Enantioselective intramolecular hydroarylation of alkenes via directed C-H bond activation

Article abstract of DOI:10.1021/jo801098z

(Chemical Equation Presented) Highly enantioselective catalytic intramolecular ortho-alkylation of aromatic imines containing alkenyl groups tethered at the meta position relative to the imine directing group has been achieved using [RhCl(coe)₂]₂ and chiral phosphoramidite ligands. Cyclization of substrates containing 1,1- and 1,2-disubstituted as well as trisubstituted alkenes were achieved with enantioselectivities >90% ee for each substrate class. Cyclization of substrates with Z-alkene isomers proceeded much more efficiently than substrates with E-alkene isomers. This further enabled the highly stereoselective intramolecular alkylation of certain substrates containing Z/E-alkene mixtures via a Rh-catalyzed alkene isomerization with preferential cyclization of the Z-isomer.

Full text of DOI:10.1021/jo801098z

Enantioselective Intramolecular Hydroarylation of Alkenes via
Directed C-H Bond Activation
Hitoshi Harada, Reema K. Thalji, Robert G. Bergman,* and Jonathan A. Ellman*
Department of Chemistry, UniVersity of California, and DiVision of Chemical Sciences, Lawrence Berkeley
National Laboratory, Berkeley, California 94720
jellman@berkeley.edu; rbergman@berkeley.edu
ReceiVed May 22, 2008
Highly enantioselective catalytic intramolecular ortho-alkylation of aromatic imines containing alkenyl
groups tethered at the meta position relative to the imine directing group has been achieved using
[RhCl(coe)2]2 and chiral phosphoramidite ligands. Cyclization of substrates containing 1,1- and 1,2-
disubstituted as well as trisubstituted alkenes were achieved with enantioselectivities >90% ee for each
substrate class. Cyclization of substrates with Z-alkene isomers proceeded much more efficiently than
substrates with E-alkene isomers. This further enabled the highly stereoselective intramolecular alkylation
of certain substrates containing Z/E-alkene mixtures via a Rh-catalyzed alkene isomerization with
preferential cyclization of the Z-isomer.
Introduction
cantly broadened reaction scope over intermolecular coupling
reactions.4 For example, substrates with di- and even trisubsti-
tuted alkenes underwent cyclization, and aromatic aldimines and
ketimines with heteroatom tethers such as vinyl ethers, allylic
ethers, and allylic amines also reacted cleanly. The synthetic
utility of this transformation was demonstrated in its application
to the synthesis of potent biologically active natural products
and drug candidates.5
Examples of effective enantioselective catalytic C-H bond
functionalizations are rare despite the high degree of activity
in this area.6 Murai reported a chelation-assisted enantioselective
alkylation utilizing the pyridine directing group in the intramo-
lecular coupling of olefinic C-H bonds with alkenes; however,
this transformation proceeds with only modest ee’s.7 While the
cyclization of the analogous imidazolyl-1,5-diene gave signifi-
Transition-metal-catalyzed carbon-hydrogen (C-H) bond
activation1 is one of the most powerful strategies for carbon-carbon
(C-C) bond formation. Because the C-H bond is ubiquitous
in organic substances, this method has broad potential. More-
over, direct conversion of C-H bonds into C-C bonds without
intermediate preactivation should shorten reaction sequences and
reduce waste resulting in environmental benefits. Finally,
catalytic C-H activation should enable novel bond connections
to rapidly give rise to structurally complex molecules. In spite
of these attractions, challenges in both the reactivity and
selectivity for these transformations remain.
Following Murai’s ground-breaking discovery of Ru-cata-
lyzed chelation-assisted alkylation of aromatic ketones,2 Jun
reported that the scope of the reaction could be extended to
isomerizable alkenes by the use of an imine directing group
and Rh catalyst.3 Previous work in our group extended this
chemistry to intramolecular reactions, which showed signifi-
(3) (a) Jun, C.-H.; Hong, J.-B.; Kim, Y.-H; Chung, K.-Y. Angew. Chem.
Int. Ed. 2000, 39, 3440–3442. (b) Lim, S.-G.; Ahn, J.-A.; Jun, C.-H. Org. Lett.
2004, 6, 4687–4690.
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Chem. Soc. 2001, 123, 9692–9693. (b) Ahrendt, K. A.; Bergman, R. G.; Ellman,
J. A. Org. Lett. 2003, 5, 1301–1303. (c) Thalji, R. K.; Ahrendt, K. A.; Bergman,
R. G.; Ellman, J. A. J. Org. Chem. 2005, 70, 6775–6781.
(5) (a) O’Malley, S. J.; Tan, K. L.; Watzke, A.; Bergman, R. G.; Ellman,
J. A. J. Am. Chem. Soc. 2005, 127, 13496–13497. (b) Wilson, R. M.; Thalji,
R. K.; Bergman, R. G.; Ellman, J. A. Org. Lett. 2006, 8, 1745–1747. (c) Watzke,
A.; Wilson, R. M.; O’Malley, S. J.; Bergman, R. G.; Ellman, J. A. Synlett 2007,
2383–2389.
