Highly enantioselective iridium-catalysed allylic aminations with anionic N-nucleophiles

Article abstract of DOI:10.1039/b505197e

Iridium-catalysed allylic substitutions with anionic N-nucleophiles were achieved with regioselectivity of up to 49:1 and enantiomeric excess of up to 98%. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b505197e

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Highly enantioselective iridium-catalysed allylic aminations with
anionic N-nucleophiles{
Robert Weihofen, Axel Dahnz, Olena Tverskoy and G u¨ nter Helmchen*
Received (in Cambridge, UK) 13th April 2005, Accepted 11th May 2005
First published as an Advance Article on the web 9th June 2005
DOI: 10.1039/b505197e
Iridium-catalysed allylic substitutions with anionic N-nucleo-
philes were achieved with regioselectivity of up to 49:1 and
enantiomeric excess of up to 98%.
The development of asymmetric allylic substitutions has led to very
successful procedures, which have enriched the methodology of
1
organic synthesis. Recently, reactions of monosubstituted allylic
derivatives according to Scheme 1 have come into focus. While Pd-
2
catalysts are useful in special cases, Ir-complexes of electron-poor
ligands seem to be the catalysts of choice for asymmetric allylic
3
alkylations, aminations and etherifications of aryl- as well as
4
5
6
alkylallyl derivatives. With ligands L1–L3 (Fig. 1) regioselectivities
Fig. 1 Chiral phosphorus amidite ligands.
of .95:5 in favour of the branched products and enantio-
selectivities of up to 98% ee have been obtained.
2
phosphates with a nucleophile PhCONHOCH Ph/CsOH, which
furnished .90% ee in special cases (Scheme 1, R 5 Ph and
1-naphthyl, X 5 O(PO)OEt , L* 5 Pybox).
2
We have resumed activities in this field and, based on the
recently accumulated knowledge cited above, found interesting
and fairly general solutions. The incentive for this pursuit was: (a)
The direct formation of non-basic allylamine derivatives, i.e.
protected amines, simplifies further transformations, for example
Scheme 1 Ir-catalysed allylic substitutions.
10
ring closing metathesis as was demonstrated by P. A. Evans et al.
Substitutions with N-nucleophiles have so far been generally
4
successful only with amines as nucleophiles. An early attempt by
(b) Modularity and variability of the reactants are high, which is
advantageous in asymmetric catalysis. (c) Many amides and
sulfonamides are crystalline; thus enantiomeric enrichment by
recrystallisation is often possible.
3b
7
2
this group of using LiN(CH Ph)p-Ts, i.e. a nucleophile with
anionic nitrogen (cf. Scheme 2), gave low selectivity because a less
8
suited phosphorus amidite (MonoPhos) was chosen. Moreover,
Reactions were run using conditions previously described for
solubility of the nucleophile was a problem. Very recently,
9
Takemoto et al. have reported on reactions of arylallyl
4
a
intramolecular aminations (cf. General Procedure{), i.e., the
catalyst was prepared by in situ activation of a mixture of
2
[Ir(COD)Cl] and chiral ligand L* with the base TBD (1,5,7-
triazabicyclo-[4.4.0]dec-5-ene). The solvent was dry THF. Initial
experiments were carried out with the previously employed
2
LiN(CH Ph)p-Ts as nucleophile (Table 1, entries 1,2). Excellent
enantio- as well as acceptable regioselectivity were obtained with
2
3
an allylic carbonate with a sp - and one with a sp -substituent.
1
1
Next a synthetically convenient N-(o-nitrophenylsulfonyl)-a-
mine, N-(o-Ns)-NHCH Ph, was probed. In view of the relatively
2
Scheme 2 Ir-catalysed allylic substitutions with sulfonamides as
12
high acidity of N-nosyl-amines we opted for an ammonium
amide as nucleophile, prepared in situ by mixing
nucleophiles.
2 3
N-(o-Ns)NHCH Ph with NEt . Again, enantioselectivity was
{
Electronic supplementary information (ESI) available: X-ray crystal
high, however, regioselectivity was not satisfactory (entries 3–6).
Furthermore, there was a surprising dependence on steric effects
apparent, in that the sterically demanding ligands L2 and L3 gave
rise to linear product 3. According to control experiments, the
formation of 3 was not caused by the non-catalysed reaction,
which is very slow.
structure data for 7t and data on separation of enantiomers by HPLC. See
http://www.rsc.org/suppdata/cc/b5/b505197e/
Organisch-Chemisches Institut der Ruprecht-Karls-Universit a¨ t
Heidelberg, Im Neuenheimer Feld 270, 69207 Heidelberg, Germany.
