Generation of ortho-quinone methides by p-TsOH on silica and their hetero-Diels-Alder reactions with styrenes

Article abstract of DOI:10.1021/jo900504y

(Chemical Equation Presented) 2-Arylchromans were readily prepared from the hetero-Diels-Alder reactions of styrenes with the ortho-quinone methides (o-QMs) which, in turn, were generated by treating the MOM-protected benzylacetate derivatives with p-TsOH immobilized on silica (PTS-Si) in toluene under mild conditions (0°C to rt). The corresponding chromans were obtained in moderate to excellent yields (42-97%) and in moderate to excellent diastereoselectivity (up to >99:1).

Full text of DOI:10.1021/jo900504y

Generation of ortho-Quinone Methides by
p-TsOH on Silica and Their Hetero-Diels-Alder
Reactions with Styrenes
Paratchata Batsomboon,† Wong Phakhodee,‡
Somsak Ruchirawat,†,‡,§ and Poonsakdi Ploypradith*,†,‡
Laboratory of Medicinal Chemistry, Chulabhorn Research
Institute, Program in Chemical Biology, Chulabhorn
Graduate Institute, VipaVadee-Rangsit Highway,
Bangkok, Thailand 10210, and Program on Research and
DeVelopment of Synthetic Drugs, Institute of Science and
Technology for Research and DeVelopment, Mahidol
UniVersity, Salaya Campus, Nakhon Pathom, Thailand
poonsakdi@cri.or.th
FIGURE 1. Eriodictyol (1), hesperetin (2), selective ERꢀ agonists
(3-9), and sideroxylonal (10).
ReceiVed March 6, 2009
anxiolytic, and myorelaxant properties.1 Eriodictyol (1) and
hesperitin (2) are antioxidant 2-arylchromanone natural products
(Figure 1). In addition, some synthetic 2-arylchromans (3-9)
have been developed as selective estrogen receptor ꢀ (ERꢀ)
agonists (SERBAs).2,3 However, some of the steps in these
synthetic routes were low-yielding, and the overall processes
involved many chemical steps. Moreover, synthesis of com-
pounds with substituents at the 4-position, such as sideroxylonal
A (10), involved the hetero-Diels-Alder reaction of the ortho-
quinone methide (o-QM).4
The hetero-Diels-Alder reactions have been employed in a
number of syntheses to construct the heteroatom-containing ring
systems.5 Reactions between the o-QMs as the heterodienes and
the properly activated olefins as the dienophiles furnish the
benzopyran as well as the spiroketal frameworks.6 Among the
most commonly used procedures to generate the highly reactive
o-QMs are thermal and base initiations.7 These procedures
2-Arylchromans were readily prepared from the hetero-
Diels-Alder reactions of styrenes with the ortho-quinone
methides (o-QMs) which, in turn, were generated by treating
the MOM-protected benzylacetate derivatives with p-TsOH
immobilized on silica (PTS-Si) in toluene under mild
conditions (0 °C to rt). The corresponding chromans were
obtained in moderate to excellent yields (42-97%) and in
moderate to excellent diastereoselectivity (up to >99:1).
(2) (a) Ullrich, J. W.; Miller, C. P. Expert Opin. Ther. Pat. 2006, 16, 559–
572. (b) Wallace, O. B.; Richardson, T. I.; Dodge, J. A. Curr. Top. Med. Chem.
2003, 3, 1663–1680. (c) Miller, C. P. Curr. Pharm. Des. 2002, 8, 2089–2111.
