Iridium-catalyzed intermolecular asymmetric hydroheteroarylation of bicycloalkenes

Article abstract of DOI:10.1021/ja312360c

Catalytic hydroarylation of alkenes is a desirable process because it can occur under neutral conditions with regioselectivity complementary to that of acid-catalyzed reactions and stereoselectivity derived from the catalyst. We report an intermolecular asymmetric addition of the C-H bonds of indoles, thiophenes, pyrroles, and furans to bicycloalkenes in high yield with high enantiomeric excess. These heteroarene alkylations occur ortho to the heteroatom. This selectivity is observed even with unprotected indoles, which typically undergo alkylation at the C3 position. Initial mechanistic studies revealed that oxidative addition of a heteroarene C-H bond to a neutral Ir ^I species occurs within minutes at room temperature and occurs in the catalytic cycle prior to the turnover-limiting step. Products from syn addition of the C-H bond across the olefin were observed.

Full text of DOI:10.1021/ja312360c

Communication
pubs.acs.org/JACS
Iridium-Catalyzed Intermolecular Asymmetric Hydroheteroarylation
of Bicycloalkenes
Christo S. Sevov and John F. Hartwig*
Division of Chemical Sciences, Lawrence Berkeley National Laboratory, Berkeley, California 94720, United States, and Department of
Chemistry, University of California, Berkeley, California 94720, United States
S
* Supporting Information
Mechanistic studies showed that the addition of the heteroaryl
ABSTRACT: Catalytic hydroarylation of alkenes is a
C−H bond to Ir is rapid and occurs before turnover-limiting
desirable process because it can occur under neutral
conditions with regioselectivity complementary to that of
acid-catalyzed reactions and stereoselectivity derived from
the catalyst. We report an intermolecular asymmetric
addition of the C−H bonds of indoles, thiophenes,
pyrroles, and furans to bicycloalkenes in high yield with
high enantiomeric excess. These heteroarene alkylations
occur ortho to the heteroatom. This selectivity is observed
even with unprotected indoles, which typically undergo
alkylation at the C3 position. Initial mechanistic studies
revealed that oxidative addition of a heteroarene C−H
bond to a neutral IrI species occurs within minutes at room
temperature and occurs in the catalytic cycle prior to the
turnover-limiting step. Products from syn addition of the
C−H bond across the olefin were observed.
insertion of the alkene.
Our observation of asymmetric hydroheteroarylation of
bicycloalkenes stemmed from our recent work on Ir-catalyzed
additions of N−H bonds of amides and sulfonamides to alkenes.8
While investigating potential hydroaminations involving alkenes
and heteroaryl N−H bonds, we observed the addition of
heteroaryl C−H bonds across alkenes. We then evaluated a range
of Ir catalysts for potential asymmetric hydroheteroarylations.
The results of reactions of indole with norbornene (nbe)
catalyzed by combinations of [Ir(coe)2Cl]2 (coe = cyclooctene)
with a series of bisphosphine ligands under a range of conditions
are summarized in Table 1. Ir complexes of Segphos were more
Table 1. Development of the Ir-Catalyzed Enantioselective
Addition of Indole to Norbornene
a
rene and heteroarene alkylation is one of the most
Afundamental transformations in synthetic chemistry. The
Friedel−Crafts reaction is the most common method for arene
alkylation, but this reaction often generates stoichiometric
quantities of waste, forms byproducts from isomerization of
intermediate carbocations, and occurs without control of the
stereochemistry of the product.1 Metal-catalyzed additions of
aromatic C−H bonds across alkenes to form alkyl arenes can
occur under conditions that are milder than those of classical
methods2 with site selectivity complementary to that of acid-
catalyzed reactions and with enantioselectivity.3 Thus, many
groups have sought catalysts for regioselective and enantiose-
lective hydroarylation of alkenes.
Additions of heteroaryl C−H bonds are particularly valuable
because of the importance of heteroarenes in biologically active
structures4 and materials applications.5 Recently, the Shibata
group reported the hydroarylation of N-acyl indoles, which is one
of the few cases of intermolecular alkene hydroheteroarylation
with selectivity complementary to that of Friedel−Crafts
alkylation.6 However, the reactions reported by Shibata require
a directing group on the indole nitrogen and occur with low
enantioselectivities. No systems for asymmetric intermolecular
hydroheteroarylation of unconjugated alkenes with high
enantioselectivity have been reported.7
a
b
Reactions were performed with 0.2 mmol of indole. Determined by
c
GC analysis. Determined by HPLC analysis using a chiral stationary
phase. dcpm = bis(dicyclohexylphosphino)methane.
