Ru-catalyzed tandem cross-metathesis/intramolecular-hydroarylation sequence

Article abstract of DOI:10.1002/anie.200705194

(Chemical Equation Presented) Sometimes it only takes one to tango: A novel ruthenium-catalyzed tandem cross-metathesis/intramolecular-hydroarylation reaction of alkenyl indoles has been developed which relies on a single catalyst for the tandem sequence and provides an efficient synthesis of fused polycyclic indole compounds with good to excellent overall yields (see scheme; Ts = 4-toluenesulfonyl, DCE = 1,2-dichloroethane, Mes = 2,4,6-Me₃C ₆H₂).

Full text of DOI:10.1002/anie.200705194

Angewandte
Chemie
DOI: 10.1002/anie.200705194
Tandem Reactions
Ru-Catalyzed Tandem Cross-Metathesis/Intramolecular-
Hydroarylation Sequence**
Jia-Rong Chen, Chang-Feng Li, Xiao-Lei An, Ji-Ji Zhang, Xiao-Yu Zhu, and Wen-Jing Xiao*
New synthetic strategies that facilitate the
rapid and efficient construction of com-
plex molecules remain a preeminent goal
in the chemical sciences. Compared to
stepwise syntheses, tandem transforma-
tions represent an attractive strategy for
building molecular complexity because
multiple-bond-cleavage and multiple-
bond-forming transformations are com-
bined in a single reaction operation.[1] The
diversity of reactions catalyzed by
Grubbsꢀ ruthenium alkylidenes (1–4) sug-
Scheme 1. Concept of the Ru-catalyzed tandemCM/intramolecular-hydroarylation reaction.
Ts =4-toluenesulfonyl, EWG=electron-withdrawing group, Mes=2,4,6-Me3C6H2.
gests that potential tandem processes
should be achievable by using Ru cata-
lysts.[2] Indeed, such tandem reactions
have been reported over the past few
years. Elegant examples include ring-closing metathesis
(RCM) with transfer dehydrogenation–hydrogenation,[3]
RCM with isomerization,[4] RCM with Kharasch addition,[5]
RCM with dihydroxylation,[6] enyne metathesis with Claisen
rearrangement,[7] enyne metathesis with cyclopropanation,[8]
ring-opening metathesis polymerization (ROMP) with hydro-
genation,[9] and cross-metathesis (CM) with aza-Michael
addition.[10] Critical to the success of these tandem protocols
is the use of additional catalysts (such as a Lewis acid[10]) or
reagents[4–9] to carry out the sequential processes. In contrast,
the use of a single species to catalyze a tandem process is
rare.[3]
In our search for novel and efficient Ru-catalyzed
reactions,[11] we envisaged the ruthenium alkylidene catalyzed
cross-metathesis of w-indolyl alkenes 5 with electron-defi-
cient alkenes 6 as the first step in the tandem reaction leading
to polycyclic indoles 7. We propose that the active ruthenium
species A (derived from the catalyst precursor) would
catalyze not only the CM process, but also an intramolecular
hydroarylation owing to its Lewis acidity (Scheme 1). Herein,
we describe a new tandem protocol: a one-pot CM/intra-
molecular-hydroarylation sequence catalyzed by a single
metal complex to afford diverse and structurally complex
tetrahydrocarbazoles. These heterocycles are an important
class of naturally occurring and biologically active mole-
cules,[12,13] which we can now access in a concise fashion
(Scheme 1).
Our tandem catalysis strategy was first examined by using
compound 5a and crotonaldehyde (6a) and a series of Grubbs
catalysts under various reaction conditions (Table 1). Pre-
liminary studies revealed that the proposed catalytic cascade
Table 1: Optimization of conditions for the tandem CM/intramolecular-
hydroarylation reaction.[a]
[*] J.-R. Chen, C.-F. Li, X. L. An, J.-J. Zhang, X.-Y. Zhu, Prof. Dr. W.-J. Xiao
Key Laboratory of Pesticide & Chemical Biology
Ministry of Education
College of Chemistry
Central China Normal University
152 Luoyu Road, Wuhan, Hubei 430079 (China)
Fax: (+86)27-6786-2041
E-mail: wxiao@mail.ccnu.edu.cn
Homepage: http://chem-xiao.ccnu.edu.cn/default.aspx
Entry
Catalyst/solvent
T [oC]
t
Yield [%][b]
1
2
3
4
5
6
1/DCM
2/DCM
3/DCM
4/DCM
3/toluene
3/DCE
40
40
40
40
110
80
60 min
60 min
60 min
60 min
40 min
30 min
40 min
12 h
5
15
90
79
90
97
93
63
[**] We are grateful to the National Science Foundation of China
(20472021 and 20672040) and the Programfor New Century
Excellent Talents in University (NCET-05-0672) for support of this
research. We thank Prof. Vy Dong for fruitful discussions and
Materia, Inc., Pasadena, CA for the generous gift of ruthenium
catalysts.
