Iridium-catalyzed asymmetric allylic substitutions-very high regioselectivity and air stability with a catalyst derived from dibenzo[a,e]cyclooctatetraene and a phosphoramidite

Article abstract of DOI:10.1002/anie.200802480

A final tweak: A new phosphoramidite iridium catalyst (see scheme) allows allylic substitutions to be run with a higher degree of regioselectivity than with other iridium catalysts and under aerobic conditions. Mechanistic aspects, in particular, the reversibility of the catalyst formation by C-H activation, are also presented. LL=dibenzocyclooctatetraene.

Full text of DOI:10.1002/anie.200802480

Communications
DOI: 10.1002/anie.200802480
Allylic Substitution
Iridium-Catalyzed Asymmetric Allylic Substitutions—Very High
Regioselectivity and Air Stability with a Catalyst Derived from
Dibenzo[a,e]cyclooctatetraene and a Phosphoramidite**
Stephanie Spiess, Carolin Welter, GØraldine Franck, Jean-Philippe Taquet, and
Günter Helmchen*
Transition-metal-catalyzed asymmetric allylic substitutions
are widely employed. Steric course and regioselectivity of
these reactions vary considerably, depending on the metal ion,
ligands, the nucleophile, and the leaving group. Today, Pd
catalysts[1] are usually employed for 1,3-disubstituted allylic
substrates, while Ir catalysts[2] serve well for a broad range of
monosubstituted allylic substrates.
several deficiencies: 1) It is sensitive towards oxygen.
2) Long-term stability is low. 3) High selectivities are
obtained only with solvents of low polarity, preferably THF.
The catalyst system is stable against water and alcohols;
however, enantioselectivity in these solvents is lower than in
THF. 4) Regioselectivity can be as low as 3:1 (2/3), for
example, with substrates 1b–e.[3]
The currently best Ir catalysts are prepared from [{Ir-
(cod)Cl}2] (cod = cycloocta-1,5-diene) and a chiral phosphor-
We have now developed a modified catalyst derived from
dibenzo[a,e]cyclooctatetraene (dbcot) and L2, which allows
substitutions to be run without inert gas for the first time. In
addition, regioselectivities with the new catalyst are consid-
erably improved over those with presently used catalysts.
Furthermore, we have observed that catalyst preparation by
À
amidite by C H activation with base (Scheme 1). Although
enantioselectivity is high, this catalyst system suffers from
À
C H activation is reversible for complexes of L2 under the
standard reaction conditions.
The ligand cod can be removed from iridium or altered by
a number of reactions. For improvement, dbcot appeared
promising because its bonding to Ir is stronger than that of
À
cod, its Ir complexes do not undergo intramolecular C H
activation at the dbcot moiety, and it is a better electron
acceptor than cod.[4]
Preparations of dbcot[5] and [{Ir(dbcot)Cl}2][4] were
À
straightforward. The latter was subjected to C H activation
under argon by treatment with 1,5,7-triazabicyclo-[4.4.0]dec-
5-ene (TBD)[6] or n-propylamine (Scheme 3).[7] Substitution
reactions were investigated with ligands L1–L3 (Scheme 1);
the best results were obtained with L2.
Scheme 1. Ir-catalyzed allylic substitutions.
[*] S. Spiess, C. Welter, G. Franck, Dr. J.-P. Taquet, Prof. Dr. G. Helmchen
Organisch-Chemisches Institut
Ruprecht-Karls-Universität Heidelberg
Im Neuenheimer Feld 270, 69120 Heidelberg (Germany)
Fax: (+49)6221-544-205
Scheme 2. Intramolecular allylic amination.
E-mail: g.helmchen@oci.uni-heidelberg.de
[**] This work was supported by the Fonds der Chemischen Industrie,
the Deutsche Forschungsgemeinschaft (SFB 623), and the Land-
esgraduiertenförderung. We thank Dr. F. Rominger for the X-ray
crystal structure analysis. Visits to Oxford by C.W. for initial NMR-
related studies were funded by a Royal Society IJP grant to Dr. J. M.
Brown and G.H. We thank Dr. Brown and his colleagues for
generous help and fruitful discussions.
