Enantioselective rhodium(I)-catalyzed [3+2] annulations of aromatic ketimines induced by directed C-H activations

Article abstract of DOI:10.1002/anie.201105766

Triple selectivity: Highly substituted indenylamines can be obtained with high enantioselectivity by formal [3+2] additions of aryl ketimines with internal alkynes. These rhodium(I)-catalyzed processes proceed by selective C-H activation of one of the two

Full text of DOI:10.1002/anie.201105766

Communications
DOI: 10.1002/anie.201105766
À
C H Activation
Enantioselective Rhodium(I)-Catalyzed [3+2] Annulations of
À
Aromatic Ketimines Induced by Directed C H Activations**
Duc N. Tran and Nicolai Cramer*
À
Directed functionalizations of unactivated arene C H bonds
with transition-metal catalysts[1] have evolved to be a highly
prosperous field in organic chemistry, and enable a comple-
mentary and highly efficient access to a broad variety of
building blocks.[2] Most often, the directing group itself
remains intact during the reaction and needs to be cleaved
or modified accordingly in follow-up steps. In this respect, a
tion that leads to free and unsubstituted chiral amines remains
challenging. Although catalytic enantioselective methods for
the direct preparation of free primary amines are very
desirable and the products are highly valuable synthetic
intermediates, examples of enantioselective processes in the
À
context of stereoselective C H functionalizations are very
scarce.[12,13] In the case of rhenium-catalyzed [3+2] annula-
tions reported by Kuninobu, Yu, and Takai, only the unligated
complex [{HRe(CO)4}n] was employed.[3f] In related rhodium-
catalyzed processes of ketones and alkynes to form indenols,
Glorius,[4c] Cheng,[4d] and their respective co-workers
employed rhodium(III) complexes that contain only a Cp*
ligand (Cp* = pentamethylcyclopentadienyl). In all of these
cases, the development of a catalytic enantioselective version
is a difficult task because of the lack of a steering ligand. In
stark contrast, the rhodium(I)-promoted reactions proceed
best with complexes ligated by phosphines, thus representing
a potential handle for asymmetric catalysis. Only two
individual examples of the targeted directed activation/
enantioselective readdition to the imine directing group
have been reported. One example, which was reported by
Zhao and co-workers, involved an alkyne acceptor,[8] and the
other, which was reported by our research group, used a
terminal allene.[3e] However, both reactions proceed with only
modest enantioselectivities and are not general. Herein, we
report a robust enantioselective process and illustrate its
additional potential for positional activation and regioselec-
tive migratory insertion.
À
modification or direct incorporation of this group in the C H
functionalization reaction is an attractive strategy that
induces additional complexity. For instance, important direct-
ing groups such as imines and carbonyl groups could be
transformed into amino or hydroxyl groups by an addition
reaction across the C N or C O bonds, or, more often,
participate in the formation of C O or C N bonds. Our
[3]
[4]
=
=
[5]
[6]
À
À
À
continuous interest in C H functionalization for selective
carbocylizations[7] prompted us to explore enantioselective
reactions of ketimines with alkynes for formal [3+2] cyclo-
additions.[8] Such processes lead to densely functionalized
indenylamines, which are key substructures in targets, as well
as building blocks for various biologically active molecules,[9]
and there are only few known strategies to access this class of
compounds.[10] In contrast, the envisioned process represents
a very efficient and direct route, although several synthetic
challenges need to be addressed. Besides the requirement to
establish selectivity-determining rules to differentiate
between the two aryl substituents of the ketimine, a selective
incorporation of unsymmetrically substituted alkynes is
desirable. Whereas regioselective migratory insertions are
observed for alkyl aryl substituted alkynes, the differentiation
between two different alkyl groups is significantly more
challenging.[11] Most importantly, the enantioselective addi-
The envisioned reaction is initiated by a cyclometalation
of imine 1 with a rhodium(I) complex (Scheme 1).[14] To avoid
undesired hydroarylation reactivity and obtain compound 3,
it is essential to remove the hydrogen atom from the metal
center, for example, by reductive elimination of either water
or amine, respectively. A subsequent carborhodation of the
internal alkyne 4 provides a vinyl rhodium species 5. We
speculated that the regioselectivity of this addition step could
be controlled with suitable coordinating groups of an unsym-
metrically substituted alkyne.[15] In turn, species 5 adds in an
enantioselective manner across the ketimine moiety to give 6.