(3) (a) Norman, B. H.; Dodge, J. A.; Richardson, T. I.; Borromeo, T. S.;
Lugar, C. W.; Jones, S. A.; Chen, K.; Wang, Y.; Durst, G. L.; Barr, R. J.;
Montrose-Rafizadeh, C.; Osborne, H. E.; Amos, R. M.; Guo, S.; Boodhoo, A.;
Krishnan, V. J. Med. Chem. 2006, 49, 6155–6157. (b) Richardson, T. I.; Norman,
B. H.; Lugar, C. W.; Jones, S. A.; Wang, Y.; Durbin, J. D.; Krishnan, V.; Dodge,
J. A. Bioorg. Med. Chem. Lett. 2007, 17, 3570–3574. (c) Richardson, T. I.; Dodge,
J. A.; Durst, G. L.; Pfeifer, L. A.; Shah, J.; Wang, Y.; Durbin, J. D.; Krishnan,
V.; Norman, B. H. Bioorg. Med. Chem. Lett. 2007, 17, 4824–4828. (d) Norman,
B. H.; Richardson, T. I.; Dodge, J. A.; Pfeifer, L. A.; Durst, G. L.; Wang, Y.;
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The chroman, or the benzopyran, can be found as the core
structure in a number of natural products such as those in the
flavonoid families, which have been shown to exhibit antioxi-
dant, antiallergic, anti-inflammatory, antimicrobial, anticancer,
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1928.
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A.; Yamamoto, T.; Taira, M.; Arishige, T.; Konishi, R.; Hamabata, M.;
Shirahama, M.; Hiramatsu, T.; Kuyama, K.; Ohira, S. Tetrahedron Lett. 2008,
49, 2558–2561.
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A. V. W.; Pritchard, G. J. Org. Lett. 2002, 4, 3009–3011. (c) Zhou, G.; Zhu, J.;
Xie, Z.; Li, Y. Org. Lett. 2008, 10, 721–724. (d) Marsini, M. A.; Huang, Y.;
Lindsey, C. C.; Wu, K.-L.; Pettus, T. R. R. Org. Lett. 2008, 10, 1477–1480. (e)
El Kaim, L.; Grimaud, L.; Oble, J. Org. Biomol. Chem. 2006, 4, 3410–3413. (f)
Rosenau, T.; Netscher, T.; Ebner, G.; Kosma, P. Synlett 2005, 243–246.
† Chulabhorn Graduate Institute.
‡ Chulabhorn Research Institute.
§ Mahidol University.
(1) (a) Zaloni, P.; Avallone, R.; Baraldi, M. Fitoterapia 2000, 71, S117–
S123. (b) Welton, A. F.; Tobias, L. D.; Fiedler-Nagy, C.; Anderson, W.; Hope,
W.; Meyers, K.; Coffey, J. W. In Plant FlaVonoids in Biology and Medicine;
Cody, V., Middleton, E., Jr., Harborne, J. B., Eds.; Alan R. Liss Inc.: New York,
1986; pp 1-592. (c) Hirano, T.; Oka, K.; Akiba, M. Res. Commun. Chem. Pathol.
Pharmacol. 1989, 64, 69–78. (d) Cassady, J. M.; Baird, W. H.; Chang, C.-J. J.
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10.1021/jo900504y CCC: $40.75
Published on Web 04/22/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 4009–4012 4009

SCHEME 1. General Structure for the o-QM Precursor
SCHEME 2. Synthesis of the o-QM Precursors
provided the products in moderate to excellent yields with good
to excellent stereoselectivity. In contrast to the thermal and base
initiation procedures, only a limited number of accounts have
reported the use of acid to generate the o-QMs, mainly due to
the low compatibility of acidic conditions with the dienophiles,
as well as the low stereoselectivity in the resulting products
due to the greater ionic character of the reaction conditions.8
In recent years, our research group has investigated and
reported the utility of various solid-supported reagents in total
synthesis as well as in developing some synthetic methods for
selective deprotection of aromatic ethers using solid-supported
acids.9 Herein, we wish to report the use of p-TsOH on silica
(PTS-Si) to generate the o-QMs and their subsequent intermo-
lecular hetero-Diels-Alder reactions with styrene derivatives,
yielding the desired 2-arylchromans.