Regioselectivities of all reactions run under anaerobic
conditions with the dbcot complex were considerably
improved compared to those run with the cod complex
(Table 1).[8] In some cases (entries 9, 11, 15, and 18, Table 1),
mostly reactions under salt-free conditions,[9] a reaction
temperature of 508C was used to shorten the reaction times.
This was generally possible without significant loss of
selectivity. The enantioselectivity, not the regioselectivity,
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200802480.
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Table 1: Allylic substitutions carried out under argon according to Scheme 1 using catalysts derived from
L2 and [{Ir(cod)Cl}2][8] or [{Ir(dbcot)Cl}2].[a]
reduced by running reactions at
508C (entries 3, 6, and 9, Table 2);
selectivities were only marginally
diminished.
Entry Coligand Base for Carbonate (Pro)nucleophile T [8C] t [h] Yield of 2/3[c]
ee [%][d]
2+3 [%][b]
À
C H
activation
The new catalyst was also exam-
ined in an intramolecular allylic
amination (Scheme 2). With the
[{Ir(dbcot)Cl}2]/L2 catalyst it was
possible to carry out the reaction
under air to completion within one
hour. In this case enantioselectivity
was slightly lower than that
obtained with [{Ir(cod)Cl}2]/L2.[10]
In the course of this work with
the new catalyst, we were also able
to shed new light on the mechanism
of catalyst preparation with the cod
and dbcot complexes, building on
the mechanistic work of Hartwig
et al., which was mainly based on
reactions of cod/L1 complexes.[11]
1
2
3
cod
nPrNH2
nPrNH2
nPrNH2
nPrNH2
nPrNH2
nPrNH2
nPrNH2
TBD
TBD
TBD
nPrNH2
TBD
TBD
1a
1a
1a
1a
1a
1b
1b
1c
1c
1c
1c
1d
1d
1d
1d
1e
1e
1e
BnNH2
BnNH2
PhNH2
NaHC(CO2Me)2 RT
H2C(CO2Me)2
BnNH2
RT
RT
RT
3
3
2
4
5
2
3.5
8
4
2
2
6
18
18
2
18
18
1
94
88
95
87
77
65
79
85
91
68
87[f]
79
85
90
88
90
95
93
96:4
98:2
97:3
99:1
99:1
85:15
96:4
76:24
94:6
73:27
98
98
98
97
98.5
95
94
98.5
92
97
dbcot
dbcot
dbcot
dbcot
cod
dbcot
cod
dbcot
cod
dbcot
cod
dbcot
cod
dbcot
cod
dbcot
dbcot
4[e]
5
RT
RT
RT
RT
50
RT
50
RT
RT
RT
50
RT
RT
50
6
7
8
9
10
11
12
13
14
15
16
17
18
BnNH2
H2C(CO2Me)2
H2C(CO2Me)2
BnNH2
BnNH2
o-NsNH2
>95:5[f] 90
87:13
97:3
82:18
94:6
74:26
97:3
94
93
99
94
92
95
96
o-NsNH2
TBD
TBD
TBD
TBD
H2C(CO2Me)2
H2C(CO2Me)2
H2C(CO2Me)2
H2C(CO2Me)2
H2C(CO2Me)2
TBD
93:7
À
To date it is assumed that C H-
[a] Catalyst preparation (Scheme 3): argon atmosphere, [{Ir(cod)Cl}2] or [{Ir(dbcot)Cl}2] (0.01 mmol), L2
(0.02 mmol), n-propylamine (0.3 mmol), THF (0.5 mL), 1 h, 508C or TBD (0.04 mmol), THF (0.5 mL),
10 min, RT; substitution reaction: carbonate 1 (0.5 mmol), pronucleophile (0.65 mmol), THF (0.5 mL),
RT. Abbreviations: Bn=benzyl, o-Ns=o-nitrophenylsulfonyl. [b] Yield of isolated product, combined
regioisomers. [c] Determined by 1H NMR spectroscopy of the crude products or by isolation of the
individual regioisomers. [d] Determined by HPLC with a chiral stationary phase (see the Supporting
Information). [e] 2 equiv pronucleophile. [f] The isolated linear product contained ca. 15% of an
unidentified by-product.
activated species of type K2/K4 are
necessary precatalysts (Scheme 3).
