Ruthenium-catalyzed enantioselective carbon-carbon bond forming reaction via allenylidene-ene process: Synthetic approach to chiral heterocycles such as chromane, thiochromane, and 1,2,3,4-tetrahydroquinoline derivatives

Article abstract of DOI:10.1021/ja8038745

Our previously disclosed ruthenium-catalyzed carbon-carbon bond forming reactions between propargylic alcohols and alkenes via an allenylidene-ene type pathway have been successfully applied to an enantioselective intramolecular cyclization for a variety of chiral heterocycles such as chromane, thiochromane, and 1,2,3,4-tetrahydroquinoline derivatives (up to 99% ee) by use of a suitable optically active diruthenium complex as a catalyst. The methodology described in this paper becomes a novel synthetic approach to chiral heterocycles, the structures of which are widely found in many natural and biologically active compounds. Copyright

Full text of DOI:10.1021/ja8038745

Published on Web 07/22/2008
Ruthenium-Catalyzed Enantioselective Carbon-Carbon Bond Forming
Reaction via Allenylidene-Ene Process: Synthetic Approach to Chiral
Heterocycles Such As Chromane, Thiochromane, and
1,2,3,4-Tetrahydroquinoline Derivatives
Koji Fukamizu, Yoshihiro Miyake, and Yoshiaki Nishibayashi*
Institute of Engineering InnoVation, School of Engineering, UniVersity of Tokyo, Bunkyo-ku, Tokyo 113-8656, Japan
Received May 23, 2008; E-mail: ynishiba@sogo.t.u-tokyo.ac.jp
Table 1. Ru-Catalyzed Formation of Chiral Chromanes (3)a
Heterocycles containing oxygen, sulfur, and nitrogen atoms such
as chromane, thiochromane, and 1,2,3,4-tetrahydroquinoline derivatives
are widely found in many natural and biologically active compounds.1
In addition to classical synthetic approaches to these heterocycles, a
variety of preparative methods catalyzed by transition metal complexes
have been reported including its asymmetric version for the optically
active heterocycles.1,2
We have recently disclosed the ruthenium-catalyzed inter- and
intramolecular carbon-carbon bond forming reactions between pro-
pargylic alcohols and alkenes which proceeded via an allenylidene3-
ene type pathway (Scheme 1).4 We have now envisaged the application
of this reaction system to the preparation of a variety of optically active
heterocycles via an intramolecular cyclization of propargylic alcohols
bearing an alkene moiety at a suitable position. In fact, we have
succeeded in obtaining chiral chromanes, benzochromenes, thiochro-
manes, and 1,2,3,4-tetrahydroquinolines in good to high yields with
up to 99% ee. Preliminary results are described here.
Scheme 1
a All reactions of 1 (0.20 mmol) were carried out in the presence of 2a
(0.01 mmol) and NH4BF4 (0.02 mmol) at 60 °C in CICH2CH2CI (5 mL).
b Isolated yield. c Determined by 1H NMR. d Determined by HPLC.
e Enantiomeric excess of anti-isomer.
With 2a as a catalyst, the nature of a substituent on an alkene moiety
of the starting compound 1 was revealed to be the most important
factor to achieve a high enantioselectivity. Typical results are shown
in Table 1. The introduction of an unsymmetrical (E)-alkene moiety
to the starting compound (1a-1d) generally gave satisfactory results
in both product yield and diastereoselectivity as well as enantioselec-
tivity of the major isomer (Table 1, runs 1-4). In contrast, the reaction
of propargylic alcohol bearing a (Z)-alkene moiety (1e) proceeded quite
slowly under the same reaction conditions to give the corresponding
product 3a, in 65% yield, where the anti-isomer (syn-3a/anti-3a )
1/2.5) was mainly obtained with 33% ee (Table 1, run 5).
Intramolcular cyclization of a variety of propargylic alcohols bearing
an (E)-alkene moiety (1) was investigated using 2a as a catalyst.
Typical results are shown in Table 2. The presence of a substituent
such as a methyl moiety on the benzene backbone of propargylic
alcohols (1f-1g) did not affect much the enantioselectivity of the
produced chromanes (Table 2, runs 2 and 3). However, the introduction
of a chloro moiety to the 4-position of the benzene ring (1h) decreased
the reactivity (Table 2, run 4), a larger amount of 2a (10 mol %) being
necessary to obtain the cyclic product (3h) in high yield. The nature
of an aryl group in the alkene part (1i) gave some effects on the
diastereomeric ratio, but not on the enantioselectivity of the major
isomer (Table 2, run 5). On the other hand, reactions of propargylic
alcohols bearing a naphthyl backbone (1j-1l) were sluggish under
identical conditions, and a prolonged reaction time and/or a larger
amount of 2a were necessary to obtain the corresponding benzochro-
manes (3j-3l) in good yields with a high enantioselectivity (Table 2,
runs 6-8). The highest enantioselectivity (99% ee) was achieved in
the case of 1k. After one recrystallization of crude cyclic product, the
