Pt(IV)-catalyzed generation and [4+2]-cycloaddition reactions of o-quinone methides

Article abstract of DOI:10.1016/j.tet.2011.03.059

Novel intermolecular and intramolecular generations of ortho-quinone methides and their formal [4+2]-cycloaddition reactions with olefins catalyzed by PtCl₄ and AuCl₃ under mild conditions have been developed. Good to excellent yields (up to 99%) and diastereoselectivity (up to >99:1) of the chromans were obtained. PtCl₄ was found to be effective and compatible with various functional groups present in the substrates. A mechanism accounting for its catalytic cycle is proposed and discussed.

Full text of DOI:10.1016/j.tet.2011.03.059

Tetrahedron 67 (2011) 3904e3914
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Pt(IV)-catalyzed generation and [4þ2]-cycloaddition reactions of o-quinone
methides
,
,
Suttipol Radomkit a b, Pakornwit Sarnpitak a b, Jumreang Tummatorn c, Paratchata Batsomboon c,
Somsak Ruchirawat c, Poonsakdi Ploypradith a
,b,c,
*
a Program in Chemical Biology, Chulabhorn Graduate Institute, Vipavadee-Rangsit Highway, Bangkok 10210, Thailand
b The Center for Environmental Health, Toxicology and Management of Chemicals (ETM), Chulabhorn Graduate Institute, Vipavadee-Rangsit Highway, Bangkok 10210, Thailand
c Laboratory of Medicinal Chemistry, Chulabhorn Research Institute, Vipavadee-Rangsit Highway, Bangkok 10210, Thailand
a r t i c l e i n f o
a b s t r a c t
Article history:
Novel intermolecular and intramolecular generations of ortho-quinone methides and their formal [4þ2]-
cycloaddition reactions with olefins catalyzed by PtCl4 and AuCl3 under mild conditions have been de-
veloped. Good to excellent yields (up to 99%) and diastereoselectivity (up to >99:1) of the chromans
were obtained. PtCl4 was found to be effective and compatible with various functional groups present in
the substrates. A mechanism accounting for its catalytic cycle is proposed and discussed.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 16 December 2010
Received in revised form 2 March 2011
Accepted 21 March 2011
Available online 26 March 2011
Keywords:
Cycloaddition
Stereoselective
ortho-Quinone methide
Metal catalysis
Chroman
1. Introduction
exhibiting a wide array of biological properties.4 Herein, we report,
for the first time, a novel Pt(IV)- and Au(III)-catalyzed generation of
Metal-catalyzed reactions have revolutionized modern syn-
thetic methodologies and their development has made possible
total syntheses of structurally complex natural products. In recent
years, platinum and gold salts/complexes have drawn much at-
tention and their use as catalysts for various organic trans-
formations have been developed.1 The chemistry of Pt(II), Pt(IV),
Au(I), and Au(III) and their use in organic synthesis has been
studied and reported.1fei However, chemistry of these metal salts/
o-QMs and their cycloaddition reactions via Pt(IV)- and Au(III)-ac-
tivation of olefin and coordination with o-QM (Scheme 1).
X
X
X
R
L
Y
Y
Y
M
R
M
OMOM
L = Leaving group
O
O
R
complexes has largely involved activation of the
p-system of the
Scheme 1. Metal-catalyzed generation of o-QMs and cycloaddition reactions.
alkyne rather than that of the olefin.1eꢀi
A number of methods have been developed to generate the
transient highly reactive ortho-quinone methides (o-QMs). In ad-
dition to thermal and base initiation, some Lewis acids and tran-
sition metal salts/complexes of Os, Rh, Ir, Mn, and Pd were reported
to mediate the generation of o-QMs.2 Recently, our research group
has been involved with acid-mediated generation of o-QMs and
their cycloaddition reactions using p-TsOH immobilized on silica
(PTSeSi).3 The resulting 2-aryl chromans can be functionalized to
provide the core structures of natural and synthetic compounds
2. Results and discussion
We envisioned that, upon coordination with metal salts/com-
plexes, the o-QM may be stabilized for the subsequent cycloaddi-
tion reactions to provide the chroman products. One drawback,
albeit a minor one, of our previously developed method for the
generation of o-QM and its cycloaddition reactions using PTSeSi
was the required stoichiometric amount of the acid, which may not
be compatible with a number of functional groups present on the o-
QM precursor or the olefin. Taken together, with appropriate metal
salts/complexes, a catalytic process may be developed to circum-
vent the drawback.
* Corresponding author. Tel.: þ662 574 0622; fax: þ662 574 2027; e-mail address:
poonsakdi@cri.or.th (P. Ploypradith).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.03.059

S. Radomkit et al. / Tetrahedron 67 (2011) 3904e3914
3905
2.1. Intermolecular [4D2]-cycloaddition reactions
compound 48 containing a hydroxy group (58%) as the leaving
group at the benzylic position under similar conditions (entries
1e3). The importance of MOM as a phenol protecting group was
evident as compound 5, with an i-Pr group, failed to give any
product while compound 6,8 with a MEM group, gave the product
only in 49% yield (entries 4 and 5).
Our preliminary data using PTSeSi to generate o-QMs showed
that compound 1 gave the best results and was thus chosen as the
o-QM precursor for the screening of Lewis acids and transition
metal salts/complexes.3,5 As summarized in Table 1, it was found
that stoichiometric amount of AlCl3, TiCl3, TiCl4, ZrCl4, FeCl3, ZnCl2,
AuCl, AuCl3, InCl3, PtCl2, and PtCl4 gave the desired product 2 in
26e85% yields while catalytic amount (10e30 mol %) of only PtCl4,
AuCl3, and InCl3,6 furnished the chroman in 62e88% yields. In
a larger scale reaction, the required amount of the PtCl4 could be
reduced to 4 mol %, which gave the product in a slightly lower yield
(76%). In fact, the reactions using catalytic amount of metal salts
proceeded more cleanly than those using stoichiometric amount,
giving the product in higher yields (entries 7 and 10). An increase in
electrophilicity, rather than the oxidation state, of the metal center
(Pt) is an important factor responsible for the successful catalysis of
generating o-QMs and mediating cycloaddition reactions. Whilst
possessing the same oxidation state (Pt(IV)) and ligand (Cl), PtCl4,
but not K2PtCl6, is a useful catalyst (entries 10 and 11). Previous
work suggested that an increase in oxidation state increases the
electrophilicity of the metal center, resulting in increasing the re-
activity of the catalyst.1h Thus, successful catalysis of PtCl4 may be
due to its higher Lewis acidity.
Table 2
Effects of the substituents on the aromatic ring, the leaving group, the phenol
protecting groups, and the method to generate the o-QMs and mediate their cy-
cloaddition reactionsa
X
X
Ph
L
method A or B
Y
OP
Y
O
Ph
0 oC to rt
4-6 h
1, 3-15
2, 16-23
Entry Compound
X
Y
L
P
Product Methodb Yield (%)c
1
2
3
4
1
3
4
5
Br
OMe OAc
MOM
2
2
2
2
2
A
B
A
B
A
B
A
B
A
A
B
A
B
A
B
A
A
B
A
B
A
B
A
B
A
B
88
81
88
44
58
46
0d
Br
Br
Br
OMe OTBDMS MOM
OMe OH
OMe OAc
OMe OAc
MOM
i-Pr
0e
5
6
6
7
Br
Br
MEM
49
traced
46
75
66
84
60
56
46
17
91
39
88
23
0d
H
OAc
MOM 16
MOM 17
MOM 18
Table 1
7
8
8
9
F
OMe OAc
OMe OAc
Screening of the metal salts/complexes for o-QMs and cycloaddition reactions with
styrenea
OMe
Br
Br
Ph
OAc
9
10
10
11
OMe
OMe
OMe OTBDMS MOM 18
catalyst
DCM
H
OAc
MOM 19
MeO
OMOM
MeO
O
Ph
2
1
0 oC to rt
4-6 h
11
12
13
14
12
13
14
15
OMe
Br
OAc
MOM 20
CO2Me OMe OTBDMS MOM 21
Entry
Catalyst
mol (%)
Yield (%)b
1c
AlCl3
TiCl3
TiCl4
100
100
100
100
100
100
30
10
100
10
26
48
68
39
63
83
84 (75)
84 (85)
62
88 (75)
0
H
H
OMe OAc
OAc
MOM 22
MOM 23
0d
2c
H
23d
48
3c
4c
ZrCl4
FeCl3
ZnCl2
AuCl
AuCl3
PtCl2
PtCl4
K2PtCl6
InCl3
PTSeSi
5c
a
Unless otherwise noted, all reactions were performed using 10 equiv of styrene.
Method A¼PtCl4 (10 mol %) in DCM; method B¼PTSeSi (1.1 equiv) in toluene.
Isolated yields.
The reactions gave complex mixtures of unidentifiable products.
Starting material was not consumed.
6c
b
c
7d
8e
9c
d
e
10
11
12
13f
10
10
100
In order to investigate the effects of the substituents, o-QM
62 (41)
81
precursors 7e15 were synthesized8 for the cycloaddition reactions
leading to the expected chromans 16e23. In general, PtCl4 can
tolerate a range of substituent X on the aromatic ring with different
electronic properties, such as halogens (F and Br), electron-donat-
ing group (EDG; OMe), and electron-withdrawing group (EWG;
CO2Me). In case of Y¼H, the effects of substituent X on the reactions
using PtCl4 were evident for compounds 7, 11, and 15. If the result of
compound 15 (X¼Y¼H) was considered as a point of reference (23%
yield; entry 14), a substrate bearing an EWG (7; X¼Br; Y¼H) gave
only trace amounts of the corresponding product 16 and thus had
a detrimental effect on the reaction yield (entry 6). Compound 11
(X¼OMe; Y¼H), on the other hand, with an EDG gave the product
19 in moderate 46% yield (entry 10). Such a trend was not observed
for the reactions using PTSeSi as similar yields were obtained for
compounds 7 and 15 (46e48%) while a much lower yield was ob-
served for compound 11 (17% yield), suggesting that similar o-QMs
may be generated by different mechanisms when PtCl4 or PTSeSi
was employed.
a
Unless otherwise noted, all reactions were performed in DCM, using 10 equiv of
styrene.
b
Isolated yields. Numbers in parenthesis are yields of 2 when using stoichio-
metric amount of catalysts.
c
Substoichiometric (30e50 mol %) and catalytic (10e30 mol %) amounts of cat-
alysts resulted in no reaction with recovery of o-QM precursor.
d
Compound 2 (91%) was obtained (based on recovered starting materials) if
10 mol % of AuCl was employed.
e
The reaction using 10 mol % AuCl3 required 36 h to complete.
For reference, the reaction using PTSeSi was performed in toluene.
f
The use of dichloromethane (DCM) as solvent was important.7
Toluene, which was the solvent of choice when PTSeSi was
employed, gave no desired product with complete recovery of 1
regardless of the metal salts/complexes under current investigation.
Because of the higher yield, shorter reaction time, and easier han-
dling, PtCl4 was chosen as catalyst for the subsequent studies.
The effects of substituents on the aromatic ring as well as those
of the leaving group at the benzylic position and the phenol pro-
tecting groups were also investigated. As summarized in Table 2,
both compound 1 (with the acetate) and 38 (with the tert-butyl-
dimethylsilyloxy (OTBDMS) group) gave better yields (88%) than
The position of an EDG on the aromatic ring appeared crucial for
the successful generation of the corresponding o-QMs and the
subsequent cycloaddition reactions. Compound 14 (X¼H; Y¼OMe)
gave no desired product 22 regardless of whether PTSeSi or PtCl4

3906
S. Radomkit et al. / Tetrahedron 67 (2011) 3904e3914
was employed. A mixture of products presumably arising from the
displacement of acetate by styrene followed by partial polymeri-
zation of the resulting intermediate(s) with other styrene mole-
cule(s) was obtained. In these cases, the presence of OMe para to
the benzyl acetate rendered the system too reactive. Upon pro-
tonation (PTSeSi) or coordination (PtCl4), the p-quinone methide
(p-QM) might be formed as a result of the departure of acetate
before the cleavage of the MOM group to generate the o-QM.