TABLE 1. The Hetero-Diels-Alder Reactions of 14-21a
Our previous investigations in the protecting group chemistry
of aromatic ethers indicated that a number of protecting groups
could be cleaved under relatively mild conditions using PTS-
Si in the nonpolar solvent toluene.9b,c Thus, an appropriate
precursor to o-QM could assume a structure containing a phenol-
protected moiety and a leaving group at the benzylic position
(Scheme 1).
entry
compound
X
Y
Z
P
yield (%)
1
2
14
15
16
18
19
20
21
H
H
H
Br
H
Br
Br
Br
Br
OAc
OAc
OAc
OAc
OAc
OAc
OMe
MOM
MOM
MOM
MOM
i-Pr
46
48
0
81
0
3b
4
OMe
OMe
OMe
OMe
OMe
5b c
,
6b c
Bn
MOM
0
61
,
7
As shown in Scheme 2, the o-QM precursors were prepared
to investigate the effect of substituents on the aromatic ring,
protecting group, and leaving group. From the aldehydes 11-13,
the phenol groups were protected as their MOM ethers using
standard procedures followed by NaBH4 reduction of the
aldehyde and the conversion of the resulting hydroxy group to
the corresponding acetates 14-16. Bromination of 13 gave the
aldehyde 17 in 60% yield. Subsequent phenol protection as Bn,
i-Pr, or MOM ether, NaBH4 reduction, and acetylation furnished
the corresponding products 18-20 in 62-92% yields. It should
be noted that the preparation of these o-QM precursors, while
not entirely a one-pot procedure, required only one purification
by column chromatography in the final step as the crude
products from phenol protection and reduction could be used
in the subsequent steps without purification.
a Unless otherwise noted, the reactions were performed in toluene at 0
°C to rt. b Starting materials were consumed, but complex mixtures were
obtained. c The protecting groups were cleaved.
reference, substituting bromine (X ) H; Y ) Br) for proton in
15 showed no effect on the yields of 22 and 23. Without
bromine, but with the methoxy group (X ) OMe; Y ) H) in
16, the reaction gave no desired product.10 The best yield was
obtained with 18, which contained both the methoxy group and
bromine (X ) OMe; Y ) Br).
The effect of the protecting group was then investigated. The
reaction of the o-QM precursor with the MOM group gave the
product in 81% yield (entry 4), while those with the Bn and
i-Pr groups gave complex mixtures (entries 5 and 6).11 For the
leaving group, the best result was obtained with the acetate.12
Compound 21 with OMe gave 24 in 61% yield.
As summarized in Table 1, the nature of substituents on the
aromatic ring played an important role (entries 1-4). If
considering the o-QM precursor 14 (X ) Y ) H) as the
Various acids were explored for the cycloaddition reactions
of the o-QM precursor 18 with styrene or styrene derivative 25
(7) (a) Van De Water, R. W.; Pettus, T. R. R. Tetrahedron 2002, 58, 5367–
5405. (b) Sugimoto, H.; Nakamura, S.; Ohwada, T. J. Org. Chem. 2007, 72,
10088–10095. (c) Crawley, S. L.; Funk, R. L. Org. Lett. 2003, 5, 3169–3171.
(d) Rodriguez, R.; Adlington, R. M.; Moses, J. E.; Cowley, A.; Baldwin, J. E.
Org. Lett. 2004, 6, 3617–3619. (e) Selenski, C.; Pettus, T. R. R. Tetrahedron
2006, 62, 5298–5307. (f) Jones, R. M.; Selenski, C.; Pettus, T. R. R. J. Org.
Chem. 2002, 67, 6911–6915. (g) Barrero, A. F.; Qu´ılez del Moral, J. F.; Herrador,
M. M.; Arteaga, P.; Corte´s, M.; Benites, J.; Rosello´n, A. Tetrahedron 2006, 62,
6012–6017. (h) Patel, A.; Netscher, T.; Rosenau, T. Tetrahedron Lett. 2008, 49,
2442–2445.