E-mail: g.helmchen@urz.uni-heidelberg.de; Fax: +49 6221 544205;
Tel: +49 6221 548401
*g.helmchen@urz.uni-heidelberg.de
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a
Table 1 Ir-catalysed allylic substitutions according to Scheme 2
Nucleophile
1
R
2
R
b
Time (h)
c
d
Entry
ArSO
2
Base
Ligand
Yield (%)
2:3
Ee (%) (Abs. Conf.)
1
2
Ph
CH
p-Ts
p-Ts
CH
CH
2
Ph
Ph
LiHMDS
LiHMDS
L2
L2
2.5
2
92
60
49:1
4:1
98 (S)
95 (R)
2
CH
2
Ph
Ph
2
3
4
5
6
Ph
Ph
Ph
CH
o-Ns
o-Ns
o-Ns
o-Ns
CH
CH
CH
CH
2
2
2
2
Ph
Ph
Ph
Ph
NEt
NEt
NEt
NEt
3
3
3
3
L1
L2
L3
L2
12
1
0.5
0.5
44
82
87
79
3:1
0:1
0:1
3:1
91
—
—
97 (R)
2
CH
2
e
7
8
9
Ph
Ph
Ph
p-Ns
p-Ns
p-Ns
p-Ns
p-Ns
p-Ns
p-Ns
H
H
NEt
—
—
3
L2
L2
L2
L2
L2
L2
L2
14
18
18
18
18
3
91
66
91
71
50
85
93
16:1
32:1
13:1
2.5:1
6:1
93
90
96
93
90
88
84
CH
CH
CH
CH
CH
2
2
2
2
2
Ph
Ph
Ph
Ph
Ph
10
11
12
13
CHLCHPh
NEt
—
3
CHLCHPh
CH
CH
2
CH
CH
2
Ph
Ph
NEt
—
3
7:1
4:1
2
2
3
14
15
16
17
Ph
Ph
3-Pyridyl
3-Pyridyl
p-Ns
p-Ns
p-Ns
p-Ns
CH
CH
CH
CH
2
2
2
2
CHLCH
CHLCH
CHLCH
CHLCH
2
2
2
2
NEt
—
3
L2
L2
L2
L2
6
6
18
12
89
68
89
86
10:1
19:1
4:1
88
90
91
92.5
NEt
—
3
13:1
e
18
19
20
21
a
Ph
Ph
3-Pyridyl
3-Pyridyl
p-Ns
p-Ns
p-Ns
p-Ns
(CH
(CH
(CH
(CH
2
2
2
2
)
2
)
2
)
2
)
2
CHLCH
CHLCH
CHLCH
CHLCH
2
2
2
2
NEt
—
3
L2
L2
L2
L2
18
18
72
18
80
78
60
57
19:1
32:1
5:1
96.5
90
97
95
NEt
—
3
32:1
2
If not stated otherwise, reactions were carried out on a 1 mmol scale of 1 using 2 mol% of [Ir(COD)Cl] , 4 mol% of ligand and 8 mol% of
1
TBD (activation for 2 h). Reaction time. Yield of the isolated product. Note that the descriptor of 2 can change upon variation of R as a
consequence of CIP priorities. The assignments given in the Table refer to ref. 16. The enantiomerically pure compound was obtained by
recrystallisation from n-pentane/ether.
b
c
d
e
1
4
In order to reduce steric effects, p-nosylamides were investigated.
Indeed, with the parent compound p-Ns-NH excellent enantio-
as nucleophile have opened a route to interesting N-heterocycles.
2
Accordingly, we have probed a corresponding reaction using p-Ns-
2
NH as nucleophile (Scheme 4). The reaction with the dicarbonate
and regioselectivity were obtained (entry 7). Considering that
methyl carbonate liberated in the reaction likely dissociates into
6 proceeded smoothly to give the expected trans-pyrrolidine
derivative in good yield and excellent selectivity. For once, the best
results were obtained with ligand L3. The very high ee of .99% is
due to double stereoselection.