d
reactive than complexes of MeOBiphep and Binap (entries 1−3),
suggesting that a small dihedral angle in the ligand is important
for generating a more active and selective catalyst. In a similar
vein, substantial yields were obtained from reactions catalyzed by
Ir complexes of one-carbon methylene-bridged bisphosphines
(entry 6), whereas no addition product was observed from
Here we report enantioselective, Ir-catalyzed additions of the
C−H bonds of indoles, thiophenes, pyrroles, and furans across
bicycloalkenes. These reactions form a single constitutional
isomer in both high yield and high enantioselectivity.
Received: December 18, 2012
Published: January 24, 2013
© 2013 American Chemical Society
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Communication
reactions catalyzed by complexes containing analogous two- or
three-carbon-bridged phosphines. An increase in the steric bulk
from the parent Segphos ligand to the DTBM-Segphos (DTBM
= 3,5-di-tert-butyl-4-methoxy) derivative led to an increase in the
yield and enantiomeric excess (ee) of 1 (entry 5). These
reactions constitute the first enantioselective intermolecular
additions of indoles across alkenes at the non-nucleophilic C2
position with high ee.
of the bicycloalkane was the exclusive isomer formed. Indoles
bearing chloride and bromide substituents underwent oxidative
homocoupling to a greater extent than did the other indoles
studied, but the yields of the addition products remained high.
The absolute stereochemistry of ester-substituted 6 was
determined to be 2R by single-crystal X-ray analysis with a
copper radiation source. The solid-state analysis also confirmed
that the indole was connected at C2. Thus, these reactions occur
at the C2 position of the indole without a protecting or directing
group on nitrogen.
The solvent had a pronounced effect on the yields of the
reaction of indole with nbe catalyzed by [Ir(coe)2Cl]2 and (S)-
DTBM-Segphos. Reactions conducted in relatively nonpolar
aliphatic solvents proceeded with complete consumption of the
starting material (Table 1, entries 7 and 8). However, the
reaction yields were lower than the conversions by 10−15% in
these solvents because of the formation of a side product from
oxidative dimerization of the heteroarene starting material.9 The
reactions conducted in coordinating solvents (e.g., acetonitrile,
dimethylformamide, and dimethyl sulfoxide) did not occur,
presumably because of competitive binding of these solvents to
the Ir catalyst. However, full conversion and high product yields
were observed when the reaction was conducted in the
moderately polar solvent tetrahydrofuran (THF) (entry 9).
The amount of nbe and indole affected the rate and
enantioselectivity of the reaction. Reactions conducted with an
excess amount of nbe were significantly slower than those
conducted with 1.2 equivalents of nbe (entries 14 vs 9), and the
ee of the product of the reaction with 4 equiv of nbe was lower
(90% ee) than that of the reaction conducted with 1.2 equiv of
nbe. Reactions with a lower 0.6 M concentration of indole
formed the hydroarylation product 1 in 97% yield with no
detectable amount of product from indole homocoupling (entry
12).
The scope of the hydroheteroarylation process extends to
furans, thiophenes, and pyrroles, as summarized in Chart 2.
Chart 2. Ir-Catalyzed Enantioselective Addition of Furans,
a
Thiophenes, and Pyrroles to Norbornene
The scope of the Ir-catalyzed addition of indoles to nbe by this
procedure is summarized in Chart 1. High yields and ee’s were
obtained from the reactions of indoles possessing electron-
donating or electron-withdrawing substituents. Halides, pro-
tected alcohols, and esters were tolerated under the reaction
conditions. The 2-substituted indole located at the exo position
a
Chart 1. Ir-Catalyzed Enantioselective Addition of Indoles to
Norbornene
Reactions were performed with 0.4 mmol of heteroarene and 1.2
a
equiv of nbe. Isolated yields are reported. The ee’s were determined by
HPLC analysis using a chiral stationary phase. The reaction was
performed with 0.9 equiv of nbe relative to heteroarene. Yield of the
2,5-dialkylated product. The ee could not be determined because the
b
c
d
signals of the mono- and dialkylated products overlapped.
These heteroarenes did not undergo oxidative homocoupling
reactions under the catalytic conditions. Therefore, the rates
could be increased without a reduction in yield by running the
reactions at concentrations higher than those for the reactions of
indoles (see the Supporting Information for reaction develop-
ment).
