A new synthetic approach to phenol derivatives: Use of ring-closing olefin metathesis

Article abstract of DOI:10.1021/ja050853x

Phenol derivatives, which are one of the most important classes of aromatic compounds in organic chemistry, were synthesized by ruthenium-catalyzed ring-closing olefin metathesis (RCM) of 1,4,7-trien-3-ones with versatile substitution patterns. The RCM reaction for producing phenol derivatives was also successful with 1,5,7-trien-3-one as another precursor. Most of the phenols prepared here could not be obtained easily by conventional methods. Copyright

Full text of DOI:10.1021/ja050853x

Published on Web 07/12/2005
A New Synthetic Approach to Phenol Derivatives: Use of Ring-Closing Olefin
Metathesis
Kazuhiro Yoshida* and Tsuneo Imamoto*
Department of Chemistry, Faculty of Science, Chiba UniVersity, Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
Received February 9, 2005; E-mail: kyoshida@faculty.chiba-u.jp; imamoto@faculty.chiba-u.jp
Scheme 1
Electrophilic aromatic substitution, which is represented by the
Friedel-Crafts reaction, is a very important means for preparing
substituted aromatic compounds.1 However, because of its stringent
reaction conditions and the nonselective substitution onto the
aromatic rings, it often does not give the product demanded by
synthetic chemists. One alternative approach is the direct construc-
tion of aromatic rings from linear components. For example, the
cyclotrimerization of acetylenes, which was first developed by
Reppe, offers a straightforward synthesis of aromatic derivatives.2
However, in most cases, the unsolved problem of the selective
orientation of the substituents on the aromatic rings surfaces again.
Ring-closing olefin metathesis (RCM) has become one of the
of the functional group tolerance of the Grubbs’ catalysts, it seemed
most important methods for constructing cyclic compounds of
promising to adopt these compounds even if they possessed
various sizes in organic synthesis.3 The tremendous success of this
carbonyl and phenol hydroxyl groups on their frameworks.
Two synthetic strategies for the required trienone 3 are outlined
in Scheme 1. The upper route involves the oxidation of trienol 4,
reaction is largely due to the discovery by Grubbs et al. of active
and well-defined ruthenium catalysts,4,5 which exhibit not only high
reactivity but also tolerance to a variety of functional groups. Herein
we report a new synthetic approach to phenol derivatives, which
the coupling of bromodiene 5 with R,â-unsaturated aldehyde, and
the palladium-catalyzed bromoallylation7 of alkyne with allyl
are one of the most important classes of aromatic compounds, from
bromide 6. The formation of 3 can also be achieved through the
linear precursors, utilizing the ruthenium-catalyzed RCM reaction.6
As phenol 1 is in equilibrium with ketonic tautomer 2, we
lower route in Scheme 1. Thus, trienone 3 might be derived from
7 by the cis-addition of an adduct to the triple bond (e.g.,
anticipated that 1,4,7-trien-3-one 3 would be a potential precursor
hydrogenation with Lindlar catalyst). 7, in turn, would result from
of 1 if the RCM reaction were carried out to form 2 (eq 1). Because
the oxidation of 8, which could be prepared by the coupling of
enyne 9 with R,â-unsaturated aldehyde.
In fact, several trienones 3 with versatile substitution patterns
were easily prepared with these synthetic sequences in high yields.8
With the desired precursors in hand, the RCM reactions were
performed, and the results are summarized in Table 1. When the
reaction of 3a was carried out with 7.5 mol % Grubbs’ first-
Table 1. Synthesis of Phenol Derivatives 1 by Ruthenium-Catalyzed Ring-Closing Olefin Metathesisa
entry
substrate
R1
R2
R3
R4
R5
R6
R7
product
catalyst (mol %)
temp
yieldb (%)
1
3a
3a
3a
3a
3b
3c
3d
3e
3f
3g
3h
3h
3i
H
H
nPr
nPr
nPr
nPr
nPr
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
1a
1a
1a
1a
1b
1c
1d
1e
1f
1g
1h
1h
1i
10 (7.5)
11 (7.5)
11 (5.0)
11 (2.5)
11 (7.5)
11 (7.5)
11 (7.5)
11 (7.5)
11 (7.5)
11 (7.5)
11 (7.5)
11 (7.5)
11 (7.5)
r.t.
