Efficient synthetic routes to aromatic compounds using ring-closing olefin metathesis followed by dehydration, oxidation, and tautomerization

Article abstract of DOI:10.1039/b705581a

A simple synthetic approach to aromatic compounds using combinations of RCM, dehydration, oxidation, and tautomerization is described. The Royal Society of Chemistry.

Full text of DOI:10.1039/b705581a

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Efficient synthetic routes to aromatic compounds using ring-closing
olefin metathesis followed by dehydration, oxidation, and
tautomerization{
Kazuhiro Yoshida,* Takeharu Toyoshima and Tsuneo Imamoto*
Received (in Cambridge, UK) 12th April 2007, Accepted 20th June 2007
First published as an Advance Article on the web 5th July 2007
DOI: 10.1039/b705581a
Our strategy is outlined in Scheme 1 and has the following three
core objectives: 1) use of highly reliable transformations and easily
accessible reagents in all steps; 2) keeping back the problematic
formation of the internal cis double bond in the last steps (namely,
after cyclization); and 3) divergent output (benzene, phenol, and
resorcinol) from common precursors. The synthetic route would
start from the allylation of readily available aldol product 5 with
various allylic metal reagents (M = Mg, B, Sn, etc.) to afford 1,7-
diene-3,5-diol 6, which would be the fountainhead for benzene,
phenol, and resorcinol derivatives. The formation of benzene
derivatives 4 would be achieved by the RCM/dehydration/
dehydration of 6 via 4-cyclohexene-1,3-diol 7 (route 6–7–4).
After oxidation of 6 at the allylic alcohol position, the RCM/
dehydration/tautomerization of 5-hydroxy-1,7-octadien-3-one 8
would produce phenol derivatives 2 via 5-hydroxy-2-cyclohexe-
none 9 (route 6–8–9–2). The RCM/tautomerization/tautomeriza-
tion of 1,7-octadiene-3,5-dione 10, which would be prepared by the
oxidation of 6, would result in the formation of resorcinol
derivatives 11 (route 6–10–11). It should be mentioned that there
are other promising routes including 6–7–9–2 and 6–8–9–11.
Among the above-mentioned routes, we chose to investigate
route 6–8–9–2 first, and the results are shown in Table 1.7,8 In all
A simple synthetic approach to aromatic compounds using
combinations of RCM, dehydration, oxidation, and tauto-
merization is described.
Because of the important roles played by substituted aromatic
compounds in organic chemistry, the discovery of new methods
for their preparation continues to be an active area of research.
From a large number of reactions available, the most commonly
used for substituted aromatic compounds is electrophilic aromatic
substitution.1 However, despite advances of the reaction, its
potential weak point in terms of difficulty in controlling the
regioselectivity of substitution has limited its use with some
substitution patterns and substituents. Alternatively, a significant
amount of work has been devoted to the stepwise construction of
aromatic rings from linear components because it enables perfect
regioselective access to the desired aromatic compounds.2 Most
recently, the ring-closing olefin metathesis (RCM), which is one of
the most powerful methods to form carbon–carbon double bonds
of cyclic compounds,3 has begun to apply this strategy.4–6
Along these lines, we have also reported that phenol derivatives
25m and benzene derivatives 45h can be obtained from tandem
RCM/tautomerization of 1,4,7-trien-3-ones 1 and RCM/dehydra-
tion of 1,4,7-trien-3-ols 3, respectively (eqn (1) and (2)). However,
precursors 1 and 3 could not be readily prepared, especially with
regard to the internal cis double bond (geometrically). Motivated
by this problem, we strived to search for more efficient and general
synthetic approaches. Herein we report new efficient and general
synthetic methods for phenol, benzene, and resorcinol derivatives,
in which the stereoselective construction of the internal double
bond of the precursors is no longer a problem.
ð1Þ
ð2Þ
Department of Chemistry, Graduate School of Science, Chiba
University, Yayoi-cho, Inage-ku, Chiba 263-8522, Japan.
E-mail: kyoshida@faculty.chiba-u.jp; imamoto@faculty.chiba-u.jp;
Fax: +81 43 290 2791; Tel: +81 43 290 2790
{ Electronic supplementary information (ESI) available: experimental
procedures and compound characterization data. See DOI: 10.1039/
b705581a
Scheme 1
3774 | Chem. Commun., 2007, 3774–3776