Subsequently, styrene reacted with the p-QM to yield the carbo-
cation-like intermediate, which underwent further reaction(s) with
other styrene molecule(s).
When substituents X and Y are not hydrogen, the yields
(75e91%) from the reactions using PtCl4 were largely unaffected by
the nature of these substituents (entries 1, 7, 8, 11, and 12).
Switching of Br and OMe (12, entry 11) does not seem to affect the
reactions; the corresponding chroman product 20 was furnished in
high yield (91%). Interestingly, a good yield (84%) of the product 18
was obtained from 9, which contain the methoxy groups as both
substituents (entry 8). Replacing Br with F only gave a slightly lower
yield of the product (entry 7). Even with a strong EWG in 13, a good
yield (88%) of the product 21 was obtained (entry 12). Thus, it ap-
pears that the effects of substituents X and Y should not be con-
sidered separately; both substituents may altogether modulate
electron density in the aromatic ring for the generation of o-QMs as
well as in the o-QM intermediates for their cycloaddition reactions.
In contrast to the reactions for substrates bearing no hydrogen
as substituents X and Y using PtCl4 as the catalyst, the reactions
using PTSeSi gave lower yields of the corresponding products
(23e81%). All the changes in substituents X and Y presumably
changed the electron density in the aromatic ring. In addition, some
side reactions presumably from OeSi cleavage also occurred when
PTSeSi was used with compound 3, resulting in a lower yield (44%;
entry 2).
As shown in Scheme 2, the ring-fused cis-styrene (indene)
reacted to provide 29 in 45% yield as a single diastereomer.12 Simple
non-conjugated alkene, such as cyclopentene furnished the corre-
sponding product 30 albeit in lower yield.13 The addition of p-TsOH
on silica (PTSeSi) accelerated the reactions but gave only a slightly
better yield of the product. Conjugated 1,3-cyclohexadiene gave
a better yield of the corresponding product 31 in 75% as a single
regioisomer and diastereomer. However, a non-cyclic conjugated
2,3-dimethyl-1,3-butadiene gave 32 only in 25% yield.
H
Br
Br
OAc
PtCl4
45%
MeO
OMOM
MeO
O
1
29
H
Br
PtCl4
33%
PtCl4, 25%
Br
MeO
H
O
32
H
Br
MeO
PtCl4
75%
O
H
MeO
O
H
30
31
Scheme 2. PtCl4-catalyzed generation and cycloaddition of o-QMs with other olefins.
To further investigate the effects of conjugation on the dien-
ophile, dienes 33e36 were employed in the reactions (Scheme 3).
Interestingly, both diene 338 and 34,8 which contain a 1,3-diene
system in conjugation with an aryl system, furnished the corre-
sponding products 37 and 38 in 80% and 33% yields, respectively, as
single regioisomers. The reactions occurred exclusively on the ter-
minal olefin of the conjugated system. The presence of an EWG at the
end of diene 34 had no effect on the regioselectivity of the reaction
but dramatically affected the yield (33%) and diastereoselectivity (a
10:1 mixture of diastereomers favoring the C2eC3 trans relation-
ship) of the resulting chroman 38. When a non-conjugated diene 358
was employed, the product 39 arising solely from the reaction on the
styrene moiety was obtained albeit in low yield (30%). Moreover,
non-styrene non-conjugated diene 36 furnished the corresponding
product 40 as a single isomer (dr>99:1) from the reaction occurring
exclusively on the more substituted olefin in moderate 62% yield.14
Due to the ease of preparation, the o-QM precursor 1 was used as
the substrate for the subsequent studies. As summarized in Table 3,
moderate to excellent yields (33e99%) and diastereoselectivity of
the 2,3-disubstituted chromans 24e28 were obtained. The trans
olefins gave the products as single diastereomers while the cis olefin
provided the product as a 1:19 mixture of diastereomers. Cinnamyl
benzoate furnished 26 in 99% yield as a single diastereomer.10,11 In
addition, evenwith an electron-withdrawing group(CO2Et) in trans-
ethyl cinnamate, 27 was obtained in moderate 33% yield;12 a better
yield (76%) of 28, as a single diastereomer, was obtained with the
(p-OMe)Ph trans-ethyl cinnamate.10 The CH2OBz and CO2Et groups
in 26e28 at C3 allow further modifications on the 2-aryl chromans.
H
Br
Br
X
PtCl4
OAc
X
MeO
OMOM
Ph MeO
O
Ph
H
1
33, X = H
37, X = H (80%)
PtCl4
30%
34, X = CO2Et
2
38, X = CO2Et (33%)
10:1 (trans:cis)
s
35
36
PtCl4
62%
H
H
Br
MeO
Br
s
Table 3
Stereoselective PtCl4-catalyzed cycloaddition reactions of o-QMs for 2,3-di-
substituted chromansa
O
Ph
MeO
O
39
H
40
Br
X
Br
X
OAc
Ar
Scheme 3. PtCl4-catalyzed generation and cycloaddition of o-QMs with other olefins.
3
2
PtCl4, DCM
MeO
OMOM
MeO
O
Ar
1
H
The precursors 41e438 furnished the 2,4-disubstituted and
2,3,4-trisubstituted chroman systems 44e47 in moderate to good
yields but only in moderate diastereoselectivity favoring the 2,4-cis
relationship (Scheme 4). For comparison, 44 was previously syn-
thesized from 41 in 51% yield as a single diastereomer.3a Thus, the
use of PtCl4 for the 2,4-disubstituted chromans improved the yield
but lowered the diastereoselectivity.
Entry
X
Ar
Olefin
Prod
Yield (%)b
dr
(trans:cis)
1
2
3
n-Pr
n-Pr
Me
CH2OBz
CO2Et
CO2Et
Ph
Ph
Ph
Ph
cis
24a
24b
25
26
27
78
72
99
99
33
76
1:1
>99:1
>99:1
>99:1
>99:1
>99:1
trans
trans
trans
trans
trans
4
5
Ph
6c
Ph(OMe-p)
28
2.2. Scope and limitation of using PtCl4 as catalyst
a
Unless otherwise noted, all reactions were performed using 10 mol % of PtCl4
and 10 equiv of styrenes.
b
Even though the use of a catalytic amount of PtCl4 in the gen-
eration of o-QMs and their cycloaddition reactions appears general,
Isolated yields.
Cinnamate (2 equiv) was used.
c

S. Radomkit et al. / Tetrahedron 67 (2011) 3904e3914
3907
2.3. Intramolecular [4D2]-cycloaddition reactions
Both PtCl4 and AuCl3 effectively catalyzed the intramolecular
cycloaddition reactions of the o-QM tethered with styrene or
simple olefin (Scheme 7).15 The alcohol 583b could be used directly
in the reactions to furnish the corresponding tricyclic ketone 59 in
one step and 70% yield (as a 1.5:1 mixture of diastereomers). Al-
ternatively, conversion of the
b-hydroxyketone to the corre-
sponding bis-acetate intermediate, which upon generating the o-
QM and the ensuing cycloaddition reaction, gave the chroman 60 in
58% yields over 3 steps (as an 11.8:1 mixture of diastereomers).
Thus, the direct use of precursor 58 furnished the tricyclic system in
better yield and in fewer chemical steps albeit in lower diaster-
eoselectivity. A similar reaction with precursor 61 containing sim-
ple non-styrene olefin gave the corresponding chroman 62 in 72%
yield as a 1.9:1 mixture of diastereomers. Thus, the 3,4-trans iso-
mers are the major products from these intramolecular reactions.
Scheme 4. 2,4-Disubstituted and 2,3,4-trisubstituted chromans from PtCl4-catalyzed
generation and cycloaddition of o-QMs with styrenes.
there are a few exceptions. Electron-rich dienophiles (48e52,
Scheme 5), such as enol ethers and oxygenated aromatic systems
did not furnish any chroman products. A 1H NMR study suggested
that p-methoxystyrene 51 underwent a facile PtCl4-mediated po-
lymerization under the reaction condition. It also appeared that
polymerization occurred at a faster rate than the generation of the
o-QM from the precursor. Reactions of precursor 1 with 48e50
using PTSeSi gave similar results. However, the use of PTSeSi, in
case of the oxygenated aromatic systems 51 and 52, gave the de-
sired products 53 and 54, respectively, in good to excellent yields
(73%e99%).
X
OZ
48, Z = Et
49, Z = Ac
Y
51, X = H; Y = OMe
52, X = OBn; Y = OMe
50
O
51
PtCl4
DCM
1
1
polymerization of 551
Br
Scheme 7. Intramolecular PtCl4- or AuCl3-catalyzed generation and cycloaddition re-
actions of o-QMs with tethered alkenes.
H
51 or 52
X
Y
PTS-Si
MeO
O
2.4. Mechanistic studies of the generation of o-QMs and
[4D2]-cycloaddition reactions via PtCl4
toluene
53, X = H; Y = OMe (99%)
54, X = OBn; Y = OMe (73%)
A plausible mechanism was proposed to involve first the co-
Scheme 5. Electron-rich dienophiles 53e56 and cycloaddition reactions.
ordination of Pt(IV) to the
p-system of olefin (Scheme 8). This
Pt(IV)-olefin complex then mediated the generation of o-QM from
the precursor 1. In these reactions, it appears that PtCl4 also serves
as a mild Lewis acid, which facilitates the ensuing cycloaddition
reaction.16 The product chroman was produced in concomitant
with the regeneration of the catalytic species, completing the cat-
alytic cycle.
It should be noted also that the presence of sulfone appeared
incompatible with PtCl4. Generation of the o-QM from the pre-
cursor 558 containing sulfone and its cycloaddition reaction with
styrene using PtCl4 gave no desired product. However, when similar
reactions were performed with styrene or 51 using PTSeSi, the
corresponding chromans 56 and 57 were obtained in 37% and 44%
yields, respectively (Scheme 6). The stereoselectivity at C2eC4
cannot be determined due to the complex and overlapping 1H NMR
signals.
PtCl4
Br
MeO
O
Ar
Ar
Ar
Br
Pt(IV)
Pt(IV)
O
O
Me
O
O
Me
Ar
MeO
O
O
undeterminable
H :H
S
S
Br
OAc
Ph
Br
Br
OAc +
or 51
Br
MeO
OAc
OMOM
OAc
MeO
OMOM
PTS-Si
DCM
1
MeO
MeO
O
O
55
MeO
Pt(IV)
Ar
56, X = H (37%)
57, X = OMe (44%)
X
Scheme 8. A proposed catalytic cycle of the Pt(IV)-catalyzed generation of o-QM and
Scheme 6. Reactions of precursor 55 containing sulfone with styrene derivatives.
cycloaddition reactions.

3908
S. Radomkit et al. / Tetrahedron 67 (2011) 3904e3914
Some supporting evidence for this mechanism was as follows.
Sequential addition of olefin to the reaction after premixing PtCl4
with 1 was not successful, giving an unidentifiable mixture of
MOM and acetate groups. In addition, these peaks started to dis-
appear after t¼30 min, implying that the nature of the intermediate
giving rise to these signals is only transient. Together with the
products and signifying the first step of Pt(IV)-
p
coordination. In
observation that the new sets of signals around
likely to correspond to the acetate group(s), these singlets at
d
2.01e2.15 were
8.25
addition, in the complete absence of styrene, a similar un-
identifiable mixture of products was obtained, suggesting that the
o-QM was formed from 1 in the presence of PtCl4 alone.17 Thus, it
is likely that the o-QM remains bound to Pt(IV) for the subsequent
cycloaddition reaction.18 The bound state of Pt(IV) to the o-QM
intermediate might account for the moderate diastereoselectivity
for some substrates, presumably due to the steric demand and the
positioning of the metal center.19 The role of PtCl4 in the cleavage
of the MOM group as Lewis acid was evident from the facile
cleavage of the MOM ether of salicylaldehyde by PtCl4 under
similar reaction condition to provide salicylaldehyde in 92% yield.