(1) For recent reviews of C-H activation, see: (a) Alberico, D.; Scott, M. E.;
Lautens, M. Chem. ReV. 2007, 107, 174–238. (b) Godula, K.; Sames, D. Science
2006, 312, 67–72. (c) Kakiuchi, F; Chatani, N. Top. Organomet. Chem. 2004,
11, 45–79. (d) Davies, H. M. L.; Beckwith, R. E. J. Chem. ReV. 2003, 103,
2861–2903. (e) Ritleng, V.; Sirlin, C.; Pfeffer, M. Chem. ReV. 2002, 102, 1731–
1769. (f) Jia, C.; Kitamura, T; Fujiwara, Y. Acc. Chem. Res. 2001, 34, 633–
639. (g) Miura, M.; Satoh, T. Top. Organomet. Chem. 2005, 14, 55–83. (h)
Campeau, L.-C.; Fagnou, K. Chem. Soc. ReV. 2007, 37, 1058–1068.
(2) Murai, S.; Kakiuchi, F.; Sekine, S.; Tanaka, Y.; Kamatani, A.; Sonoda,
M.; Chatani, N. Nature 1993, 366, 529–531.
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insertions, see: Davies, H. M. L.; Manning, J. R. Nature 2008, 451, 417–424.
6772 J. Org. Chem. 2008, 73, 6772–6779
10.1021/jo801098z CCC: $40.75 2008 American Chemical Society
Published on Web 08/06/2008

EnantioselectiVe Intramolecular Hydroarylation of Alkenes
CHART 1. Chiral Monodentate Phosphorus Ligands
cantly higher enantioselectivities, the reaction is limited in
generality.7 The atropselective alkylation of 2-arylpyridines by
transition-metal-catalyzed C-H functionalization has also been
reported, although the ee did not exceed 49%.8 More recently,
Widenhoefer has reported the enantioselective platinum-
catalyzed intramolecular alkylation of indoles tethered to
unactivated terminal alkenes with selectivities up to 90% ee.9
On the other hand, high stereoselectivity and broader substrate
scope have been obtained in intramolecular hydroacylation as
initially reported for the cyclization of 4-pentanals into ꢀ-sub-
stituted cyclopentanones.10 In addition, Yu has very recently
also reported on the Pd-catalyzed enantioselective alkylation
of diphenyl(2-pyridyl)methane with alkylboronic acids using
monoprotected amino acids as the chiral ligands.11
expanded substrate scope, including the intramolecular hy-
droarylation of 1,2-disubstituted and 1,1,2-trisubstituted alkene
substrates. Cyclization of substrates with Z-alkene isomers
proceeded much more efficiently than substrates with E-alkene
isomers. This further enabled the highly stereoselective intramo-
lecular alkylation of certain substrates containing Z/E-alkene
mixtures via a Rh-catalyzed alkene isomerization with prefer-
ential cyclization of the Z-isomer.
We previously communicated the catalytic enantioselective
alkylation of aromatic ketimines with tethered 1,1-disubstituted
alkenes (eq 1),12 which represented one of the first highly
enantioselective catalytic reactions involving aromatic C-H
bond activation. Herein, we disclose the full details of this work
and further report on ligand optimization that has enabled greatly
Results and Discussion
A. Enantioselective Cyclization of 1,1-Disubstituted Alk-
enes.
A.1. Ligand Screening. We initiated our study by testing
the cyclization of alkene 1 using Rh complexes with various
ligands in order to identify the optimal ligand for this reaction.
Our efforts focused on chiral monodentate ligands13 because
catalysts derived from chelating phosphines were inefficient for
this reaction.4 Of the range of chiral monodentate phosphines
screened (Chart 1), only phosphoramidites gave acceptable
enantioselectivities. A brief summary of results for chiral
(7) Fujii, N.; Kakiuchi, F.; Yamada, A.; Chatani, N.; Murai, S. Chem. Lett.
1997, 26, 425–426.
(8) Kakiuchi, F.; Le Gendre, P.; Yamada, A.; Ohtaki, H.; Murai, S.
Tetrahedron: Asymmetry 2000, 11, 2647–2651.
(9) Han, X.; Widenhoefer, R. A. Org. Lett. 2006, 8, 3801–3804.
(10) (a) Taura, Y.; Tanaka, M.; Wu, X.-M.; Funakoshi, K.; Sakai, K
Tetrahedron 1991, 47, 4879–4888. (b) Barnhart, R. W.; Wang, X.; Noheda, P.;
Bergens, S. H.; Whelan, J.; Bosnich, B. J. Am. Chem. Soc. 1994, 116, 1821–
1830. (d) Barnhart, R. W.; McMorran, D. A.; Bosnich, B. Chem. Commun. 1997,
589–590. (e) For an innovative strategy for the intramolecular hydroacylation
of alkynes for the catalytic asymmetric synthesis of cyclopentenones via kinetic
resolution, see: Tanaka, K.; Fu, G. C. J. Am. Chem. Soc. 2002, 124, 10296–
10297. (f) Kundu, K.; McCullagh, J. V; Morehead, A. T, Jr. J. Am. Chem. Soc.
2005, 127, 16042–16043.
(13) (a) Arnold, L. A.; Imbos, R.; Mandoli, A.; de Vries, A. H. M.; Naasz,
R.; Feringa, B. L. Tetrahedron 2000, 56, 2865–2878. (b) Watanabe, T.; Kno¨pfel,
T. F.; Carreira, E. M. Org. Lett. 2003, 5, 4557–4558. (c) Hua, Z.; Vassar, V. C.;
Choi, H.; Ojima, I. Proc. Nat. Acad. Sci. U.S.A. 2004, 101, 5411–5416. (d) Zhang,
F.-Y.; Chan, A. S. C. Tetrahedron: Asymmetry 1998, 9, 1179–1182. (e) Duursma,
A; Minnaard, A. J.; Feringa, B. L. Tetrahedron 2002, 58, 5773–5778. (f)
Alexakis, A.; Burton, J; Vastra, J; Benheim, C; Fournioux, X.; van den Heuvel,
A; Leveˆque, J.-M; Maze´, F.; Rosset, S. Eur. J. Org. Chem. 2000, 4011–4027.
