Convergent synthesis of 2H-chromenes - A formal [3+3] cycloaddition by a one-pot, three-step cascade

Article abstract of DOI:10.1016/j.tet.2011.09.068

In cases in which the palladium-catalyzed coupling of a bromoquinone with a vinyl stannane affords a vinyl quinone that enolizes, the resulting ortho-quinone methide undergoes an oxa-6π electrocyclization. Enolization is promoted by the presence of a pola

Full text of DOI:10.1016/j.tet.2011.09.068

Tetrahedron 67 (2011) 9779e9786
Contents lists available at SciVerse ScienceDirect
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Convergent synthesis of 2H-chromenesda formal [3þ3] cycloaddition by
a one-pot, three-step cascade
,
b
,
b,c,
*
Kathlyn A. Parker a , Thomas L. Mindt
*
a Department of Chemistry, State University of New York at Stony Brook, Stony Brook, NY 11794, USA
b Department of Chemistry, Brown University, Providence, RI 0291, USA
c Division of Radiological Chemistry, University of Basel and University Hospital Basel, 4031 Basel, Switzerland
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 21 August 2011
Received in revised form 15 September 2011
Accepted 16 September 2011
Available online 22 September 2011
In cases in which the palladium-catalyzed coupling of a bromoquinone with a vinyl stannane affords
a vinyl quinone that enolizes, the resulting ortho-quinone methide undergoes an oxa-6
p electro-
cyclization. Enolization is promoted by the presence of a polar additive. The net conversion is a formal
[3þ3] cycloaddition that gives 2H-chromenes. Because the first two steps of the cascade are catalyzed,
the overall conversion is an example of multicatalysis. Yields for the optimized, one-pot protocol are
dramatically improved over the conventional stepwise process.
Keywords:
Electrocyclization
Cascade
Ó 2011 Elsevier Ltd. All rights reserved.
ortho-Quinone methide
Stille coupling
Formal [3þ3] cycloaddition
1. Introduction
O
OMe
O
In the course of our research directed toward the synthesis of
aryl C-glycoside natural products,1 we discovered that the coupling
reaction of bromobenzoquinone (1) with vinyl stannane 22 did not
provide the desired vinyl quinone 3. Instead, 2H-chromene 4 and
hydroquinone 5 were isolated, each in modest yield (20e30%),
along with small amounts of benzofuran 6 (approx. 5%, Scheme 1).3
We had not originally set out to prepare chromene com-
pounds;4,5 nonetheless, we were aware of the incidence of this
structural feature among biologically active natural products.6
Therefore we set out to elucidate the mechanism of the chro-
mene synthesis and to examine its generality and practicality.
We soon discovered that vinyl quinone 3, prepared by an in-
dependent route (see below), underwent conversion to chromene
along with previously observed by-products when exposed to the
Pd(PPh3)4 coupling conditions We concluded that quinone 3 was, as
expected, the initial product of the Pd(0) catalyzed reaction and that
the conversion of quinone 1 to 2H-chromene 4 took place by trans-
formations of this intermediate under the coupling conditions.
In further experiments with quinone 3, we took the precaution
of excluding light from the reaction vessel. Both overhead
Bu3Sn
O
O
O
OMe
Br
2
a
O
1
3
O
OMe
O
O
OMe
OMe
OH
O
O
+
+
OH
OH
OH
4
5
6
Scheme 1. Unexpected products from Stille coupling. (a) 5 mol % (Ph3P)4Pd, toluene
(10 mM), reflux.
fluorescent fixtures and sunlight can initiate photochemistry with
quinones.7 In fact, the photochemical isomerization of vinyl qui-
nones to benzofurans is known.8 We ourselves have seen efficient
* Corresponding authors. E-mail addresses: kparker@notes.cc.sunysb.edu (K.A.
Parker), TMindt@uhbs.ch (T.L. Mindt).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.09.068

9780
K.A. Parker, T.L. Mindt / Tetrahedron 67 (2011) 9779e9786
isomerization of a vinyl quinone imine to the isomeric indole in
a sunlight induced reaction.9
The approach to chromenes in which the Stille coupling and
enolization/electrocyclization conversions are effected in separate
steps can be considered relatively efficient by today’s standards. We
applied this strategy (Scheme 3) to the synthesis of five additional
chromenes and utilized one of these in a short synthesis of the
purported structure of the juvenile hormone from Ageratum con-
yzoides. This preliminary work has been reported.3
Although the presence of catalytic amounts of Pd(PPh3)4 con-
verted quinone 3 to chromene 4, heating the substrate in toluene
alone or in the presence of Pd2(dba)3 did not effect this change.
Further experimentation revealed that the presence of 0.2e5 equiv
of a phosphine or a phosphine oxide in the reaction medium was
sufficient to lead to the formation of product mixtures. (It is likely
that the phosphines are being converted to phosphine oxides in the
reaction medium). We also found that DMPU (1,3-dimethyl-3,4,5,6-
tetrahydro-2(1H)-pyrimidinone) had the same effect. All of this
indicated that a polar additive or Lewis base was essential for
effecting the observed transformation (3/4).
A particularly convenient protocol involved the addition of
traces of hexamethylphosphoramide (HMPA) to a toluene solution
of vinyl quinone 3 before heating. In these experiments, we ob-
served the appearance of a dark red color immediately upon the
mixing of the HMPA with the solution of substrate. This color was
maintained during the course of the reflux, gradually being
replaced by a brown color as the reaction went to completion.
Under these conditions,10 the reaction was complete in a matter of
hours. These improvements, when applied to quinone 3 gave
chromene 4 as a single clean product.
