1,3-Methoxy rearrangement of masked o-benzoquinones: A novel synthesis of p-quinol ethers

Article abstract of DOI:10.1021/ol702136r

(Chemical Equation Presented) p-Quinol ethers are valuable synthons in synthetic organic chemistry. MOBs 1a-1l can be converted to p-quinol ethers 2a-2i in a highly efficient manner via 1,3-methoxy migration catalyzed by Lewis acids. The migration was fou

Full text of DOI:10.1021/ol702136r

ORGANIC
LETTERS
2007
Vol. 9, No. 23
4809-4812
1,3-Methoxy Rearrangement of Masked
o-Benzoquinones: A Novel Synthesis of
p-Quinol Ethers
Ching-Shun Yang and Chun-Chen Liao*
Department of Chemistry, National Tsing Hua UniVersity, Hsinchu, Taiwan 30013
ccliao@mx.nthu.edu.tw
Received August 31, 2007
ABSTRACT
p-Quinol ethers are valuable synthons in synthetic organic chemistry. MOBs 1a−1i can be converted to p-quinol ethers 2a−2i in a highly
efficient manner via 1,3-methoxy migration catalyzed by Lewis acids. The migration was found to be reversible and dependent on the electronic
effect of substituent R3 of MOBs.
Ortho- and paraquinones and their quinol variants are
potential synthons for the syntheses of a myriad of complex
molecular ensembles which in turn are utilized in the
syntheses of biologically active products.1 These valuable
intermediates are commonly encountered in Diels-Alder
reactions1,2 and in the preparation of various useful precursors
including their asymmetric versions.3 For the past few years,
we have been exploiting masked o-benzoquinones (MOBs)
A (Figure 1) for finding new synthetic methodologies based
(1) (a) Liao, C.-C. Synthetic Applications of Masked Benzoquinones.
In Modern Methodology in Organic Synthesis; Sheno, T., Ed.; Kodansha:
Tokyo, 1992; p 409. (b) Quideau, S.; Pouysegu, L. Org. Prep. Process Int.
1999, 31, 617. (c) Singh, V. Acc. Chem. Res. 1999, 32, 324. (d) Liao, C.-
C.; Peddinti, R. K. Acc. Chem. Res. 2002, 35, 856. (e) Takagi, R.; Miyanaga,
W.; Tamura, Y.; Ohkata, K. Chem. Commun. 2002, 2096. (f) Carren˜o, M.
C.; Ribagorda, M.; Somoza, A.; Urbano, A. Angew. Chem., Int. Ed. 2002,
41, 2755. (g) Magdziak, D.; Meek, S. J.; Pettus, T. R. R. Chem. ReV. 2004,
104, 1383.
(2) (a) Danishefsky, S. J.; Mazza, S. J. Org. Chem. 1974, 39, 3610. (b)
Deslongchamps, P.; Belanger, A.; Berney, D. J. F.; Borschberg, H.-J.;
Brousseau, R.; Doutheau, A.; Durand, R.; Katayama, H.; Lapalme, R.;
Leturc, D. M.; Liao, C.-C.; MacLachlan, F. N.; Maffrand, J. P.; Marazza,
F.; Martino, R.; Moreau, C.; Ruest, L.; Saint-Laurent, L.; Saintonge, R.;
Soucy, P. Can. J. Chem. 1990, 68, 127. (b) Genisson, Y.; Tyler, P. C.;
Young, R. N. J. Am. Chem. Soc. 1994, 116, 759. (c) Carren˜o, M. C.;
Gonzalez, M. P.; Fisher, J. Tetrahedron Lett. 1995, 36, 4893.
(3) (a) Ponpipom, M. M.; Yue, B. Z.; Bugianesi, R. L.; Brooker, D. R.;
Chang, M. N.; Shen, T. Y. Tetrahedron Lett. 1986, 27, 309. (b) Fujioka,
H.; Annoura, H.; Murano, K.; Kita, Y.; Tamura, Y. Chem. Pharm. Bull.
1989, 37, 2047. (c) Imbos, R.; Brilman, M. H. G.; Pineschi, M.; Feringa,
B. L. Org. Lett. 1999, 1, 623. (d) Pettus, L. H.; Van De Water, R. W.;
Pettus, T. R. R. Org. Lett. 2001, 3, 905. (e) Mori, K.; Yamaura, S.;
Nishiyama, S. Tetrahedron 2001, 57, 5533.
Figure 1. Cyclohexadienones A and B.
on their Diels-Alder reactions. MOBs are found to be
excellent Diels-Alder partners with several dienophiles;4
their cycloaddition reactions proceed in a regio- and stereo-
selective manner to provide highly functionalized systems
of great synthetic value.5 In our efforts to reduce the reactivity
(4) (a) Chu, C.-S.; Lee, T.-H.; Liao, C.-C. Synlett 1994, 635. (b) Hsu,
P.-Y.; Lee, Y.-C.; Liao, C.-C. Tetrahedron Lett. 1998, 39, 659. (c) Chen,
C.-H.; Rao, P. D.; Liao, C.-C. J. Am. Chem. Soc. 1998, 120, 13254. (d)
Liao, C.-C.; Chu, C.-S.; Lee, T.-H.; Rao, P. D.; Ko, S.; Song, L.-D.; Shiao,
H.-C. J. Org. Chem. 1999, 64, 4102.
(5) (a) Hsu, D.-S.; Rao, P. D.; Liao, C.-C. Chem. Commun. 1998, 1795.
(b) Arjona, O.; Medel, R.; Plumet, J. Tetrahedron Lett. 1999, 40, 8431. (c)
Gao, S.-Y.; Ko, S.; Lin, Y.-L.; Peddinti, R. K.; Liao, C.-C. Tetrahedron
2001, 57, 297. (d) Gao, S.-Y.; Lin, Y.-L.; Rao, P. D.; Liao, C.-C. Synlett
2000, 421.
10.1021/ol702136r CCC: $37.00
© 2007 American Chemical Society
Published on Web 10/20/2007