(11) Shi, B.-F.; Maugel, N.; Zhang, Y.-H.; Yu, J.-Q Angew. Chem., Int. Ed.
2008, 47, 4882–4886.
(12) Thalji, R. K.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2004,
126, 7192–7193.
J. Org. Chem. Vol. 73, No. 17, 2008 6773

Harada et al.
TABLE 1. Asymmetric Cyclization of Alkene 1 Using Various
Chiral Monophosphine Ligands
all gave quantitative cyclizations of 1 at 125 °C (Table 1).
Indeed, at 50 °C, 1 cyclized using L10 in 95% ee and 94%
yield in only 9 h (Table 2, entry 2). Increases in enantioselec-
tivities were also obtained using ligands L9 and L11 at lower
temperatures, although the reactions were significantly slower
(Table 2, entries 1 and 3).
A.3. Substrate Scope. To explore the scope of this enanti-
oselective cyclization, substrates 3, 5, 7, and 9 were evaluated
using the optimal ligands L9, L10, and L11 (Table 2). These
substrates cyclized in nearly quantitative yields under the optimal
conditions for each substrate. Ligands L10 and L11 consistently
gave faster reaction rates than L9. Ligands L10 and L11 also
showed higher enantioselectivities for all substrates except the
sterically encumbered silyl substrate 3, for which the least
hindered ligand L9 gave the optimal result (70% ee, entry 4).
Vinyl ether 9 exhibited the most efficient reaction of all the
substrates explored. Even at room temperature, the reaction
proceeded cleanly with ligand L10 giving the desired product
(R)-10 in high yield and with 96% ee (entry 16). Ligand L11
afforded a less efficient catalyst but provided the same high
level of selectivity as that obtained with diastereomer L10 (entry
18).
A4. Applications of Enantioselective Cyclizations of 1,1-
Disubstituted Alkene Substrates. The substrate examples shown
above demonstrate the utility of this methodology for the synthesis
of a diversity of chiral products including chiral indans, dihydro-
pyrroloindoles, and dihydrobenzofurans. In addition, the cyclization
of alkene 3 enables the introduction of a hydroxyl group, as the
SiMe2Ph functionality can be oxidized with retention of configu-
ration using the conditions developed by Fleming15 and Tamao.16
Phenylsilane (S)-11 was converted to the fluorosilane, which was
cleanly oxidized using mild hydrogen peroxide conditions to give
(S)-12 in 92% overall yield (eq 2).12 Furthermore, we also applied
the enantioselective cyclization methodology to the asymmetric
synthesis of the potent protein kinase C inhibitor tricyclic indole
15 (eq 3).5b In the course of the synthesis, a key intermediate
14 was prepared in 61% yield and 90% ee by the cyclization of
alkene 13. This synthesis is noteworthy not only because it
provided much more efficient entry to inhibitor 15 but also
because it represents the first example of the enantioselective
catalytic cyclization of an aldimine rather than a ketimine
substrate.
entry ligand ligand (mol%) T (°C) time (h) % yielda % eeb
1
2
3
4
5
6
7
8
L1
L2
L3
L4
L5
L6
L7
L8
L9
L9
L9
L9
L9
L10
L11
15
15
15
15
15
15
15
15
5
10
15
20
30
15
15
75
75
75
20
20
20
20
20
2.5
2.5
2.5
1
1
<2
6
6
<2
<2
93c
94c
91c
34c
6c
17 (R)
9 (R)
38 (R)
0
n.t.
19 (S)
0
58 (S)
83 (S)
83 (S)
83 (S)
125
125
125
125
125
125
125
125
125
125
125
125
15c
14c
52c
96d
98d
100
0
9
10
11
12
13
14
15
0
100
99
88 (S)
87 (S)
a Yields based on 1H NMR integration relative to 2,6-dimethoxy-
toluene internal standard. b Ee’s determined after hydrolysis of 2 with 1
N HCl (aq) using chiral GC or HPLC. Sense of induction is indicated in
parentheses. n.t.: not tested. c Remainder of mass balance is unreacted
starting material. d Remainder of mass balance is the double bond
isomer of 1.
phosphoramidites and the structurally related TADDOL-based
ligands is given in Table 1.
High enantioselectivities and complete conversions were
obtained with the (S)-binol-derived phosphoramidites with a
bulky amine substituent (L9–11, entries 11, 14, and 15). Alkene
1 cyclized quantitatively in the presence of 5 mol % of
[RhCl(coe)2]2 and 15 mol % of L10 to give 2 in 88% ee within
2 h at 125 °C. In contrast, (-)-TADDOL-based phosphites
L1-3 (entries 1-3), (-)-TADDOL-based phosphonite L4
(entry 4), (S)-binol-derived phosphites L5 (entry 5), and
phosphoramidites L6-8 (entries 6-8) that incorporate unhin-
dered secondary amines all proved to be ineffective catalysts,
giving either poor conversions, poor ee’s, or both. Both
diastereomeric ligands L10 and L11 afforded the same enan-
tiomer in the same yield and with comparable enantioselectivi-
ties (entries 14 and 15). These data, combined with the result
that L9, bearing an achiral amine substituent, also gave the same
sense of induction (entry 11), indicates that the chirality of the
binaphthyl moiety is primarily responsible for the asymmetric
induction and that the sterics of the amine substituent, rather
than its chirality, contribute to the overall induction and catalyst
efficiency.