The reactions of substituted thiophenes and pyrroles formed
products from alkylation at the 2-position in high yield with
excellent ee. Reactions of thiophenes substituted at the 2- or 3-
position with alkyl groups or ketone and halogen functionality
occurred in high yield and ee. Reactions of pyrrole and a 2-
alkylpyrrole occurred in high yield and enantioselectivity.
However, the reactions of 2-acetylpyrrole or methyl pyrrole-2-
carboxylate did not form detectable amounts of product, most
likely because the substrate or product chelates to the Ir center
through the nitrogen and oxygen atoms. The reactions of N-
a
Reactions were performed with 0.5 mmol of indole and 1.2 equiv of
nbe. Isolated yields are reported. The ee’s were determined by HPLC
analysis using a chiral stationary phase.
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methyl- and N-phenylpyrrole also formed the corresponding
products in only trace amounts, in this case because the
substituent leads to steric hindrance at the 2-position. This steric
influence also leads to a lower yield for the reaction of 2,4-
dimethylpyrrole (21) than for 2-ethylpyrrole.
The reactions of furans also formed products in good yield.
Although the enantioselectivity was lower than in the reactions of
thiophenes and pyrroles, a broad range of functional groups that
can undergo further transformations (e.g., esters, ketones, and
nitriles) were tolerated by the hydroheteroarylation reaction.10,6
The scope of the hydroheteroarylation also encompasses the
addition of the C−H bonds of heteroarenes to norbornadiene
(nbd). However, some modification of the reaction conditions
was needed to obtain good yields of the product from addition to
the diene. The reactions of nbd conducted under the same
conditions as the reactions of nbe with thiophenes and furans
gave a significant amount of product from heteroarene oxidative
homocoupling. Moreover, the equivalent of hydrogen formed by
oxidative coupling led to the formation of substituted
norbornanes via reduction of the substituted norbornenes, and
the two classes of products could not be separated (eq 1).
halides, ketones, esters, and nitriles allows further trans-
formations to be conducted on the addition products.
Initial mechanistic studies of the addition reactions of
heteroarenes across bicycloalkenes were conducted by deute-
rium labeling and by studying the individual steps of the process.
The reaction of nbe with 2-D-indole formed syn-deutero-
(indolyl)norbornane (eq 4). This relative stereochemistry
implies that the hydroheteroarylation occurs by a mechanism
involving olefin insertion into an Ir−C or Ir−H bond.
Comparison of the initial rates for the addition of 2-H- and 2-
D-indole to nbe in separate vessels revealed a kinetic isotope
effect (KIE) of 1.4. This small but greater than unity KIE could
result from reversible addition of the indole C−H bond to the Ir
center prior to the turnover-limiting step.
To probe whether cleavage of the C2−H bond occurs prior to
the turnover-limiting step, reactions of 2-H- and 2-D-indole with
nbe under the catalytic conditions were followed by 1H and 2H
NMR spectroscopy. Illustrative spectra are shown in Figure 1.
Thus, the reaction conditions were modified to reduce the
amount of product formed by homocoupling of the heteroarene.
The reactions were conducted at a heteroarene concentration of
0.5 M instead of 1.3 M, and 2.5 equiv of the alkene was used
instead of 1.2 equiv (Chart 3). Under these modified conditions,
Chart 3. Ir-Catalyzed Enantioselective Addition of
a
Heteroarenes to Norbornadiene
a
Reactions were performed with 1.0 mmol of heteroarene and 2.5
Figure 1. Comparison of the hydride regions of the 1H and 2H NMR
spectra of the resting-state Ir complex under catalytic conditions with 2-
H-indole and 2-D-indole.
equiv of nbd. Isolated yields are reported. The ee’s were determined by
HPLC analysis using a chiral stationary phase.
the products of the addition of indoles and thiophenes to nbd
were formed in high yields with excellent ee. Like the reactions of
furans with nbe, the reaction of methyl 2-furoate with nbd
occurred in high yield but with low ee. The origin of the low
enantioselectivity in the reactions of furans is unknown at this
time. No products from additions of the heteroarenes to α-
olefins such as 1-octene or styrene were obtained under the
conditions for the additions to nbe and nbd.