of some underutilized quinones which are prone toward
dimerization and rearomatization, we were able to discover
new protocols for stabilizing these MOBs.1d In continuation
of our efforts to develop novel methodologies for organic
synthesis, we became interested in Lewis acid catalyzed
transformations of MOBs.
MOBs are structurally similar to cyclohexadienone B, the
only difference being the presence of dialkoxy groups for A
in the place of dialkyl groups for B (Figure 1). However,
many rearrangements of cyclohexadienones B have been
well-studied; for example, [1,2], [1,3],[1,4],[1,5], [3,3], [3,4],
[3,5], and [5,5] rearrangements are observed under acidic
conditions.6
Several Lewis acids bearing chiral ligands are known to
both enhance the rate of Diels-Alder reactions and induce
chirality in the obtained adduct.7 With two possibilities in
the presence of a Lewis acid, namely, Diels-Alder reaction
and rearrangement process, we were curious to test the
selectivity in the reaction pathway for MOB. Recently,
Quideau prepared stable monoketal orthoquinone conve-
niently and found 1,3-acetoxy migration on silica gel via
[3,3] and [3,5] sigmatropic rearrangements.8
complexes such as [Rh(COD)Cl]2 and RhPPh3Cl failed to
give the migration product. It is in the same group of the
periodic table as Rh and so we expected that the 1,3-methoxy
migration of MOB could also be catalyzed by the Ir complex.
Accordingly, cationic Ir(COD)2BF49 was utilized to test this
concept; in fact, the migration product 2a was obtained in
high yield. This interesting transformation of MOB to
p-quinol ether is notable since the latter are molecules of
unrealized potential in organic synthesis.1g This result
inspired us to study in more detail the scope and limitation
of 1,3-methoxy migration of MOBs.
With the use of Rh(COD)2BF4, we investigated the scope
of this procedure using a series of isolable MOBs generated
from the corresponding 2-methoxyphenols by oxidation with
diacetoxyiodobenzene.11 The results of this investigation are
summarized in Table 1. All the rearrangement products were
Table 1. 1,3-Methoxy Migration of MOBs 1a-m to p-Quinol
Ethers 2a-m
Our initial study started with isolable MOB 1a as a diene
and dimethyl acetylene dicarboxylate (DMAD) as a dieno-
phile in the presence of Cu(OTf)2 as a catalyst (Scheme 1).
Scheme 1. An Effective Transformation of MOB 1a to
p-Quinol 2a
MOBa
R1
R2
R3
R4
product/
yield (%)b
2a (80)
2b (82)
2c (60)
2d (64)
2e (68)
2f (65)
1a
1b
1c
1d
1e
1f
1g
1h
1i
H
ketal
H
t-Bu
ketal
Me
H
H
H
H
H
H
H
H
H
H
H
Me
ketal
H
H
H
H
H
Me
n-Pr
i-Pr
t-Bu
Me
i-Pr
Me
Me
Me
H
H
H
H
H
H
H
H
H
Me
Me
H
H
CO2Me
2g (70)
2h (58)
2i (60)
1j
1k
1l
2j (NR)c
2k (NR)c
2l (NR)c
2m (NR)c
TMS
Br
H
H
H
1m
a Stable MOBs synthesized in our lab. b Isolated yields of p-quinol ethers.
c No reaction, starting material was recovered even at reflux temperature.
We expected to obtain a cycloadduct such as 3 or the
migration product 2a, but no characterizable products were
detected following 1H NMR spectroscopy of the crude
reaction mixture. When stronger Lewis acids BF3‚OEt2 and
AlEtCl2 were exploited, a similar result was obtained. We
continued to test other milder Lewis acids Sc(OTf)3, ZnI2,
Pd(OAc)2, Pd(PPh3)4, AuPPh3Cl, and PTSA with MOB and
DMDA, only to observe dimerization product via homo-
Diels-Alder reaction of two 1a monomers. However, when
Rh(COD)2BF4 was used as a catalyst,9,10 we obtained the
p-quinol ether 2a via 1,3-methoxy migration. Neutral Rh
identified by means of 1H NMR, 13C NMR, and mass spectral
analyses.
In a general procedure, after 0.5 h of mixing MOBs 1a-m
in CH2Cl2 with Rh(COD)2BF4, at room temperature, the
MOBs 1a-i reacted to give p-quinol ethers 2a-i with
isolated yields 58-82%. Further analysis of the data in Table
1 reveals that the transformation is strikingly general and
(9) Schenck, T. G.; Downes, J. M.; Milne, C. R. C.; Mackenzie, P. B.;
Boucher, H.; Whelan, J.; Bosnich, B. Inorg. Chem. 1985, 24, 2334.
(10) Evans, P. A. Modern Rhodium-Catalyzed Organic Reactions; Wiley-
VCH: Weinheim, Germany, 2005.
(6) Miller, B. Acc. Chem. Res. 1975, 8, 245.
(11) (a) Yen, C.-F.; Peddinti, R. K.; Liao, C.-C. Org. Lett. 2000, 2, 2909.
(b) Lai, C.-H.; Shen, Y.-L.; Wang, M.-N.; Kameswara Rao, N. S.; Liao,
C.-C. J. Org. Chem. 2002, 67, 6493. (c) Chittimalla, S. K.; Liao, C.-C.
Tetrahedron 2003, 59, 4039.
(7) Liu, D.; Canales, E.; Corey, E. J. J. Am. Chem. Res. 2007, 129, 1498.
(8) Quideau, S.; Looney, M. A.; Pouysegu, L.; Ham, S.; Birney, D. M.
Tetrahedron Lett. 1999, 40, 615.
4810
Org. Lett., Vol. 9, No. 23, 2007

