ami-
nations, using phosphinooxazolines or phosphorus amidites as
ligands, provided ee values of > 90%, at a catalyst loading of
enhanced isomerisation of intermediary (allyl)Ir complexes.9c,d
The reason for the decrease of enantioselectivity at 100 °C cannot
presently be explained (Table 1, entry 4). (c) The influence of the
solvent can be very substantial (entries 3, 5, 6). (d) The use of LiCl
as an additive had previously been found to lead to enhanced levels
of selectivity.9b For the cyclisation reactions an unusually pro-
nounced effect of halide additives was found (entries 13–16). An
explanation is not possible at present.15 (e) The catalyst induced
low selectivity with carbonate 1b (entry 9) and was ineffective with
linear substrate 2a (entry 12).
<
0.5 mol-%, and displayed a marked preference for intra- over
corresponding intermolecular reactions.
Despite numerous reports on enantioselective allylic substitutions,1
the number of reports on intramolecular asymmetric reactions is
relatively small.2 All of them refer to Pd-catalysed reactions.
Generally, with Pd-catalysts intramolecular substitutions leading to
5-, 6- or 7-membered rings seem to be inferior to corresponding
Phosphorus amidites16 are a second class of ligands suitable for
intermolecular variants, requiring, for example, a low concentration
Ir-catalysed allylic substitutions.9b Ligand L3 induces high degrees
3
9d
10
of substrate. One reason for this is likely to be the pronounced
of enantioselectivity in both alkylations and aminations. After
recently having obtained excellent degrees of regio- and enantio-
preference of the Pd-catalysed reaction for the linear rather than the
4
branched substitution product. Another reason is the competition
between cyclisation and equilibration of intermediary diaster-
5
eomeric (p-allyl)Pd complexes.
Acting on this observation, it appeared of interest to investigate
corresponding Ir-catalysed cyclisations, because in allylic substitu-
tions Ir-, Mo- and Ru-catalysts mainly give rise to the branched
products.6 A very important advantage of Ir-catalysis is the fact
–8
9
that it is broadly applicable in allylic alkylations as well as
aminations,10 and high selectivity can be obtained, not only with
aryl- but also with alkyl-substituted achiral allylic substrates.
Extending our previous work, we have now studied intra-
molecular aminations according to Scheme 1 and are able to report
1
1
the first intramolecular asymmetric Ir-catalysed allylic substitu-
tions.
Fig. 1 Chiral ligands used in allylic substitutions.
Table 1 Ir-catalysed allylic cyclisation of substrates 1 according to Scheme
1
using phosphinooxazolines (S)-L1 and (S)-L2 as ligands
Sub- Ligand/
Entry strate additive Solvent
Yield ee (%)c
a
b
T/°C t /d
(%)
(confign.)
1
2
3
4
5
6
7
8
9
0
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1c
2a
1a
1a
1a
1a
L1
L1
L1
L1
L1
L1
L1
L2
L1
L1
L2
L1
Toluene
Toluene
Toluene
Toluene
DMF
20
60
80
100
80
80
65
65
65
65
65
65
65
65
65
65
4
4
4
4
4
4
4
4
4
6
6
4
4
4
4
4
83
91
92
81
80
80
92
99
98
83
99
36
99
99
86
97
3a: 36 (R)
3a: 62 (R)
3a: 80 (R)
3a: 65 (R)
3a: 29 (R)
3a: 48 (R)
3a: 80 (R)
3a: 85 (R)
3a: 56 (R)
3b: 83 (R)
3b: 79 (R)
3a: 26 (R)
3a: 88 (R)
3a: 59 (R)
3a: 51 (R)
3a: 6 (R)
Scheme 1
In initial experiments, we used phosphinooxazolines L1 and
3
CH CN
L212 (Fig. 1) in combination with [Ir(COD)Cl]
(4) (ratio L1:4 =
:1). With racemic branched acetates 1a and 1c, yields of
2
THF
THF
THF
THF
THF
THF
THF
2
cyclisation products were high and enantioselectivities moderate to
high (Table 1†). The absolute configuration of product 3a was
determined as (-)(S)-3a by transformation into (R)-N-benzyl-
coniine.13 The absolute configuration of 3b was known.
Results obtained with phosphinooxazolines as ligands are
presented in Table 1. The following observations are particularly
interesting. (a) Alkyl-substituted allylic derivatives display very
low reactivity in intermolecular substitutions. The generally high
yields obtained for cyclisations indicate superiority of intra- over
intermolecular substitution with Ir-catalysts. (b) Enantioselectivity
is a function of temperature (cf. entries 1–4). It was previously
1
11
12
13
14
L1/LiF
L1/LiCl THF
L1/LiBr THF
1
1
1
a
4
5
6
L1/LiI
THF
Reaction time. b Yield of isolated product. c Determined by HPLC
(
column: Daicel Chiralcel OD–H, eluent: n-hexane/i-PrOH 99.9:0.1, 250 3
21
4
R
.6 mm, 5 mm, + guard cartridge 10 3 4 mm, 5 mm, flow: 0.5 ml min ),
t
R R R
[(S)-3a] = 11 min, t [(R)-3a] = 14 min; t [(S)-3b] = 11 min, t [(R)-3b]
9
b
observed for intermolecular substitutions that an increase of
temperature gives rise to an increase of enantioselectivity, due to
=
25 min.