Interestingly, no reactions occurred when styrene and PtCl4 were
mixed with nucleophile (phenol) or electrophile (BnOH/BnOAc) or
both,20 implying that the reaction proceeded via the intermediacy
of o-QM rather than a stepwise addition/substitution reaction
mechanism.
d
and 9.67 were tentatively assigned to an intermediate either (1)
resulting from the PtCl4-mediated cleavage of the MOM group or
(2) possessing a highly unshielded quinone methide-type moiety.
Thus, a PtCl4-catalyzed cleavage of the MOM group of the MOM
ether-containing benzaldehyde (similar structure to compound 1
with the aldehyde moiety in place of the benzyl acetate) was car-
ried out to clarify whether the PtCl4-catalyzed MOM cleavage
process alone without the possibility of generating any o-QM in-
termediate could generate some species with a signal at d 9.67 (See
Supplementary data for the overlay of the spectra). The cleavage of
the MOM group alone by PtCl4 did not generate any singlets at
d
8.25 or 9.67. However, some similar peaks were observed be-
tween the two reactions, especially those new sets of signals
around 3.30e5.30, suggesting a similar course of reaction for the
d
MOM cleavage. Thus, it is reasonable to postulate that the singlets
at 8.25 and 9.67 may come from the Pt(IV)-stabilized o-QM
intermediate.
In the presence of styrene, to our delight, a similar reaction
course occurred. The singlets at d 8.25 and 9.67 were still observed,
suggesting the formation of the Pt(IV)-stabilized o-QM in-
termediate. In addition, the presence of styrene made the overall
reaction proceed at a faster rate. Such observation was in good
accordance with the role of styrene as dienophile trapping the
o-QM, thus driving the reaction to completion faster. Taken to-
gether, the mechanisms of the reactions both in the absence and in
the presence of styrene proceeded via the intermediacy of o-QM.
In order to follow the reactions in more detail, 1H NMR studies
were performed. As shown in Figs. 1 and 2, the NMR studies of the
reactions both in the absence and in the presence of styrene with 1
using PtCl4 as catalyst were conducted. In the absence of styrene, it
is evident that the signals of protons belonging to the MOM (sin-
glets at
d 3.45 and 5.19) and the acetate (a singlet at d 2.03) groups
in the precursor 1 slowly disappeared and the new sets of signals
could be observed. In particular, the observation of a sharp singlet
at
d 9.67 and a broad one at d 8.25 was remarkable because the
increment of these peaks at the beginning of the reaction corre-
sponded with the diminishing height of the sets of peaks of the
Fig. 1. 1H NMR study of the reaction between the precursor 1 and PtCl4 in the absence of styrene in CD2Cl2.

S. Radomkit et al. / Tetrahedron 67 (2011) 3904e3914
3909
Fig. 2. 1H NMR study of the reaction between the precursor 1 and PtCl4 in the presence of styrene in CD2Cl2.
3. Conclusion
indicated by TLC (4e6 h). At that time, the reaction mixture was
concentrated under reduced pressure to give a crude product
mixture, which was further purified by preparative TLC (10e30%
EtOAc/hexanes) to furnish the desired products.
In summary, the mild and facile generation of o-QMs under the
catalysis of PtCl4 and their formal [4þ2]-cycloaddition reactions
with styrenes and other activated olefins have been successfully
developed. The reactions furnished the 2-alkylor 2-aryl chromans in
moderate to excellent yields and moderate to excellent diaster-
eoselectivity. When compared with our previously reported method
using PTSeSi, this novel Pt(IV)-catalyzed process provided some
significant advantages of wider range of the substituents on the
aromatic ring of the o-QM precursors including better functional
group compatibility. In addition, most dienophiles, with a few ex-
ceptions, gave the products in higher yields when PtCl4 was
employed. However, it should be noted that use of PtCl4 led to
somewhat lower diastereoselectivity at C2eC4. For the intra-
molecular reactions, the conversion of benzyl alcohol to the corre-
sponding benzyl acetate was not necessary when using PtCl4, thus
resulting in fewer chemical steps in the synthesis of the desired
chroman systems. The intermediacy of o-QM in the reactions under
the PtCl4 catalysis was also proposed and the Pt(IV)-stabilized o-QM
involved in the reactions was detected spectroscopically.
4.1.1. 6-Bromo-7-methoxy-2-phenylchroman (2). Following the
general procedure and purification by PTLC (30% EtOAc/hexanes),
the product was obtained as colorless oil (0.018 g, 0.058 mmol, 88%,
using PtCl4; 0.016 g, 0.053 mmol, 81%, using PTSeSi). Rf (30% EtOAc/
hexanes) 0.72. 1H NMR (200 MHz, CDCl3):
d 1.97e2.28 (m, 2H),
2.66e2.79 (m, 1H), 2.84e3.01 (m, 1H), 3.85 (s, 3H), 5.05 (dd, J¼9.4,
3.0 Hz, 1H), 6.52 (s, 1H), 7.26 (s, 1H), 7.35e7.44 (m, 5H). 13C NMR
(50 MHz, CDCl3):
d 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. TOF-HRMS calcd for
C16H16BrO2 (MþHþ) 319.0328, found 319.0327. These spectroscopic
data were identical to those reported previously.3a
4.1.2. 6-Bromo-2-phenylchroman (16). Following the general pro-
cedure and purification by PTLC (30% EtOAc/hexanes), the product
was obtained as colorless oil (trace, using PtCl4; 0.010 g,
0.035 mmol, 46%, using PTSeSi). Rf (30% EtOAc/hexanes) 0.55. 1H
NMR (200 MHz, CDCl3):
d 1.94e2.24 (m, 2H), 2.67e2.80 (m, 1H),
4. Experimental section
2.86e3.03 (m, 1H), 5.02 (dd, J¼9.6, 2.8 Hz, 1H), 6.78 (d, J¼9.6 Hz,
1H), 7.20 (m, 2H), 7.27e7.38 (m, 5H). 13C NMR (50 MHz, CDCl3):
4.1. General procedure for the hetero-DielseAlder reactions
of 2-arylchroman products
d 24.8, 29.4, 77.8, 112.3, 118.7, 124.0, 125.9, 127.9, 128.5, 130.1, 131.9,
141.1, 154.2. TOF-HRMS calcd for C15H12BrO (MꢀHþ) 287.0063,
found 287.0077. These spectroscopic data were identical to those
reported previously.3a
To a stirred solution of o-QM precursors (1.0 equiv) in CH2Cl2
(10 mL/mmol of benzyl acetates) were added styrene derivatives
(2.0e10.0 equiv) at room temperature. The resulting mixture was
stirred at 0 ꢁC for 10 min, and then Lewis acids, transition metal
salts or complexes (stoichiometric 100 mol %; substoichiometric
30e50 mol %, and catalytic 10e30 mol %) were added. The reaction
mixture was stirred until all o-QM precursors were consumed as
4.1.3. 6-Fluoro-7-methoxy-2-phenylchroman (17). Following the
general procedure andpurification by PTLC (30% EtOAc/hexanes), the
productwasobtainedascolorless oil(0.013 g, 0.048 mmol, 75%, using
PtCl4; 0.012 g, 0.046 mmol, 66%, using PTSeSi). Rf (30% EtOAc/hex-
anes) 0.58. IR (neat): nmax 2928, 1631, 1515, 1446, 1274, 1216, 1195,

3910
S. Radomkit et al. / Tetrahedron 67 (2011) 3904e3914
1162, 1118 cmꢀ1
.
1H NMR (200 MHz, CDCl3):
d
1.95e2.23 (m, 1H),
0.009 g, 0.044 mmol, 48%, using PTSeSi). Rf (30% EtOAc/hexanes)
0.66. 1H NMR (200 MHz, CDCl3):
2.01e2.32 (m, 2H), 2.75e2.89 (m,
2.62e3.00 (m, 1H), 3.82 (s, 3H), 5.00 (dd, J¼9.8, 2.8 Hz, 1H), 6.53 (d,
d
J¼7.6 Hz, 1H), 6.80 (d, J¼11.4 Hz, 1H), 7.28e7.44 (m, 5H). 13C NMR
1H), 2.95e3.12 (m, 1H), 5.09 (dd, J¼9.4, 3.0 Hz, 1H), 6.87e6.96 (m,
(50 MHz, CDCl3):
d
24.4, 29.7, 56.2, 77.9, 102.2, 112.9 (d, JCeF¼3.2 Hz),
2H), 7.10e7.21 (m, 2H), 7.34e7.48 (m, 5H). 13C NMR (50 MHz,
115.7 (d, JCeF¼19.2 Hz),126.0,127.9,128.5,141,146.5(d, JCeF¼12.8Hz),
146.8 (d, JCeF¼235.9 Hz), 150.9. LRMS (EI) m/z (rel intensity) 259
(MþHþ, 17), 258 (Mþ, 100), 227 (20), 167 (30), 154 (28), 104 (73), 91
(33). TOF-HRMS calcd for C16H15FO2 (Mþ) 258.1051, found 258.1055.
CDCl3): d 25.1, 29.9, 77.7, 116.9,120.3, 121.8, 126.0, 127.3, 127.8, 128.5,
129.5, 141.7, 155.1. TOF-HRMS calcd for C15H15O (MþHþ) 211.1117,
found 211.1114. These spectroscopic data were identical to those
reported previously.3a
4.1.4. 6,7-Dimethoxy-2-phenylchroman (18). Following the general
procedure and purification by PTLC (30% EtOAc/hexanes), the
product was obtained as yellowish oil (0.014 g, 0.052 mmol, 84%,
using PtCl4; 0.012 g, 0.045 mmol, 60%, using PTSeSi). Rf (30% EtOAc/
hexanes) 0.61. IR (neat): nmax 2929, 2849,1736,1619,1511,1450,1413,
1261, 1224, 1193, 1170, 1125, 1018 cmꢀ1. 1H NMR (200 MHz, CDCl3):
4.1.9. 1:1 Mixture of cis- and trans-6-bromo-7-methoxy-2-phenyl-3-
propylchroman (24a). Following the general procedure and purifi-
cation by PTLC (30% EtOAc/hexanes), the product was obtained as
a 1:1 mixture of 2,3-cis and 2,3-trans diastereomers as colorless oil
(0.018 g, 0.048 mmol, 78%). Rf (30% EtOAc/hexanes) 0.68. IR (neat):
nmax 2957, 2929, 2871,1610,1575,1496,1443,1430,1311,1282,1200,
d
1.98e2.25 (m, 2H), 2.65e3.03 (m, 2H), 3.83 (s, 3H), 3.84 (s, 3H), 4.99
1155, 1058 cmꢀ1. 1H NMR (400 MHz, CDCl3):
d
0.77 (t, J¼7.04 Hz, 3H,
(dd, J¼9.5, 2.9 Hz,1H), 6.51 (s,1H), 6.59 (s,1H), 7.32e7.45 (m, 5H).13C
trans), 0.81 (t, J¼7.13 Hz, 3H, cis), 1.01e1.45 (m, 4H), 2.04e2.13 (m,
1H, trans), 2.16e2.22 (m, 1H, cis), 2.48 (dd, J¼16.1, 9.9 Hz, 1H, trans),
2.61 (dd, J¼16.1, 4.4 Hz, 1H, cis), 2.81 (dd, J¼16.2, 5.0 Hz, 1H, trans),
2.97 (dd, J¼16.1, 5.4 Hz, 1H, cis), 3.81 (s, 3H, trans), 3.85 (s, 3H, cis),
4.71 (d, J¼8.6 Hz, 1H, trans), 5.22 (d, J¼2.6 Hz, 1H, cis), 6.47 (s, 1H,
trans), 6.52 (s, 1H, cis), 7.23 (s, 1H, trans), 7.24 (s, 1H, cis), 7.28e7.41
NMR (50 MHz, CDCl3): d 24.7, 30.1, 55.9, 56.5, 77.8,101.1,112.2,126.0,
127.8, 128.3, 128.5, 141.7, 143.1, 148.3, 148.9. LRMS (EI) m/z (rel in-
tensity) 270 (Mþ, 100), 239 (13), 166 (40), 138 (16), 91 (11). TOF-
HRMS calcd for C17H19O3 (MþHþ) 271.1329, found 271.1325.
