An Iridium(I) N-Heterocyclic Carbene Complex Catalyzes Asymmetric Intramolecular Allylic Amination Reactions

Article abstract of DOI:10.1002/anie.201603266

A chiral iridium(I) N-heterocyclic carbene complex was reported for the first time as the catalyst in the highly enantioselective intramolecular allylic amination reaction. The current method provides facile access to biologically important enantioenriched indolopiperazinones and piperazinones in good yields (74–91 %) and excellent enantioselectivities (92–99 % ee). Preliminary mechanistic investigations reveal that the C?H activation occurs at the position ortho to the N-aryl group of the ligand.

Full text of DOI:10.1002/anie.201603266

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201603266
German Edition: DOI: 10.1002/ange.201603266
Asymmetric Catalysis
An Iridium(I) N-Heterocyclic Carbene Complex Catalyzes
Asymmetric Intramolecular Allylic Amination Reactions
Ke-Yin Ye, Qiang Cheng, Chun-Xiang Zhuo, Li-Xin Dai, and Shu-Li You*
3
À
Abstract: A chiral iridium(I) N-heterocyclic carbene complex
was reported for the first time as the catalyst in the highly
enantioselective intramolecular allylic amination reaction. The
current method provides facile access to biologically important
enantioenriched indolopiperazinones and piperazinones in
good yields (74–91%) and excellent enantioselectivities (92–
99% ee). Preliminary mechanistic investigations reveal that the
of iridium center into the C(sp ) H bond in the methyl group
of the amine part of the ligand, is the active catalytic species.[7]
Inspired by these findings, our group developed an N-aryl
phosphoramidite (Me-THQphos; Figure 1) from which the
2
À
active complex is formed by C(sp ) H activation of the N-aryl
group in the ligand.[8] The same C(sp ) H activation mode
2
À
was also identified in the iridium complex derived from
2
BHPphos.[9] These findings suggest that C(sp ) H activation
À
À
C H activation occurs at the position ortho to the N-aryl group
of the ligand.
is a useful strategy when designing new chiral ligands for
iridium-catalyzed enantioselective allylic substitution reac-
tions.
I
ridium-catalyzed allylic substitution reactions featuring high
regio- and enantioselective control for a broad scope of
nucleophiles with disubstituted E-allylic substrates have
witnessed significant progress during the past decade.[1,2]
Since the first asymmetric reaction enabled by an Ir/Phox
complex, introduced by the group of Helmchen,[3] the
development of chiral ligands has been one of the most
important tasks in this field. Among the many chiral ligands
used, the bulk of work on iridium-catalyzed allylic substitu-
tion reactions mainly focused on catalysts derived from chiral
phosphoramidite ligands, represented by the Feringa[4]/Alex-
akis[5] P,C ligands and Carreira P,olefin ligand[6] (Figure 1). In
N-Heterocyclic carbenes (NHCs) have witnessed rapid
development in the last decade both as ligands[10] and
organocatalysts.[11] However, chiral NHCs have not been
employed in the iridium-catalyzed asymmetric allylic substi-
tution reactions,[12] despite rare examples in palladium
catalysis[13] and extensive studies in copper catalysis.[14] As
part of our ongoing program towards iridium-catalyzed allylic
substitution reactions,[15] we envisaged that chiral NHCs
would be promising ligands for iridium and the corresponding
Ir/NHC complexes might be efficient catalysts in allylic
substitution reactions. Herein, we report the first example of
using an iridium(I) N-heterocyclic carbene complex as the
catalyst for the highly enantioselective intramolecular allylic
amination reaction of indoles and pyrroles.
Iridium-catalyzed asymmetric intramolecular allylic ami-
nation reactions can provide facile access to versatile
biologically important enantioenriched N-containing hetero-
cycles.[16] Instead of aliphatic amines and anilines generally
used as the nucleophiles, we began our study on the Ir/NHC
complex catalyzed intramolecular enantioselective allylic
amination reaction by utilizing the indole 1a as a model
substrate (Table 1). The results of examining NHCs derived
from different triazolium salts are summarized as shown. To
our delight, in the presence of 5 mol% of [{Ir(cod)Cl}2],
10 mol% of L1,[17] and 10 mol% of DBU, the reaction of 1a in
CH2Cl2 at room temperature afforded the desired allylic
amination product 2a in 75% yield and 92% ee without the
observation of Friedel–Crafts alkylation reaction at C3 of the
indole. Only trace amounts of 2a were formed with the
amino-indanol-derived triazolium salt L2.[18] The reaction
proceeded smoothly with the (1R,2R)-DPEN-derived triazo-
lium salt L3,[19] however, the asymmetric induction was
negligible. The ee value was increased to 76% and 89%
with L4[20] and L5,[21] respectively, as the chiral ligand
precursor. When the l-t-butylalaninol-derived triazolium
salt L6, introduced by the group of Enders,[22] was used, the
reaction afforded 2a in 82% yield and with 99% ee. No
deleterious effect of yield and enantioselectivity was observed
with 2.5 mol% of [{Ir(cod)Cl}2]. The reaction with 1.25 mol%
Figure 1. Phosphoramidite ligands in iridium-catalyzed allylic substitu-
tion reactions.