(8) (a) Lu, Z. G.; Sato, N.; Inoue, S.; Sato, K. Chem. Lett. 1992, 21, 1237–
1238. (b) Chiba, K.; Hirano, T.; Kitano, Y.; Tada, M. Chem. Commun. 1999,
691–692. (c) Miyazaki, H.; Honda, K.; Asami, M.; Inoue, S. J. Org. Chem.
1999, 64, 9507–9511. (d) Miyazaki, H.; Honda, Y.; Honda, K.; Inoue, S.
Tetrahedron Lett. 2000, 41, 2643–2647.
(10) The underlying reasons for the effect of aromatic substituents on the
yields of the hetero-Diels-Alder reactions are currently under our investigation.
The 0% yield of the corresponding product from compound 16 was presumably
due to the formation of competing transient para-quinone methide (p-QM) from
the protonation on the acetate group. The departure of protonated acetate could
be assisted by the p-OMe group. Subsequent nucleophilic addition of p-QM
with styrene gave the intermediate which could react further with additional
styrene monomer(s) prior to the cleavage of the MOM group. Therefore, the
reactions led to the formation of a complex mixture of inseparable product(s).
For compound 18, which gave the corresponding product in 81% yield, the
presence of Br on the aromatic ring presumably resulted in the preferential
formation of the o-QM over the p-QM. For the schematic proposed mechanism(s),
see Supporting Information.
(9) (a) Ploypradith, P.; Kagan, R. K.; Ruchirawat, S. J. Org. Chem. 2005,
70, 5119–5125. (b) Petchmanee, T.; Ploypradith, P.; Ruchirawat, S. J. Org. Chem.
2006, 71, 2892–2895. (c) Ploypradith, P.; Cheryklin, P.; Niyomtham, N.; Bertoni,
D. R.; Ruchirawat, S. Org. Lett. 2007, 9, 2637–2640.
(11) The rate of styrene polymerization in acid might be faster than those of
acid-mediated cleavage of the Bn or i-Pr groups in compound 19 and 20, resulting
in no cycloaddition product.
(12) Other o-QM precursors with the iodide or mesylate decomposed.
4010 J. Org. Chem. Vol. 74, No. 10, 2009

TABLE 2. Effect of Acids on the Hetero-DielssAlder Reactions of
the o-QM precursor 18a
SCHEME 3. Reactions of 18 with r,ꢀ-Disubstituted
Styrenes
SCHEME 4. Synthesis of Benzyl-Substituted Compounds
32-35
a Unless otherwise noted, the reactions were performed in toluene at 0
than those with styrene. Interestingly, only the reactions
employing PTS-Si gave both the products 24 and 26 in
comparable yields (73-81%), while other acids furnished both
24 (entries 2 and 5-7) and 26 (entries 9 and 12-14) in lower
yields. When TFA and HCl were used, only 24 but none of 26
was obtained.
Three R,ꢀ-disubstituted styrenes were employed to investigate
the diastereoselectivity between the C2-C3 positions. Indene,
(E)-1-phenylpentene (27),13 and (E)-3-methyl-1-phenylbutene
(28)13 furnished the products 29-31 in 97, 69, and 71% yields,
respectively (Scheme 3). Both 29 (C2-C3 cis) and 31 (C2-C3
trans) were obtained as their single C2-C3 isomers, while 30
was obtained as a 91:9 mixture of diastereomers favoring the
trans isomer. The observed diastereoselectivity between the
C2-C3 positions suggested the concerted cycloaddition for
the formation of both products (29 and 31).
°C to rt (normally 4-5 h). b TFA
)
CF3COOH; PTA
)
phosphotungstic acid hydrate; PMA ) phosphomolybdic acid hydrate;
TSA ) tungstosilicic acid hydrate. c The reactions took 18 h.