4.1.5. 6-Methoxy-2-phenylchroman (19). Following the general
procedure and purification by PTLC (30% EtOAc/hexanes), the
product was obtained as colorless oil (0.011 g, 0.047 mmol, 46%,
using PtCl4; 0.003 g, 0.014 mmol, 17%, using PTSeSi). Rf (30% EtOAc/
hexanes) 0.57. IR (neat): nmax 3338, 2927, 2851, 1612, 1494, 1431,
1268, 1220, 1149, 1067, 1048, 1035, 1000 cmꢀ1. 1H NMR (200 MHz,
(m, 5H). 13C NMR (100 MHz, CDCl3):
d 14.0, 19.5 (trans), 20.5 (cis),
28.2 (cis), 28.4 (cis), 29.4 (trans), 33.8 (trans), 36.5 (cis), 37.1 (trans),
56.2, 80.2 (cis), 83.2 (trans), 100.7 (trans), 100.8 (cis), 101.8 (cis),
101.9 (trans), 114.5 (cis), 115.2 (trans), 125.9 (cis), 127.0 (trans), 127.3
(cis), 128.1 (cis), 128.2 (trans), 128.5 (trans), 133.0 (trans), 133.5 (cis),
139.6 (cis), 140.0 (trans), 154.8, 154.9. LRMS (EI) m/z (rel intensity)
362 (Mþþ2, 43), 360 (Mþ, 44), 271 (60), 269 (63), 190 (100), 117
(97), 115 (40), 104 (38), 91(42). TOF-HRMS calcd for C19H22BrO2
(MþHþ) 361.0798, found 361.0798.
CDCl3): d 1.97e2.25 (m, 2H), 2.71e3.09 (m, 2H), 3.77 (s, 3H), 5.01 (dd,
J¼9.6, 3.0 Hz, 1H), 6.64 (d, J¼3.0 Hz, 1H), 6.71 (dd, J¼8.8, 3.0 Hz, 1H),
6.85 (d, J¼8.8 Hz, 1H), 7.29e7.45 (m, 5H). 13C NMR (50 MHz, CDCl3):
d
25.5, 30.0, 55.8, 77.6 (superimposed with CDCl3),113.4,114.0,117.5,
122.3, 126.0, 127.7, 128.5, 141.8, 153.2, 153.3. LRMS (EI) m/z (rel in-
tensity) 240 (Mþ, 100), 149 (41), 136 (89), 108 (31), 91 (25). TOF-
HRMS calcd for C16H17O2 (MþHþ) 241.1223, found 241.1218.
4.1.10. trans-6-Bromo-7-methoxy-2-phenyl-3-propylchroman
(24b). Following the general procedure and purification by PTLC
(30% EtOAc/hexanes), the product was obtained as colorless oil
(0.016 g, 0.044 mmol, 72%). Rf (30% EtOAc/hexanes) 0.63. 1H NMR
4.1.6. 7-Bromo-6-methoxy-2-phenylchroman (20). Following the
general procedure and purification by PTLC (30% EtOAc/hexanes), the
product was obtained as colorless oil (0.017 g, 0.052 mmol, 91%, using
PtCl4; 0.008 g, 0.024 mmol, 39%, using PTSeSi). Rf (30% EtOAc/hexanes)
0.51. IR (neat): nmax 3027, 2927, 2847,1603,1490,1401,1312,1194,1046,
(400 MHz, CDCl3):
d
0.81 (t, J¼3.61 Hz, 3H), 1.01e1.45 (m, 4H),
2.01e2.13 (m,1H), 2.48 (d, J¼16.1, 9.9 Hz,1H), 2.81 (d, J¼16.2, 5.1 Hz,
1H), 3.82 (s, 3H), 4.71 (d, J¼8.6 Hz, 1H), 6.47 (s, 1H), 7.23 (s, 1H),
7.33e7.41 (m, 5H). 13C NMR (100 MHz, CDCl3):
d 14.0, 19.5, 29.4,
33.8, 37.1, 56.2, 83.2, 100.7, 101.8, 115.3, 127.0, 128.2, 128.6, 133.1,
140.1, 154.8, 154.9. TOF-HRMS calcd for C19H22BrO2 (MþHþ)
361.0798, found 361.0812. These spectroscopic data were identical
to those reported previously.3a
1006 cmꢀ1.1H NMR (200 MHz, CDCl3):
d
1.96e2.27 (m,1H), 2.67e3.05
(m,1H), 3.83 (s, 3H), 5.01 (dd, J¼9.8, 2.8 Hz,1H), 6.62 (s,1H), 7.14 (s,1H),
7.31e7.41 (m, 5H). 13C NMR (50 MHz, CDCl3):
25.2, 29.6, 56.9, 77.6,
d
109.6,112.7,121.5,127.6,127.9,128.3,128.5,141.3,149.4,149.8. LRMS(EI)
m/z (rel intensity) 320 (Mþþ2, 87), 318 (Mþ, 88), 216 (66), 214 (70),178
(49), 148 (58), 104 (48), 91 (97), 81 (53), 77 (57), 69 (100). TOF-HRMS
calcd for C16H15BrO2 (Mþ) 318.0250, found 318.0235.
4.1.11. trans-6-Bromo-7-methoxy-3-methyl-2-phenylchroman
(25). Following the general procedure and purification by PTLC
(30% EtOAc/hexanes), the product was obtained as colorless oil
(0.020 g, 0.061 mmol, 99%). Rf (30% EtOAc/hexanes) 0.68. IR (neat):
nmax 2925, 1611, 1575, 1496, 1443, 1404, 1310, 1281, 1201, 1156, 1051,
4.1.7. Methyl 7-methoxy-2-phenylchroman-6-carboxylate (21). Follo
wing the general procedure and purification by PTLC (30% EtOAc/
hexanes), the product was obtained as colorless oil (0.012 g,
0.042 mmol, 88%, using PtCl4; 0.006 g, 0.020 mmol, 23%, using
PTSeSi). Rf (30%EtOAc/hexanes)0.38. IR (neat):nmax 2923, 2853,1722,
1697, 1619, 1573, 1495, 1434, 1280, 1260, 1193, 1144, 1079 cmꢀ1. 1H
1019 cmꢀ1
.
1H NMR (400 MHz, CDCl3):
d
0.83 (d, J¼6.8 Hz, 3H),
2.11e2.23 (m, 1H), 2.54 (dd, J¼16.1, 10.8 Hz, 1H), 2.77 (dd, J¼16.2,
5.1 Hz, 1H), 3.81 (s, 3H), 4.58 (d, J¼9.3 Hz, 1H), 6.47 (s, 1H), 7.22 (s,
1H), 7.33e7.41 (m, 5H). 13C NMR (100 MHz, CDCl3):
d 17.7, 32.6, 32.8,
56.2, 84.4, 100.8, 101.8, 115.4, 127.1, 128.3, 128.5, 132.8, 139.7, 154.8,
155.0. LRMS (EI) m/z (rel intensity) 334 (Mþþ2, 37), 332 (Mþ, 38),
162 (33), 118 (42), 117 (100), 115 (34), 91 (73). TOF-HRMS calcd for
C17H18BrO2 (MþHþ) 333.0485, found 333.0475.
NMR (200 MHz, CDCl3):
(s, 3H), 3.862 (s, 3H), 5.10 (dd, J¼9.9, 2.5 Hz,1H), 6.51 (s,1H), 7.33e7.42
(m, 5H), 7.68 (s, 1H). 13C NMR (50 MHz, CDCl3):
24.0, 29.7, 51.7, 56.0,
d 1.98e2.30(m, 2H), 2.68e3.01 (m, 2H), 3.855
d
78.4, 100.5, 111.8, 113.4, 125.9, 128.0, 128.5, 133.6, 140.8, 159.5, 166.2.
LRMS (EI) m/z (rel intensity) 299 (MþHþ, 19), 298 (Mþ, 93), 239 (89),
179 (43), 178 (61), 149 (52), 104 (51), 91 (52), 71 (68), 57 (100). TOF-
HRMS calcd for C18H19O4 (MþHþ) 299.1278, found 299.1282.
4.1.12. trans-(6-Bromo-7-methoxy-2-phenylchroman-3-yl)methyl
benzoate (26). Following the general procedure and purification by
PTLC (15% EtOAc/hexanes), the product was obtained as colorless
oil (0.029 g, 0.063 mmol, 99%). Rf (15% EtOAc/hexanes) 0.34. IR
4.1.8. 2-Phenylchroman (23). Following the general procedure and
purification by PTLC (30% EtOAc/hexanes), the product was
obtained as colorless oil (0.005 g, 0.021 mmol, 23%, using PtCl4;
(neat): nmax 2920, 2853, 1718, 1495, 1268, 1109 cmꢀ1
.
1H NMR
2.75e2.55 (m, 1H), 2.88 (d, J¼7.8 Hz, 2H), 3.83
(s, 3H), 4.07 (dd, J¼11.4, 6.0 Hz, 1H), 4.28 (dd, J¼11.3, 4.7 Hz, 1H),
(200 MHz, CDCl3):
d

S. Radomkit et al. / Tetrahedron 67 (2011) 3904e3914
3911
5.04 (d, J¼8.4 Hz, 1H), 6.52 (s, 1H), 7.63e7.25 (m, 9H), 8.00e7.92 (m,
2H). 13C NMR (50 MHz, CDCl3):
26.9, 37.7, 56.3, 65.0, 79.9, 100.9,
(30% EtOAc/hexanes), the product was obtained as colorless oil
(0.011 g, 0.037 mmol, 75%). Rf (30% EtOAc/hexanes) 0.63. IR (neat):
nmax 2924, 2853, 1677, 1610, 1576, 1496, 1443, 1476, 1198, 1160,
d
102.4, 114.2, 126.0, 126.3, 126.4, 126.7, 127.2, 128.4, 128.6, 128.8,
129.5, 129.7, 133.1, 138.9, 154.5, 155.1, 166.2. LRMS (EI) m/z (rel in-
tensity) 454 (Mþ2, 15), 452 (Mþ, 13), 332 (30), 330 (24), 251 (21),
115 (26), 105 (90), 91 (22), 77 (100), 51 (43). TOF-HRMS calcd for
C24H22BrO4 (MþHþ) 453.0696, found 453.0706.
1051 cmꢀ1 1H NMR (200 MHz, CDCl3):
. d 1.53e1.59 (m, 1H),
1.63e1.73 (m, 1H), 2.09e2.26 (m, 4H), 2.50 (dd, J¼16.4, 3.5 Hz, 1H),
2.96 (dd, J¼16.4, 6.6 Hz, 1H), 3.81 (s, 3H), 4.48 (t, J¼3.6 Hz, 1H),
5.92e5.96 (m, 1H), 6.01 (td, J¼10.0, 3.4 Hz, 1H), 6.41 (s, 1H), 7.18 (s,
1H). 13C NMR (50 MHz, CDCl3):
d 23.0, 25.0, 28.7, 30.4, 56.1, 70.6,
4.1.13. trans-Ethyl 6-bromo-7-methoxy-2-phenylchroman-3-carbox-
ylate (27). Following the general procedure and purification by
PTLC (15% EtOAc/hexanes), the product was obtained as colorless
oil (0.010 g, 0.024 mmol, 33%). Rf (15% EtOAc/hexanes) 0.32. IR
100.8, 101.6, 113.9, 125.8, 132.9, 133.1, 1153.5, 1154.7. LRMS (EI) m/z
(rel intensity) 296 (Mþþ2, 47), 294 (Mþ, 48), 217 (91), 215 (98), 97
(38), 92 (49), 91 (36), 83 (40), 80 (70), 79 (100). TOF-HRMS calcd for
C14H16BrO2 (MþHþ) 295.0328, found 295.0324.
(neat): nmax 2925, 1728, 1612, 1442, 1151, 1024 cmꢀ1
.