A.2. Further Optimization of Reaction Parameters. The
ratio of ligand to Rh had a significant effect on the reaction
efficiency. The optimal phosphoramidite to Rh ratio for the
cyclization of 1 was found to be between 1:1 and 1.5:1.
Increasing this ratio dramatically inhibited the reaction (Table
1, entries 9-13). Similar results have been observed in Rh-
catalyzed hydrogenation using phosphoramidite ligands.14
To further enhance the enantioselectivity, the reaction tem-
perature was lowered using ligands L9, L10, and L11, which
B. Enantioselective Cyclization of 1,2-Disubstituted
Alkenes. Next, our study focused on 1,2-disubstituted alkenes,
which were more difficult substrates for enantioselective cy-
clization because Z/E-alkenes isomerization occurs at rates that
are competitive with cyclization.
B.1. Initial Evaluation of Olefin Isomers. We began our
study on 1,2-disubstituted alkene substrates by examining which
of three isomeric alkenes, 16, 17, and 18, provided the 2,3-
dihydro-3-methylbenzofuran product 19 with the greatest ef-
ficiency and selectivity (Table 3). We also monitored alkene
(14) van den Berg, M.; Minnaard, A. J.; Haak, R. M.; Leeman, M.; Schudde,
E. P.; Meetsma, A.; Feringa, B. L.; de Vries, A. H. M; Malijaars, C. E. P.;
Willans, C. E.; Hyett, D.; Boogers, J. A. F; Henderickx, H. J. W; de Vries, J. G.
AdV. Synth. Catal. 2003, 345 (1&2), 308–323.
(15) (a) Fleming, I.; Henning, R.; Parker, D. C.; Plaut, H. E.; Sanderson,
P. E. J. J. Chem. Soc., Perkin Trans. 1 1995, 4, 317. (b) Fleming, I. Chemtracts:
Org. Chem. 1996, 9, 1.
(16) Tamao, K. AdV. Silicon Chem. 1996, 3, 1.
6774 J. Org. Chem. Vol. 73, No. 17, 2008

EnantioselectiVe Intramolecular Hydroarylation of Alkenes
TABLE 2. Asymmetric Cyclization of 1,1-Disubstituted Alkenesa, b
a Reactions performed using 5 mol % of [RhCl(coe)2]2 and 15 mol % of ligand in toluene-d8. b The absolute configurations of(S)-6 and (R)-10 were
assigned by chemical derivatization and X-ray structure determination (see reference 12). The absolute configurations of (S)-2, (S)-4, and (R)-8 were
assigned by analogy. c Yields based on 1H NMR integration relative to 2,6-dimethoxytoluene internal standard. d Ee’s determined after hydrolysis of the
imine product using chiral GC or HPLC. e Performed using 10 mol % of ligand. f Yield is low due to unreacted material (9%) and formation of double
bond isomer (20%).
[RhCl(coe)2]2 and 20 mol % of L10 to give (R)-19 in 82% yield
and 85% ee in 96 h at 50 °C. None of the benzopyran that
might be produced upon isomerization of the alkenyl group from
vinyl to allyl was seen. Much lower yield and enantioselectivity
were observed in the reaction of allyl substrate 16 (entry 1).
The reaction of E-alkene 17 was slower than that of the Z-isomer
18 (entry 2). However, both isomers gave the same stereose-
lectivity, and Z/E isomerization of the substrate was observed
during the cyclizations of both 17 and 18 (entries 2 and 3). It
is therefore likely that regardless of the Z or E stereochemistry
of the starting material, cyclization proceeded through the
Z-alkene.
B.2. Ligand Screening. We next screened various phos-
phoramidite ligands (Chart 1)13 for enhancing the enantiose-
lectivity of the reaction using Z-alkene 18 as a substrate (Table
4). N,N- Diisopropylphosphoramidite L9 provided high yield
and the highest enantioselectivity among the (S)-binaphthyl type
of ligands (76% yield, 87% ee, entry 2). N,N-Dicyclohexyl-
phosphoramidite L12 showed lower selectivity (77% ee, entry
5) compared to L9. Increased steric hindrance as exemplified
isomerization as the reactions proceeded. Z-Alkene 18 was the
best substrate with respect to both yield and enantioselectivity
(entry 3). Alkene 18 cyclized in the presence of 10 mol % of
J. Org. Chem. Vol. 73, No. 17, 2008 6775

Harada et al.
TABLE 3. Comparison of Isomeric Substrates in Asymmetric Cyclization
entry
substrate
time (h)
17,a
%
18,a
%
% yielda
% eeb
1
2
16
17
96
0
6
20
44
72
96
0
19
n.d.
6
<22 (S)c
83
53
35
26
23
21
n.d.
25
29
24
19
16
90
53
24
12
7
25
39
47
51
n.d.
32
57
75
80
82
84 (R)
3
18
n.d.