[*] D. N. Tran, Prof. Dr. N. Cramer
Laboratory of Asymmetric Catalysis and Synthesis
EPFL SB ISIC LCSA, BCH 4305
1015 Lausanne (Switzerland)
E-mail: Nicolai.cramer@epfl.ch
Homepage: http://isic.epfl.ch/lcsa
D. N. Tran
À
Coordination of another imine substrate, C H activation,
reductive elimination, and release of free indenyl amine 7
would then close the catalytic cycle.
Laboratory of Organic Chemistry, ETH Zurich
Wolfgang-Pauli-Strasse 10
8093 Zurich (Switzerland)
[**] We thank Dr. R. Scopelliti for X-ray crystallographic analysis of
compound 7m. This work was supported by the EPFL, ETH Zurich
(ETH-16 08-3), and a starting grant from the European Research
Council under the European Community’s Seventh Framework
Program (FP7 2007–2013)/ERC Grant agreement no. 257891. We
thank Solvias AG for MeOBiphep ligands and Takasago Interna-
tional Corporation for Segphos ligands.
As the rhodium catalyst needs to accommodate several
different steps, namely metalation, and alkyne and imine
addition, a careful tuning of the conditions and the ligand
properties was required. The reaction was initially examined
with phenyl(4-nitrophenyl)methanimine (1a) and 1,4-dime-
thoxybut-2-yne as the prototype substrate combination
(Table 1).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201105766.
11098
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Angew. Chem. Int. Ed. 2011, 50, 11098 –11102

entries 1–4). We believe that the coordinating nature of the
counterion OR’ plays a pivotal role in the initial catalytic
cycle by converting the rhodium complex into the catalytically
active species (Scheme 1). Hence, by using [{Rh(cod)-
(tBuNH)}2] as an approximation of the hypothesized species
6, a comparable result was obtained (Table 1, entry 5).
However, the addition of 1.5 equivalents of tert-butylamine
to the reaction mixture dramatically reduced the conversion
and yield (Table 1, entry 6), which is indicative for a product
inhibition. Premixing of the metal complex and the phosphine
ligand prior to addition of both substrates is essential to
ensure high conversions. Whilst [{Rh(cod)(OH)}2] requires a
preincubation at at least 608C for 10 min, the complex
[{Rh(coe)2(OH)}2] with a more labile cyclooctene ligand
allows a more convenient premixing for a few minutes at
ambient temperature (Table 1, entry 7).[16] Several different
solvent categories were evaluated and the conversion and
yield are highest in aromatic solvents. However, the selectiv-
ity of the reaction is similar in octane, DMF, and tert-amyl
alcohol (Table 1, entries 8–11). A screening of different chiral
phosphine ligands (Scheme 2) showed that biaryl phosphines
À
Scheme 1. Mechanistic model for the rhodium(I)-catalyzed C H func-
tionalization/cyclization of aryl ketimines with internal alkynes.
À
Table 1: Screening of rhodium precursors and ligands in the C H
activation/cyclization sequence.[a]
Entry [RhI]
L
Yield[b] [%]
7a:8a[c]
e.r.[d]
1
2
3
4
[{Rh(coe)2(OMs)}2]
L5
L5
L5 83
L5 88
0
0
–
–
–
–
[Rh(coe)2(acac)]
[{Rh(cod)(OMe)}2]
[{Rh(cod)(OH)}2]
>20:1
>20:1
>20:1
–
>20:1
>20:1
>20:1
–
96:4
96.5:3.5
96:4
5
[{Rh(cod)(NHtBu)}2] L5 80
6[e]
7
[{Rh(coe)2(OH)}2]
[{Rh(coe)2(OH)}2]
[{Rh(cod)(OH)}2]
[{Rh(cod)(OH)}2]
[{Rh(cod)(OH)}2]
[{Rh(cod)(OH)}2]
[{Rh(cod)(OH)}2]
[{Rh(cod)(OH)}2]
[{Rh(cod)(OH)}2]
[{Rh(cod)(OH)}2]
[{Rh(cod)(OH)}2]
[{Rh(cod)(OH)}2]
[{Rh(cod)(OH)}2]
[{Rh(cod)(OH)}2]
L5 <5
L5 89
L5 32
L5 73
–
96.5:3.5
96:4
96:4
–
96:4
58:42
77:23
80:20
69:31
76:24
71:29
93.5:6.5
90.5:9.5
Scheme 2. Chiral phosphine ligands utilized in this study.