CO and strongly basic methoxide, the reaction was run without
2
an additional base; the result was a marked improvement of
regioselectivity (entry 8). For the further examples given in Table 1
regioselectivities were found to be significantly higher in reactions
run without NEt . Enantioselectivity was little affected by NEt ,
The pure trans-isomer 7t was obtained by recrystallisation
3
3
(HCCl /n-hexane) in 64% isolated yield. It was possible to
3
there are examples for increase (entries 10, 18 and 20) as well as for
decrease (entries 14 and 16) of enantiomeric excess.
2
determine both the absolute and the relative configuration, as
15
given in Scheme 4, by X-ray structure analysis. The correspond-
Reactions with the nucleophiles (p-Ns)[H CLCH(CH ) ]N
ing steric course of the substitution reaction is in accordance with
2
2 n
4
a
described in entries 14–21 of Table 1 were investigated with a
view to their potential for subsequent ring closing metathesis,
leading to analogues of tobacco alkaloids in the cases R 5
the general rule stated previously. In addition, we found that the
steric course for the reactions according to entries 1 and 6 of
Table 1 is the same as that of the corresponding reactions with
1
3
3
-pyridyl. As an example, the diene 4, obtained from the reaction
described in entry 18, was subjected to standard RCM to furnish
the tetrahydropyridine derivative 5 in excellent yield (Scheme 3).
Scheme 3 RCM using Grubbs’ catalyst I.
We have shown that Ir-catalysed intramolecular aminations
14
are particularly facile and highly selective.
Furthermore,
sequential inter- and intramolecular reactions with benzylamine
Scheme 4 Sequential inter- and intramolecular allylic aminations.
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3
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4
benzylamine as nucleophile. This was established in obvious
3
4
(a) B. Bartels and G. Helmchen, Chem. Commun., 1999, 741; (b)
B. Bartels, C. Garcia-Yebra, F. Rominger and G. Helmchen, Eur. J.
Inorg. Chem., 2002, 2569; (c) G. Lipowsky, N. Miller and G. Helmchen,
Angew. Chem. Int. Ed., 2004, 43, 4595; (d) G. Lipowsky and
G. Helmchen, Chem. Commun., 2004, 116; (e) A. Alexakis and
D. Polet, Org. Lett., 2004, 6, 3529; (f) K. Tissot-Croset,
D. Polet and A. Alexakis, Angew. Chem. Int. Ed., 2004, 43, 2426.
(a) C. Welter, O. Koch, G. Lipowsky and G. Helmchen, Chem.
Commun., 2004, 896; (b) A. Leitner, C. Shu and J. F. Hartwig, Proc.
Nat. Am. Sci., 2004, 101, 5930; (c) C. Shu, A. Leitner and J. F. Hartwig,
Angew. Chem. Int. Ed., 2004, 43, 4797; (d) A. Leitner, C. Shu and
J. F. Hartwig, Org. Lett., 2005, 7, 1093; (e) D. Polet and A. Alexakis,
Org. Lett., 2005, 7, 1621.
manner by N-tosylation of the products of the latter reactions.
Further corroboration for the correctness of our assignments is
16
based on work by Evans and Robinson.
In summary, new reaction conditions have allowed iridium-
catalysed allylic substitutions with anionic N-nucleophiles to be
carried out inter- as well as intramolecularly with high degrees of
enantio- and regioselectivity to give protected amines, which are
useful in organic synthesis and medicinal chemistry. We are
currently pursuing further investigations, concerning in particular
extension of the range of nucleophiles and the choice of base,
counter ion and other variables.
5 (a) F. Lopez, T. Ohmura and J. F. Hartwig, J. Am. Chem. Soc., 2003,
25, 3426; (b) C. Shu and J. F. Hartwig, Angew. Chem. Int. Ed., 2004,
3, 4794.
1
4
This work was supported by the Deutsche Forschungs-
gemeinschaft (SFB 623). We thank Dr. G. Egri (Reuter
Chemischer Apparatebau KG), for (S)-BINOL and Dr. K.
Ditrich (BASF AG) for enantiomerically pure 2-arylethylamines.
For the X-ray crystal structure of compound 7t we are indebted to
Dr. T. Oeser of our institute.
6
(a) Review and L1: B. L. Feringa, Acc. Chem. Res., 2000, 33, 346; (b)
L2: K. Tissot-Croset, D. Polet, S. Gille, C. Hawner and A. Alexakis,
Synthesis, 2004, 2586; (c) L3: L. A. Arnold, R. Imbos, A. Mandoli,
A. H. M. De Vries, R. Naasz and B. L. Feringa, Tetrahedron, 2000, 56,
2865.