particular, the Feringa and Alexakis ligands have been proven
to be privileged ones, thus affording excellent regio- and
enantioselectivity. Mechanistic studies disclosed that the
À
iridium complex formed by C H activation, that is, addition
[*] Dr. K.-Y. Ye, Q. Cheng, Dr. C.-X. Zhuo, Prof. L.-X. Dai,
Prof. Dr. S.-L. You
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
345 Lingling Lu, Shanghai 200032 (China)
E-mail: slyou@sioc.ac.cn
Homepage: http://shuliyou.sioc.ac.cn/
Prof. Dr. S.-L. You
Collaborative Innovation Center of Chemical Science and
Engineering, Tianjin (China)
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201603266.
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Table 1: Screening of various chiral triazolium salts.[a,b,c]
Table 2: Substrate scope of the iridium-catalyzed allylic amination
reaction of indoles.[a,b,c]
[a] Reaction conditions: [{Ir(cod)Cl}2]/L/1a/DBU=0.05:0.1:1.0:0.1,
0.1m of 1a in CH2Cl2. [b] Yield of isolated product. [c] The ee value was
determined by HPLC analysis. [d] 2.5 mol% of [{Ir(cod)Cl}2] used.
[e] 1.25 mol% of [{Ir(cod)Cl}2] used. cod=1,5-cyclooctadiene,
DBU=1,8-diazabicyclo[5-4-0]undec-7-ene, TMS=trimethylsilyl.
[a] Reaction conditions: [{Ir(cod)Cl}2]/L6/1/DBU=0.025:0.05:1.0:0.1,
0.1m of 1 in CH2Cl2 at room temperature. [b] Yield is that of isolated
product. [c] The ee value was determined by HPLC analysis. PMB=
p-methoxybenzyl.
[{Ir(cod)Cl}2] also led to 2a in 96% ee. However, when the
triazolium salt L7 bearing an N-t-butyl group was used, no
detectable product was observed. Notably, the commonly
used phosphoramidite ligands only afforded moderate enan-
tioselectivities in this reaction (see Table S1 in the Supporting
Information).
Table 3: Substrate scope of iridium-catalyzed allylic amination of
pyrroles.[a,b,c]
Under the optimal reaction conditions (2.5 mol% of
[{Ir(cod)Cl}2], 5 mol% of L6, 0.2 mmol of 1, and 10 mol% of
DBU in 2 mL CH2Cl2 at room temperature), the substrate
scope was examined (Table 2). Indole-derived substrates
bearing either an electron-withdrawing group (5-F, 5-Cl,
5-Br, 6-Cl, 6-Br; 2b–f) or an electron-donating group (5-Me,
5-MeO, 6-MeO; 2g–i) on the phenyl ring of the indoles were
well tolerated and led to their corresponding indolopiperazi-
nones in good yields (77–91%) and excellent enantioselec-
tivities (97–99% ee). In addition, substrates with various
substituents on the amide N (Bn, Me, allyl, and PMB; 2a, 2j–
l) also reacted smoothly to afford amination products in good
yields (74–89%) with excellent enantioselectivities (96–99%
ee). In addition, when the substrates 1m and 1n, designed,
respectively for a seven- and eight-membered ring formation
of the intramolecular amination products, were applied, no
reaction occurred.
Notably, pyrrole-derived substrates are less reactive
compared with indoles but still well tolerated (Table 3).
Under the standard reaction conditions, only moderate
conversions were observed with pyrrole substrates. By
increasing the catalyst loading (5 mol% of [{Ir(cod)Cl}2])
and the reaction temperature (reflux), the piperazines 4m and
4n were obtained in good yields (81–85%) and excellent
enantioselectivities (98% ee). Introducing an extra electron-
withdrawing group on the pyrrole ring resulted in a lower
pKa value of the NH of pyrrole, thus increasing the reaction
rate. Therefore, the cyclization of the substrates 3o and 3p
[a] Reaction conditions: [{Ir(cod)Cl}2]/L6/3/DBU=0.025:0.05:1.0:0.1,
0.1m of 3 in CH2Cl2 at refluxed temperature. [b] Yield is that of isolated
product. [c] The ee value was determined by HPLC analysis. [d] 5 mol%
of [{Ir(cod)Cl}2] used.
proceeded smoothly to afford the 4o and 4p, respectively, in
the presence of 2.5 mol% of [{Ir(cod)Cl}2] and 5 mol% of L6.