O
OMe
OR
OR
OR
OR
Br
2
b
d
10: R = TES
5: R = H
8: R = H
9: R = TES
c
a
3
7
4
e
We suspected that the red color represented quinone methide 7
(presumably both 7a and 7b), the enol form of the vinyl quinone. In
fact, we could observe the appearance of a new species corre-
sponding to approximately 80% of the substrate in solution in the
NMR spectrum of quinone 3 in THF-d8 as soon as traces of hex-
amethylphosphoramide (HMPA) were added. This intermediate
Scheme 3. Multistep synthesis of 2H-chromenes. (a) triethylsilyl triflate (TESOTf),
imidazole, DMF, rt; (b) 10 mol % (Ph3P)4Pd, toluene, cat. amounts of 2,6-di-tert-butyl-4-
methylphenol (radical scavenger), reflux; (c) THF, 50% aq AcOH, rt; (d) Ag2O, O2,
MgSO4, THF, rt; (e) toluene, HMPA (0.5% v/v), reflux in the dark.
Nevertheless, we recognized the potential advantages of a one-
pot transformation as suggested by the original observation of the
direct production of chromene 4 from bromoquinone 1. Multi-
catalysis and other cascade procedures14 offer opportunities to
optimize yields and to minimize the time, effort, and waste in-
curred in multistep transformations. Here we complete the survey
of the stepwise convergent chromene synthesis and we also de-
scribe the development of a three-step cascade sequence that ef-
fects the equivalent conversion in a single reaction vessel (Scheme
4). This formal [3þ3] cycloaddition has three steps, the Pd(0) cat-
alyzed coupling, the HMPA-promoted enolization, and the thermal
electrocyclization. However, no change in reaction conditions is
required from one step to the next. We suggest that this is a case of
‘tandem catalysis’ or, more generally, multicatalysis and we utilize
the relevant notation for the first two steps in Scheme 4.15 Finally,
we demonstrate the superiority of this protocol to the stepwise
approach for the preparation of selected annulated chromene
products.
was stable in the NMR solution at 10 ꢀC for several hours. An oxa-6
p
electrocyclization would convert enol 7a to the observed product 4.
Enol 7b, if present, must undergo isomerization to enol 7a before
the electrocyclization; it is reasonable to believe that low energy
proton transfers, facilitated by HMPA, effect this change.11 The oxa-
6
p electrocyclization then would complete the two-step trans-
formation of vinyl quinone 3 or the three-step transformation of
bromoquinone 1 to chromene 4 (Scheme 2).12,13
O
O
OMe
4
O
OMe
OH
O
O
7a
2
polar
additive
1
Pd
catalyst
O
3
CO2Me
OH
7b
Scheme 4. One-pot synthesis of 2H-chromenes by a tandem catalysis cascade.
Scheme 2. Mechanism of the formation of 2H-chromene from vinyl quinone.
It is clear that the conversion of quinone 3 to a reactive in-
termediate requires the presence of a polar organic additive that
promotes the enolization step by changing the polarity of the re-
action medium, by acting as a Lewis base, or by both mechanisms.
The additive accelerates the conversion to chromene and is not,
itself, changed in the process. Therefore, it fits the classical defini-
tion of a catalyst.
2. Results and discussions
2.1. Scope of the stepwise synthesis
We tested the generality of the stepwise procedure (Scheme 3)
by extending it to a series of bromohydroquinone substrates that

K.A. Parker, T.L. Mindt / Tetrahedron 67 (2011) 9779e9786
9781
bear one or more methyl or methoxy substituents, structural fea-
tures frequently found in naturally occurring benzo- and naph-
thopyrans (Table 1).16 Thus each of the hydroquinones 8, 8a, and
8cee was converted to its bis TES ether 9. Coupling with the known
tin reagent 2 was followed by deprotection and oxidation of in-
termediates 10 to the corresponding quinones 3. Quinone 3b was
most conveniently prepared by the AgO oxidation of the 1,3,4-
trimethoxyphenyl butenoate 12 derived from the known 2-
bromo-1,3,4-trimethoxybenzene (11; Scheme 5).32 Heating vinyl
bromohydroquinones with stannane 2 and, in some cases, the
enolization/electrocyclization steps are especially unsatisfying. In
an effort to improve the efficiency of the chromene synthesis, we
therefore focused attention again on the original one-pot protocol.
In this approach, enolization/electrocyclization occurs in-situ, of-
fering the possibility that vinyl quinones 3 could be converted to
chromene products 4 as soon as they are formed.20 The one-pot
protocol avoids the Stille coupling of the relatively unreactive,21
electron rich benzene derivative 9 entirely.
Table 1
Multistep synthesis of chromenes via protected hydroquinones
e
e
M
e
e
M
O
M
M
O
O
O
O
O
O
O
O
H
TE
OTES
H
H
O
O
O
S
O
1
R6
R5
R6
R5
B
R6
R5
R6
R5
R6
R5
R6
R5
r
r
B
2
R3
R3
R3
R3
R3
OTES
10
R3
4
H
O
8
TE
O
3
O
9
S
H
O
4
O
5
Example
8R3¼R5¼R6¼H
Yield 9 [%]
9: 98
Yield 10 [%]
10: 70
Yield 5 [%]
5: 92a
Yield 3 [%]
Yield 4 [%]
Overall yield [%]
3: quant. (trans)
3: quant. (cis)
3a: quant.
3b: 98
3c: 97
3d: 98
4: 76
4: 86
4a: 70
4b: 58
4c: 70
4d: 63
4: 48b
4: 54b
4a: 38
4b: 30d
4c: 29b
4d: 17
8ac R3¼H, R5¼R6¼CH3
9a: 98
d
10a: 69
d
5a: 80
d
8b R3¼OMe, R5¼H, R6¼H
8ce R3¼H, R5¼OMe, R6¼H
8df R3¼R5¼H, R6¼OMe
9c: 99
9d: 85
10c: 53
10d: 42
5c: 81
5d: 75
8eg R3¼H, R5¼R6¼
9e: 89
10e: 83
5e: 86
3e: 94
4e: 59
4e: 35b
a
65% trans compound and 25% cis compound isolated by chromatography.
b
c
d
e
f
Experimental procedures and compound characterization data for this entry are reported in the Supplementary data for Ref. 3.
Hydroquinone 8a was prepared by bromination of 2,3-dimethyl-1,4-hydroquinone according to Takanashi and Mori, Ref. 17.
30% yield from 2-bromo-1,3,4-trimethoxybenzene; see text.