6
12
10
12
10
10
21
45
74
96
4
85 (R)
a Amount of 17 and 18, and yields based on 1H NMR integration relative to 2,6-dimethoxytoluene internal standard. n.d.: not detected. b Ee’s
determined after hydrolysis of 19 with silica gel using chiral HPLC. Sense of induction is indicated in parentheses. c Approximate value due to peak
overlapping in HPLC analysis.
TABLE 4. Asymmetric Cyclization of Alkene 18 Using Various
Chiral Phosphoramidite Ligands
TABLE 5. Solvent Effects in Asymmetric Cyclization of Alkene 18
entry
1
solvent
T (°C)
time (h)
% yielda
% eeb
entry
ligand
time (h)
% yielda
% eeb
n.t.
toluene-d8
50
45
96
20
47
46
65
82
93
74
82
1
2
L8
L9
44
20
96
45
96
96
96
20
96
95
21
43
96
68
96
95
7
44
76
75
82
61
71
2
64
27
81
76
82
79
20
6
91
89
91
90
2
3
4
toluene-d8
THF-d8
dioxane-d8
75
50
50
87
3
L10
85
85
77
n.t.
90
80
86
88
91
87
78
5
a Yields based on 1H NMR integration relative to 2,6-dimethoxy-
toluene internal standard. b Ee’s determined after hydrolysis of (R)-19
with silica gel using chiral HPLC.
4
5
6
7
8
9
10
11
12
13
14
L11
L12
L13
L14
L15
L16
L17
L18
L19
L20
L21
enantioselectivity (90% ee, entry 7), and the (S)-VANOL-
based ligand L16 (entry 9) and the (S)-VAPOL-based ligand
L17 (entry 10) accelerated the cyclization; however, none
of these were better than L18 overall. The hindered (S)-
biphenol-, (S)-octahydrobinaphthol-, and (-)-TADDOL-
based ligands, L15 (entry 8), L20 (entry 13), and L21 (entry
14), respectively, all gave dramatically reduced yields.
B.3. Further Optimization of Reaction Parameters. In the
interest of exploring reaction efficiency, we further investigated
the reaction conditions using 18 as a substrate and L18 as a
ligand (Table 5). Increasing the temperature from 50 to 75 °C
accelerated the reaction and resulted in only a modest reduction
in selectivity (entry 2). Although high enantioselectivities were
obtained in all solvents that were investigated (entries 1, 3, and
4), 1,4-dioxane provided both the fastest reaction and the highest
conversion (entry 4).
B.4. Substrate Scope. We also studied the scope of 1,2-
disubstituted alkenes in this enantioselective cyclization reaction
using the optimal ligands (Table 6). The ethyl-, isobutyl-, and
phenyl-substituted substrates 20, 22, and 24 all cyclized with
high enantioselectivities (entries 2-4). In the reactions of
aldimine substrate 26, enantioselectivities were high, but the
yields were much lower than for the corresponding ketimine
a Yields based on 1H NMR integration relative to 2,6-dimethoxy-
toluene internal standard. b Ee’s determined after hydrolysis of (R)-19
with silica gel using chiral HPLC. n.t.: not tested.
by the N-tert-butyl, N-isopropylphosphoramidite L13 (entry 6)
resulted in a dramatic decrease in yield as did the less hindered
N,N-dibenzylphosphoramidite L8 (entry 1). Ligand L11, the
diastereomer of L10, provided lower yield but the same
stereoselectivity as L9 and L10 (61% yield, 85% ee, entry
4). These results indicate that the stereoselectivity is pre-
dominantly controlled by the diol moiety of the phosphora-
midite ligands, in analogy to what was observed in the
reaction of 1,1-disubstituted alkenes. Accordingly, the chiral
diol was varied, keeping the diisopropylamino group intact.
(S)-Octahydrobinaphthol-based ligand L18 gave the best
result (82% yield and 91% ee, entry 11). (S)-Dimethylbi-
naphthol-based ligand L14 also resulted in increases in
6776 J. Org. Chem. Vol. 73, No. 17, 2008

EnantioselectiVe Intramolecular Hydroarylation of Alkenes
TABLE 6. Asymmetric Cyclization of 1,2-Disubstituted and 1,1,2-Trisubstituted Alkenesa
a Reactions performed using 10 mol % of [RhCl(coe)2]2 and 20 mol % of ligand in 1,4-dioxane-d8 or 1,4-dioxane. b Yield of N-benzylimine product
determined by 1H NMR using 2,6-dimethoxytoluene as an internal standard. c Ee’s determined after hydrolysis of products with silica gel or HCl/
H2O-dioxane using chiral HPLC. d Figures in parentheses are for the experiments for ketone product isolation. e Isolated yield obtained after hydrolysis
with HCl/H2O-dioxane, which hydrolyzed not only the N-benzylimine but also any unreacted vinyl ether starting material. f Reaction carried out in
toluene-d8. g In the NMR-experiment, the reaction solution was heated at 50 °C for 6 h before increasing the temperature to 75 °C.
substrate 18 regardless of ligand used (entries 5-7). In addition,
L19 rather than L18 provided the highest enantioselectivity for
the cyclization of aldimine substrate 26 (87-89% ee, entry 7).
