An efficient route to benzene and phenol derivatives via ring-closing olefin metathesis

Article abstract of DOI:10.1055/s-2007-982548

Without the formation of inseparable regioisomers, various substituted phenol derivatives 2 and benzene derivatives 4 were prepared through RCM-tautomerization and RCM-dehydration protocols. A new synthetic route to precursors 1 and 3 enabled efficient access to these aromatic compounds. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-982548

LETTER
1561
An Efficient Route to Benzene and Phenol Derivatives via Ring-Closing Olefin
Metathesis
S
ynthesis of Pheno
a
l
D
erivativ
z
es and
B
en
u
z
ene
D
erivat
hives iro Yoshida,* Shingo Horiuchi, Noriyuki Iwadate, Fumihiro Kawagoe, Tsuneo Imamoto*
Department of Chemistry, Faculty of Science, Chiba University, Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
Fax +81(43)2902791; E-mail: kyoshida@faculty.chiba-u.jp; E-mail: imamoto@faculty.chiba-u.jp
Received 31 January 2007
For the synthesis of precursors 1 and 3, we employed the
Abstract: Without the formation of inseparable regioisomers,
various substituted phenol derivatives 2 and benzene derivatives 4
were prepared through RCM–tautomerization and RCM–dehydra-
tion protocols. A new synthetic route to precursors 1 and 3 enabled
efficient access to these aromatic compounds.
upper retrosynthetic route in Scheme 1. In this route,
1,4,7-trien-3-ols 3, which are the precursors not only of
benzene derivatives 4 but also of 1, were constructed by
the coupling reaction between a,b-unsaturated aldehydes
and 5. Bromodienes 5 were obtained via the palladium-
catalyzed cis-selective bromoallylation3 of alkynes with
allyl bromides 6. Although this route provided a variety of
precursors 1 and 3, there was an important limitation. In
the palladium-catalyzed bromoallylation step, available
alkynes were limited to terminal or symmetrical internal
alkynes. The use of unsymmetrical internal alkynes most-
ly resulted in a mixture of inseparable regioisomers of 5.
Key words: annulations, metathesis, ring closure, ruthenium,
tautomerism
Ruthenium-catalyzed ring-closing olefin metathesis
(RCM) has emerged as a valuable tool for the preparation
of substituted aromatic compounds in recent years.1,2 We
have also been interested in the development of synthetic
methods for carbocyclic aromatic compounds using
RCM.2g,j In our first report, we showed that derivatives of
phenol (2), which are one of the most important classes of
aromatic compounds, can be prepared from the corre-
sponding 1,4,7-trien-3-ones 1 using the RCM–tautomer-
ization protocol in which the ketonic tautomers of the
phenols are advantageously generated (Equation 1).2j In
this connection, we recently extended the method to the
RCM–dehydration protocol to obtain derivatives of ben-
zene (4) by use of the corresponding 1,4,7-trien-3-ols 3 as
the starting material (Equation 2).2g The most important
benefit offered by these methods is that aromatic com-
pounds having various structures can be produced without
the formation of inseparable regioisomers.
Br
CHO
Br
O
OH
[O]
6
8
5
[O]
CHO
1
3
OH
X
7
Scheme 1
Herein, we report our continuing study of the synthesis of
phenol derivatives 2 and benzene derivatives 4 using
RCM, in which precursors 1 and 3 were prepared via the
lower retrosynthetic route in Scheme 1. The new route,
which extends the scope of resulting aromatic com-
pounds, includes the coupling reaction between 2,5-hexa-
dienals 7 and vinyl halides for the preparation of 3, and the
oxidation of 2,5-hexadienols 8 into 7.
O
O
OH
RCM
tautomerization
1
2
Equation 1
The route to 1 and 3 performed in this study is exemplified
by the synthesis of 1e and 3e in Scheme 2. Starting mate-
rial 8e was prepared by stereoselective carbometalation of
propargyl alcohol followed by allylation4 developed by
Fallis and co-workers. After the oxidation of 8e with
Dess–Martin periodinane, the Nozaki–Hiyama–Kishi
reaction5 of resulting 7e with 2-iodoallyl acetate gave
1,4,7-trien-3-ol 3e. Treatment of 3e with MnO2 gave cor-
responding 1,4,7-trien-3-one 1e. A series of 1 and 3 were
likewise prepared in this way6,7 and were subjected to the
RCM reaction.