Hydroqinone 8c was prepared by bromination of methoxyhydroquinone according to Guzikowski et al., Ref. 18.
Hydroquinone 8d was prepared according to Zhu et al., Ref. 19.
g
Hydroquinone 8e was prepared by reduction of the corresponding quinone and used immediately; see the Supplementary data for Ref. 3.
2.2. Development of the one-pot synthesis
The development of one-pot multi-reaction cascades requires
not only the careful optimization of each step but also the es-
tablishment of conditions under, which the reagents and in-
termediates do not interfere with each other in
counterproductive phenomena. For the transformation discussed
herein, particular attention had to be paid to eliminating pho-
tochemical transformations of the quinone intermediates. Thus,
light was excluded from the reaction mixtures in all attempts to
develop the one-pot procedure. Also, we needed to minimize the
redox chemistry of the bromoquinones and vinyl quinones along
the reaction pathway and promote the conversion of the delicate
ortho-quinone methide intermediates to stable chromene
products.
Scheme 5. (a) 10 mol
methylphenol (radical scavenger), reflux; (b) AgO, HNO3, THF, rt.
% (Ph3P)4Pd, toluene, cat. amounts of 2,6-di-tert-butyl-4-
quinone substrate 3e3e in toluene in the presence of small
amounts of HMPA gave, as expected, the corresponding chromene
in each case. Yields for each step and the overall yields for the
stepwise preparative sequence are shown in Table 1.
The low to modest overall yields of the multistep syntheses of
2H-chromenes reflect, in part, the losses affiliated with the ma-
nipulation and the isolation procedures of up-to five sequential
reactions. The yields of the coupling reactions of TES-protected
Optimization studies were performed with the parent bromo-
benzoquinone system. Reaction of substrate 1 with stannane 2 in
toluene (10 mM) containing traces of HMPA (0.5% v/v) and
(Ph3P)4Pd (10e20 mol %) at reflux in the dark gave a 1:1 mixture of
desired 2H-chromene 4 and vinyl hydroquinone 5 in combined

9782
K.A. Parker, T.L. Mindt / Tetrahedron 67 (2011) 9779e9786
yields of approximately 70%. Thus, the formation of benzofuran 6
was prevented.
With these optimized reaction conditions, we set out to in-
vestigate the general utility of the one-pot procedure and compare
it to the stepwise synthesis. Except for the known 1b,25 each of the
bromoquinone starting materials was prepared according to the
literature. 2-Bromo-5,6-dimethylbenzoquinone (1a)26 was pre-
pared by oxidation of the known hydroquinone.17 2-Bromo-5-
methoxybenzoquinone (1c) and 2-bromo-6-methoxybenzoqui-
none (1d), were prepared according to Blatchly et al.25 and 2-
bromojuglone methylether 1e was prepared according to Jung.27
Quinone 1b was prepared by AgO oxidation of known compound
11. Each was subjected to reaction with vinyl stannane 2 under the
optimized multicatalysis conditions (Table 2). The yields of isolated
products 4e4e were uniformly good and in all cases superior to the
overall yields achieved by the alternative multistep procedure
(Table 1). It can therefore be concluded that neither methyl (entry
2) nor methoxy (entries 3e5) substituents on the bromoquinone
substrate interfere with the reaction cascade. In addition, the
methodology can be applied to extended aromatic systems (e.g.,
naphthopyrans; entry 6). It is noteworthy that the multicatalysis
method provides crude materials uncontaminated with by-
products; only extractive removal of the polar additive and filtra-
tion through a short pad of silica gel is required for purification.
Vinyl hydroquinone 5, arises from a redox reaction, most likely
between the phosphine ligand of the palladium catalysts and the
quinone starting material and/or vinyl quinone intermediate.22
Since vinyl hydroquinone 5 does not undergo the enolization/
electrocyclic ring closure transformation, its formation helps to
explain the moderate yield of 2H-chromene 4. To overcome the
problems encountered with phosphine ligands of the palladium
catalyst we attempted to make use of ‘ligand-free’ (or phosphine-
free) conditions23 reported for the successful Stille coupling of
delicate substrates.24 However, employment of Pd(OAc)2,
Pd2(dba)3 or (CH3CN)2PdCl2 in the absence of phosphine ligands
gave complex product mixtures, in some cases even at rt. Exper-
iments in which the quantity of catalyst was reduced 1e2 mol %
instead of 10e20 mol % (Ph3P)4Pd were slow; complete conversion
to chromene products could not be achieved within reasonable
times.
Although only traces (0.5% v/v) of HMPA are adequate for
catalyzing the conversion of quinone 3 to dihydrochromene 4,3
increasing the amount of HMPA in the reaction medium of the
one-pot reaction (1/4) was advantageous. When only 1e2% of
(Ph3P)4Pd was used, concentrations of 2e5% v/v, HMPA acceler-
ated the overall conversion so that it was complete within a con-
venient timeframe. Furthermore, we found that more dilute
reaction solutions (3 mM instead of 10 mM) gave cleaner products.
Presumably, the presence of HMPA increases the rate of enoliza-
tion, if not the rates of coupling and electrocyclization, and low-
ering the concentration of substrate decelerates bimolecular redox
reactions.
3. Conclusions
A one-pot, three-step cascade that consists of a Stille-coupling/
enolization/oxa-6p electrocyclization cascade effects the conver-
sion of bromoquinones and vinyl stannanes to annulated 2H-
chromenes. Although the yields for these transformations (1/4)
could be termed modest, each represents three individual reactions
and compares favorably with the corresponding stepwise se-
quences. This suggestsdas is sometimes the case with cascade
reactionsdthat unstable intermediates may be forwarded in the
direction of the desired product before they can partition along
undesired pathways.
Thus we developed suitable conditions for the one-pot, three-
step procedure. Heating of a dilute toluene solution (3 mM) of
equimolar amounts of bromobenzoquinone (1) and vinyl stannane
2 in the dark, in the presence 2e5% v/v HMPA and 1e2 mol %
catalyst ((Ph3P)4Pd) for 30 min provided 2H-chromene 4 cleanly
and in good yields (Table 2; entry 1).