C. Stereoselective Cyclization of 1,1,2-Trisubstituted
Alkenes. Finally, we explored the challenging stereoselective
cyclization of 1,1,2-trisubstituted alkenes, in which two stereo-
centers would be set. We began our investigation with olefin
isomers 28 and 29. We again monitored not only conversion to
product but also alkene isomerization (Table 7). Reaction of
the E-alkene isomer 28 using L16 in toluene at 75 °C for 68 h
gave 30 in modest yield and with low enantioselectivity (40%
yield and 31% ee, entry 1). In contrast, a faster reaction that
resulted in a higher yield and enantioselectivity was observed
for substrate 29, which was a 4:1 mixture of Z and E isomers
(81% yield and 69% ee, entry 2). The enantioselectivity of the
reaction was increased by lowering the reaction temperature and
by using 1,4-dioxane as the solvent (80% ee, entry 3). Ligands
L18 and L19 resulted in additional increases in enantioselec-
tivity, although the reaction efficiency was lower than that
observed for L16 (entries 4 and 5). The highest selectivity was
achieved with L19 (91% ee, entry 5), and with this ligand, the
E-isomer 28 was completely unreactive to either cyclization or
alkene isomerization. Additionally, trisubstituted alkene substrate
31 also cyclized to yield (2S,3R)-32 with high enantioselectivity,
although a higher reaction temperature was required in this case
(Table 6, entry 9). Interestingly, cyclization of the 1,1,2-
trisubstituted alkene substrates 29 and 31, which were Z/E
mixtures, gave only the syn-isomer products as determined by
NMR and X-ray structural analysis (see the Supporting Infor-
mation and section D), further indicating that when Z/E mixtures
of trisubstituted alkene substrates are used only the Z-alkene
isomer, which is expected to give the syn-product, cyclizes.
D. Determination of Absolute Configuration for Cycliza-
tion Products. The absolute configuration of the two cyclization
products, (R)-19 and (2R,3R)-30, were determined by X-ray
crystallography after their derivatization. The N-benzylimine
J. Org. Chem. Vol. 73, No. 17, 2008 6777

Harada et al.
TABLE 7. Asymmetric Cyclization of Alkene 28 and 29
SCHEME 1
temp
(°C),
solvent
time E-alkene Z-alkene
%
%
entry substrate ligand
(h)
(%)
(%) yielda eeb
1
28
L16
75, toluene-d8
0
6
20
47
68
0
6
20
0
6
22
0
84
55
41
33
31
18
10
4
19
15
13
17
16
16
14
13
21
21
20
20
20
n.d.
n.d.
2
3
5
69
14
4
75
10
n.d.
70
45
20
7
n.d.
21
32
38
40
n.d.
66
81
n.d.
72
81
n.d.
30
60
69
74
n.d.
29
59
74
80
31
69
80
2
3
4
29
29
29
L16
L16
L18
75, toluene-d8
50, dioxane-d8
50, dioxane-d8
6.5
22
46
72
0
2
88
91
E. Mechanistic Discussion. Phosphoramidites have recently
gained prominence as ligands for asymmetric catalysis due to
their remarkable effects in catalytic asymmetric conjugate
additions17 and Rh-catalyzed hydrogenation reactions.14 The
exceptional rates and stereoselectivities observed may be
attributed to the unique binding properties of the phosphora-
midite ligands, which include σ donation to the metal center
and enhanced π acceptor ability compared to phosphines.
The results presented in Table 1 (entries 9-13), which display
the effect of the ligand-to-Rh ratio, strongly suggest that only
one ligand is bound to one Rh center throughout the catalytic
cycle. Excess ligand most likely generates an inactive Rh species
having more than one phosphoramidite ligand bound. This
conclusion is also supported by the fact that phosphoramidites
bind very strongly to Rh as a result of their π acceptor
properties.14 Thus, it seems likely that multiple phosphoramidite
ligands on a Rh center could render it inactive.
5
29
L19
50, dioxane-d8
78
49
22
<10c
<7c
6
21
48
72
a Amount of olefin isomers and yields based on 1H NMR integration
relative to 2,6-dimethoxytoluene internal standard. n.d.: not detected.
b Ee’s determined after hydrolysis of (2R,3R)-30 with silica gel using
c
1
chiral HPLC. Approximate value due to peak overlapping in H NMR.
FIGURE 1. Absolute configuration determined by X-ray structure
obtained for sulfinyl imine (Ss,R)-33.
Based on our results, and in accordance with the catalytic
cycle described by Jun18 for the analogous intermolecular
reaction, a possible catalytic cycle is given in Scheme 1.
Precoordination of the imine and successive C-H oxidative
addition to the Rh center would generate a Rh-H complex 35.
Coordination of the alkenyl group to the metal, followed by
migratory insertion of the double bond into the Rh-H bond,
would provide metallacycle 36, which can then undergo
reductive elimination to afford the product. Deuterium labeling
studies performed by Jun and co-workers on the analogous
intermolecular reaction indicate that the reductive elimination
step is rate-determining.18
FIGURE 2. Absolute configuration determined by X-ray structure
obtained for hydrazone (2R,3R)-34.
The stereoselectivities are presumably due to highly diaste-
reoselective migratory insertion. The fact that both Z- and
E-isomers of 1,2-disubstituted alkenes give the same selectivity
(Table 3, entries 2 and 3) can be rationalized by the observation
that the E-olefin isomer was converted to the Z-isomer during
the reaction, which could then react. The trisubstituted E-alkene
substrate 28 reacted much more slowly and with lower selectiv-
ity than that of the corresponding substrate 29 with a 4:1 Z- to
(R)-19 was hydrolyzed under acidic conditions, and the resulting
ketone was converted to the N-sulfinylimine (SS,R)-33 by
condensation with (S)-2,4,6-trimethylbenzenesulfinamide (Figure
1). (2R,3R)-30 was similarly derivatized to hydrazone (2R,3R)-
34 (Figure 2). CIF files for the X-ray crystal structures of (SS,R)-
33 and (2R,3R)-34 are provided in the Supporting Information.