However, work of the Alexakis
group[12] with L2 showed that good
results can be obtained without
explicit base activation. Further-
more, Alexakis et al. described the
recovery of a catalytically fully
active orange powder, which they
was somewhat reduced only in the case of the particularly
bulky tBuPh2Si-protected carbonate 1c (entries 8–11,
Table 1).
Allylic substitutions with the new catalyst were also
possible under aerobic conditions. The results are presented
in Table 2. Control experiments using the catalyst derived
from [{Ir(cod)Cl}2] and L2 did not proceed at all under air
(entries 1 and 4, Table 2). Reaction times under air were
longer than those under argon; however, they could be
did not characterize. We identified this compound as the
starting complex K1. This finding was an incentive to
investigate the activation process, both for cod and dbcot
complexes, with respect to reversibility.
The orange-colored complex K1 was prepared according
to Scheme 3and was characterized spectroscopically and by
an X-ray crystal structure analysis.[13] The 31P NMR spectrum
(Figure 1, I) showed two singlets at d = 121 and 132 ppm with
an intensity ratio of 4:1. The latter resonance correlates with
À
an Ir H resonance at d = À17 ppm
1
(doublet, J = 6 Hz) in the H NMR
Table 2: Allylic substitutions carried out under air according to Scheme 1 using catalysts derived from
L2 and [{Ir(cod)Cl}2] or [{Ir(dbcot)Cl}2].[a]
spectrum; accordingly we propose
that in solution an equilibrium
exists between K1 and the hydrido-
complex K1H.
Entry
Coligand
Carbonate
(Pro)nucleophile T [8C]
t [h]
Yield of
2/3[c]
ee [%][d]
2+3 [%][b]
[e]
The reaction of K1 with nPrNH2
(15 equiv, [D8]THF, 508C) gave rise
to a yellow solution after 1 h (sol-
ution A), and the 31P NMR spec-
trum showed doublets at d = 155/
129 ppm, J = 47 Hz, and 152/
142 ppm, J = 72 Hz, with an inten-
sity ratio of 5:4 (Figure 1, II).[14]
Based on the results of Hartwig
et al. with ligand L1,[15] we assume
the new complexes to be K2 and a
diastereomer.
1
2
3
4
5
6
7
cod
1a
1a
1a
1b
1b
1b
1a
1a
1a
BnNH2
BnNH2
BnNH2
BnNH2
BnNH2
BnNH2
PhNH2
NaHC(CO2Me)2
NaHC(CO2Me)2
RT
RT
50
RT
RT
50
RT
RT
50
0
–
–
dbcot
dbcot
cod
dbcot
dbcot
dbcot
dbcot
dbcot
20
89
88
0
46
75
94
71[g]
83
99:1
99:1
–
94:6
92:8
98:2
98:2
95:5
98
96
–
94
93
98
97
95
3
[e]
72
7
2
70
1.5
8[f]
9[f]
À
[a] Catalyst preparation and conditions as in Table 1; n-propylamine was used for C H activation; then
argon was exchanged for air. [b] Yield of isolated product, combined regioisomers. [c] Determined by
1H NMR spectroscopy of the crude products or by isolation of the individual regioisomers.
[d] Determined by HPLC with a chiral stationary phase (see the Supporting Information). [e] No
reaction after >70 h. [f] 2 equiv pronucleophile. [g] Corrected yield: 90%.
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Communications
reaction of 1a with dimethyl malonate under salt-free
conditions K1 constituted the resting state (NMR). Full
conversion of K2 into K1 could also be effected with acetic
acid (see the Supporting Information).
Corresponding experiments as described above were
carried out with dbcot complexes. The complex K3 was
prepared according to Scheme 3by addition of L2 (20 mmol)
to a solution of [{Ir(dbcot)Cl}2] (10 mmol) in THF (0.5 mL).
K3 was obtained as orange-colored glass. The 31P NMR
spectrum (Figure 1, III) showed a singlet at d = 106 ppm. A
hydrido complex analogous to K1H was not observed. K3 was
1
characterized by H NMR (TOCSY, NOESY, ROESY) and
13C NMR spectroscopy (HSQC, HMBC) as well as by FAB+
mass spectrometry.