7[c]
8[d]
3/DCE
3/DCE
80
80
[a] Conditions: 5a (0.30 mmol), 6a (10 equiv), Ru catalyst (3 mol%),
solvent (3 mL). [b] Yield of isolated product. [c] 5 equiv 6a was used.
[d] 1 mol% of catalyst 3 was used.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or fromthe author.
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[a]
Table 2: Scope of Ru-catalyzed tandemCM/intramolecular-hydroarylation sequence.
was indeed possible to afford 7a.
Significant amounts of product
were formed by using ruthenium
alkylidenes 1–4 in dichlorome-
thane (DCM) at 408C (Table 1,
entries 1–4). Among these com-
plexes, ruthenium complex 3 (com-
monly known as Hoveyda–Grubbs
second-generation catalyst) was
the most efficient catalyst, provid-
ing 7a in 90% yield (Table 1,
entry 3). A brief survey of reaction
media showed that 1,2-dichloro-
ethane (DCE) was the optimal
solvent for this catalytic sequence.
Reducing the 6a/5a reactant ratio
to 5:1 (from 10:1) also afforded the
product in excellent yield (Table 1,
entry 7). A moderate yield was
obtained with 1 mol% catalyst
loading (Table 1, entry 8). The
superior levels of the reaction effi-
ciency provided by ruthenium cat-
alyst 3 in DCE at 808C (Table 1,
entry 7, 93% yield in 40 min, 5a/6a
1:5) prompted us to select these
conditions for further exploration.
Experiments that probe the
Entry Alkenyl indole
Product
R1, R2, R3
t
Yield
[min] [%][b]
1
2
5a
5b
7a
7b
R1 =Me
R1 =H
40
70
93
82
3
4
5
6
5c
5d
5e
5 f
7c
7d
7e
7 f
R1 =Me, R2 =Me
R1 =H, R2 =Me
R1 =Me, R2 =Cl
R1 =Me, R2 =F
40
40
90
90
95
82
86
90
7
8
9
5g
5h
5i
7g
7h
7i
R1 =Me, R2 =Me
R1 =Me, R2 =OMe
R1 =Me, R2 =F
40
90
90
90
88
95
10
11
5j
5k
7j
7k
R1 =Me, R2 =Me
R1 =Me, R2 =Cl
30
55
88
81
12
13
5l
5m
7 l
R1 =Me, R2 =Me
30
60
96
80
7m R1 =Me, R2 =Et
scope of substrates are summarized
in Table 2. Significant structural
variation in the w-indolyl alkene
component can be tolerated. The
reaction displays excellent general-
ity and functional-group tolerance.
Both free N-H and N-methyl sub-
strates could be utilized without
substantial loss in yield (Table 2,
entries 1 vs. 2 and 3 vs. 4). Incor-
poration of a methyl, ethyl, or
methoxy group at positions C4–
C7 of the indole ring reveals that
steric modification of the indole
architecture can be accomplished
14
5n
5o
7n
7o
R1 =Me, R2 =Me, R3 =Me 30
91
99
15[c]
R1 =Me, R2 =Me, R3 =Cl
40
16[d]
17[e]
5a
5a
7p
7q
R=Me
R=OEt
30
90
98
95
[a] Conditions: 5 (0.30 mmol), 6 (5 equiv), 3 (3 mol%), DCE (3 mL). [b] Yield of isolated product. [c] The
structure of 7o was further confirmed by X-ray analysis; see reference [16]. [d] Methyl vinyl ketone (6b)
was used. [e] Ethyl acrylate (6c) was used, and 10 mol% BF3·Et2O was added.