The absolute stereochemistry of the representative cyclized
products was thus determined to be (R)-19 and (2R,3R)-30. The
absolute configurations of (R)-21, (R)-23, (R)-25, (R)-27, and
(2S,3R)-32 were assigned by analogy to the absolute configura-
tions of (R)-19 and (2R,3R)-30.
(17) Feringa, B. L. Acc. Chem. Res. 2000, 33, 346–353.
(18) Jun, C.-H.; Moon, C. W.; Hong, J.-B.; Lim, S.-G.; Chung, K.-Y.; Kim,
Y.-H. Chem. Eur. J. 2002, 8, 485–492.
6778 J. Org. Chem. Vol. 73, No. 17, 2008

EnantioselectiVe Intramolecular Hydroarylation of Alkenes
1
1256, 1236. H NMR (400 MHz, CDCl3): δ 7.38 (d, J ) 8.0 Hz,
E-isomer ratio (Table 7, entries 1 and 2). This lower selectivity
can perhaps be explained by isomerization of the double bond
from vinyl to allyl, which then cyclized with decreased
selectivity, similar to that observed in the reaction of 16 (Table
3, entry 1).
1H), 7.23 (t, J ) 8.0 Hz, 1H), 6.99 (d, J ) 8.0 Hz, 1H), 4.54 (t, J
) 8.6 Hz, 1H), 4.29 (dd, J ) 2.8, 8.6 Hz, 1H), 4.04-3.96 (m,
1H), 2.60 (s, 3H), 1.24 (d, J ) 6.8 Hz, 3H). 13C{1H} NMR (100
MHz, CDCl3): δ 199.0, 160.5, 133.8, 133.6, 128.2, 122.1, 114.1,
79.0, 37.0, 28.1, 20.1. HRMS (EI): m/z calcd for C11H12O2 (M+)
176.08373, found:176.08366. Chiral HPLC (Chiralcel AS column,
1% i-PrOH/hexanes, 1 mL/min): major, 6.41 min; minor, 5.90 min;
90% ee. [R]25D: +135.35 (c 0.99, CHCl3). Maximum value based
upon sample enantiomeric purity: [R]25D +150.39 (c 0.99, CHCl3).
By a similar procedure starting from benzyl-[1-{3-[((Z)-
propenyl)oxy]phenyl}ethylidene]amine (132.8 mg, 0.5005 mmol),
[RhCl(coe)2]2 (36.0 mg, 0.0502 mmol), and (S)-diisopropyl-
(8,9,10,11,12,13,14,15-octahydro-3,5-dioxa-4-phosphacyclohepta[2,1-
a;3,4-a′]dinaphthalen-4-yl)amine (42.5 mg, 0.100 mmol), the title
compound was also obtained as a colorless oil in 57.3 mg (65%
yield) and 90% ee.
Conclusions
In summary, we have developed a highly stereoselective
intramolecular hydroarylation of alkenes via directed C-H bond
activation using a Rh/chiral phosphoramidite catalyst system,
which represents a very rare example of an enantioselective
catalytic reaction involving aromatic C-H bond activation.
Moreover, the identified catalyst system enables the intramo-
lecular alkylation reaction to proceed at low temperatures,
leading to increased selectivity. Finally, good substrate scope
was achieved with 1,1- and 1,2-disubstituted as well as 1,1,2-
trisubstituted alkenes all serving as effective substrates. For the
cyclization of the 1,2-disubstituted and 1,1,2-trisubstituted
alkenes, the Z-alkene isomers were much more effective
substrates than the corresponding E-isomers. This stereoselective
catalytic transformation provides access to a range of chiral
indanes, dihydrobenzofurans, and dihydropyrroloindoles with
different substitution patterns and therefore should be applicable
to the asymmetric synthesis of a range of biologically active
compounds.