87
93
88
48
90
92
92
97
93
98
40
92
0
2
H
H
H
H
H
H
H
H
H
H
H
Me
H
nPr
nPr
nPr
Ph
H
H
H
H
H
H
H
H
H
H
H
H
Me
r.t.
3
H
H
r.t.
4
H
H
r.t.
5
H
H
r.t.
6
H
Ph
D
H
r.t.
7
Me
Et
nPr
SiMe3
Ph
nPr
H
H
r.t.
8
H
r.t.
9
C2H4OH
C2H4OAc
Me
Me
H
H
H
r.t.
10
11
12
13
Ph
H
H
r.t.
Ph
H
Me
Me
H
r.t.
Ph
H
40 °C
40 °C
t
H
H
OSi(Me)2 Bu
a Reactions were carried out with trienone 3 and ruthenium catalyst (10 or 11, 2.5-7.5 mol %) in CH2Cl2 for 2 h. b Isolated yield by silica gel chromatography.
9
10470
J. AM. CHEM. SOC. 2005, 127, 10470-10471
10.1021/ja050853x CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
generation catalyst 104 at room temperature for 2 h, 2,3-dipropyl-
phenol (1a) was formed in 87% yield (entry 1). Switching to
Grubbs’ second-generation catalyst 115 resulted in a faster reaction
in 93% yield (entry 2). When the amount of catalyst 11 was de-
creased to 5.0 or 2.5 mol %, the chemical yields were decreased to
88% and 48%, respectively (entries 3 and 4).9 Therefore, we decided
that the conditions for entry 2 were the optimum. Under those
conditions, precursors 3b and 3c were converted in 90% yield into
2-phenylphenol (1b) and in 92% yield into 3-deuterio-2-phenylphe-
nol (1c), respectively (entries 5 and 6). The formation of a
trisubstituted double bond in the RCM reactions that gave phenols
1d-g proceeded without any problems (entries 7-10). Although
the RCM reaction of 3h, where a tetrasubstituted double bond was
formed, was slow at room temperature (entry 11), an increase in
the temperature led to the full conversion into 1h in 92% yield
(entry 12). One exception was the cyclization of trienone 3i that
bore no terminal olefins, which resulted in recovery of the substrate,
even when 11 was used under reflux in CH2Cl2 (entry 13).
We were interested in the tandem cross-metathesis/RCM between
dienone 12 and diene 13 to construct phenol derivatives (eq 2),
because there would be many difficulties derived from predictability
in product selectivity and stereoselectivity. Unfortunately, our
preliminary investigations met with failure. None of the desired
As expected, the RCM reaction of 15j11 in CH2Cl2 at 40 °C for
2 h gave the corresponding phenol 1j, although the chemical yield
was moderate (eq 4). Further attempts at improving the conversion
by changing the solvent to toluene and increasing the temperature
to 80 °C as well as the reaction time led to an 84% yield.
In conclusion, we have developed a new synthetic approach to
phenol derivatives, utilizing the ruthenium-catalyzed RCM reaction.
Most of the phenols prepared here cannot be easily obtained by
conventional methods. Ongoing research involves the extension of
the RCM reaction to other substrates and the development of tandem
cross-metathesis/RCM from two linear components for the synthesis
of phenol derivatives.
Acknowledgment. We appreciate the financial support from
Sankyo Co. Ltd. (K.Y.) and from a Grant-in-Aid for Scientific
Research, the Ministry of Education, Culture, Sports, Science and
Technology, Japan.
Supporting Information Available: Experimental procedures and
compound characterization data. This material is available free of charge
via the Internet at http://pubs.acs.org.
References
(1) March, J. AdVanced Organic Chemistry, 4th ed.; Wiley: New York, 1992;
Chapter 11, p 501.
1
(2) For reviews, see: (a) Grotjahn, D. B. Transition Metal Alkyne Complexes.
In ComprehensiVe Organometallic Chemistry II; Abel, E. W., Stone, F.