OH
OH
RCM
dehydration
3
4
Equation 2
SYNLETT 2007, No. 10, pp 1561–1564
Advanced online publication: 07.06.2007
DOI: 10.1055/s-2007-982548; Art ID: U00807ST
© Georg Thieme Verlag Stuttgart · New York
1
8
.0
6
.2
0
0
7
Table 1 shows the results of the synthesis of benzene
derivatives 4.8 In all cases, the RCM–dehydration of 3
proceeded well and corresponding benzene derivatives 4

1562
K. Yoshida et al.
LETTER
conditions using Grubbs’ first-generation catalyst 99 at
room temperature sufficed for the full conversion (entries
1 and 2). In contrast, the reaction of 3c,d that have a
methyl group at R1 or R8 position required more active
Grubbs’ second-generation catalyst 1010 and higher tem-
perature (40 °C), even though a disubstituted double bond
was formed as a result (entries 3 and 4). The formation of
a trisubstituted double bond in the RCM also required the
latter conditions (entries 5 and 6). A further increase in
temperature (80–100 °C) was required for the reactions of
3g,h in which tetrasubstituted double bonds were formed
(entries 7 and 8).
OH
Me
Me
Ph
a
b
OH
c
O
Mg
Ph
Ph
8e
OAc
OAc
OH
O
Me
Me
Ph
M
e
CHO
d
e
Ph
Ph
3e
7e
1e
Next, the RCM–tautomerization protocol for the synthesis
of phenol derivatives 2 from 1 was examined, and the re-
sults are summarized in Table 2.11 In agreement with the
known propensity of the electron-deficient dienic system
to be poorly reactive in RCM reactions,12 the reactivities
of 1,4,7-trien-3-ones 1 were lower than those of 1,4,7-
trien-3-ols 3. However, the reactions of 3 proceeded
smoothly to give 2 in excellent yields by increasing
temperature in the range of 20 °C to 40 °C based on the
temperature of the reactions of the corresponding 3
(Table 1 vs. Table 2).
Scheme 2 Reagents and conditions: (a) MeMgCl (3.2 equiv), THF–
toluene, reflux, 18 h; (b) allyl iodide (3.6 equiv), reflux, 24 h, 79%;
(c) Dess–Martin periodinane (2.0 equiv), CH2Cl2, r.t., 1 h, 96%; (d) 2-
iodoallyl acetate (2.5 equiv), CrCl2 (3.5 equiv), NiCl2 (0.35 mol%),
DMF, r.t., overnight, 63%; (e) MnO2 (30 equiv), CH2Cl2, r.t., 24 h,
70%.
were obtained in excellent yields. The rate of the RCM
reaction was highly dependent on the number of substitu-
ents and their steric hindrance at the reacting double
bonds. For the formation of a disubstituted double bond in
the RCM reactions that gave benzene derivatives 4a,b, the
Table 1 Synthesis of Benzene Derivatives 4 by Ruthenium-Catalyzed RCM–Dehydrationa
R3 OH
R3
N
R3 OH
N
R4
R2
R1
PCy3
Cl
R4
R5
R2
R7
R4
R5
R2
R7
9 or 10 (7.5 mol%)
Cl
R5
R6
Ru
Ru
– H2O
solvent, temp, 2 h
Ph
Ph
Cl
Cl
R8
R6
R6
PCy3
PCy3
R7
3
4
9
10
Entry
Sub-
strate
R1
R2
R3
H
R4
R5
R6
R7
R8
Product Cat.
Temp
Yield
(%)b
1c
3a
H
H
Ph
H
Me
H
H
H
4a
4b
4c
4d
4e
4f
9
9
r.t.
>99
98
98
97
87
94
97
90
2d
3b
3c
H
H
Me
H
C2H4OTIPS
H
H
H
r.t.