A key feature of the method is the use of HMPA to promote the
formation of the quinone methide that undergoes the oxa-6
p
Table 2
electrocyclization. It is reasonable to believe that HMPA acts cata-
Synthesis of substituted benzo- and naphthopyrans by multicatalysis
lytically as a proton shuttle.28 Similar enolizations of allyl quinones
e
M
O
O
O
that preface oxa-6p electrocyclizations are promoted by basic
alumina,29 pyridine,30 and triethyl amine.31 In any case, the con-
version of vinyl quinone to chromene requires the presence of
a polar additive, leading us to apply the term ‘multicatalytic’ to the
three-step cascade. Furthermore, we suggest that, as the field of
multicatalysis develops, there will be additional examples of se-
quences in which an additive, such as HMPA plays a critical role in
one of the steps.
O
O
R6
R5
R6
R5
B
r
2
a
R3
R3
H
O
This new synthetic methodology enhances the portfolio of
synthetic approaches by which structurally diverse benzo- and
naphthopyrans can be prepared. Because it tolerates structural
variants of the bromoquinone substrate, this attractive approach
appears well suited for general applications in natural product total
synthesis and compound library design.
Entry
Bromoquinone substrates
Product (yield)b
1
2
3
4
5
1: R3¼R5¼R6¼H
4 (66%)
1a: R3¼H, R5¼R6¼CH3
1b: R3¼OMe, R5¼R6¼H
1c: R3¼H, R5¼OMe, R6¼H
1d: R3¼R5¼H, R6¼OMe
4a (71%)
4b (70%)
4c (64%)
4d (66%)
4. Experimental section
4.1. General information
6
1e: c R3¼H R5¼R6¼
4e (70%)
Reagents and solvents from SigmaeAldrich, and TCI and cata-
lysts from Strem Chemicals were used as supplied. Flash chroma-
tography was performed with Fisher brand silica gel
(170e400 mesh) and preparative TLC on Analtech precoated silica
gel GF, 1000-microns glass plates (20ꢁ20 cm). All experiments
were monitored by thin layer chromatography performed on EM
Science precoated silica gel 60 F254 glass supported plates.
a
Stoichiometric amounts of the bromoquinones and vinyl stannane 2 (scale:
0.1e0.15 mmol) in toluene (30e45 mL; approx. 3 mM), 2e5% v/v HMPA, 1e2 mol %
(Ph3P)4Pd, 1e5 h reflux in the dark.
b
Yields of isolated products.
c
Compound
1e¼2-bromo-5-methoxynaphthoquinone
(2-bromojuglone
methylether).

K.A. Parker, T.L. Mindt / Tetrahedron 67 (2011) 9779e9786
9783
Reactions in the dark were performed by covering the reaction flask
in aluminum foil.
stirred at reflux in the dark until TLC indicated complete conversion
of the vinyl quinone substrate (0.25e36 h). The reaction mixture
was diluted with toluene and washed with water (twice). The or-
ganic phase was dried over MgSO4 and concentrated under reduced
pressure. The crude product was purified by flash chromatography
or preparative TLC on silica gel with mixtures of ethyl acetate and
hexane to afford the final product.
Nuclear magnetic resonance spectra were recorded with
a Bruker 300 or 400 MHz spectrometer with the corresponding
solvent signal as an internal standard. Chemical shifts are reported
in parts per million (ppm) relative to tetramethylsilane (0.00 ppm).
Values of coupling constants, J, are given in hertz (Hz). The fol-
lowing abbreviations are used in the Experimental section for the
description of 1H NMR spectra: singlet (s), doublet (d), triplet (t),
quartet (q), doublet of doublets (dd), doublets of triplets (dt), and
broad singlet (br s). Low-resolution mass spectra were measured
with a Kratos MS80RFA (LRFAB, NBA/NaI) or with an HPGCD (LRGC-
MS). Infrared spectra were recorded with a PerkineElmer 1600
Series FT-IR. Melting points were taken on a Thomas-Hoover ap-
paratus and are uncorrected.
4.2.6. General procedure 6: one-pot synthesis of 2H-chromenes. -
Bromoquinone substrates and vinyl stannane 2 were dissolved in
equimolar amounts (0.1e0.25 mmol) in toluene (30e80 mL;
approx. 3 mM) and HMPA (2e5 %v/v) and (Ph3P)4Pd (1e2 mol %)
were added. The solution was stirred at reflux in the dark for
0.5e1.5 h after which time TLC indicated complete conversion of
the substrates. The reaction mixture was diluted with toluene and
washed twice with water. The water phases were extracted two
more times with toluene. The organic phases were then combined
and the resulting solution was dried over MgSO4 and concentrated
under reduced pressure. The crude product was purified either by
flash chromatography on silica gel or by filtration through a short
pad of silica gel using mixtures of ethyl acetate and hexane.
4.2. General synthetic procedures
4.2.1. General procedure 1: synthesis of TES-protected hydro-
quinones. Bromohydroquinones (1.5e3.2 mmol) were dissolved in
DMF (1 mL/mmol) and imidazole (5 equiv) and TESOTf (3 equiv)
were added at 0 ꢀC. The resulting solution was warmed to rt, stirred
for 30e60 min and poured into water (10e20 mL). The mixture was
extracted three times with ether. The organic phases were com-
bined and the resulting solution was washed twice with brine,
dried over MgSO4, and concentrated under reduced pressure. The
crude product was purified by flash chromatography on silica gel
with hexane to afford the TES-protected product.
4.3. Synthesis and characterization of compounds
For additional characterization of compounds 4, 4c, and 4e and
their respective precursors, see the Supplementary data for Ref. 3.
4.3.1. Synthesis of bromoquinone 1a26. From 5-bromo-2,3-
dimethylbenzene-1,4-diol17 (44 mg, 0.2 mmol) according to gen-
eral procedure 4; reaction time: 15 min. Orange crystals (42 mg,
98%); mp 47e49 ꢀC.