The resulting indolopiperazinones[23,24] could further
undergo versatile transformations (Scheme 1). Treating 2a
with LiAlH4 led to the corresponding indole-fused piperazine
5a. The indolyl C3-position could be further functionalized
with a formyl group by a Vilsmeier–Haack reaction in 73%
yield (6a). The double bond of the enantioenriched allylic
indolopiperazinones could be easily hydrogenated with Pd/C
in methanol at room temperature in 95% yield (7h). An
olefin cross-metathesis reaction of 2a and n-butyl acrylate
afforded the a,b-unsaturated ester 8a in 60% yield. It is worth
mentioning that there is no notable loss of enantiomeric
purity for any of the above-mentiomed transformations.
2
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In summary, this study introduces the chiral triazolium
salts as a class of efficient NHC ligands for iridium-catalyzed
asymmetric allylic substitution reactions and provides facile
access to biologically important enantioenriched indolopiper-
azinones and piperazinones in good yields and excellent
enantioselectivities. Preliminary mechanistic investigation
À
revealed that C H activation occurs at the ortho-position of
the N-aryl group of the ligand. An in-depth mechanistic
investigation and further applications of Ir/NHC complexes
are in progress.
Experimental Section
General procedure for the iridium-catalyzed allylic amination
reaction of indoles: A flame-dried Schlenk tube was cooled to room
temperature and filled with argon. To this flask were added
[{Ir(cod)Cl}2] (3.4 mg, 0.005 mmol, 2.5 mol%), chiral triazolium salt
L6 (3.3 mg, 0.01 mmol, 5 mol%), 1 (0.20 mmol), DBU (3.1 mg,
0.02 mmol), and CH2Cl2 (2 mL). The reaction mixture was stirred at
RT. After the reaction was complete (monitored by TLC), the
solvents were evaporated in vacuo. The crude reaction mixture was
filtrated through celite and washed with EtOAc. The solvents were
removed under reduced pressure. Then the residue was purified by
silica gel column chromatography to afford the product (eluent:
petroleum ether/EtOAc = 4:1).
Scheme 1. Transformations of the products. DMF=N,N-dimethylfor-
mamide, THF=tetrahydrofuran.
The iridium(I) NHC complex C1 can be conveniently
synthesized in 76% yield by treating [{Ir(cod)Cl}2] with L6 in
the presence of Et3N [Eq. (1)]. C1 is not sensitive to oxygen
and moisture and can be subjected to alumina column
chromatography for purification. The structure of C1 was
confirmed by X-ray diffraction analysis (see the Supporting
Information).[25]
Acknowledgements
A preliminary mechanistic study was carried out to shed
light on the active catalytic species. To probe the possible
We thank the National Basic Research Program of China (973
Program 2015CB856600) and the National Natural Science
Foundation of China (21332009, 21421091 and 21572252) for
generous financial support.
À
existence of the C H activation of the catalyst, we treated C1
with AgBF4 in [D6]benzene. A singlet at d = À35.6 ppm was
1
observed by H NMR spectroscopy after 10 minutes and it
was assigned as a hydride [Eq. (2)]. In addition, when C1 was
Keywords: allylic compounds · asymmetric catalysis ·
enantioselectivity · iridium · N-heterocyclic carbenes
treated with AgBF4 and allyl methyl carbonate in THF at
2
À
room temperature for 24 h, C2 with C(sp ) H activation of
the N-aryl group in the ligand was obtained after simple
filtration [Eq. (3)]. The complex C2 was fully characterized
by NMR spectroscopy (see the Supporting Information). This
air- and moisture-sensitive species C2 was able to catalyze the
allylic substitution reaction of 1a [93% yield, 99% ee;
Eq. (4)], and is comparable to the results obtained with the
in situ formed catalyst.
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Received: April 3, 2016
Published online: && &&, &&&&
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Angew. Chem. Int. Ed. 2016, 55, 1 – 5
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Angewandte
Communications
Chemie
Communications
Asymmetric Catalysis
K.-Y. Ye, Q. Cheng, C.-X. Zhuo, L.-X. Dai,
S.-L. You*
&&&& — &&&&
An Iridium(I) N-Heterocyclic Carbene
Complex Catalyzes Asymmetric
Intramolecular Allylic Amination
Reactions
A chiral iridium(I) N-heterocyclic carbene
complex catalyzes highly enantioselective
intramolecular allylic amination reac-
tions. This method provides facile access
to biologically important enantioenriched
indolopiperazinones and piperazinones
in good yields. Mechanistic investiga-
À
tions reveal that the C H activation
occurs at the position ortho to the N-aryl
group of the ligand.
Angew. Chem. Int. Ed. 2016, 55, 1 – 5
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!