(2R,3R)-1-(2,3-Dimethyl-2,3-dihydrobenzofuran-4-yl)etha-
none ((2R,3R)-53) (Table 6, Entry 8). In a glovebox, to a medium-
walled NMR tube was added a mixture of [RhCl(coe)2]2 (3.5 mg,
0.0049 mmol) and (S)-(8,9,10,11,12,13,14,15-octahydro-3,5-dioxa-
4-phosphacyclohepta[2,1-a;3,4-a′]dinaphthalen-4-yl)-bis((R)-1-phe-
nylethyl)amine (5.5 mg, 0.010 mmol) in 1,4-dioxane (0.40 mL)
and a solution of benzyl[1-[3-(1-methylpropenyloxy)phenyl]eth-
ylidene]amine (Z/E ) 4/1 for olefin) (13.9 mg, 0.0497 mmol) in
1,4-dioxane (0.10 mL). The tube was fitted with a Cajon adapter,
the mixture was frozen, and then the tube was flame sealed under
vacuum. The NMR tube was then placed in oil bath heated to 50
°C for 72 h. After the reaction, the sealed tube was opened and the
mixture was concentrated. To the residue were added 1,4-dioxane
(0.50 mL) and concentrated HCl/H2O (1/1) (0.50 mL). The mixture
was stirred at room temperature for 3 h and then was extracted
with diethyl ether four times. The combined organic layer was
concentrated, and the residue was purified by silica gel column
chromatography (silica gel: 15 mL, eluted with 20:1 hexanes/ethyl
acetate) to give the title compound as a colorless oil (5.6 mg, 59%
yield). IR (ZnSe, thin film) νmax (cm-1): 1680, 1583, 1442, 1355,
Experimental Section
General Procedure for 1H NMR Experiments. In a glovebox,
to a medium-walled NMR tube was added a mixture of [RhCl-
(coe)2]2 (0.005 mmol, 10 mol%) and phosphoramidite ligand (0.010
mmol, 20 mol %) in 0.40 mL of solvent and a solution of imine
(0.050 mmol) and 2,6-dimethoxytoluene internal standard (0.010
mmol) in 0.10 mL of solvent. The tube was fitted with a Cajon
adapter, the mixture was frozen using liquid N2, and then the tube
was flame sealed under vacuum. The NMR tube was then placed
in oil bath heated to the appropriate temperature, and the progress
1
1263, 1231. H NMR (400 MHz, CDCl3): δ 7.38 (d, J ) 8.0 Hz,
1H), 7.21 (t, J ) 8.0 Hz, 1H), 6.96 (d, J ) 8.0 Hz, 1H), 4.75 (quint,
J ) 6.8 Hz, 1H), 3.83 (quint, J ) 6.8 Hz, 1H), 2.60 (s, 3H), 1.49
(d, J ) 6.8 Hz, 3H)1.06 (d, J ) 6.8 Hz, 3H). 13C{1H} NMR (100
MHz, CDCl3): δ 199.0, 160.1, 135.4, 133.6, 128.0, 122.3, 114.0,
83.3, 40.0, 28.1, 15.0, 13.8. HRMS (EI): m/z calcd for C12H14O2
(M+) 190.0994, found 190.0993. Chiral HPLC (Chiralcel AS
column, 0.5% i-PrOH/hexanes, 1 mL/min): major, 13.5 min; minor,
12.7 min; 93% ee. CD (c ) 4 × 10-5 M, MeOH): λmax (∆ꢀ) 251
(+6.20). A 1H-1H NOESY spectrum of (2R,3R)-53 indicated that
the geometry of the two protons on the dihydrofuran ring was cis.
1
of the reaction was monitored periodically by H NMR spectros-
copy. After the indicated reaction time, the sealed tube was opened
and the mixture was concentrated. The residue was dissolved in a
small amount of methylene chloride, silica gel was added, and the
mixture was concentrated to dryness. The residue was subjected to
silica gel column chromatography and eluted with a 1:20 mixture
of ethyl acetate and hexanes for chiral HPLC analysis. Racemates
for HPLC analysis were prepared as crude material by using PCy3
or FcPCy2 as a ligand instead of a chiral phosphoramidite.
(R)-1-(3-Methyl-2,3-dihydrobenzofuran-4-yl)ethanone ((R)-
48) (Table 6, Entry 1). In a glovebox, to a medium-walled NMR
tube was added a mixture of [RhCl(coe)2]2 (3.6 mg, 0.0050 mmol)
and (S)-diisopropyl-(8,9,10,11,12,13,14,15-octahydro-3,5-dioxa-4-
phosphacyclohepta[2,1-a;3,4-a′]dinaphthalen-4-yl)amine (4.2 mg,
0.0099 mmol) in 1,4-dioxane (0.40 mL) and a solution of benzyl-
[1-{3-[((Z)-propenyl)oxy]phenyl}ethylidene]amine (13.4 mg, 0.0505
mmol) in 1,4-dioxane (0.10 mL). The tube was fitted with a Cajon
adapter, the mixture was frozen, and then the tube was flame sealed
under vacuum. The NMR tube was then placed in oil bath heated
to 50 °C for 48 h. After the reaction, the sealed tube was opened
and the mixture was concentrated. To the residue were added 1,4-
dioxane (0.50 mL) and concentrated HCl/H2O (1/1) (0.50 mL). The
mixture was stirred at room temperature for 3 h and then extracted
with diethyl ether four times. The combined organic layer was
concentrated, and the residue was purified by silica gel column
chromatography (silica gel: 15 mL, eluted with 20:1 hexanes/ethyl
acetate) to give the title compound as a colorless oil (6.3 mg, 71%
yield). IR (ZnSe, thin film) νmax (cm-1): 1680, 1584, 1442, 1355,
Acknowledgment. This work was supported by NIH Grant
No. GM069559 (to J.A.E.) and the Director and Office of
Energy Research, Office of Basic Energy Sciences, Chemical
Sciences Division, U.S. Department of Energy, under Con-
tract DE-AC03-76SF00098 (to R.G.B.). Support for H.H. by
Eisai Co., Ltd., is also gratefully acknowledged. We thank
Dr. Frederick J. Hollander of the UC Berkeley CHEXray
facility for solving the X-ray crystal structures of the
N-sulfinyl imine (SS,R)-33 and hydrazone (2R,3R)-34 used
to determine the absolute configurations of (R)-19 and
(2R,3R)-30, respectively.
Supporting Information Available: Experimental details,
including synthetic procedures, characterization, and X-ray
crystallographic data of (SS,R)-33 and (2R,3R)-34 (CIF). This
material is available free of charge via the Internet at
http://pubs.acs.org.
JO801098Z
J. Org. Chem. Vol. 73, No. 17, 2008 6779