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Table 1 Synthesis of phenol derivatives 2 by RCM/dehydration/tautomerization
RCMa
D/Tb
Yieldc (%) Method Yieldc (%)
Entry Substrate R1
R2
R3
R4
R5
Solvent T/uC
1d
2
3
4
5
6
7
8
9
8a
8b
8c
8d
8e
8f
8g
8h
8i
H
Me Et
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Me
CH2Cl2 rt
84 (9a)
89 (9b)
94 (9c)
.99 (9d)
.99 (9e)
99 (9f)
A
A
A
A
A
B
A
A
A
B
85 (2a)
91 (2b)
Me
Me
Me
Me
H
H
H
H
CH2Cl2 40 uC
CH2Cl2 40 uC
CH2Cl2 40 uC
CH2Cl2 40 uC
CH2Cl2 40 uC
CH2Cl2 40 uC
H
4-ClC6H4
.99 (2c)
.99 (2d)
.99 (2e)
88 (2f)e
.99 (2g)
97 (2h)
–(CH2)4–
t
CH2OSiMe2 Bu
H
H
Me
Ph
H
H
H
H
81(9g)f
Me Ph
toluene
80 uC
80 uC
.99 (9h)
84 (9i)
H
H
H
CH2OBn toluene
Me toluene
90 (2i)
.99 (2j)e
10
a
8j
CH2C(Me)LCH2
100 uC 87 (9j)
b
Ring-closing olefin metathesis was carried out with 8 and ruthenium catalyst (12, 7.5 mol%) for 2 h. Method A: p-toluenesulfonic acid
c
(10 mol%), benzene, 70 uC, overnight. Method B: t-BuOK (4.4 eq.), MsCl (3.2 eq.), CH2Cl2, rt, 2.5 h. Isolated yield by silica gel
d
chromatography. An one pot procedure using 12 (7.5 mol%) and p-toluenesulfonic acid (10 mol%) at the same time in toluene at 70 uC gave
a mixture of 83% of 9a and 17% of 2a. The corresponding mesylated phenol was obtained. When the amount of catalyst 12 was decreased
to 2.5 mol%, the isolated yield of 9g was decreased to 50%.
e
f
cases, as expected, the RCM of 8 with Grubbs’ second-generation
catalyst 129 proceeded cleanly to afford desired cyclized product 9
as the only identifiable material. Although increasing the steric
bulk of the substituents tends to decrease the reaction rates as
usual, increasing the temperature led to completion of the reaction
in 2 h. For the next dehydration/tautomerization step, we
employed two conditions. Most of the isolated 9 (9a–9e, 9g–9i)
were converted into the corresponding phenols 2 by treatment of
Scheme 3 (a) 12 (7.5 mol%), toluene, 80 uC, 2 h; (b) ClCOCOCl,
their benzene solution with a catalytic amount of p-toluenesulfonic
DMSO, Et3N, CH2Cl2, 278 uC, 1.5 h.
acid. In the case of 9f that has an acid-sensitive silyl ether,
basic conditions (mesylation of the hydroxyl group with t-BuOK,
In summary, we have developed new efficient synthetic routes
followed by elimination) were employed. Similarly, the mesylation/
to aromatic compounds, which hold great promise for broad
elimination process was also effective for 9j that was subjected
applicability. The advantages are that no inseparable regioisomers
to isomerization of the carbon–carbon double bond from
are produced, and that all the mild transformations employed,
terminal to internal at the R3 position in the presence of
highlighted by RCM, may enable introduction of a wide variety of
p-toluenesulfonic acid.10
substituents on aromatic rings. We are currently studying the other
Our attention was next turned to the formation of benzene
routes indicated in Scheme 1 and the routes for the synthesis of
derivatives 4 (route 6–7–4) and resorcinol derivatives 11 (route 6–
catechols and hydroquinones with similar methodology.
8–9–11). Preliminary experiments revealed that both routes show
We appreciate the financial support from the Sumitomo
promise. As shown in Scheme 2, the double dehydration of 7d,
foundation and from a Grant-in-Aid for Scientific Research, the
which was prepared by RCM of 6d, with p-toluenesulfonic acid
Ministry of Education, Culture, Sports, Science and Technology,
gave corresponding benzene derivative 4d in quantitative yield.
Japan.
Moreover, Swern oxidation of 9i followed by automatic double
tautomerization gave 11i in good yield (Scheme 3).11
Notes and references
1 For a comprehensive review, see: Modern Arene Chemistry, ed.
D. Astruc, Wiley-VCH, Weinheim, 2002.
2 For example, see: (a) R. L. Danheiser and S. K. Gee, J. Org. Chem.,
1984, 49, 1672; (b) P. Turnbull and H. W. Moore, J. Org. Chem., 1995,
60, 644; (c) K. H. Do¨tz and P. Tomuschat, Chem. Soc. Rev., 1999, 28,
187; (d) A. R. Katritzky, J. Li and L. Xie, Tetrahedron, 1999, 55, 8263;
(e) S. Saito and Y. Yamamoto, Chem. Rev., 2000, 100, 2901; (f) S. Serra,
C. Fuganti and A. Moro, J. Org. Chem., 2001, 66, 7883; (g)
Scheme 2 (a) 12 (7.5 mol%), CH2Cl2, 40 uC, 2 h; (b) p-toluenesulfonic
acid (10 mol%), benzene, overnight, 70 uC.
T. Takahashi, M. Ishikawa and S. Huo, J. Am. Chem. Soc., 2002,
124, 388; (h) X. Bi, D. Dong, Q. Liu, W. Pan, L. Zhao and B. Li, J. Am.
This journal is ß The Royal Society of Chemistry 2007
Chem. Commun., 2007, 3774–3776 | 3775