8
96
C h e m . C o m m u n . , 2 0 0 4 , 8 9 6 – 8 9 7
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4

Table 2 Ir-catalysed allylic cyclisations of substrates 2 to give 3a according
to Scheme 1 using phosphorus amidite L3 as ligand
thank Brigitte Nowak for technical assistance, Matthias Krämer for
a sample of ligand L2 and Degussa AG for iridium salts.
Sub-
Yield
(%)c
ee (%)d
(Confign.)
Entry strate Catalysta
t /h
b
Notes and references
1
2
3
4
2b
2b
2a
2b
0.02 eq. [Ir(COD)Cl]
0.02 eq. [Ir(COD)Cl]
0.02 eq. [Ir(COD)Cl]
0.02 eq. [Ir(COD)Cl]
2
2
2
2
/2L3 300
74
77
22
84 (R)
81 (R)
37 (R)
86 (R)
† General procedure for cyclisations using ligands L1,L2: Under argon,
a solution of [Ir(COD)Cl] (4) (16.8 mg, 0.025 mmol), the ligand (0.05
2
e
/2L3
/2L3
/2L3,
80
96
0.25 95
mmol) (ratio Ir:ligand = 1:1) in dry toluene or THF (5 ml) was stirred at
room temperature for 10 min. The substrate was added (1.0 mmol) and the
mixture heated at reflux with stirring until TLC showed complete
conversion. The solvent was removed under reduced pressure and the
residue was subjected to flash chromatography or Kugelrohr distillation.
‡ General procedure for cyclisations using ligand L3: Under argon, a
0
2
.08 eq. P -tBu, 3 h
5
6
7
a
2b
2b
2b
0.02 eq. [Ir(COD)Cl]
2
/2L3,
1
93
85
96
91 (R)
92 (R)
91 (R)
b
f
0
.08 eq. TBD, 5 h
0.002 eq. [Ir(COD)Cl]
.008 eq. TBD, 9 h
0.02 eq. [Ir(COD)Cl]
eq. pyrrolidine, 6 h
2
/2L3, 19
0
2
solution of [Ir(COD)Cl] (4) (0.01 mmol) and ligand L3 (0.02 mmol) in dry
2
/2L3,
1
THF (0.5 ml) was stirred at room temperature for 15 min. If base was used,
it was added together with THF and the mixture was stirred for 5 h at room
temperature. Then the substrate (0.5 mmol) was added and the mixture was
stirred at the indicated temperature until NMR monitoring showed complete
conversion. The solvent was removed under reduced pressure and the crude
product was purified by Kugelrohr distillation.
1
Catalyst preparation is described in the general procedure. Reaction
c
d
time. Yield of isolated product. Determined by HPLC as described in
Table 1. Reaction temperature: 50 °C. Trade name of Fluka/Sigma-
Aldrich.
e
f
1
B. M. Trost and C. Lee, in Catalytic Asymmetric Synthesis, I. Ojima, ed.,
Wiley-VCH, New York, 2000, 2nd edn., p. 593; A. Pfaltz and M.
Lautens, in Comprehensive Asymmetric Catalysis I–III, E. N. Jacobsen,
A. Pfaltz and H. Yamamoto, ed., Springer, Berlin, 1999, p. 833.
The literature up to 1999 is covered in ref. 1. For more recent examples,
see: K. Ito, S. Akashi, B. Saito and T. Katsuki, Synlett., 2003, 1809; B.
M. Trost, K. L. Sacchi, G. M. Schroeder and N. Asakawa, Org. Lett.,
2002, 4, 3427; L. Jiang and S. D. Burke, Org. Lett., 2002, 4, 3411; B. M.
Trost and M. R. Machacek, Angew. Chem., Int. Ed., 2002, 41, 4693; J.-
R. Labrosse, P. Lhoste and D. Sinou, Eur. J. Org. Chem., 2002, 1966;
K. Hiroi, Y. Hiratsuka, K. Watanabe, I. Abe, F. Kato and M. Hiroi,
Tetrahedron: Asymmetry, 2002, 13, 1351.
selectivity with dienyl carbonates,10c we are pleased to report
remarkably efficient cyclisations here.