4.2.2. General procedure 2: Stille coupling of protected bromohy-
droquinones with vinyl stannane 2. Protected bromohydroquinones
(0.6e2 mmol) and vinyl stannane 2 (1.2 equiv) were dissolved in
toluene (10e100 mL/mmol) and (Ph3P)4Pd (10 mol %) and a few
crystals of 2,6-di-tert-butyl-4-methylphenol (radical scavenger)
were added. The mixture was stirred at reflux until TLC indicated
complete conversion of the bromohydroquinone substrate
(7e20 h). The reaction mixture was filtered through CeliteÒ and
concentrated under reduced pressure. The crude product was pu-
rified by flash chromatography or preparative TLC on silica gel with
mixtures of ethyl acetate and hexane to afford the final product.
4.3.2. Synthesis of vinyl quinone 3a. From vinyl hydroquinone 5a
(cis/trans 1:7; 12 mg, 0.05 mmol) according to the general pro-
cedure 3; reaction time: 30 min. Brown oil (12 mg, quant.; mixture
of trans/cis isomers 7:1): IR (neat)
n
2954, 1739, 1650, 1252,
1165 cmꢂ1; 1H NMR (THF-d8)
d
6.79e6.65 (m, 1.87H, trans-isomer),
6.57e6.46 (m, 1H), 6.20 (dt, 0.13H, 3J¼12.0, 7.2 Hz, cis-isomer), 3.65
and 3.64 (each s, total 3H, cis/trans 1:7 in the order given), 3.33 and
3.26 (each dd, total 2H, 3J¼7.2 Hz, 4J¼1.9 Hz and 3J¼7.1 Hz,
4J¼1.2 Hz, respectively, cis/trans 1:7 in the order given), 2.00, 1.99,
1.98, and 1.97 (each s, total 6H) ppm; 13C NMR (THF-d8) (dominant
4.2.3. General procedure 3: removal of TES-protective groups from
vinyl hydroquinones. Protected vinyl hydroquinones (0.1e1 mmol)
were dissolved in THF (12 mL/mmol) and 50% aq AcOH (12 mL/
mmol) was added. The mixture was stirred at rt until TLC indicated
complete conversion of the protected vinyl hydroquinone substrate
(18e48 h). The reaction mixture was poured into 5% aq NaHCO3 and
extracted with ether (three times). The organic phases were com-
bined and the resulting solution was washed twice with water,
dried over MgSO4, and concentrated under reduced pressure. The
crude product was purified by flash chromatography or preparative
TLC on silica gel with mixtures of ethyl acetate and hexane to afford
the final product.
signals of the major trans-isomer)
d 187.8, 187.2, 171.3, 142.2, 141.5,
141.3, 132.6, 129.3, 125.9, 52.0, 39.1, 12.4, 12.1 ppm; LRFAB-MS:
[MþNa]þ¼257 (calcd for C13H14O4Na: 257).
4.3.3. Synthesis of vinyl quinone 3b. 1,3,4-Trimethoxy butenoate 12
(cis/trans 1:3, 19 mg, 0.07 mmol) was dissolved THF (1.5 mL) and
AgO (69 mg, 0.28 mmol) was added. The suspension was sonicated
for 1 min and 6 N HNO3 (71 mL, 0.43 mmol) was added to the ho-
mogenous suspension. The reaction mixture was stirred at rt for
10 min during which the precipitate was dissolved. The solution
was poured into water (5 mL) and the resulting mixture was
extracted with ether (3ꢁ5 mL). The organic layers were washed
with water (2ꢁ5 mL) and then combined, dried over MgSO4 and
concentrated under reduced pressure affording a cis/trans-mixture
4.2.4. General procedure 4: oxidation of vinyl hydroquinones. Vinyl
hydroquinones (0.05e0.2 mmol) were dissolved in THF
(20e200 mL/mmol) and Ag2O (5e10 equiv) and MgSO4 (ca.
50e100 mg, ca.10 equiv) were added. The suspension was stirred at
rt under an oxygen atmosphere (O2-balloon) until TLC indicated
complete conversion of the vinyl hydroquinone substrate
(30e45 min). The reaction mixture was filtered through CeliteÒ and
concentrated under reduced pressure to afford the final product.
(1:3) of pure quinone 3b as a brown oil (16 mg, 98%): IR (neat)
n
2953, 1737, 1658, 1572, 1443, 1323, 1208, 1165, 1057, 847 cmꢂ1 1H
;
NMR (CD2Cl2)
d
6.97 (dt, 0.75H, 3J¼16.2, 7.3 Hz, trans-isomer),
6.68e6.59 (m, 2H), 6.49 (dt, 0.75H, 3J¼16.2 Hz, 4J¼1.5 Hz, trans-
isomer), 6.20 (d, 0.25H, 3J¼11.7 Hz, cis-isomer), 6.11 (dt, 0.25H,
3J¼11.7, 5.9 Hz, cis-isomer), 4.06 and 3.96 (each s, total 3H, trans/cis
3:1 in the order given), 3.68 and 3.66 (each s, total 3H, trans/cis 3:1
in the order given), 3.26 (dd, 1.5H, 3J¼7.3 Hz, 4J¼1.5 Hz, trans-
isomer), 2.98 (br d, 0.5H, 3J¼5.9 Hz, cis-isomer) ppm; 13C NMR
4.2.5. General procedure 5: synthesis of 2H-chromenes from vinyl
quinones. Vinyl quinones (0.05e0.1 mmol) were dissolved in tol-
uene (5 mM) and HMPA (0.5% v/v) was added. The mixture was
(CD2Cl2)
d 188.0, 187.8, 184.0, 183.8, 171.94, 171.85, 155.1, 155.0,

9784
K.A. Parker, T.L. Mindt / Tetrahedron 67 (2011) 9779e9786
137.04, 137.02, 135.5, 135.4, 134.1, 130.7, 125.6, 125.5, 122.2, 121.1,
61.5, 61.4, 52.4, 52.2, 40.3, 36.0 ppm; LRFAB-MS: [MþNa]þ¼259
(calcd for C12H12O5Na: 259).