The products of asymmetric hydroheteroarylation of
bicycloalkenes can be elaborated to chiral, enantioenriched
building blocks. Ring-opening metathesis of 26 with ethylene
formed the highly functionalized cyclopentane 27 as a single
diastereomer with no erosion of ee (eq 2). Oxidation of the furan
in 9 led to the alkyl carboxylic acid, also with no erosion of ee (eq
3). Finally, the compatibility of the catalyst with a broad range of
The combination of indole, nbe, and Ir−bisphosphine complex
28, which was formed from 1-octene, DTBM-Segphos, and
[Ir(coe)2Cl]2, formed a light-yellow solution (from the initial red
solution) within 10 min at room temperature. A doublet-of-
1
doublets hydride resonance at −20.8 ppm was observed by H
NMR spectroscopy. A similar experiment with 2-D-indole gave
rise to an Ir−deuteride resonance at −20.8 ppm in the 2H NMR
spectrum and a much smaller hydride resonance in the 1H NMR
spectrum. No hydroheteroarylation products were detected after
24 h at room temperature. These data indicate that C−H
activation occurs at the 2-position of indole at temperatures
below those required for catalytic turnover.
Because oxidative addition at the C2 position of indole occurs
much faster than the overall catalytic cycle, the turnover-limiting
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step likely follows the C−H cleavage process. Because reductive
eliminations to form carbon−carbon bonds from an Ir center are
rare or unknown, we propose that the C−H bond addition
reaction is followed by insertion of the alkene into the Ir−C bond
and C−H bond-forming reductive elimination, as illustrated in
Scheme 1. For the product to form by insertion of the alkene into
the Ir−H bond, C−C bond-forming reductive elimination must
occur from an alkyliridium aryl intermediate.
Scheme 1. Proposed Catalytic Cycle
In summary, we have reported examples of intermolecular
asymmetric additions of the C2−H bonds of indoles, thiophenes,
pyrroles, and furans to bicycloalkenes. The additions of indoles,
thiophenes, and pyrroles occurred in high yields with high ee’s.
Alkylation of the heteroarene occurs at the C−H bond adjacent
to the heteroatom by the transition-metal catalyst, even for
indoles, which typically undergo alkylation at C3. The neutral
catalyst that we have developed for this reaction tolerates a broad
range of functional groups, which can be elaborated to form
additional enantioenriched products. Initial mechanistic studies
of the identity of the catalyst resting state and the measured KIE
demonstrated that heteroarene C−H bond oxidative addition to
an IrI species occurs prior to the turnover-limiting step. Efforts to
extend the scope of the enantioselective reactions to encompass
unstrained alkenes are in progress.
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ASSOCIATED CONTENT
* Supporting Information
Experimental procedures, characterization data, and crystallo-
graphic data (CIF). This material is available free of charge via
the Internet at http://pubs.acs.org.
5868. (b) Mishra, A.; Ma, C.-Q.; Bauerle, P. Chem. Rev. 2009, 109, 1141.
̈
■
(c) Schipper, D. J.; Fagnou, K. Chem. Mater. 2011, 23, 1594.
S
(6) Pan, S.; Ryu, N.; Shibata, T. J. Am. Chem. Soc. 2012, 134, 17474.
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AUTHOR INFORMATION
Corresponding Author
jhartwig@berkeley.edu
Notes
■
̀ ́
Backvall, J.-E.; Krause, N.; Pamies, O.; Dieguez, M. Chem. Rev. 2008,
̈
108, 2796. (e) You, S. L.; Cai, Q.; Zeng, M. Chem. Soc. Rev. 2009, 38,
2190.
(8) Sevov, C. S.; Zhou, J.; Hartwig, J. F. J. Am. Chem. Soc. 2012, 134,
11960.
The authors declare no competing financial interest.
(9) Norbornane was detected, indicating that nbe was the terminal
reductant for the oxidative consumption of the heteroarene.
(10) For selected examples of directed olefin hydroheteroarylation and
alkylation at the C2 position of indole, see: (a) Baran, P. S.; Guerrero, C.
A.; Corey, E. J. J. Am. Chem. Soc. 2003, 125, 5628. (b) Wilson, R. M.;
Thalji, R. K.; Bergman, R. G.; Ellman, J. A. Org. Lett. 2006, 8, 1745.
(c) Jiao, L.; Bach, T. J. Am. Chem. Soc. 2011, 133, 12990. (d) Jiao, L.;
Herdtweck, E.; Bach, T. J. Am. Chem. Soc. 2012, 134, 14563.
ACKNOWLEDGMENTS
■
This work was supported by the Director, Office of Science, U.S.
Department of Energy, under Contract DE-AC02-05CH11231.
We thank Johnson Matthey for a gift of IrCl3 and Takasago for a
gift of (S)-DTBM-Segphos. C.S.S. thanks the NSF for a graduate
research fellowship.
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