1H NMR
0.96 (t, J¼7.2 Hz, 3H), 3.25e2.83 (m, 3H), 3.82
(s, 3H), 3.94 (q, J¼7.2 Hz, 2H), 5.07 (d, J¼8.4 Hz, 1H), 7.27 (s, 1H),
7.40e7.35 (m, 6H). 13C NMR (50 MHz, CDCl3):
13.8, 27.7, 29.7, 45.5,
(200 MHz, CDCl3):
d
4.1.18. 6-Bromo-7-methoxy-2-methyl-2-(prop-1-en-2-yl)chroman
(32). Following the general procedure and purification by PTLC
(30% EtOAc/hexanes), the product was obtained as colorless oil
(0.005 g, 0.016 mmol, 25%). Rf (30% EtOAc/hexanes) 0.61. IR (neat):
d
56.2, 60.8, 79.3, 101.0, 102.7, 113.5, 127.0, 128.5, 128.7, 132.8, 138.3,
154.3, 155.1, 172.1. LRMS (EI) m/z (rel intensity) 392 (Mþþ2, 99), 390
(Mþ, 100), 346 (81), 344 (84), 265 (96), 238 (60), 237 (56), 131 (55),
91 (93), 77 (66). TOF-HRMS calcd for C19H20BrO4 (MþHþ) 391.0539,
found 391.0532.
nmax 2924, 2851, 1610, 1574, 1496, 1443, 1200, 1149, 1090, 1051 cmꢀ1
.
1H NMR (200 MHz, CDCl3):
d 1.46 (s, 3H), 1.77 (s, 3H), 1.68e1.83 (m,
1H), 2.11 (dt, J¼13.6, 4.9 Hz, 1H), 2.56 (dd, J¼4.8, 8.0 Hz, 2H), 3.84 (s,
3H), 4.85 (s, 1H), 4.90 (s, 1H), 6.44 (s, 1H), 7.15 (s, 1H). 13C NMR
(50 MHz, CDCl3):
d 35.3, 37.4, 41.0, 43.6, 62.1, 78.9, 94.1, 94.3, 101.7,
4.1.14. trans-Ethyl 6-bromo-7-methoxy-2-(4-methoxyphenyl)chro-
man-3-carboxylate (28). Following the general procedure and pu-
rification PTLC (15% EtOAc/hexanes), the desired product was
obtained as colorless oil (0.020 g, 0.048 mmol, 76%). Rf (15% EtOAc/
hexanes) 0.21. IR (neat): nmax 2933, 1721, 1612, 1574, 1515, 1447,
104.2, 116.9, 126.5, 132.1, 132.6. LRMS (EI) m/z (rel intensity) 298
(Mþþ2, 41), 296 (Mþ, 42), 217 (71), 215 (51), 178 (100). TOF-HRMS
calcd for C14H18BrO2 (MþHþ) 297.0485, found 297.0485.
4.1.19. (E)-6-Bromo-7-methoxy-2-styrylchroman
(37). Following
1372, 1243, 1201, 1186, 1153, 1032. 1H NMR (400 MHz, CDCl3):
d
0.99
the general procedure and purification by PTLC (20% EtOAc/hex-
anes), the desired compound was obtained as colorless oil (0.026 g,
0.074 mmol, 80%). Rf (20% EtOAc/hexanes) 0.50. IR (neat): nmax 3020,
2960, 2925, 2854,1723,1610,1572,1495,1443,1403,1307,1261,1187,
(t, J¼7.1 Hz, 3H), 2.92 (dd, J¼15.6, 4.9 Hz, 1H), 3.02 (ddd, J¼10.9, 9.3,
4.9 Hz, 1H), 3.19 (dd, J¼15.5, 11.0 Hz, 1H), 3.81 (s, 6H), 3.947 (q,
J¼7.1 Hz, 1H), 3.953 (q, J¼7.1 Hz, 1H), 5.00 (d, J¼9.3 Hz, 1H), 6.48 (s,
1H), 6.90 (AA0BB0, J¼8.7 Hz, 2H), 7.26 (s, 1H), 7.32 (AA0BB0, J¼8.7 Hz,
1154, 1047, 1028 cmꢀ1. 1H NMR (200 MHz, CDCl3):
d 1.81e2.00 (m,
2H). 13C NMR (100 MHz, CDCl3):
d
13.9, 28.0, 45.4, 55.3, 56.2, 60.7,
1H), 2.06e2.17 (m, 1H), 2.73e2.83 (m, 2H), 3.84 (s, 3H), 4.66e4.73
(m, 1H), 6.31 (dd, J¼16.1, 6.3 Hz, 1H), 6.48 (s, 1H) 6.72 (d, J¼16.0 Hz,
79.0, 101.0, 102.5, 113.5, 113.9, 128.4, 130.3, 132.8, 154.5, 155.1, 159.9,
172.2. LRMS (EI) m/z (rel intensity) 422 (Mþþ2, 76), 421 (MþHþ,18),
420 (Mþ, 77), 376 (97), 374 (100), 295 (46), 269 (42), 267 (60), 206
(35), 161 (83), 134 (92), 121 (52). TOF-HRMS calcd for C20H21BrO5
(Mþ) 420.0572, found 420.0575.
1H), 7.11e7.44 (m, 6H). 13C NMR (50 MHz, CDCl3):
d 23.4, 27.8, 56.2,
101.1, 101.9, 115.2, 126.0, 127.9, 128.2, 128.5, 131.9, 133.1, 136.3, 154.5,
154.9. LRMS (EI) m/z (rel intensity) 346 (Mþþ2, 53), 345 (MþHþ,18),
344 (Mþ, 54), 265 (22), 216 (14), 215 (13),174 (19),143 (32),142 (54),
141 (15),137 (23),130 (57),129 (100),128 (34),115 (45), 91 (59). TOF-
HRMS calcd for C18H18BrO2 (MþHþ) 345.0485, found 345.0492.
4.1.15. 8-Bromo-7-methoxy-4b,10,10a,11-tetrahydroindeno[1,2-b]
chromene (29). Following the general procedure and purification
by PTLC (15% EtOAc/hexanes), the desired compound was obtained
as colorless oil (0.008 g, 0.024 mmol, 45%). Rf (15% EtOAc/hexanes)
4.1.20. (E)-Ethyl 6-bromo-7-methoxy-2-styrylchroman-3-carboxyl-
ate (38). Following the general procedure and purification by PTLC
(10% EtOAc/hexanes), the desired compound was obtained as a 10:1
mixture of C2eC3 trans:cis diastereomers as colorless oil (0.014 g,
0.034 mmol, 33%). Rf (10% EtOAc/hexanes) 0.29. IR (neat): nmax 2980,
0.51. 1H NMR (200 MHz, CDCl3):
d 2.46e2.58 (m, 1H), 2.73e3.13 (m,
4H), 3.79 (s, 3H), 5.48 (d, J¼5.8 Hz, 1H), 6.45 (s, 1H), 7.19 (s, 1H),
7.23e7.30 (m, 3H), 7.48e7.52 (m, 1H). 13C NMR (50 MHz, CDCl3):
d
26.7, 36.6, 37.5, 56.1, 81.5, 101.5, 101.7, 116.0, 125.1, 125.2, 126.9,
2937, 1729, 1612, 1575, 1496, 1443, 1256, 1200, 1187, 1154, 1018 cmꢀ1
.
128.9, 132.5, 142.2, 142.6, 154.7, 155.2. TOF-HRMS calcd for
C17H16BrO2 (MþHþ) 331.0328, found 331.0325. These spectroscopic
data were identical to those reported previously.3a
1H NMR (200 MHz, CDCl3):
d
1.17 (t, J¼7.1 Hz, 3H),1.27 (t, J¼7.2 Hz, 3H,
minor), 2.79e3.00(m, 2H), 3.06e3.21 (m,1H), 3.83 (s, 3H), 3.85(s, 3H,
minor), 4.13 (q, J¼7.1 Hz, 3H), 4.76 (app t, J¼7.9 Hz,1H), 5.21e5.24 (m,
1H, minor), 6.19 (dd, J¼16.0, 6.6 Hz, 1H, minor), 6.26 (dd, J¼15.8,
7.4 Hz, 1H), 6.64 (d, J¼16.6 Hz, 1H, minor), 6.73 (dd, J¼16.0 Hz, 1H),
4.1.16. 7-Bromo-6-methoxy-1,2,3,3a,9,9a-hexahydrocyclopenta[b]
chromene (30). Following the general procedure and purification
by PTLC (15% EtOAc/hexanes), the desired compound was obtained
as colorless oil (0.008 g, 0.027 mmol, 33%). Rf (15% EtOAc/hexanes)
7.25e7.43 (m, 6H). 13C NMR (50 MHz, CDCl3):
d 14.2, 23.5 (minor),
26.9, 42.0 (minor), 44.1, 56.2, 61.1, 75.5 (minor), 77.6 (superimposed
with CDCl3),100.9,102.6,113.4,125.5,126.7,128.2,128.5,132.8,134.2,
135.9,153.6,155.1,172.1. LRMS (EI) m/z (rel intensity) 418 (Mþþ2, 64),
417 (MþHþ,18), 416 (Mþ, 66), 372 (57), 370 (53), 281 (100), 279 (88),
204 (55), 202 (49), 129 (63), 128 (61), 115 (39). TOF-HRMS calcd for
C21H22BrO4 (MþHþ) 417.0696, found 417.0708.
0.71. IR (neat): nmax 2941, 1496, 1445, 1200, 1160, 1053 cmꢀ1
.
1H
NMR (400 MHz, CDCl3):
d 1.46e1.35 (m, 2H), 2.00e1.64 (m, 4H),
2.31e2.22 (m, 1H), 2.55 (dd, J¼8.2, 1.4 Hz, 1H), 2.94 (dd, J¼8.4,
3.2 Hz, 1H), 3.82 (s, 3H), 4.36 (dt, J¼2.8, 1.0 Hz, 1H), 6.39 (s, 1H), 7.18
(s, 1H). 13C NMR (100 MHz, CDCl3):
d 21.8, 25.5, 28.1, 32.9, 37.5, 56.1,
79.6, 101.1, 101.6, 114.3, 133.2, 154.4, 154.6. LRMS (EI) m/z (rel in-
tensity) 284 (Mþþ2, 100), 282 (Mþ, 99), 217 (36), 215 (33), 203 (17).
TOF-HRMS calcd for C13H15BrO2 (Mþ) 282.0250, found 282.0244.
4.1.21. 6-Bromo-3-(but-3-enyl)-7-methoxy-2-phenylchroman
(39). Following the general procedure and purification by PTLC
(15% EtOAc/hexanes), the desired compound was obtained as col-
orless oil (0.009 g, 0.023 mmol, 30%). Rf (15% EtOAc/hexanes) 0.52.
IR (neat): nmax 2930, 2854, 1611, 1576, 1496, 1444, 1201, 1158,
4.1.17. 7-Bromo-6-methoxy-2,4a,9,9a-tetrahydro-1H-xanthene
(31). Following the general procedure and purification by PTLC
1053 cmꢀ1 1H NMR (400 MHz, CDCl3):
. d 1.13e1.37 (m, 2H),

3912
S. Radomkit et al. / Tetrahedron 67 (2011) 3904e3914
1.88e2.01 (m, 2H), 2.05e2.17 (m, 2H), 2.49 (dd, 1H, J¼4.9, 8.1 Hz),
2.82 (dd, 1H, J¼2.2, 8.4 Hz), 3.82 (s, 3H), 4.73 (d, 1H, J¼4 Hz), 4.92 (d,
1H, J¼4.4 Hz), 4.95 (d, 1H, J¼8 Hz), 5.61e5.72 (m, 1H), 6.47 (s, 1H),
a 2.7:1 mixture of C2-C4 cis:trans diastereomers as colorless oil
(0.015 g, 0.034 mmol, 70%). Rf (30% EtOAc/hexanes) 0.54. IR (neat):
nmax 2960, 2228, 1608, 1574, 1486, 1443, 1399, 1311, 1261, 1197, 1159,
7.23 (s, 1H), 7.30e7.41 (m, 5H). 13C NMR (100 MHz, CDCl3):
d
29.3,
1052, 1020 cmꢀ1. 1H NMR (400 MHz, CDCl3):
d
0.54 (d, J¼7.0 Hz, 3H,
30.5, 30.8, 36.6, 56.1, 83.0, 100.7, 101.8, 115.0, 115.1, 126.9, 128.3,
128.6, 133.0, 137.9, 139.9, 154.7, 154.9. LRMS (EI) m/z (rel intensity)
374 (Mþþ1, 17), 372 (Mþꢀ1, 17), 241 (14), 239 (17), 217 (24), 215
(24), 178 (51), 161 (30), 149 (30), 117 (100), 91 (53), 71 (46), 69 (88).