G. A., Wilkinson G., Eds.; Hegedus, L. S., Vol. Ed.; Pergamon: Oxford,
1995; Vol. 12, p 741. (b) Lautens, M.; Klute, W.; Tam, W. Chem. ReV.
1996, 96, 49. (c) Saito, S.; Yamamoto, Y. Chem. ReV. 2000, 100, 2901.
(3) For reviews, see: (a) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54,
4413. (b) Fu¨rstner, A. Angew. Chem., Int. Ed. 2000, 39, 3012. (c) Trnka,
T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18. (d) Handbook of
Metathesis; Grubbs, R. H., Ed.; Wiley-VCH: Weinheim, Germany, 2003.
(4) (a) Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R. H. Angew. Chem.,
Int. Ed. Engl. 1995, 34, 2039. (b) Schwab, P.; Grubbs, R. H.; Ziller, J.
W. J. Am. Chem. Soc. 1996, 118, 100. (c) Belderrain, T. R.; Grubbs, R.
H. Organometallics 1997, 16, 4001.
phenols could be detected by TLC or H NMR measurement of
the crude reaction mixtures, probably owing to oligomerization. A
detailed design of the substrates with regard to steric and electronic
properties will be necessary to achieve this kind of reaction.10
(5) (a) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953. (b) Trnka, T. M.; Morgan, J. P.; Sanford, M. S.; Wilhelm, T. E.;
Scholl, M.; Choi, T.-L.; Ding, S.; Day, M. W.; Grubbs, R. H. J. Am.
Chem. Soc. 2003, 125, 2546.
(6) For representative reports on the construction of condensed aromatic rings
from benzene derivatives utilizing the RCM reaction, see: (a) Evans, P.;
Grigg, R.; Ramzan, M. I.; Sridharan, V.; York, M. Tetrahedron Lett. 1999,
40, 3021. (b) Huang, K.-S.; Wang, E.-C. Tetrahedron Lett. 2001, 42, 6155.
(c) Arisawa, M.; Theeraladanon, C.; Nishida, A.; Nakagawa, M. Tetra-
hedron Lett. 2001, 42, 8029.
(7) (a) Kaneda, K.; Uchiyama, T.; Fujiwara, Y.; Imanaka, T.; Teranishi, S. J.
Org. Chem. 1979, 44, 55. (b) Llebaria, A.; Camps, F.; Moreto´, J. M.
Tetrahedron 1993, 49, 1283. (c) Ba¨ckvall, J.-E.; Nilsson, Y. I. M.; Gatti,
R. G. P. Organometallics 1995, 14, 4242. (d) Thadani, A. N.; Rawal, V.
H. Org. Lett. 2002, 4, 4317.
(8) The yield ranges were 70-36% (5 to 4), 84-52% (4 to 3), 92% (9i to
8i), 78% (8i to 7i), and 77% (7i to 3i). See Supporting Information for
experimental details.
(9) The reaction of 3a with 2.5 mol % Hoveyda-Grubbs’ catalyst gave a
similar result (47% yield), see: Hoveyda, A. H.; Gillingham, D. G.; Van
Veldhuizen, J. J.; Kataoka, O.; Garber, S. B.; Kingsbury, J. S.; Harrity, J.
P. A. Org. Biomol. Chem. 2004, 2, 8.
(10) For recent representative reports on cross-metathesis, see: (a) Chatterjee,
A. K.; Grubbs, R. H. Angew. Chem., Int. Ed. 2002, 41, 3171. (b)
Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J. Am. Chem.
Soc. 2003, 125, 11360. (c) Connon, S. J.; Blechert, S. Angew. Chem., Int.
Ed. 2003, 42, 1900.
Finally, we conducted another experiment as an extension of
the RCM reaction. Because phenol 1 is also in equilibrium with
ketonic tautomer 14, we speculated that phenol 1 might be formed
from 1,5,7-trien-3-one 15 as well as trienone 3 (eq 3).
(11) Known compound, see: Hamura, T.; Kawano, N.; Tsuji, S.; Matsumoto,
T.; Suzuki, K. Chem. Lett. 2002, 1042.
JA050853X
9
J. AM. CHEM. SOC. VOL. 127, NO. 30, 2005 10471