3c
Me
H
H
i-Pr
Me
Me
Me
H
4-FC6H4
H
H
H
10
10
10
10
10
10
40 °C
40 °C
40 °C
40 °C
80 °C
100 °C
4c,e
5d
3d
3e
H
H
Ph
Me
H
H
Me
H
H
CH2OAc
Xf
H
Ph
H
6d
3f
H
H
Ph
H
H
H
7d,g
8d,g
3g
H
Me
H
C2H4OTIPS
Me
H
Me
Me
H
4g
4h
3h
H
CH2OAc
H
Ph
H
H
a RCM was carried out with 3 and ruthenium catalyst (9 or 10, 7.5 mol%) in CH2Cl2 for 2 h.
b Isolated yield.
c For the dehydration, the reaction mixture after RCM was treated with PTSA (10 mol%) and stirred for 1 h at r.t.
d For the dehydration, the reaction mixture after RCM was treated with silica gel (SiO2, excess) and stirred for 1 h at r.t.
e When the amount of catalyst 10 was decreased to 5.0 mol% or 2.5 mol%, the isolated yield of 4d was decreased to 94% and 80%, respectively.
f X =
N
g Reaction was carried out in toluene.
Synlett 2007, No. 10, 1561–1564 © Thieme Stuttgart · New York

LETTER
Synthesis of Phenol Derivatives and Benzene Derivatives
1563
Table 2 Synthesis of Phenol Derivatives 2 by Ruthenium-Catalyzed RCM–Tautomerizationa
O
N
O
OH
N
R3
R2
R1
R3
R4
R2
R6
R3
R4
R2
R6
10 (7.5 mol%)
Cl
R4
R5
Ru
toluene, temp, 2 h
Ph
Cl
R7
R5
R5
PCy3
R6
1
2
10
Entry
Substrate R1
R2
H
R3
R4
R5
H
R6
R7
H
Product
Temp
Yield (%)b
1
2
3
4
5
1c
1e
1f
1g
1i
Me
i-Pr
4-FC6H4
H
2c
2e
2f
2g
2i
80 °C
80 °C
95
95
97
91
91
H
H
H
H
CH2OAc Me
Ph
H
H
H
Xc
Me
H
Ph
H
H
H
80 °C
Me
Me
C2H4OTIPS
Ph
H
Me
H
H
100 °C
100 °C
Me
Me
Me
a Reaction was carried out with 1 and ruthenium catalyst (10, 7.5 mol%) in toluene for 2 h.
b Isolated yield.
c X =
N
Ngidi, E. L.; Coyanis, E. M.; de Koning, C. B. Tetrahedron
Lett. 2003, 44, 311. (j) Yoshida, K.; Imamoto, T. J. Am.
Chem. Soc. 2005, 127, 10470.
In summary, we have established an efficient synthetic
route to carbocyclic aromatic compounds using RCM.
Starting with readily available 2,5-hexadienols 8, a vari-
ety of benzene derivatives 4 and phenol derivatives 2 were
successfully synthesized. Most of the benzene derivatives
and phenol derivatives prepared here cannot be easily ob-
tained by our previous synthetic route. Further develop-
ments will be reported in due course.
(3) (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) Bäckvall, 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.
(4) Tessier, P. E.; Penwell, A. J.; Souza, F. E. S.; Fallis, A. G.
Org. Lett. 2003, 5, 2989.
Acknowledgment
(5) Taylor, R. E.; Ciavarri, J. P. Org. Lett. 1999, 1, 467.
(6) The yield ranges were >99–62% (8 to 7), 76–61% (7 to 3),
85–32% (3 to 1). For the preparation of 3b, the reaction of
(E)-4-[2-(triisopropylsiloxy)ethyl]-3,6-heptadien-2-one
which was easily prepared from 7b, with C2H3MgCl/CeCl3
was performed.
We appreciate the financial support from the Sumitomo foundation
and from a Grant-in-Aid for Scientific Research, the Ministry of
Education, Culture, Sports, Science and Technology, Japan.
(7) The stereoselective hydroalumination of propargyl alcohol
followed by allylation developed by Langille and Jamison
was employed only for the synthesis of 8b and 8g, see:
Langille, N. F.; Jamison, T. F. Org. Lett. 2006, 8, 3761.
(8) Typical Experimental Procedure for RCM–Dehydration
– Synthesis of 4-Acetoxymethyl-2-methylbiphenyl (4e)
To a solution of 1,4,7-trien-3-ol 3e (43.0 mg, 0.150 mmol) in
CH2Cl2 (15 mL) was added 7.5 mol% of catalyst 10 (9.3 mg,
0.011 mmol) in one portion under nitrogen. After stirring for
2 h at 40 °C, the reaction mixture was treated with silica
gel(excess) and stirred for 1 h at r.t. The mixture was passed
through Celite® and the filtrate was concentrated under
reduced pressure. Purification by PTLC on silica gel
(hexane–EtOAc, 5:1) gave 4e (31.5 mg, 0.131 mmol, 87%).