À
Scheme 3. Base-induced C H activation. Ar=o-(MeO)C6H4.
K3 was reacted with nPrNH2 under
the same conditions as described above
for the formation of K2 in solution A. The
resultant yellow solution (solution B)
showed the anticipated two doublets, at
d = 148/124, J = 30 Hz (Figure 1, IV),
which we ascribe to complex K4. The
À
spectrum clearly shows that C H activa-
tion yields a single compound in the case
of the dbcot complex. Removal of the
excess of nPrNH2 did not effect reversal of
À
C H activation. However, addition of
acetic acid led to clean transformation of
K4 into K3 (see the Supporting Informa-
tion).
Analogous to solution A, solution B
contained 0.5 equiv [{Ir(dbcot)Cl}2]. In
order to avoid the presence of this com-
À
pound, C H activation was carried out
with [{Ir(dbcot)Cl}2]/L2 (1:4). This proce-
1
dure allowed very clean H NMR spectra
to be obtained; K4 was characterized by
1H NMR (COSY) and 13C NMR spectros-
copy (HMQC, DEPT) as well as by FAB+
mass spectrometry.
These experiments demonstrate that
the Ir complexes based on L2 and dbcot
are formed with high selectivity and are
Figure 1. 31P NMR spectra ([D8]THF); I: K1, prepared from [{Ir(cod)Cl}2] (10 mmol) and L2
(20 mmol) in [D8]THF (0.5 mL), RT; II: K2, prepared from [{Ir(cod)Cl}2] (10 mmol), L2
(20 mmol), and nPrNH2 (300 mmol) in [D8]THF (0.5 mL), À608C; III: K3, prepared from
[{Ir(dbcot)Cl}2] (10 mmol) and L2 (20 mmol) in [D8]THF (0.5 mL), RT; IV: K4, prepared from
[{Ir(dbcot)Cl}2] (30 mmol), L2 (60 mmol), and nPrNH2 (900 mmol) in [D8]THF (0.5 mL), RT.
Ar=o-(MeO)C6H4.
À
more stable to reversal of C H activation
than those of cod.
In conclusion, we have developed a
new phosphoramidite iridium catalyst. In
allylic substitutions, the new catalyst led to
an unprecedented level of regioselectivity
and made it possible for the first time to
It is important to note that solution A also contained
nPrNH3Cl and 0.5 equiv [{Ir(cod)Cl}2]. Upon removal of
volatiles in vacuo and dissolving the residual yellow powder in
anhydrous [D8]THF, an orange solution was obtained. The
31P NMR spectrum now showed only the signals of K1.
run the reactions in the presence of oxygen. In addition, we
have for the first time demonstrated the reversiblity of the
cyclometalation for phosphoramidite iridium complexes.
Received: May 27, 2008
Published online: September 2, 2008
À
Clearly, reversal of C H activation must have occurred. The
source of the requisite HCl must have been residual
nPrNH3Cl not removed by evaporation. This result indicates
that an equilibrium exists between K1 and K2. Mild base
suffices to shift the equilibrium in the direction of K2. In a
Keywords: allylic amines · allylic substitution ·
.
asymmetric catalysis · cyclization · iridium
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Supporting Information). Nevertheless, these reactions were
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dbcot-containing catalyst in order to ensure identical reaction
conditions.
[9] R. Weihofen, O. Tverskoy, G. Helmchen, Angew. Chem. 2006,
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[5] Preparation from a,a’-dibromo-o-xylene: S. Chaffins, M. Bret-
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[13] Crystal data for K1: See the Supporting Information.
[14] The 31P NMR spectrum was measured at À608C in order to
obtain sharp doublets for the minor diastereomer at d = 152/
142 ppm. At RT the 31P NMR spectrum showed a broadened
signal for the doublet at 142 ppm.
3
[15] Hartwig et al. found doublets at d = 152.6 and 127.8 ppm, J =
46 Hz (94%) and d = 149.4 and 146.0 ppm, 3J = 78 Hz (6%) for
diastereomers of type K2 derived from L1, cf. Ref. [11].
[8] Most of the substitution reactions using the cod-containing
catalyst have already been reported (see Refs. [3–5] in the
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