TOF-HRMS calcd for C20H22BrO2 (MþHþ) 373.0798, found
373.0793.
minor), 0.58 (d, J¼6.6 Hz, 3H), 2.17e2.27 (m, 1H), 2.45e2.55 (m, 1H,
minor), 3.81 (d, J¼10.8 Hz, 1H), 3.813 (s, 3H), 3.86 (s, 3H, minor),
4.08 (d, J¼5.4 Hz, 1H, minor), 4.73 (d, J¼10.1 Hz, 1H), 4.75 (d,
J¼10.0 Hz, 1H, minor), 6.51 (s, 1H), 6.58 (s, 1H, minor), 6.69 (d,
J¼0.8 Hz, 1H), 7.05 (s, 1H, minor), 7.22e7.42 (m, 5H), 7.62 (AA0BB0,
J¼8.4 Hz, 2H), 7.64 (AA0BB0, J¼8.3 Hz, 2H). 13C NMR (100 MHz,
CDCl3):
d 15.2 (minor), 15.4, 36.8 (minor), 40.8, 45.8 (minor), 50.4,
4.1.22. 6-Bromo-7-methoxy-2,2-dimethyl-3-((S)-3-methyl pent-4-
enyl)chroman (40). Following the general procedure and purifica-
tion by PTLC (15% EtOAc/hexanes), the desired compound was
obtained as colorless oil (0.022 g, 0.062 mmol, 62%). Rf (15% EtOAc/
hexanes) 0.60. IR (neat): nmax 2931, 2865, 1610, 1577, 1486, 1497,
56.2, 79.3 (minor), 84.3, 100.7 (minor), 100.9, 102.7 (minor), 102.8,
110.8 (minor), 111.1, 116.7(minor), 118.4 (minor), 118.7, 125.5 (mi-
nor), 127.1 (minor), 127.4, 128.5, 128.6 (minor), 128.7, 128.8, 130.0,
130.8 (minor),131.9 (minor),132.6,133.3,133.6 (minor),138.8, 139.1
(minor), 147.2 (minor), 149.0, 154.8 (minor), 155.4, 155.5, 155.8
(minor). LRMS (EI) m/z (rel intensity) 435 (Mþþ2, 98), 433 (Mþ,
100), 344 (40), 342 (42), 317 (46), 316 (88), 315 (43), 314 (72), 263
(46), 118 (74), 117 (74). TOF-HRMS calcd for C24H21BrNO2 (MþHþ)
434.0750, found 434.0749.
1315, 1203, 1161, 1134, 1054 cmꢀ1. 1H NMR (400 MHz, CDCl3):
d 1.00
(d, 3H, J¼2.2 Hz), 1.02 (d, 3H, J¼2.2 Hz), 1.13 (s, 3H), 1.14 (s, 3H),
1.20e1.72 (m, 2H), 2.06e2.16 (m, 1H), 2.26e2.37 (m, 1H), 2.77 (td,
1H, J¼7.8, 2.5 Hz), 3.82 (s, 3H), 4.94 (d, 1H, J¼4.6 Hz), 4.97 (d, 1H,
J¼8.3 Hz), 5.60e5.75 (m, 1H), 6.36 (s, 1H), 7.18 (s, 1H). 13C NMR
(100 MHz, CDCl3):
d
19.9, 20.4, 20.5, 20.7, 27.1, 27.2, 27.5, 27.6, 28.2,
4.1.26. 6-Bromo-7-methoxy-3-methyl-2-phenyl-4-(4-(tri-
fluoromethoxy)phenyl) chroman (47). Following the general pro-
cedure and purification by PTLC (30% EtOAc/hexanes), the desired
compound was obtained as a 1.9:1 mixture of C2-C4 cis:trans di-
astereomers as colorless oil (0.010 g, 0.020 mmol, 51%). Rf (30%
EtOAc/hexanes) 0.62. IR (neat): nmax 2928, 1608, 1572, 1488, 1440,
28.3, 34.3, 34.5, 37.8, 37.9, 40.6, 41.0, 56.1, 78.2, 78.3, 101.2, 112.8,
113.1, 115.0, 132.9, 144.1, 144.5, 153.7, 154.9. LRMS (EI) m/z (rel in-
tensity) 354 (Mþþ2, 23), 352 (Mþ, 24), 217 (95), 215 (100). TOF-
HRMS calcd for C18H26BrO2 (MþHþ) 353.1111, found 353.1112.
4.1.23. 6-Bromo-7-methoxy-2-phenyl-4-(4-(trifluoromethoxy)phe-
nyl)chroman (44). Following the general procedure and purifica-
tion by PTLC (30% EtOAc/hexanes), the desired compound was
obtained as a 4:1 mixture of C2-C4 cis:trans diastereomers as col-
orless oil (0.019 g, 0.039 mmol, 83%). Rf (30% EtOAc/hexanes) 0.63.
1399, 1310, 1256, 1195, 1153, 1119, 1053, 1019 cmꢀ1
.
1H NMR
(200 MHz, CDCl3):
d
0.54 (d, J¼7.0 Hz, 3H, minor), 0.58 (d, J¼6.6 Hz,
3H), 2.16e2.26 (m,1H), 2.40e2.50 (m,1H, minor), 3.75 (d, J¼10.8 Hz
1H), 3.81 (s, 3H), 3.85 (s, 3H, minor), 4.03 (d, J¼5.2 Hz, 1H, minor),
4.73 (d, J¼10.1 Hz, 1H), 4.79 (d, J¼10.1 Hz, 1H, minor), 6.50 (s, 1H),
6.57 (s, 1H, minor), 6.77 (d, J¼0.9 Hz, 1H), 7.09e7.46 (m, 10H). 13C
1H NMR (400 MHz, CDCl3):
d
2.17 (ddd, J¼11.9, 11.8, 11.8 Hz, 1H),
2.38 (ddd, J¼13.8, 5.9, 1.8 Hz, 1H), 2.42e2.48 (m, 1H, minor), 3.85 (s,
3H), 3.89 (s, 3H, minor), 4.17 (dd, J¼5.5, 3.3 Hz, 1H, minor), 4.31 (dd,
J¼12.0, 5.8 Hz, 1H), 4.98 (dd, J¼10.5, 2.2 Hz, 1H, minor), 5.17 (dd,
J¼11.4, 1.5 Hz, 1H), 6.54 (s, 1H), 6.60 (s, 1H, minor), 6.89 (s, 1H), 7.12
(s, 1H, minor), 7.14e7.26 (m, 4H), 7.31e7.47 (m, 5H). 13C NMR
NMR (100 MHz, CDCl3): d 15.2 (minor), 15.4, 36.9 (minor), 40.9, 45.1
(minor), 49.6, 56.2, 79.3 (minor), 84.5, 100.6 (minor), 100.8, 102.6,
117.7 (minor), 119.3, 120.5 (minor), 121.1, 125.5 (minor), 127.2, 127.4,
128.4, 128.6 (minor), 128.7, 130.5, 131.3 (minor), 133.5, 133.7 (mi-
nor), 139.1, 140.3 (minor), 141.9, 154.8 (minor), 155.2, 155.5. LRMS
(EI) m/z (rel intensity) 494 (Mþþ2, 19), 492 (Mþ, 19), 191 (27), 289
(27), 278 (33), 277 (100), 117 (57), 91(26). TOF-HRMS calcd for
C24H21BrF3O3 (MþHþ) 493.0621, found 493.0618.
(100 MHz, CDCl3): d 40.5, 42.1, 56.2, 78.4, 101.1, 102.6, 113.6 (minor),
118.5, 121.0 (minor), 121.3, 126.0, 128.3, 128.57 (minor), 128.65,
129.6, 129.8 (minor), 133.1, 134.0 (minor), 140.3, 142.6, 148.1, 155.4,
155.7. TOF-HRMS calcd for C23H18BrF3O3 (Mþ) 478.0386, found
478.0379. These spectroscopic data were identical to those reported
previously.3a
4.1.27. 6-Bromo-7-methoxy-2-(4-methoxyphenyl)chroman
(53). Following the general procedure and purification by PTLC
(20% EtOAc/hexanes), the desired compound was obtained as col-
orless oil (0.032 g, 0.092 mmol, 99%). Rf (20% EtOAc/hexanes) 0.56.
IR (neat): nmax 3000, 2929, 2852, 1732, 1611, 1573, 1514, 1495, 1443,
1403, 1305, 1246, 1193, 1153, 1034 cmꢀ1. 1H NMR (200 MHz, CDCl3):
4.1. 24. 4-Allyl-6-bromo-7-methoxy-2-phenylchroman
(45). Following the general procedure and purification by PTLC
(15% EtOAc/hexanes), the desired compound was obtained as col-
orless oil (0.013 g, 0.033 mmol, 49%). Rf (15% EtOAc/hexanes) 0.52.
IR (neat): nmax 2916, 2853, 1609, 1568, 1488, 1443, 1199, 1156,
d
1.92e2.21 (m, 2H), 2.65e3.00 (m, 2H), 3.82 (s, 6H), 4.97 (dd, J¼9.6,
3.0 Hz, 1H), 6.48 (s, 1H), 6.93 (app. td, J¼8.8, 2.6 Hz, 2H), 7.24 (s, 1H),
1052 cmꢀ1
.
1H NMR (400 MHz, CDCl3):
d
1.98e2.14 (m, 1H),
7.34 (app. td, J¼8.8, 1.8 Hz, 2H). 13C NMR (50 MHz, CDCl3):
d 29.2,
2.17e2.29 (m, 2H), 2.27e2.44 (m, minor), 2.53e2.61 (m, minor),
2.68e2.475 (m, 1H), 2.80e2.88 (m, minor), 3.07e3.17 (m, 1H), 3.82
(s, 3H), 3.83 (s, minor), 4.98e5.15 (m, 3H), 5.71e5.90 (m, 1H), 6.49
(s, 1H), 6.51 (s, minor), 7.31e7.45 (m, 6H). 13C NMR (100 MHz,
29.5, 55.3, 56.2, 77.8, 101.3, 102.0, 114.0, 115.3, 127.4, 133.0, 133.5,
155.0,155.3,159.5. LRMS (EI) m/z (rel intensity) 351 (Mþþ3,14), 350
(Mþþ2, 78), 349 (MþHþ, 17), 348 (Mþ, 80), 271 (8), 269 (31), 134
(62), 121 (36), 91 (100). TOF-HRMS calcd for C17H18BrO3 (MþHþ)
349.0434, found 349.0435.
CDCl3):
d 32.8, 33.1, 33.8, 36.4, 38.8, 41.9, 73.9, 78.4, 101.1(minor),
101.3, 102.3, 117.4 (minor), 117.5, 118.8, 118.9 (minor), 125.9 (minor),
126.0, 128.0 (minor), 128.1, 128.6, 131.1, 133.1, 135.2, 135.9, 141.1,
154.9, 155.5. LRMS (EI) m/z (rel intensity) 360 (Mþþ2, 18), 358 (Mþ,
19), 319 (89), 317 (93), 238 (100), 223 (26), 115 (40), 104 (33), 91
(58). TOF-HRMS calcd for C19H20BrO2 (MþHþ) 359.0641, found
359.0650.