regioselective. MOBs with at least an electron-donating group
(EDG) for R3 such as 1a-h undergo 1,3-methoxy migration,
whereas MOBs with electron-withdrawing groups (EWGs)
such as 1k, 1l, and 1m are insensitive to undergoing migra-
tion. Various reaction temperatures were examined for pro-
viding the migration product in these cases, but no desired
product was obtained, and the starting material was recov-
ered.
Scheme 3. Plausible Mechanism for the Rearrangement of 1a
in Isopropanol Solvent
From the results of 1a-1d, the steric hindrance of R3 has
shown slight influence on the yield of the transformation.
Even when the acid-sensitive ketal group was installed for
MOBs 1b, 1e, and 1h, migration occurred in good yields.
Both R3 and R4 were installed with methyl groups, and the
migration product was generated in good yield. The absence
of a methyl group for R3 as in 1j led to the recovery of
starting material. It may be noted that the energy of 1j is
more stable than 2j by 6.6 kcal/mol from theoretical
calculation (RHF/3-21G*).
The contrasting chemical behavior between electron-
donating and electron-withdrawing MOBs toward 1,3-
methoxy migration suggests the intermediate of the migration
reaction is a carbocationic species which can be stabilized
by the EDG.12 To further justify our assumption, we
determined the reactivity of 1a in isopropanol (IPA)/CH2-
Cl2 (1:1) solvent system and obtained the transformation
products 2a and 2p in trace amounts and the p-quinols 2n
and 2o with a combined isolated yield of 58% (Scheme 2).
The propensity of the reaction to proceed toward 2n can be
attributed to the higher concentration of isopropanol in the
system and the greater interaction of the catalyst with the
less bulky methoxy group, which is easily dislodged from
MOB 5.
Scheme 2. Allylic Rearrangement of 1a in the Presence of
Isopropanol Solvent
The proposed mechanism that 1,3-methoxy rearrangement
of 1a is reversible and competes with the dimerization of
1a can be proved by the following experiments monitored
with 1H NMR spectral method. We mixed 2a with 5 mol %
of Rh(COD)2BF4 in CH2Cl2 at room temperature. Thirty
minutes later, the ratio of 2a and the dimer of 1a was 15:1;
2a was not found from 1H NMR after 2 h. We also examined
2a with 5 mol % of Rh(COD)2BF4 at -20 °C, and only 2a
was recovered after 2 h.
This suggests the reversibility of p-quinol 2a to MOB 1a
and that 1a subsequently transformed to the corresponding
dimer via Diels-Alder reaction of two MOB monomers. If
we assume that 2a and the dimer of 1a are kinetically and
thermodynamically controlled products, respectively (Scheme
4), then lowering the temperature would probably affect the
Intervention of the nucleophilic solvent during the rearrange-
ment process to yield the products 2n-p is reminiscent of a
cationic intermediate. The reaction mechanism is proposed
as shown in Scheme 3.
The rhodium catalyst acting as a Lewis acid interacts with
one of the methoxy groups to generate the oxonium
intermediate 3, which can be quenched with a nucleophilic
solvent isopropanol to furnish the MOB 5 and the resonance
form 3′, which will pick up either nucleophilic isopropanol
molecule to afford p-isopropoxy quinol 2p or methanol to
furnish p-methoxy quinol 2a. The MOB 5 undergoes
demethoxylation catalyzed by the cationic rhodium catalyst
to generate the oxonium species 6; its resonance form 6′
would pickup either the nucleophilic molecule isopropanol
to afford p-quinol 2n or methanol to furnish p-quinol 2o.
Scheme 4. Potential-Energy Diagram of 1a in the Presence of
Lewis Acids
(12) Boga, S. B.; Balasubramanian, K. K. ARKIVOC 2004, 87.
Org. Lett., Vol. 9, No. 23, 2007
4811