1H NMR (CDCl3): d = 2.12 (s, 3 H), 2.29 (s, 3 H), 5.12 (s, 2
H), 7.22–7.36 (m, 6 H), 7.41 (t, J = 7.7 Hz, 2 H). 13C NMR
(CDCl3): d = 20.42, 21.06, 66.19, 125.74, 126.91, 128.10,
129.09, 130.05, 130.30, 134.77, 135.72, 141.42, 141.98,
170.95. HRMS–FAB: m/z calcd for C16H16O2 [M+]:
240.1150; found: 240.1152.
References and Notes
(1) For a review, see: Donohoe, T. J.; Orr, A. J.; Bingham, M.
Angew. Chem. Int. Ed. 2006, 45, 2664.
(2) For reports on the direct synthesis of carbocyclic aromatic
compounds using RCM, see: (a) Iuliano, A.; Piccioli, P.;
Fabbri, D. Org. Lett. 2004, 6, 3711. (b) Walker, E. R.;
Leung, S. Y.; Barrett, A. G. M. Tetrahedron Lett. 2005, 46,
6537. (c) Pelly, S. C.; Parkinson, C. J.; Van Otterlo, W. A.
L.; De Koning, C. B. J. Org. Chem. 2005, 70, 10474. For
reports on the RCM–elimination protocol, see: (d) Evans,
P.; Grigg, R.; Ramzan, M. I.; Sridharan, V.; York, M.
Tetrahedron Lett. 1999, 40, 3021. (e) Huang, K. S.; Wang,
E. C. Tetrahedron Lett. 2001, 42, 6155. (f) Chen, Y.; Dias,
H. V. R.; Lovely, C. J. Tetrahedron Lett. 2003, 44, 1379.
(g) Yoshida, K.; Kawagoe, F.; Iwadate, N.; Takahashi, H.;
Imamoto, T. Chem. Asian J. 2006, 1, 611. For a report on
the RCM–oxidation protocol, see: (h) Kotha, S.; Mandal, K.
Tetrahedron Lett. 2004, 45, 2585. For reports on the RCM–
tautomerization protocol, see: (i) van Otterlo, W. A. L.;
Synlett 2007, No. 10, 1561–1564 © Thieme Stuttgart · New York

1564
K. Yoshida et al.
LETTER
(hexane–EtOAc, 4:1) to give 2e (36.7 mg, 0.143 mmol,
(9) (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.
(10) (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.
(11) Typical Experimental Procedure for RCM–
Tautomerization – Synthesis of 2-Acetoxymethyl-6-
methyl-5-phenylphenol (2e)
95%). 1H NMR (CDCl3): d = 2.13 (s, 3 H), 2.17 (s, 3 H), 5.16
(s, 2 H), 6.82 (d, J = 7.9 Hz, 1 H), 7.15 (d, J = 7.9 Hz, 1 H),
7.27–7.30 (m, 2 H), 7.33 (tt, J = 7.4, 1.2 Hz, 1 H), 7.40 (t,
J = 7.7 Hz, 2 H), 8.01 (s, 1 H). 13C NMR (CDCl3): d = 13.62,
20.95, 63.85, 119.89, 121.78, 124.55, 126.92, 128.03,
128.96, 129.13, 141.53, 144.98, 154.01, 173.97. HRMS–
FAB: m/z calcd for C16H16O3 [M+]: 256.1099; found:
256.1095.
(12) (a) Love, J. A.; Morgan, J. P.; Trnka, T. M.; Grubbs, R. H.
Angew. Chem. Int. Ed. 2002, 41, 4035. (b) Chatterjee, A.
K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J. Am. Chem.
Soc. 2003, 125, 11360. (c) 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.
A solution of 1,4,7-trien-3-one 1e (42.6 mg, 0.150 mmol) in
CH2Cl2 (15 mL) was treated with 7.5 mol% of catalyst 10
(9.3 mg, 0.011 mmol) in one portion under nitrogen and
stirred for 2 h at 80 °C. The mixture was concentrated under
reduced pressure and purified by PTLC on silica gel
Synlett 2007, No. 10, 1561–1564 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.