8[f]
9[g]
10[h]
11[i]
12
13
14
15
16
17
18
19[j]
L5
0
are best suited (Table 1, entries 12–18). Both the yield and the
enantioselectivity are sensitive to the steric bulk of the
ligands. DTBM-MeOBiphep (L5) and DTBM-Segphos (L8)
showed the best performance and gave enantiomeric ratios of
96.5:3.5 and 93.5:6.5, respectively (Table 1, entries 4 and 18).
The use of L4, which has isopropyl instead of tert-butyl
groups, resulted in a significantly reduced enantioselectivity
(Table 1, entry 15). An increase of the reaction temperature
by 408 to 1208C caused a decrease in enantioselectivity
(90.5:9.5; Table 1, entry 19). Besides control of the enantio-
selectivity, the increasing steric bulk of the ligand is also
beneficial for the chemoselectivity of the initial cyclometala-
tion step. The ratio between 7a and 8a ranges from 6:1 to 15:1
when L1–L3, L6, and L7 are used, however, product 8a is not
detected when L4, L5, and L8 are used (7a:8a > 20:1).
Scheme 3 shows the scope of the reaction under the
optimized conditions. Besides symmetrical diaryl ketimines
(1b–1d), a variety of electronically different unsymmetrical
diaryl ketimines (1e–1g) were employed. Generally, imine
substrates that possess electron-withdrawing substituents on
one of the aromatic substituents show a higher reactivity and
provide a good differentiation in preference of the more
L5 58
L1 57
L2 34
L3 64
L4 78
L6 50
L7 69
L8 92
L8 69
>20:1
15:1
9:1
7:1
>20:1
6:1
15:1
>20:1
>20:1
[a] Reaction conditions: 1a (0.1 mmol, 0.5m in toluene), dimethoxy-
butyne (0.3 mmol), [RhI] (5 mol%), L (6 mol%), 808C, 16 h. [b] Yield of
isolated product 7a. [c] Determined from the H NMR spectrum of the
crude reaction mixture. [d] Determined by HPLC analysis on a chiral
stationary phase. [e] With 1.5 equiv of tert-butylamine. [f] In octane. [g] In
DMF. [h] In dioxane. [i] In tert-amyl alcohol. [j] At 1208C. DMF=
dimethylformamide.
1
As cationic rhodium(I) or halide-counterion-containing
complexes are not reactive (data not shown), we screened
different oxygen-based counterions. Hydroxide ions provide
superior results than other anionic oxygen-based counterions
with respect to conversion and enantioselectivity (Table 1,
Angew. Chem. Int. Ed. 2011, 50, 11098 –11102
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Communications
alkyl substituted ketimines can be employed in the reaction
(7s), although a slightly lower enantiomeric ratio, which is
caused by a higher reaction temperature of 1208C, is
observed. When evaluating the reactivity of the internal
alkyne,[17] we were particularly interested in unsymmetrically
substituted compounds, which not only broaden the scope of
the reaction, but also introduce an additional element of
selectivity to control. Besides high enantiomeric ratios, alkyl
aryl substituted alkynes also provide synthetically useful
regioselectivity and gave products 7k–7m. Addressing regio-
selectivity in alkynes, especially with two different alkyl
substituents, remains a largely unsolved problem for transi-
tion-metal-catalyzed carbometalations.[11] To address this
issue, we examined different potentially coordinating func-
tional groups such as alkyl ethers, esters, phthalimides, and
sulfur-containing functional groups at different distances
from the alkyne.[15] In all cases, the migratory insertion
occurred preferentially at the carbon atom proximal to the
directing group. As already observed for the cyclometalation
step, L5 showed higher regioselectivities for the carborhoda-
tion step than propane-1,3-diylbis(diphenylphosphane)
(dppp), which was utilized to prepare the corresponding
racemic samples. Depending on the nature of the coordinat-
ing group on the alkyne, moderate regioselectivities were
obtained with ether and ester groups (7o and 7n). However, it
is particularly noteworthy that even a sensitive propargyl
ester can be utilized without side reactions to give 7n. In
contrast, phthalimide-, thioether-, or thioacetal-bearing
alkynes reacted highly regioselective and formed only one
single regioisomer (7p, 7q, and 7r, respectively).
The absolute configuration as well as the constitution of
the products was established by X-ray crystallographic
analysis of product 7m (Figure 1).[18] R-Configured amine
7m is obtained when the reaction is performed with (S)-
DTBM MeOBiphep ((S)-L5) as ligand.