(each d, each 1H, 4J¼2.8 Hz), 5.88 (dd, 1H, 3J¼9.7, 4.4 Hz), 5.35 (dd,
1H, 3J¼4.4 Hz, 4J¼1.9 Hz), 4.79 (br s, 1H), 3.83 and 3.73 (each s, each
3H) ppm; 13C NMR (CD2Cl2)
d 170.6, 151.8, 148.9, 148.8, 126.0, 122.0,
121.0, 105.3, 102.1, 73.8, 56.7, and 52.8 ppm; LRFAB-MS:
4.3.4. Synthesis of vinyl quinone 3d. From hydroquinone 5d (trans-
isomer; 24 mg, 0.10 mmol) according to the general procedure 4;
reaction time: 30 min. Yellow solid (23 mg, 98%; trans-isomer): mp
[MþNa]þ¼259 (calcd for C12H12O5Na: 259).
4.3.10. Chromene 4e3. Multistep procedure: From vinyl naph-
thoquinone 3e (cis/trans isomer 1:2, 23 mg, 0.08 mmol) according
to procedure 5; reaction time: 8 h (13.5 mg, 59%). One-pot pro-
cedure: From the reaction of 2-bromojuglone methylether 3e27
(27 mg, 0.10 mmol) and vinyl stannane 2 (40 mg, 0.1 mmol) by
general procedure 6; reaction time: 1 h; pink solid (20 mg, 70%).
113e116 ꢀC; IR (KBr)
n 2953, 1733, 1676, 1635, 1603, 1239,
1176 cmꢂ1 1H NMR (CD2Cl2)
; d 6.71e6.59 (m, 2H), 6.47 (br d, 1H,
3J¼16.1 Hz), 5.90 (d, 1H, 4J¼2.2 Hz), 3.80 and 3.69 (each s, each 3H),
3.28 (dd, 2H, 3J¼7.1 Hz, 4J¼1.2 Hz) ppm; 13C NMR (CD2Cl2)
d 187.8,
181.7, 171.4, 159.2, 140.4, 132.1, 130.1, 124.9, 108.0, 57.0, 52.5,
39.0 ppm; LRFAB-MS: [MþNa]þ¼259 (calcd for C12H12O5Na: 259).
4.3.11. Vinyl hydroquinone 5a. From protected hydroquinone 10a
(cis/trans 1:7; 240 mg, 0.52 mmol) according to the general pro-
cedure 3; reaction time: 48 h. Pale orange solid (97 mg, 80%): mp
4.3.5. Chromene 43. Multistep procedure: From vinyl quinone 3
(12.4 mg, 0.06 mmol; trans- or cis-isomer) according to procedure 5
(in the case of the trans-isomer in the presence of 3.5 equiv of FeCl3);
reaction time: 45 min (trans-isomer) and 2 h (cis-isomer): yields:
10 mg, 76% (trans-isomer) and 11 mg, 86% (cis-isomer). One-pot pro-
cedure: From the reaction of bromobenzoquinone (1, 19 mg,
0.10 mmol) and vinyl stannane 2 (40 mg, 0.10 mmol) according to
generalprocedure6;reactiontime30min. Yellowsolid(13.5mg, 66%).
66e71 ꢀC; IR (KBr)
NMR (CD2Cl2)
n ;
3405, 2953, 1715, 1438, 1213, 1079 cmꢂ1 1H
6.66 and 6.41 (each s, total 1H, trans/cis 7:1 in the
d
order given), 6.64 and 6.54 (each dt, total 1H, 3J¼15.9 Hz, 4J¼1.4 Hz
and 3J¼11.1 Hz, 4J¼1.5 Hz, respectively, trans/cis 7:1 in the order
given), 6.12 and 5.96 (each dt, total 1H, 3J¼15.9, 7.2 Hz and 3J¼11.1,
7.5 Hz, respectively, trans/cis 7:1 in the order given), 4.95 and 4.83
(each br s, total 2H), 3.70 and 3.68 (each s, total 3H, trans/cis 7:1 in
the order given), 3.24 and 3.14 (each dd, total 2H, 3J¼7.2 Hz,
4J¼1.4 Hz and 3J¼7.5 Hz, 4J¼1.5 Hz, respectively, trans/cis 7:1 in the
order given), 2.16 and 2.14 (each s, total 6H, cis/trans 1:7 in the
4.3.6. Chromene 4a. Multistep procedure: From vinyl quinone 3a
(24 mg, 0.10 mmol) according to the general procedure 5; reaction
time: 10 h (16.5 mg, 70%). One-Pot procedure: From 2-bromo-5,6-
dimethylquinone 3a (24 mg, 0.10 mmol)26 and vinyl stannane 2
(40 mg, 0.10 mmol) by general procedure 6; reaction time: 1 h
order given) ppm; 13C NMR (CD2Cl2)
d 173.1, 173.0, 148.1, 147.5,
145.4, 128.7, 128.1, 127.3, 125.1, 124.3, 123.4, 122.4, 113.0, 110.6, 52.6,
52.5, 38.8, 34.6, 12.64, 12.56, 12.4 ppm; LRFAB-MS: [MþNa]þ¼259
(calcd for C13H16O4Na: 259).