enantio- as well as diastereomerically pure 3k was isolated, and its
absolute configuration [(3S,4S)]6 was determined by X-ray analysis.
Results of a theoretical study on the reaction of propargylic alcohol
with 1,3-conjugated diene indicated that the allenylidene-ene reaction
Heating of propargylic alcohol bearing an (E)-alkene moiety (1a)
in ClCH2CH2Cl at 60 °C for 6 h in the presence of 5 mol % of an
optically active thiolate-bridged diruthenium complex [Cp*RuCl(µ2-
SR*)]2 (Cp* ) η5-C5Me5, -SR* ) (R)-SCH(Et)C6H3Ph2; 2a)5 and
10 mol % of NH4BF4 gave 4-ethynyl-3-(1-phenylethenyl)chromane
(3a) in 85% isolated yield as a mixture of two diastereoisomers, the
syn-isomer with 93% ee being the major (syn-3a/anti-3a ) 17/1)
(Scheme 2).6 Use of the complex bearing other optically active sulfur
ligands (2b and 2c) did not afford satisfactory results in both reactivity
and selectivity. We have previously found that 2c promoted enanti-
oselective propargylic substitution reactions7 and propargylation of
aromatic compounds8 with a high enantioselectivity, but it did not work
effectively for the present type of carbon-carbon bond forming
reaction.
Scheme 2
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10498 J. AM. CHEM. SOC. 2008, 130, 10498–10499
10.1021/ja8038745 CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Ru-Catalyzed Formation of Chiral Chromanes (3)a
Scheme 5
Scheme 6
a All reactions of 1 (0.20 mmol) were carried out in the presence of 2a
(0.01 mmol) and NH4BF4 (0.02 mmol) at 60 °C in CICH2CH2CI (5 mL).
b Isolated yield. c Determined by 1H NMR. d Determined by HPLC. e 2a
(0.02 mmol) and NH4BF4 (0.04 mmol) were used. f CICH2CH2CI (20 mL)
was used.
obtained by the present method may be employed for producing more
useful products.
Finally, this methodology for the preparation of chiral chromanes
and benzochromanes can also be extended to the enantioselective
formation of other hetereocycles containing a sulfur or nitrogen atom.
Thus, reactions of propargylic alcohols bearing a thioether moiety (6)
in the presence of a catalytic amount of 2a at 60 °C gave the
corresponding thiochromanes (7) in excellent yields with a high
enantioselectivity (Scheme 5). In addition, reactions of propargylic
alcohols bearing an allylic amine moiety (8) under the same reaction
conditions gave the corresponding 1,2,3,4-tetrahydroquinolines (9) in
good to high yields with an excellent enantioselectivity (Scheme 6).
In summary, we have succeeded in applying our previously
disclosed ruthenium-catalyzed carbon-carbon bond forming reaction4
to an enantioselective intramolecular cyclization by use of a suitable
chiral diruthenium complex as a catalyst for producing a variety of
optically active heterocycles such as chromane, thiochromane, and
1,2,3,4-tetrahydroquinoline derivatives.
Scheme 3
Scheme 4
Supporting Information Available: Experimental procedures and
spectroscopic data, and X-ray data. This material is available free of charge
via the Internet at http://pubs.acs.org.
References
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(6) See Supporting Information for experimental details.
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should proceed via a stepwise process (Scheme 3).9 At present, we
consider that the intramolecular attack of an alkene on the cationic
γ-carbon in I occurs from the si face7,8 to give the corresponding
alkynyl complex (II), followed by the smooth transfer of one of the
terminal protons into the alkynyl moiety to give the corresponding
vinylidene complex (III). Intramolecular cyclization step seems to be
essential for achievement of a high enantioselectivity. In fact, an
intermolecular reaction of 1-phenyl-2-propyn-1-ol with R-methylsty-
rene in the presence of a catalytic amount of 2a or 2c at 60 °C
proceeded smoothly, but only a moderate enantioselectivity in the
produced 2,4-diphenyl-1-hexen-5-yne was observed. As described in
our previous reports,10 we believe that the synergistic effect in the
diruthenium complexes is also quite important for promotion of this
catalytic reaction.
(8) (a) Matsuzawa, H.; Miyake, Y.; Nishibayashi, Y. Angew. Chem., Int. Ed.
2007, 46, 6488. (b) Matsuzawa, H.; Kanao, K.; Miyake, Y.; Nishibayashi,
Y. Org. Lett. 2007, 9, 5561.
(9) Daini, M.; Yoshikawa, M.; Inada, Y.; Uemura, S.; Sakata, K.; Kanao, K.;
Miyake, Y.; Nishibayashi, Y. Organometallics 2008, 27, 2046.
(10) Ammal, S. C.; Yoshikai, N.; Inada, Y.; Nishibayashi, Y.; Nakamura, E.
J. Am. Chem. Soc. 2005, 127, 9428.
Separately, we have already confirmed that some chiral chromanes
(3) can be converted into their derivatives (411 and 5) without any
loss of optical purity (Scheme 4), indicating that cyclized products
(11) The molecular structure of 4 was confirmed by X-ray analysis.6
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J. AM. CHEM. SOC. VOL. 130, NO. 32, 2008 10499