4.1.28. 2-(3-Benzyloxy-4-methoxy)phenyl-6-bromo-7-methoxychro-
man (54). Following the general procedure and purification by
PTLC (20% EtOAc/hexanes), the desired compound was obtained as
colorless oil (0.037 g, 0.082 mmol, 73%). Rf (20% EtOAc/hexanes)
0.44. 1H NMR (200 MHz, CDCl3):
d 1.92e2.21 (m, 2H), 2.64e2.76 (m,
1H), 2.82e3.04 (m, 1H), 3.86 (s, 3H), 3.93 (s, 3H), 4.96 (dd, J¼9.4,
4.1.25. 6-Bromo-7-methoxy-3-methyl-2-phenyl-4-(4-cyanophenyl)
chroman (46). Following the general procedure and purification by
PTLC (30% EtOAc/hexanes), the desired compound was obtained as
2.2 Hz, 1H), 5.20 (s, 2H), 6.50 (s, 1H), 6.92e7.03 (m, 3H), 7.29e7.50
(m, 6H). 13C NMR (50 MHz, CDCl3):
d
24.0, 29.4, 56.1, 56.2, 71.2, 77.8,
101.1, 101.9, 111.9, 112.4, 115.2, 119.1, 127.4, 127.8, 128.5, 133.0, 133.7,

S. Radomkit et al. / Tetrahedron 67 (2011) 3904e3914
3913
137.0, 148.3, 149.6, 154.9, 155.1. TOF-HRMS calcd for C24H24BrO4
(MþHþ) 455.0852, found 455.0866. These spectroscopic data were
identical to those reported previously.3a
4.1.32. 2-Bromo-3-methoxy-6-phenyl-6a,7,8,9,10,10a-hexahydro-
6H-benzo[c]chromen-9-yl acetate (60). To a solution of compound
58 (0.067 g, 0.15 mmol) in MeOH (3 mL) was added NaBH4
(0.0060 g, 0.16 mmol) at room temperature and then stirred for
30 min. After removal of solvent, the residue was added with H2O
and extracted with EtOAc (2ꢂ10 mL). The combined organic phases
were washed with H2O and brine, dried over Na2SO4, filtered, and
concentrated under a vacuum to give an alcohol crude product. This
crude product was dissolved in CH2Cl2 (0.15 mL), followed by ad-
dition of DMAP (0.045 g, 0.37 mmol), and the reaction mixture was
stirred until completely dissolved. Acetyl chloride (0.03 mL,
0.37 mmol) was added dropwise into this solution and then the
reaction was stirred vigorously overnight. To this mixture was
added PtCl4 (0.0050 g, 0.01 mmol) and the resulting mixture was
stirred at room temperature for 5 h. Following concentration under
reduced pressure, the residue was purified by flash chromatogra-
phy on silica gel to yield compound 60 as a white solid (0.037 g,
0.085 mmol, 58%). Rf (20% EtOAc/hexanes) 0.48. IR (neat): nmax
4.1.29. 6-Bromo-7-methoxy-4-(methylsulfonylmethyl)-2-phenyl
chroman (56). Following the general procedure and purification by
PTLC (30% EtOAc/hexanes), the desired compound was obtained as
colorless oil (0.007 g, 0.018 mmol, 37%). Rf (30% EtOAc/hexanes)
0.22. IR (neat): nmax 2924, 2854, 1609, 1568, 1488, 1443, 1400, 1300,
1197, 1153, 1051 cmꢀ1. 1H NMR (200 MHz, CDCl3):
d 1.9e2.3 (m, 2H),
2.60e2.86 (m, 1H), 3.02 (s, 3H), 3.06e3.16 (m, 1H), 3.35e3.66 (m,
1H), 3.61 (dd, 1H, J¼3.0, 13.6 Hz), 3.85 (s, 3H), 5.07 (ddd, 1H, J¼15.6,
11.3, 1.7 Hz), 6.52 (s, 1H), 7.30e7.48 (m, 6H). 13C NMR (50 MHz,
CDCl3):
d 33.4, 36.8, 42.3, 42.5, 56.3, 59.8, 60.0, 73.7, 101.4, 101.8,
102.9, 115.3, 126.0, 126.1, 128.3, 128.4, 128.7, 130.9, 132.7, 140.0,
155.7, 155.8. LRMS (EI) m/z (rel intensity) 412 (20, Mþþ2), 410 (19,
Mþ), 330 (77), 332 (74), 315 (97), 317 (100), 148 (84), 104 (86), 91
(84), 77 (74). TOF-HRMS calcd for C18H20BrO4S (MþHþ) 411.0260,
found 411.0262.
.
2944, 1732, 1610, 1444, 1243 cmꢀ1 1H NMR (400 MHz, CDCl3):
d
1.05e1.71 (m, 6H), 1.96e2.06 (m, 1H), 2.07 (s, 3H), 2.10 (s, 3H,
4.1.30. 6-Bromo-7-methoxy-2-(4-methoxyphenyl)-4-(methyl sulfo-
nylmethyl)chroman (57). Following the general procedure and pu-
rification by PTLC (30% EtOAc/hexanes), the desired compound was
obtained as colorless oil (0.013 g, 0.029 mmol, 44%). Rf (30% EtOAc/
hexanes) 0.20. IR (neat): nmax 2926, 2846, 1610, 1514, 1489, 1300,
minor), 2.60e2.68 (m, 1H), 2.88e3.02 (m, 1H, minor), 3.82 (s, 3H),
4.74 (d, J¼10.0 Hz,1H), 4.80 (d, J¼10.6 Hz,1H, minor), 4.84e4.95 (m,
1H), 5.22e5.26 (m, 1H, minor), 6.47 (s, 1H), 7.30e7.42 (m, 6H). 13C
NMR (100 MHz, CDCl3):
d 21.35, 21.44, 22.6, 26.1, 29.0, 30.8, 33.7,
35.0, 37.4, 42.5, 42.8, 56.2, 68.8, 72.2, 83.4, 100.8, 101.8, 101.9, 118.0,
118.6, 127.17, 127.23, 128.6, 129.5, 139.1, 154.6, 154.8, 155.0, 155.1,
170.4, 170.6. LRMS (EI) m/z (rel intensity) 432 (Mþþ2, 91), 430 (Mþ,
100), 372 (31), 370 (37), 291 (30), 281 (56), 279 (65), 200 (20). TOF-
HRMS calcd for C22H24BrO4 (MþHþ) 431.0852 found 431.0859.
1247, 1197, 1154, 1051, 1030 cmꢀ1 1H NMR (200 MHz, CDCl3):
.
d
1.93e2.34 (m, 1H), 2.55e2.84 (m, 1H), 3.02 (s, 3H), 3.07e3.70 (m,
2H), 3.83 (s, 6H), 5.02 (dd, 1H, J¼11.4, 15.0 Hz), 6.50 (s, 1H), 6.93 (d,
2H, J¼8.8 Hz), 7.34 (s, 1H), 7.35 (d, 2H, J¼8.8 Hz). 13C NMR (50 MHz,
CDCl3):
d 33.2, 36.6, 42.2, 42.5, 55.4, 56.3, 59.9, 60.2, 73.4, 77.4,
101.4, 101.8, 102.8, 114.1, 115.3, 115.6, 127.4, 127.5, 130.8, 132.1, 132.7,
155.2, 155.6, 156.0, 159.6. LRMS (EI) m/z (rel intensity) 442 (Mþþ2,
10), 440 (Mþ, 10), 362 (26), 360 (27), 347 (34), 345 (32), 134 (100),
119 (39), 91 (38), 77 (20). TOF-HRMS calcd for C19H22BrO5S (MþHþ)
441.0366, found 441.0376.
4.1.33. 1-(5-Bromo-4-methoxy-2-(methoxymethoxy)phenyl)-1-hy-
droxy-7-methyloct-6-en-3-one (61). To a stirred solution of LDA
prepared by treating a solution of i-Pr2NH (0.59 mL, 4.22 mmol) in
THF (20 mL) and n-BuLi (2.06 M in hexane, 2.05 mL, 4.22 mmol) at
0
ꢁC was added 6-methylhept-5-en-2-one (0.50 mL, 3.38 mmol)
dropwise at ꢀ78 ꢁC. After 1 h, a solution of 5-bromo-4-methoxy-2-
(methoxymethoxy)benzaldehyde (0.76 g, 2.81 mmol) in THF (3 mL)
was added, and the resulting mixture was stirred for 1 h at ꢀ78 ꢁC.
The reaction was quenched with H2O at ꢀ78 ꢁC, and then the
mixture was extracted with EtOAc, washed with H2O and brine,
dried over MgSO4, filtered, and concentrated at reduced pressure.
The residue was purified by flash chromatography on silica gel (30%
EtOAc/hexanes) to give compound 61 (0.97 g, 2.42 mmol, 86%) as
colorless oil. Rf (30% EtOAc/hexanes) 0.30. IR (neat): nmax 3486,
2960, 1706, 1603, 1492, 1287, 1142 cmꢀ1. 1H NMR (400 MHz, CDCl3):
4.1.31. 2-Bromo-3-methoxy-6-phenyl-7,8,10,10a-tetrahydro-6H-
benzo[c]chromen-9(6aH)-one (59). Following the general pro-
cedure and purification by PTLC (20% EtOAc/hexanes), the C3-C4
trans isomer was obtained as a white solid (0.042 g, 0.11 mmol, 42%,
using PtCl4; 0.035 g, 0.09 mmol, 44%, using AuCl3). Rf (20% EtOAc/
hexanes) 0.29. IR (neat): nmax 2953, 1713, 1609, 1488, 1443, 1202,
1052 cmꢀ1
.
1H NMR (400 MHz, CDCl3):
d
1.40 (ddd, J¼25.7, 13.4,
4.8 Hz, 1H), 1.57e1.63 (m, 1H), 2.13e2.04 (m, 1H), 2.25e2.35 (m,
2H), 2.45 (dq, J¼15.1, 2.4 Hz, 1H), 2.98e3.04 (m, 1H), 3.06 (ddd,
J¼13.3, 4.3, 2.0 Hz, 1H), 3.82 (s, 3H), 4.79 (d, J¼10.0 Hz, 1H,), 6.50 (s,
1H), 7.24 (s, 1H), 7.46e7.38 (m, 5H). 13C NMR (100 MHz, CDCl3):
d
1.59 (s, 3H), 1.66 (s, 3H), 2.16e2.30 (m, 2H), 2.41e2.49 (m, 2H),
2.68 (B of ABX, JBA¼17.6 Hz, JBX¼8.8 Hz, 1H), 2.82 (A of ABX,
JAB¼17.2 Hz, JAX¼3.4 Hz,1H), 3.46 (s, 3H), 3.48 (d, J¼3.8 Hz,1H), 3.84
(s, 3H), 4.99e5.06 (m, 1H), 5.17 (s, 2H), 5.35 (app dt, J¼8.8, 3.4 Hz,
d
27.6, 39.1, 40.3, 42.0, 44.9, 56.2, 83.0, 100.9, 102.4, 117.4, 127.2,
128.8, 128.9, 129.5, 138.7, 154.6, 155.5, 208.8. LRMS (EI) m/z (rel
intensity) 388 (Mþþ2, 93), 386 (Mþ, 100), 307 (37), 293 (25), 291
(26), 230 (25), 228 (25), 216 (26), 117 (16), 115 (20), 91 (13), 77 (4).
TOF-HRMS calcd for C20H20BrO3 (MþHþ) 387.0596, found,
387.0591.
The C3eC4 cis isomer was obtained as colorless oil (0.028 g,
0.072 mmol, 28%, using PtCl4; 0.022 g, 0.057 mmol, 27%, using
AuCl3). Rf (20% EtOAc/hexanes) 0.23. IR (neat): nmax 2945, 2099,
1715, 1609, 1488, 1443, 1199, 1158, 1053 cmꢀ1. 1H NMR (400 MHz,
1H), 6.70 (s, 1H), 7.59 (s, 1H). 13C NMR (100 MHz, CDCl3):
d 17.6, 22.1,
25.6, 43.4, 49.5, 56.1, 56.2, 64.1, 94.7, 99.3, 103.5, 122.4, 125.2, 130.4,
132.9, 153.5, 155.6, 211.4. TOF-HRMS calcd for C18H25BrNaO5
(MþNaþ) 423.0778, found 423.0787.