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Chem. Soc., 2005, 127, 4578; (i) Y. Yamamoto, J.-I. Ishii, H. Nishiyama
and K. Itoh, J. Am. Chem. Soc., 2005, 127, 9625.
J. Zhao, Synlett, 2007, 583. For reports using RCM/tautomerization
protocol, see :(l) W. A. L. van Otterlo, E. L. Ngidi, E. M. Coyanis and
C. B. de Koning, Tetrahedron Lett., 2003, 44, 311; (m) K. Yoshida and
T. Imamoto, J. Am. Chem. Soc., 2005, 127, 10470.
6 For selected recent reports on the synthesis of heterocyclic aromatic
compounds using RCM, see: (a) M. Arisawa, A. Nishida and
M. Nakagawa, J. Organomet. Chem., 2006, 691, 5109; (b) T. J.
Donohoe, L. P. Fishlock, A. R. Lacy and P. A. Procopiou, Org. Lett.,
2007, 9, 953.
7 The yield ranges to the starting materials were 92–49% (5 to 6) and
86–53% (6 to 8). See Electronic Supplementary Information{ for
experimental details.
8 The compounds appearing in this paper are fundamentally stable and
showed no deterioration after storage on a bench or in a refrigerator for
several months.
9 (a) M. Scholl, S. Ding, C. W. Lee and R. H. Grubbs, Org. Lett., 1999, 1,
953; (b) T. M. Trnka, J. P. Morgan, M. S. Sanford, T. E. Wilhelm,
M. Scholl, T.-L. Choi, S. Ding, M. W. Day and R. H. Grubbs, J. Am.
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10 The mesylated phenols were obtained under the conditions in both cases
of 9f and 9j.
11 Sulikowski and co-workers reported a hydroquinone formation by
oxidation/tautomerization/tautomerization of an RCM product in
their cycloenedione synthesis, see: W.-D. L. Kwangho, K. Kim and
G. A. Sulikowski, Org. Lett., 2005, 7, 1687.
3 For a comprehensive review, see: (a) Handbook of Metathesis, ed. R. H.
Grubbs, Wiley-VCH, Weinheim, 2003. For reviews, see: (b) R. H.
Grubbs and S. Chang, Tetrahedron, 1998, 54, 4413; (c) A. Fu¨rstner,
Angew. Chem., 2000, 112, 3140, (Angew. Chem., Int. Ed., 2000, 39, 3012);
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4 For a review, see: T. J. Donohoe, A. J. Orr and M. Bingham, Angew.
Chem., 2006, 118, 2730, (Angew. Chem., Int. Ed., 2006, 45, 2664).
5 For reports on the direct synthesis of carbocyclic aromatic compounds
using RCM, see: (a) A. Iuliano, P. Piccioli and D. Fabbri, Org. Lett.,
2004, 6, 3711; (b) E. R. Walker, S. Y. Leung and A. G. M. Barrett,
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C. J. Parkinson, W. A. L. Van Otterlo and C. B. De Koning, J. Org.
Chem., 2005, 70, 10474. For reports using RCM/elimination protocol,
see: (e) P. Evans, R. Grigg, M. I. Ramzan, V. Sridharan and M. York,
Tetrahedron Lett., 1999, 40, 3021; (f) K. S. Huang and E. C. Wang,
Tetrahedron Lett., 2001, 42, 6155; (g) Y. Chen, H. V. R. Dias and
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3776 | Chem. Commun., 2007, 3774–3776
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