o-methoxyphenols 7a, 7d, and 7h, which gave the corre-
sponding MOBs 1a, 1d, and 1h, were exposed to iodoben-
zenediacetate (IBD) and 5 mol % of Rh(COD)2BF4 at room
temperature for 1 h (Table 2). Gratifyingly, we obtained the
migration products 2a, 2d, and 2h, respectively, in moderate
isolated yields.
Table 2. One-Pot Preparation of p-Quinol Ethers
In conclusion, we found out that the selected Lewis acids
successfully transformed MOBs to p-quinol methyl ethers
through 1,3-methoxy migration. A one-pot domino process
(sequential oxidation of o-methoxyphenol followed by the
1,3-methoxy migration) also proved to be efficient for the
p-quinol methyl ether synthesis. The 1,3-migration of MOBs
is not only reversible process but also dependent on the
electronic effect of substituent at the attacking site.
rate of the production of 2a and the dimer of 1a due to the
higher energy barrier of the dimer of 1a. To prove this
assumption, we lowered the temperature of the reaction
mixture of 1a in CH2Cl2 to -20 °C for 1 h in the presence
of the following catalysts: Sc(OTf)3, Eu(OTf)3, Gd(OTf)3,
Nd(OTf)3, and Rh(COD)2BF4. Strikingly, we obtained the
migration product 2a in quantitative yield for all these
catalysts.
Acknowledgment. National Science Council, Taiwan, is
gratefully acknowledged for the financial support. We thank
Dr. S.K. Chittimalla and Dr. N.R. Villarante for helpful
discussions.
1
Supporting Information Available: H NMR spectra of
compounds 2a-2i. This material is available free of charge
via the Internet at http://pubs.acs.org.
Having established an efficient process of producing
p-quinols in a two-step process, we extended the scope
of this process by carrying out the reaction in one pot. The
OL702136R
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Org. Lett., Vol. 9, No. 23, 2007