4.1.34. 2-Bromo-3-methoxy-6,6-dimethyl-7,8,10,10a-tetrahydro-6H-
benzo[c]chromen-9(6aH)-one (62). Following the general pro-
cedure, the C3-C4 trans isomer was obtained as a white solid
(0.052 g, 0.15 mmol, 47%, using PtCl4; 0.047 g, 0.14 mmol, 44%, using
AuCl3). Rf (30% EtOAc/hexanes) 0.39. IR (neat): nmax 2926, 2860,
CDCl3):
d 1.66e1.74 (m, 1H), 1.87e1.96 (m, 1H), 2.27e2.40 (m, 2H),
2.48e2.54 (m, 1H), 2.62e2.75 (m, 2H), 3.18e3.23 (m, 1H), 3.82 (s,
3H), 5.22 (d, J¼8.6 Hz, 1H), 6.50 (s, 1H), 7.24 (s, 1H), 7.36e7.44 (m,
1716, 1609, 1488, 1199, 1055 cmꢀ1. 1H NMR (400 MHz, CDCl3):
d 1.15
5H). 13C NMR (100 MHz, CDCl3):
d
25.7, 35.0, 36.7, 37.6, 45.6, 56.2,
(s, 3H), 1.48 (s, 3H), 1.53e1.42 (m, 1H), 1.84 (td, J¼12.1, 3.0 Hz, 1H),
2.15 (qt, J¼6.5, 2.6 Hz, 1H), 2.25 (t, J¼13.6 Hz, 1H), 2.41 (td, J¼14.4,
6.5 Hz, 1H), 2.54 (dm, J¼14.8 Hz, 1H), 2.78 (td, J¼12.1, 4.3 Hz, 1H),
3.01 (ddd, J¼14.2, 4.3, 2.0 Hz, 1H), 3.82 (s, 3H), 6.38 (s, 1H), 7.19 (d,
77.8, 101.0, 102.6, 117.3, 126.5, 128.6, 128.8, 132.0, 139.2, 153.9, 155.5,
209.1. LRMS (EI) m/z (rel intensity) 388 (Mþþ2, 100), 386 (Mþ, 97),
307 (28), 230 (32), 228 (37), 216 (41), 178 (29), 149 (49), 117 (33), 91
(25). TOF-HRMS calcd for C20H20BrO3 (MþHþ) 387.0596, found
387.0588.
J¼0.7 Hz, 1H). 13C NMR (100 MHz, CDCl3):
d 19.8, 27.0, 27.9, 35.3,
40.6, 45.5, 45.8, 56.1, 77.8, 101.3, 101.9, 117.0, 129.8, 153.3, 155.4,

3914
S. Radomkit et al. / Tetrahedron 67 (2011) 3904e3914
209.0. LRMS (EI) m/z (rel intensity) 340 (Mþþ2, 97), 338 (Mþ, 100),
257 (36), 254 (46), 230 (31), 228 (32). TOF-HRMS calcd for
C16H20BrO3 (MþHþ) 339.0590, found 339.0594.
S. J. Org. Chem. 1999, 64, 9507e9511; (l) Miyazaki, H.; Honda, Y.; Honda, K.;
Inoue, S. Tetrahedron Lett. 2000, 41, 2643e2647 For catalytic enantioselective
cycloaddition reactions of o-QMs, see: (m) Alden-Danforth, E.; Scerba, M. T.;
Lectka, T. Org. Lett. 2008, 10, 4951e4953.
3. (a) Batsomboon, P.; Phakhodee, W.; Ruchirawat, S.; Ploypradith, P. J. Org. Chem.
2009, 74, 4009e4012; (b) Tummatorn, J.; Ruchirawat, S.; Ploypradith, P. Chem.
dEur. J. 2010, 16, 1445e1448.
4. (a) Ullrich, J. W.; Miller, C. P. Expert Opin. Ther. Pat. 2006, 16, 559e572; (b)
Wallace, O. B.; Richardson, T. I.; Dodge, J. A. Curr. Top. Med. Chem. 2003, 3,
1663e1680.
5. These Lewis acids or transition metal salts/complexes did not give any product:
BF3$Et2O, SnCl4, CoCl2, Ag2O, NiCl2, YbCl3$6H2O, Pd(OAc)2, K2PdCl6,
Pd(PPh3)2Cl2, (NH4)4Ce(SO4)4$2H2O, Ti(Oei-Pr)3Cl, Y(C5H7O2)3, [(COD)Ir(PCy3)
Py)]PF6, and Mg(ClO4)2. For comparison, NafionÒ NR50 and montmorillonite K
The C3eC4 cis isomer was obtained as a white solid (0.028 g,
0.083 mmol, 25%, using PtCl4; 0.025 g, 0.073 mmol, 23%, using
AuCl3). Rf (30% EtOAc/hexanes) 0.34. IR (neat): nmax 2893,1717,1607,
1489, 1443, 1166, 1150, 1054 cmꢀ1. 1H NMR (400 MHz, CDCl3):
d 1.34
(s, 3H), 1.45 (s, 3H), 1.67e1.56 (m, 1H), 2.07e2.02 (m, 1H), 2.17e2.10
(m, 1H), 2.27 (dm, J¼14.6 Hz, 1H), 2.37 (td, J¼13.9, 6.4 Hz, 1H), 2.72
(dd, J¼14.9, 6.0 Hz, 1H), 2.98 (dt, J¼14.9, 2.5 Hz, 1H), 3.63 (br s, 1H),
3.81 (s, 3H), 6.36 (s, 1H), 7.36 (d, J¼0.9 Hz, 1H). 13C NMR (100 MHz,
10, the proton source, gave the product
respectively).
2 in low yields (25% and 30%,
CDCl3):
d 22.9, 26.3, 26.6, 34.0, 39.6, 39.9, 42.7, 56.1, 101.3, 102.3,
114.0, 131.2, 153.3, 155.5, 209.4. LRMS (EI) m/z (rel intensity) 340
(Mþþ2, 100), 338 (Mþ, 99.6), 270 (14), 250 (34), 230 (30), 228 (31).
TOF-HRMS calcd for C16H20BrO3 (MþHþ) 339.0590, found 339.0585.
6. InCl3-catalyzed aqueous DielseAlder reactions, in which InCl3 served as Lewis
acid, have been reported. See: (a) Loh, T.-P.; Pei, J.; Lin, M. Chem. Commun. 1996,
2315e2316; (b) Fringuelli, F.; Piermatti, O.; Pizzo, F.; Vaccaro, L. Eur. J. Org. Chem.
2001, 439e455.
7. Except for MeOH, which gave no product, use of THF, CHCl3, and (CH2Cl)2
furnished the product in 22%, 26%, and 83% yields, respectively, but the re-
actions took 18 h. In MeCN, the reaction required 72 h to complete, giving the
product in moderate 46% yield. Thus, solubility does not seem to be an im-
portant contributing factor, which accounts for the difference in yields. In ad-
dition, toluene gave no product regardless of the Lewis acids or transition metal
salts/complexes under investigation.
Acknowledgements
Financial support from the Thailand Research Fund (BRG5180013
for P.P.) is gratefully acknowledged.
8. See the Supplementary data for the detailed preparation of 3, 4, 6e15, 33e35,
41e43, 55, and 58.
Supplementary data
9. In contrast to the proposed [4þ2]-cycloaddition of the reaction using trans
olefin, the 1:1 mixture of diastereomeric 24a from the reaction using cis olefin
may suggest a stepwise mechanism. In a separate experiment, it was found that
the cis olefin did not isomerize to the trans olefin under the reaction condition.
Thus, the trans product is likely to arise from the stepwise nature of the
reaction.
10. Cinnamyl acetate and methyl cinnamyl ether gave no product under similar
reaction conditions using PtCl4.
11. Under acid-mediated conditions (Ref. 3), cinnamyl benzoate, cinnamyl acetate,
and methyl cinnamyl ether as well as both trans-ethyl cinnamates gave no
desired products.
General methods, detailed characterization and copies of 1H and
13C NMR of all new compounds as well as the overlay of 1H NMR
(not shown in the manuscript). Supplementary data related to this
article can be found online at doi:10.1016/j.tet.2011.03.059. These
data include MOL files and InChiKeys of the most important com-
pounds described in this article.
References and notes
12. In addition to the products 27 and 29, only the baseline unidentified materials
were obtained.
13. Better yields were obtained with SnCl4 when employed with other systems.
See: Schmidt, R. R. Tetrahedron 1969, 10, 5279e5282.
1. (a) Li, Z.; Brouwer, C.; He, C. Chem. Rev. 2008, 108, 3239e3265; (b) Gorin, D. J.;
Sherry, B. D.; Toste, F. D. Chem. Rev. 2008, 108, 3351e3378; (c) Arcadi, A. Chem.
Rev. 2008, 108, 3266e3325; (d) Hashmi, A. S. K. Chem. Rev. 2007, 107,
14. The structure of chroman 40 contains a known ‘s’ stereocenter on the sidechain
€
3180e3211; (e) Furstner, A.; Davies, P. W. Angew. Chem., Int. Ed. 2007, 46,
at C3. However, the relative as well as absolute configuration at C3 has not been
29.3
3410e3449; (f) Hiroya, K.; Matsumoto, S.; Ashikawa, M.; Ogiwara, K.; Sakamoto,
T. Org. Lett. 2006, 8, 5349e5352; (g) Kobayashi, S.; Kakumoto, K.; Sugiura, M.
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2. For review, see: (a) Van De Water, R. W.; Pettus, T. R. R. Tetrahedron 2002, 58,
5367e5405; (b) Tang, Y.; Oppenheimer, J.; Song, Z.; You, L.; Zhang, X.; Hsung, R.
P. Tetrahedron 2006, 62, 10785e10813; (c) Ferreira, S. B.; da Silva, F. d. C.; Pinto,
A. C.; Gonzaga, D. T. G.; Ferreira, V. F. J. Heterocycl. Chem. 2009, 46, 1080e1097;
For transition metal-complexed o-QMs, see: (d) Poverenov, E.; Milstein, D. In
Quinone Methides; Rokita, S. E., Ed.; Wiley: New Jersey, 2009; pp 69e88; For
thermal and base initiation, see: (e) Bray, C. D. Org. Biomol. Chem. 2008, 6,
2815e2819; (f) Rodriguez, R.; Adlington, R. M.; Moses, J. E.; Cowley, A.; Bald-
win, J. E. Org. Lett. 2004, 6, 3617e3619; (g) Selenski, C.; Pettus, T. R. R. Tetra-
hedron 2006, 62, 5298e5307; (h) Jones, R. M.; Selenski, C.; Pettus, T. R. R. J. Org.
Chem. 2002, 67, 6911e6915; (i) Barrero, A. F.; Quílez del Moral, J. F.; Herrador,
determined. Compound 40 exhibited optical activity ([
a
]
ꢀ4.22 (c 1.43,
D
CHCl3)). The compound was obtained as a single diastereomer (dr>99:1). De-
termination of the absolute configuration is underway in our laboratory.
15. Similar yields and stereoselectivity were obtained with AuCl3.
16. The role of Pt(IV) as a mild Lewis acid in the cycloaddition may be similar to
that of InCl3 in the DielseAlder reactions (see Ref. 6)
17. Under other acid-mediated conditions (Ref. 3) to generate o-QMs, it is known
that, once generated in the reactions without the appropriate dienophiles
(olefins), the o-QMs similar to those in the current study are not stable and
decompose very rapidly.
18. The exact position of Pt(IV) coordination on the o-QM has not been fully de-
termined and is currently under our investigation.
19. In the bound state of o-QM with Pt(IV), the metal may position itself between
the o-QM and dienophile to disfavor the otherwise favorable endo transition
state. See Supplementary data for more details.
20. Both phenol and BnOH/BnOAc are the functional groups similar to those
present in the reactions under PtCl4 catalysis.
ꢀ
ꢀ
M. M.; Arteaga, P.; Cortes, M.; Benites, J.; Rosellon, A. Tetrahedron 2006, 62,
6012e6017 For acid initiation, see: (j) Chiba, K.; Hirano, T.; Kitano, Y.; Tada, M.
Chem. Commun. 1999, 691e692; (k) Miyazaki, H.; Honda, K.; Asami, M.; Inoue,