without compromising reaction efficiency (Table 2, entries 3,
7, 8, 10, and 12–14). Variation in the electronic contribution of
the indole ring is possible. For example, methyl, methoxy, Cl,
and F groups can be introduced on the indole ring at both the
C4 and C5 positions without significant loss in reaction yield
or efficiency (Table 2, entries 3–9). Mono-, di-, tri-, and
tetrasubstituted indole derivatives can be employed to con-
struct the tetrahydrocarbazole core, a structural motif com-
monly found among natural alkaloids and drug candidates.[14]
As shown in entries 5, 6, 9, 11, and 15 of Table 2, we have
successfully utilized halogenated indole substrates in this
tandem CM/intramolecular-hydroarylation reaction. More-
over, these products should be valuable for further chemical
transformations.[15]
and ethyl acrylate (6c) are suitable for this protocol (Table 2,
entries 16 and 17), affording 7p and 7q in 98 and 95% yields,
respectively. Note that 10 mol% of BF3·Et2O is added to
complete the intramolecular hydroarylation when 6c is
employed as the substrate (Table 2, entry 17).[17] To demon-
strate preparative utility, the tandem reaction of 5a (5.98 g)
with 6a was performed on a 30-mmol scale with 3 mol%
Hoveyda–Grubbs catalyst 3 to afford the corresponding
tetrahydrocarbazole (6.14 g) in 90% yield. More importantly,
w-indolyl alkenes 5 are easy to prepare from commercially
available reagents through a two-step procedure.[18] Thus, our
methodology is feasible on a preparative scale.
As illustrated in Equation (1), this Ru-catalyzed tandem
CM/intramolecular-hydroarylation reaction is also general
with respect to the nature of the heteroatom in the alkenyl
chain of the substrate. Substrates bearing oxygen and nitrogen
Structural variation in the electron-deficient olefin com-
ponent is also possible. For example, methyl vinyl ketone (6b)
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empty d orbital) acts as a Lewis acid and activates E.
Subsequent intramolecular cyclization forms indolium F,
which undergoes aromatization by loss of a proton to afford
7a and regenerate catalyst A for the next catalytic cycle.
In summary, a new process combining a cross-metathesis
step and an intramolecular hydroarylation has been devel-
atoms in the alkenyl chain undergo tandem catalysis
to form 9a and 9b in 74 and 85% yield, respectively.
To expand the scope of this tandem reaction, 8c,
which can be readily prepared from commercially
available indole and 5-bromo-1-pentene by a known
procedure,[19] was examined under our standard
conditions. To our delight, the reaction worked well
with the use of catalyst 3 in anhydrous toluene at
1108C, affording 9c in 80% yield of isolated product
[Eq. (2)].
Experiments to classify the Lewis acidic nature of
the ruthenium species A were performed by using N-
protected 10[18,20] as the substrate. It was found that
refluxing 10 alone or together with 3 mol% 3 in DCE
for 4 h did not give any hydroarylation product 11.
However, the experiment with a mixture of 10
(0.3 mmol), 5a (0.3 mmol), and 6a (1.5 mmol) under
the optimized conditions does give 11 in 51% yield,
along with 7a in 89% yield [Eq. (3); Boc = tert-
Scheme 2. Proposed mechanismfor the rutheniumalkylidene catalyzed tandem
CM/intramolecular-hydroarylation sequence.
oped for the efficient synthesis of complex multiring hetero-
cyclic compounds. The combination of two mechanistically
distinct transformations relying on a single catalyst precursor
makes this tandem reaction particularly useful. Further
studies to develop an asymmetric version[22] of this reaction
are in progress.
Experimental Section
Representative procedure: Ru catalyst 3 (0.009 mmol, 3 mol% based
on 5a) was added to a mixture of alkenyl indole 5a (0.30 mmol),
crotonaldehyde (6a; 1.5 mmol), and DCE (3 mL). The reaction
mixture was then stirred in boiling DCE. After completion of the
reaction (as determined by TLC), the reaction mixture was cooled to
room temperature and the solvent was removed under reduced
pressure. The crude product was purified by flash chromatography on
silica gel (hexane/ethyl acetate 10:1) to give pure 7a.
Received: November 11, 2007
Revised: December 14, 2007
Published online: February 19, 2008
butoxycarbonyl]. These results show that the active ruthe-
nium methylene A is generated after the catalytic cycle of the
CM reaction between 5a and crotonaldehyde. This Ru species
acts as a Lewis acid to catalyze the intramolecular hydro-
arylation of 10 and afford the cyclization product 11.
Using the reaction of alkenyl indole 5a and crotonalde-
hyde as a model, a possible mechanism for the ruthenium-
catalyzed tandem CM/intramolecular-hydroarylation reac-
tion is outlined in Scheme 2. In the presence of ruthenium
catalyst 3, cross-metathesis of 5a and 6a occurs.[3,21] After a
single turnover, the CM reaction generates intermediate E
and methylidene complex A. We envisioned that the ruthe-
nium complex A (which can accept electrons owing to its
Keywords: cross-metathesis · homogeneous catalysis ·
.
hydroarylation · ruthenium· tandemreactions
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