TABLE 3. Diastereoselective Hetero-Diels-Alder Reactions of
Benzyl-Substituted o-QM Precursors 32-35 to the
2,4-cis-Chromansa
The o-QM precursors 32-35 were prepared (Scheme 4) to
study the effects of the substituents at the benzylic position on
the diastereoselectivity between C2 and C4. Simple styrene,
styrene 25 bearing electron-donating groups, and indene were
the dienophiles. The results are summarized in Table 3. In all
cases, the styrenes gave the products favoring the cis isomer
between C2 and C4. The monosubstituted olefins gave the
products (36-43) favoring the C2-C4 cis relationship with
the diastereomeric ratios ranging from 75:25 to >99:1. The
electronic effect from the para position of the aryl substituent
was evident. The substrate with an electron-donating p-OMe
group (34) gave the products 38 and 42 in moderate to good
yields (57-76%) but only with moderate diastereoselectivity
(76:24 to 86:14). On the other hand, the o-QM precursor 35
with an electron-withdrawing p-OCF3 group furnished the
products 39 and 43 in moderate yields (42-53%) but with
excellent diastereoselectivity (93:7 to >99:1). The predominant
cis relationship between the C2-C4 positions suggested that
the hetero-Diels-Alder reactions of these substrates proceeded
via the endo-type concerted transition state.7a
a Unless otherwise noted, the reactions were performed in toluene at 0
°C to rt (normally 4-5 h). b Isolated yields of a mixture of 2,4-cis and
2,4-trans diastereomers. c Diastereomeric ratio between C2 and C4
1
positions as determined by H NMR.
bearing two electron-donating groups (EDG) on the phenyl ring.
The results are summarized in Table 2. Although both p-TsOH
and PTS-Si gave the product 24 in comparable yields (71-81%,
entries 1 and 2), the reaction using PTS-Si proceeded faster
perhaps due to the greater surface area of PTS-Si. Interestingly,
no desired product was obtained from (+)-camphorsulfonic acid
(CSA), albeit bearing an alkyl sulfonic acid functionality, or
from other Lewis acids (BF3 ·Et2O, AlCl3, and SnCl4). Com-
parable yields (66-67%, entries 3 and 4) of the product 24 were
obtained from the reactions using TFA and HCl, while three
heteropolyacids gave the product in lower yields (34-56%,
entries 5-7).
When indene was employed, only the cis diastereomers
between C2 and C3 were obtained from 32-35. Moreover, the
In general, the reactions of o-QM generated from 18 with
the styrene derivative 25 gave the product 26 in poorer yields
(13) See Supporting Information for preparation and characterization.
J. Org. Chem. Vol. 74, No. 10, 2009 4011

5.05 (dd, J ) 9.4, 3.0 Hz, 1H), 6.52 (s, 1H), 7.26 (s, 1H), 7.35-7.44
(m, 5H); 13C NMR (50 MHz, CDCl3) δ 24.1, 29.6, 56.2, 78.0, 101.1,
101.8, 115.2, 125.9, 128.0, 128.6, 133.0, 141.1, 154.8, 155.1; LRMS
(EI) m/z (rel intensity) 320 (M+ + 2, 100), 318 (M+, 97), 239 (16),
238 (14); TOF-HRMS calcd for C16H16BrO2 (M + H+) 319.0328,
found 319.0327.
cis relationship was also favored between C2 and C4, with
moderate to excellent diastereomeric ratios of 78:22 to >99:1.
Thus, the products 44-47 all were predominantly C2-C3-C4
cis isomers.
In summary, we have developed an efficient means to
generate the o-QMs using PTS-Si. The hetero-Diels-Alder
reactions of the o-QMs with the styrene derivatives furnished
the 2-arylchroman frameworks in moderate to good yields and
moderate to excellent diastereoselectivity.