7
This salt gave excellent results in enantiospecific Rh-catalyzed allylic
substitutions at enantiomerically pure starting materials: P. A. Evans,
J. E. Robinson and J. D. Nelson, J. Am. Chem. Soc., 1999, 121, 6761.
Cf. ref. 6a; while MonoPhos, containing a dimethylamino group, is a
reasonably suitable ligand for alkylations, it is useless for aminations.
H. Miyabe, A. Matsumura, K. Moriyama and Y. Takemoto, Org.
Lett., 2004, 6, 4631.
8
9
Notes and references
{
General procedure: Success with the following procedure requires dry
THF (,35 mg of H O per ml, Karl Fischer titration). Under argon, a
solution of [Ir(COD)Cl] (0.02 mmol) and L* (0.04 mmol) in dry THF
0.5 ml) was treated with TBD (0.08 mmol). After stirring for 2 h at rt the
allylic carbonate (1.0 mmol) was added, and the mixture was stirred for
min at rt. Then the sulfonamide (1.5 mmol) and eventually NEt (1 mmol)
or a solution of LiN(CH Ph)p-Ts (1.5 mmol) in dry THF (4 ml) was added
2
1
0 Surveys: (a) D. K. Leahy and P. A. Evans, in Modern Rhodium-
Catalyzed Organic Reactions, ed. P. A. Evans, Wiley, New York, 2005,
91; (b) P. A. Evans and D. K. Leahy, Chemtracts: Org. Chem., 2003,
6, 567.
1 (a) Reviews: P. J. Kocienski, Protecting Groups, Thieme, Stuttgart, 2005,
nd ed., 548; (b) T. Kan and T. Fukuyama, Chem. Commun., 2004, 353.
2 J. F. King, in The chemistry of sulfonic acids, esters and their derivatives,
ed. S. Patai and Z. Rappoport, Wiley, New York, 1991, 252.
3 C. Welter, R. Moreno, S. Streiff and G. Helmchen, to be published.
2
(
1
1
5
3
1
2
2
and the mixture was stirred until TLC indicated complete conversion. The
solvent was removed under reduced pressure and the residue analysed with
respect to the content of branched and linear product by H NMR. The
1
1
1
pure reaction products were obtained by flash chromatography or MPLC.
14 C. Welter, A. Dahnz, B. Brunner, S. Streiff, P. D u¨ bon and G. Helmchen,
Org. Lett., 2005, 7, 1239.
1
2
(a) B. M. Trost and C. Lee, in Catalytic Asymmetric Synthesis, ed. I.
Ojima, Wiley, New York, 2000, 2nd ed., 593; (b) A. Pfaltz and
M. Lautens, in Comprehensive Asymmetric Catalysis I-III, ed. E. N.
Jacobsen, A. Pfaltz and H. Yamamoto, Springer, Berlin, 1999, 833; (c)
B. M. Trost and M. L. Crawley, Chem. Rev., 2003, 103, 2921.
(a) S.-L. You, X.-Z. Zhu, Y.-M. Luo, X.-L. Hou and L.-X. Dai, J. Am.
Chem. Soc., 2001, 123, 7471 and cited literature; (b) Vinyl epoxides:
B. M. Trost and C. Jiang, Org. Lett., 2003, 5, 1563 and cited literature.
15 Crystal data for 7t: C14
16 2 4
H N O S, M 5 308.35, orthorhombic, space
˚
group P2 , a 5 7.7121(7), b 5 10.7290(9), c 5 17.409(1) A, a 5 90.0,
1 1 1
2 2
3
21
˚
b 5 90.0, c 5 90.0 deg, V 5 1440.5(2) A , Z 5 4, m 5 0.24 mm . 15178
reflections measured, 3572 unique (R(int) 5 0.0260), 3520 observed [I .
2s(I)]. R 5 0.025, wR 5 0.067 [I . 2s(I)], flack 20.05(4), CCDC
1 2
267826. See http://www.rsc.org/suppdata/cc/b5/b505197e/ for crystal-
lographic data in CIF or other electronic format.
16 J. E. Robinson, PhD Thesis, University of Delaware, 2004.
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Chem. Commun., 2005, 3541–3543 | 3543