In early experiments using a standard procedure, a mixture of
2
[
Ir(COD)Cl]
2
(4) and L3 was employed as catalyst. It is
that these components rapidly form a complex
9
c,10b
known
[Ir(COD)Cl(L3)] (5). In spite of very long reaction times, results
with carbonate 2b as substrate were encouraging, because high
yield and fair enantioselectivity could be obtained at a concentra-
1
7
tion as high as 1 M in THF (Table 2,‡ entries 1 and 2). The
reaction of acetate 2a was sluggish (entry 3). It was previously
found that active Ir-catalysts are generated by C–H activation
3
4
G. Koch and A. Pfaltz, Tetrahedron: Asymmetry, 1996, 7, 2213; B. M.
Trost and N. Asakawa, Synthesis, 1999, 1491. For an improvement, see
ref. 5.
For exceptions, see: S.-L. You, X.-Z. Zhu, Y.-M. Luo, X.-L. Hou and
L.-X. Dai, J. Am. Chem. Soc., 2001, 123, 7471 and refs. cited therein.
9
b,10b
promoted by the nucleophile or base.
was treated with a variety of bases, of which the Schwesinger
phosphazene base P -tBu increased catalyst activity by a factor of
Accordingly, complex 5
2
ca. 1000 (entry 4). Even better results with respect to enantiose-
lectivity were obtained upon activation with 1,5,7-triazabicyclo-
5 B. M. Trost, H. C. Shen, L. Dong and J.-P. Surivet, J. Am. Chem. Soc.,
2003, 125, 9276.
6 Review Ir: R. Takeuchi, Synlett, 2002, 1954.
[4.4.0]undec-5-ene (TBD) as base (entry 5). Of this new in situ
catalyst, 0.4 mol-% sufficed to produce N-benzyl-2-vinyl-piper-
idine (3a) with 92% ee in 85% isolated yield.
7 Mo: B. M. Trost and I. Hachiya, J. Am. Chem. Soc., 1998, 120, 1104
(arylallyl derivatives); F. Glorius and A. Pfaltz, Org. Lett., 1999, 1, 141
(alkylallyl derivatives).
A demonstration of the high relative rate of the intramolecular
reaction was accidentally found when pyrrolidine was used as base,
which was previously employed by Hartwig and co-workers.1
Although pyrrolidine is a highly reactive nucleophile in inter-
molecular aminations and in spite of the high concentration of 1 M,
the intramolecular reaction proceeded in 96% yield (entry 7).
The steric course of the intramolecular Ir-catalysed substitution
8
9
Ru: B. M. Trost, P. L. Fraisse and Z. T. Ball, Angew. Chem., Int. Ed.,
002, 41, 1059.
(a) J. P. Janssen and G. Helmchen, Tetrahedron Lett., 1997, 38, 8025;
b) B. Bartels and G. Helmchen, Chem. Commun., 1999, 741; (c) B.
2
0a,b
(
Bartels, C. Garcia-Yebra, F. Rominger and G. Helmchen, Eur. J. Inorg.
Chem., 2002, 2569; (d) B. Bartels, C. Garcia-Yebra and G. Helmchen,
Eur. J. Org. Chem., 2003, 1097.
reactions using ligands L1, L2 or L3, all with (S)-configuration, is
10 (a) T. Ohmura and J. F. Hartwig, J. Am. Chem. Soc., 2002, 124, 15 164;
(b) C. A. Kiener, C. Shu, C. Incarvito and J. F. Hartwig, J. Am. Chem.
Soc., 2003, 125, 14 274; (c) G. Lipowsky and G. Helmchen, Chem.
Commun., 2004, 116.
the same as previously found for intermolecular substitutions.9,10
The following relationship appears to be generally valid:
1
1 Intramolecular aminations using achiral complex 4 as catalyst were
recently reported: H. Miyabe, K. Yoshida, Y. Kobayashi, A. Matsumura
and Y. Takemoto, Synlett, 2003, 1031.
1
2 Ligand L2 was provided by M. Krämer (preparation: M. Krämer,
Dissertation, Universität Heidelberg, 2002).
In conclusion, enantioselective intramolecular allylic aminations
catalysed by iridium-phosphorus amidite complexes were found to
proceed with very high catalytic efficiency and ee values of > 90%.
High concentrations of substrate can be employed due to a marked
preference of intra- over the corresponding intermolecular reac-
tions.
1
1
3 M. Peer, Dissertation, Universität Heidelberg, 1996.
4 C. J. Deur, M. W. Miller and L. S. Hegedus, J. Org. Chem., 1996, 61,
2
871.
1
1
5 Review on halide effects in transition metal catalysis: K. Fagnou and M.
Lautens, Angew. Chem., Int. Ed., 2002, 41, 26–47.
6 B. L. Feringa, Acc. Chem. Res., 2000, 33, 346.
This work was supported by the Deutsche Forschungsge-
meinschaft (SFB 623) and the Fonds der Chemischen Industrie. We
17 Concentrations have probably been higher because of solvent evapora-
tion in small scale experiments in Schlenk vessels.
C h e m . C o m m u n . , 2 0 0 4 , 8 9 6 – 8 9 7
897