6-Bromo-7-methoxy-2-phenyl-3-propylchroman (31). Benzyl
acetate 18 (0.024 g, 0.076 mmol) in toluene (1 mL) was treated
with PTS-Si (0.102 g, 0.083 mmol) and styrene 28 (0.11 g, 0.76
mmol) according to the general procedure above to give the desired
2-arylchroman product 31 (0.020 g, 0.054 mmol, 71%) as a
colorless oil: IR (neat) νmax 2958, 2926, 1611, 1575, 1496, 1444,
Experimental Section
1
1402, 1310, 1283, 1201, 1157, 1063, 1049 cm-1; H NMR (400
General Procedure for the Hetero-Diels-Alder Reactions
of 2-Arylchroman Products 22-24, 26, 29-31, 36-47. To a
stirred solution of benzyl acetates 14-16, 18-21, or 32-35 (1.0
equiv) in toluene (5 mL/mmol of starting material) were added
styrene derivatives (10.0 equiv for commercially available styrenes,
27 and 28, and 1.1 equiv for 25) at room temperature. The resulting
mixture was stirred at 0 °C for 10 min, and then PTS-Si (0.81 mmol/
g, 1.1 equiv) was added. The reaction mixture was stirred until all
benzyl acetates 14-16, 18-21, or 32-35 were consumed as
indicated by TLC (typically 4-5 h). At that time, the reaction
mixture was filtered to remove the silica, which was washed with
excess CH2Cl2 (three times). The filtrate was then concentrated
under reduced pressure to give a crude product mixture which was
further purified by preparative TLC to furnish the desired product.
6-Bromo-7-methoxy-2-phenylchroman (24). Benzyl acetate 18
(0.025 g, 0.078 mmol) in toluene (1 mL) was treated with PTS-Si
(0.106 g, 0.086 mmol) and styrene (0.092 mL, 0.78 mmol)
according to the general procedure above to give the desired
2-arylchroman product 24 (0.02 g, 0.063 mmol, 81%) as a colorless
oil: IR (neat) νmax 2928, 1610, 1572, 1495, 1485, 1442, 1309, 1266,
1193, 1153, 1053 cm-1; 1H NMR (200 MHz, CDCl3) δ 1.97-2.28
(m, 2H), 2.66-2.79 (m, 1H), 2.84-3.01 (m, 1H), 3.85 (s, 3H),
MHz, CDCl3) δ 0.76 (d, J ) 6.8 Hz, 3H), 0.88 (d, J ) 6.9 Hz,
3H), 1.44-1.52 (m, 1H), 1.93-2.00 (m, 1H), 2.53 (dd, J ) 16.2,
5.3 Hz, 1H), 2.61 (dd, J ) 16.3, 9.6 Hz, 1H), 3.74 (s, 3H), 3.77 (s,
3H, minor), 4.84 (d, J ) 8.6 Hz, 1H), 5.34 (d, J ) 3.9 Hz, 1H,
minor), 6.39 (s, 1H), 6.40 (s, 1H, minor), 7.17 (s, 1H), 7.19 (s, 1H,
minor), 7.23-7.34 (m, 5H); 13C NMR (100 MHz, CDCl3) δ 16.4,
21.2, 23.4, 26.8, 42.7, 56.2, 81.4, 100.7, 101.7, 115.5, 126.5, 127.0,
128.2, 128.6, 133.2, 139.9, 154.7; LRMS (EI) m/z (rel intensity)
362 (M+ + 2, 80), 360 (M+, 83), 319 (10), 317 (11), 271 (87), 269
(100), 238 (18), 190 (40), 131 (43); TOF-HRMS calcd for
C19H22BrO2 (M + H+) 361.0798, found 361.0800.
Acknowledgment. Financial support from the Thailand
Research Fund (TRF; BRG5100813 for P.P.) is gratefully
acknowledged.
Supporting Information Available: Experimental proce-
dures and full spectroscopic data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JO900504Y
4012 J. Org. Chem. Vol. 74, No. 10, 2009