ꢀ
(16.6 mg, 71%). Beige solid: mp 130e133 C (decomposition); IR
(KBr)
n
3468, 2928, 1738, 1434, 1206, 1086 cmꢂ1; 1H NMR (CD2Cl2)
d
6.40 (dd,1H, 3J¼9.6 Hz, 4J¼1.7 Hz), 6.32 (s,1H), 5.82 (dd, 3J¼9.6 Hz,
4.6 Hz), 5.34 (dd,1H, 3J¼4.6 Hz, 4J¼1.7 Hz), 3.71 (s, 3H), 2.17 and 2.14
4.3.12. Vinyl hydroquinone 5d. From protected hydroquinone 10d
(cis/trans 1:5; 131 mg, 0.28 mmol) according to the general pro-
cedure 3; reaction time: 36 h. Pale brown solid (50 mg, 75%; mix-
ture of cis/trans isomers with the trans-isomer as the major
(each s, each 3H) ppm; 13C NMR (CD2Cl2)
d 170.9, 148.40, 148.37,
145.1, 126.0, 125.1, 120.0, 118.8, 110.7, 73.7, 52.7, 12.4, 12.0 ppm;
LRFAB-MS: [MþNa]þ¼257 (calcd for C13H14O4Na: 257).
product): mp 146e149 ꢀC; IR (KBr)
1489, 1442, 1284, 1148, 966 cmꢂ1
signals of the major trans-isomer)
n
3475, 3392, 2957, 1710, 1598,
1H NMR (acetone-d6; dominant
7.71 and 7.01 (each br s, each
4.3.7. Chromene 4b. Multistep procedure: From vinyl quinone 3b
(cis/trans isomer 1:3, 12 mg, 0.05 mmol) according to the general
procedure 5; reaction time: 36 h (7 mg, 58%). One-Pot procedure:
From 2-bromo-3-methoxyquinone (3b,25 32.5 mg, 0.15 mmol) and
vinyl stannane 2 (59 mg, 0.15 mmol) by the one-pot procedure by
general procedure 6; reaction time: 1 h (24.8 mg, 70%). Yellow oil:
;
d
1H), 6.77 (dt, 1H, 3J¼16.0 Hz, 4J¼1.4 Hz), 6.52 and 6.41 (each d, each
1H, 4J¼2.7 Hz), 6.26 (dt, 1H, 3J¼16.0, 7.2 Hz), 3.79 and 3.65 (each s,
each 3H), 3.25 (dd, 2H, 3J¼7.2 Hz, 4J¼1.4 Hz) ppm; 13C NMR (ace-
tone-d6; dominant signals of the major trans-isomer) d 172.5, 151.0,
IR (neat)
n
3436, 2953, 1739, 1479, 1437, 1240, 1097, 1042, 800 cmꢂ1
;
149.0, 138.1, 128.8, 124.3, 122.8, 104.3, 100.3, 56.4, 51.9, 38.9 ppm;
1H NMR (acetone-d6)
d
7.78 (br s, 1H), 6.71 (dd, 1H, 3J¼9.9 Hz,
LRFAB-MS: [MþNa]þ¼261 (calcd for C12H14O5Na: 261).
4J¼1.8 Hz), 6.78 and 6.49 (each d, each 1H, 3J¼8.7 Hz), 5.91 (dd, 1H,
3J¼9.9, 4.6 Hz), 5.36 (dd, 1H, 3J¼4.6 Hz, 4J¼1.8 Hz) 3.78 and 3.70
4.3.13. TES-protected bromohydroquinone 9a. Obtained from 2-
bromo-5,6-dimethyl hydroquinone 8a17 (326 mg, 1.50 mmol)
according to general procedure 1; reaction time: 1 h. Pale yellow oil
(each s, each 3H) ppm; 13C NMR (acetone-d6)
d 170.6, 147.0, 145.2,
144.4, 121.0, 120.9, 117.4, 115.8, 112.0, 73.5, 61.7, 52.5 ppm; LRFAB-
MS: [MþNa]þ¼259 (calcd for C12H12O5Na: 259).
(660 mg, 98%): IR (neat)
735 cmꢂ1 1H NMR (CD2Cl2)
each 3H), 1.05e0.85 (m, 18H), 0.83e0.70 (m, 12H) ppm; 13C NMR
n
2956, 2879, 1460, 1410, 1231, 1095, 928,
;
d
6.84 (s, 1H), 2.18 and 2.09 (each s,
4.3.8. Chromene 4c3. Multistep procedure: From vinyl quinone 3c
(cis/trans isomer 1:3, 40 mg, 0.17 mmol) according to the general
procedure 5; reaction time: 8h (28 mg, 70%). One-pot procedure:
From the reaction of 2-bromo-5-methoxybenzoquinone (1c,25
32.5 mg, 0.15 mmol) and vinyl stannane 2 (59 mg, 0.15 mmol)
according to general procedure 6; reaction time: 1.5 h. Yellow oil
(22.5 mg, 64%).
(CD2Cl2)
d 148.8, 146.6, 130.5, 128.5, 120.5, 111.6, 15.2, 13.6, 7.2, 7.0,
6.3, 5.7 ppm; LRFAB-MS: [M]þ¼446 (calcd for C20H37O2BrSi2: 446).
4.3.14. TES-protected bromohydroquinone 9d. Obtained from 2-
bromo-6-methoxy hydroquinone 8d19 (701 mg, 3.20 mmol)
according to general procedure 1; reaction time: 30 min. Colorless
oil (1.22 g, 85%): IR (neat) n 2956, 2878, 1597, 1566, 1489, 1454, 1411,
4.3.9. Chromene 4d. Multistep procedure: From vinyl quinone 3d
(14 mg, 0.06 mmol; trans-isomer) according to the general pro-
cedure 5; reaction time: 15 min (9 mg, 63%). One-pot procedure:
From the reaction of 2-bromo-6-methoxybenzoquinone (1d,25
24 mg, 0.10 mmol) and vinyl stannane 2 (40 mg, 0.10 mmol) by
general procedure 6; reaction time: 1 h (15.6 mg, 66%). Brown oil:
1242, 1207, 1147, 998, 908, 730 cmꢂ1; 1H NMR (CDCl3)
d 6.64 (d, 1H,
4J¼2.8 Hz), 6.37 (d, 1H, 4J¼2.8 Hz), 3.76 (s, 3H), 1.10e0.93 (m, 18H),
0.83e0.69 (m, 12H) ppm; 13C NMR (CDCl3)
d 151.6, 150.0, 138.0,
115.3, 115.1, 104.0, 55.5, 6.9, 6.7, 5.7, 5.1 ppm; LRFAB-MS: [M]þ¼448
(calcd for C19H35O3Si2Br: 448).