[a]
À
Scheme 3. Scope of C H activation/cyclization sequence. [a] Reaction
conditions: 1 (0.1 mmol, 0.2–1.0m in toluene), alkyne (1.5–3 equiv),
[{Rh(coe)2(OH)}2] (2.5 mol%), (S)-L5 (6.0 mol%), 100–1208C, 16 h;
7:8=20:1; r.s. =regioselectivity respective to the alkyne; e.r. values
were determined by HPLC analysis on a chiral stationary phase, and
1
isomeric ratios were determined from the H NMR spectra of the
crude reaction mixtures. [b] (R)-L5 was used. [c] 7:8=15:1.
[d] 7:8=11:1. [e] 7:8=5:1. [f] Chlorobenzene was used instead of
toluene. [g] With 5 mol% [{Rh(cod)(OH)}2] and 12 mol% L5.
Bn=benzyl, cod=cyclooctadiene, coe=cyclooctene, MOM=
methoxymethyl, Phth=phthaloyl.
Figure 1. ORTEP representation of 7m (thermal ellipsoids drawn at
50% probability).
The absolute configuration can be rationalized by the
stereochemical pathway illustrated in Scheme 4, which shows
that the imine moiety is attacked preferentially on its si face.
Intermediate A is preferred to B as it avoids an unfavorable
interaction of the ketimine portion and a DTBM residue of
ligand (S)-L5.
electron-poor ring when L5 is used. These characteristics are
maintained with heteroaromatic substituents. For instance,
pyridine-containing imine 1h reacts selectively at the pyridyl
moiety to give 7h, whereas for 1i, the electron-rich furyl
group remains untouched and 7i is formed exclusively. Aryl
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Angew. Chem. Int. Ed. 2011, 50, 11098 –11102

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Scheme 4. Stereochemical pathway with (S)-DTBM-MeOBiphep (L5;
gray).
In conclusion, we have developed enantioselective rho-
À
dium(I)-catalyzed C H functionalizations of unsubstituted
À
ketimines with internal alkynes. With this protocol, a control
of the stereogenic center of the amino group, a positional
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À
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alkynes are achievable. For the latter feature, a range of
common functional groups can direct the reaction. The
reaction is applicable to an attractive substrate range and is
tolerant to various functional groups and heterocycles. Future
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the individual steps to develop more efficient catalytic
systems and further improve the selectivity and generality
of related rhodium(I)-catalyzed functionalizations.
Experimental Section
[{Rh(coe)2(OH)}2] (1.70 mg, 2.50 mmol) and L5 (6.91 mg, 6.00 mmol)
were weighed into a vial equipped with a magnetic stirrer bar. The vial
was sealed with a rubber septum and flushed with nitrogen. Dry
toluene (0.1 mL) was added, the mixture was degassed by three
freeze-pump-thaw cycles and stirred for 15 min at 238C. This solution
of the preformed complex was transferred to another vial that
contained a degassed and preheated (808C) solution of ketimine 1a
(22.6 mg, 0.10 mmol) and 1,4-dimethoxybut-2-yne (36 mL, 0.30 mmol)
in toluene (0.1 mL). After 16 h, the reaction mixture was cooled to
238C and directly purified by column chromatography on silica gel
(EtOAc/pentane = 2:1, Rf =0.36) to give 7a (30.3 mg, 89 %, e.r. =
96.5:3.5) as a colorless oil.
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Received: August 15, 2011
Published online: October 4, 2011
À
Keywords: alkynes · annulation · asymmetric catalysis · C
H activation · rhodium
.
À
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À
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[16] For all reactions, the addition of the catalyst solution directly to a
preheated solution of the alkyne and imine proved to be crucial
for high conversion and reproducible results.
[17] Terminal and electron-deficient alkynes such as propiolic acid
derivatives do not provide the desired product 7.
[18] Crystallographic data for 7m: C21H18N2O3S, M =378.43, tetra-
gonal, space group P43, a =15.424(2) ꢀ, c =15.361(3) ꢀ,
V =3654.4(10) ꢀ3, Z =8, Dcalc =1.376 Mg mÀ3, reflections col-
lected: 12890, independent reflections: 6613 (Rint =0.0514),
R(all) =0.0664, wR(gt) = 0.1464. CCDC 837171 contains the
supplementary crystallographic data for this paper. These data
can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre www.ccdc.cam.ac.uk/data_request/cif.
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ling element, see: M. P. Huestis, L. Chan, D. R. Stuart, K.
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[13] The enantioselective synthesis of amines by C H functionaliza-
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11102 www.angewandte.org
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