IR (neat)
n
3413, 2923, 1739, 1591, 1475, 1200, 1066, 995 cmꢂ1
;
1H
4.3.15. TES-protected vinyl hydroquinone 10a. From TES-protected
2-bromo-5,6-dimethyl hydroquinone 9a (446 mg, 1.00 mmol)
NMR (CD2Cl2)
d
6.41 (dd, 1H, 3J¼9.7 Hz, 4J¼1.9 Hz), 6.38 and 6.12

K.A. Parker, T.L. Mindt / Tetrahedron 67 (2011) 9779e9786
9785
and vinyl stannane 2 (mixture of cis/trans isomers) according to
the general procedure 2; reaction time: 7 h. Pale yellow oil
(320 mg, 69%, mixture of 7:1 trans/cis isomers): IR (neat) 2955,
2877, 1745, 1469, 1415, 1223, 1092, 925, 741 cmꢂ1 1H NMR
(CD2Cl2) 6.75 and 6.52 (each s, total 1H, trans/cis 7:1 in the
Supplementary data
n
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tet.2011.09.068.
;
d
order given), 6.71 and 6.65 (each br d, total 1H, 3J¼15.9 and
11.8 Hz, respectively, trans/cis 7:1 in the order given), 6.05 and
5.81 (each dt, total 1H, 3J¼15.9, 7.1 and 3J¼11.8, 7.4 Hz, re-
spectively, trans/cis 7:1 in the order given), 3.70 and 3.69 (each s,
total 3H, trans/cis 7:1 in the order given), 3.28 and 3.24 (each dd,
total 2H, 3J¼7.4 Hz, 4J¼1.8 Hz and 3J¼7.1 Hz, 4J¼1.3 Hz, re-
spectively, cis/trans 1:7 in the order given), 2.14, 2.13 and 2.12
(each s, total 6H, trans/cis isomers), 1.07e0.88 (m, 18H),
References and notes
1. See Parker, K. A.; Mindt, T. L.; Koh, Y.-H. Org. Lett. 2006, 8, 1759e1762 and
references therein.
2. Stannane 2 was used as a mixture of cis/trans isomers: Collins, P. W.; Kramer, S.
W.; Gasiecki, A. F.; Weier, R. M.; Jones, P. H.; Gullikson, G. W.; Bianchi, R. G. J.
Med. Chem. 1987, 30, 193e197.
3. Parker, K. A.; Mindt, T. L. Org. Lett. 2001, 3, 3875e3878.
4. For selected recent references to the synthesis of chromene structures see: (a)
Bera, K.; Sarkar, S.; Biswas, S.; Maiti, S.; Jana, U. J. Org. Chem. 2011, 76,
3539e3544; (b) Ye, L.-W.; Sun, X.-L.; Zhu, C.-Y.; Tang, Y. Org. Lett. 2006, 8,
3853e3856; (c) Lu, G.; Malinakova, H. C. J. Org. Chem. 2004, 69, 4701e4715; (d)
Kurdyumov, A. V.; Hsung, R. P.; Ihlen, K.; Wang, J. Org. Lett. 2003, 5, 3935e3938;
(e) Yavari, I.; Bayat, M. Tetrahedron 2003, 59, 2001e2005.
0.84e0.65 (m, 12H) ppm; 13C NMR (CD2Cl2)
d 172.6, 172.5, 148.6,
148.0, 147.0, 146.5, 140.5, 133.7, 130.4, 129.3, 128.8, 128.5, 126.4,
125.5, 123.3, 121.3, 117.1, 113.4, 52.2, 52.1, 39.0, 34.6, 14.4, 14.3,
14.1, 13.6, 7.09, 7.08 6.2, 6.0, 5.84, 5.78, ppm; LRFAB-MS:
[M]þ¼464 (calcd for C25H44O4Si2: 464).
5. See also Ref. 3 and citations therein.
6. Chromene natural products that have stimulated recent interest include the
tuberatolides (FXR antagonists), the thiaplidiaquinones (pro-apoptotic), and
members of the puupehenone series (many activities). See: (a) Choi, H.; Hwang,
H.; Chin, J.; Kim, E.; Lee, J.; Nam, S.-J.; Lee, B. C.; Rho, B. J.; Kang, H. J. Nat. Prod.
2011, 74, 90e94; (b) Aiello, A.; Fattorusso, E.; Luciano, P.; Macho, A.; Menna, M.;
Munoz, E. J. Med. Chem. 2005, 48, 3410e3416 and; Aiello, A.; Fattorusso, E.;
Luciano, P.; Menna, M.; Calzado, M. A.; Munoz, E.; Bonadies, F.; Guiso, M.;
Sanasi, M. F.; Cocco, G.; Nicoletti, R. Bioorg. Med. Chem. 2010, 18, 719e727; (c)
For a leading reference, see Utkina, N. K.; Denisenko, V. A.; Krasokhin, V. B.
Tetrahedron Lett. 2011, 52, 3765e3768.
7. For a recent example of preparative chemistry based on the sunlight-activated
photochemistry of quinones, see, (a) Schiel, C.; Oelgemoeller, M.; Ortner, J.;
Mattay, J. Green. Chem. 2001, 3, 224e228 For reviews, see; (b) Finley, K. T.;
Quinones in Kirk-othmer Encyclopedia of Chemical Technology, 5th ed.; 2006; Vol.
21 236e270 and Maruyama, K.; Osuka, A. Recent Advances in the Photo-
chemistry of Quinones In. Chem. Quinonoid Compd.; Patai, S., Rappoport, Z., Eds.;
1988; Vol. 2, pp 759e878 Pt. 1.
4.3.16. TES-protected vinyl hydroquinone 10d. From TES-protected
bromohydroquinone 9d (448 mg, 1.00 mmol) and vinyl stannane
2 (mixture of cis/trans isomers) according to the general procedure
2; reaction time: 20 h. Pale yellow oil (195 mg, 42%; mixture of
trans/cis isomers 5:1): IR (neat)
n
2956, 2878, 1743, 1477, 1227, 1192,
6.79 and 6.67 (each
1160, 1007, 908, 732 cmꢂ1; 1H NMR (CD2Cl2)
d
dt, total 1H, 3J¼16.2 Hz, 4J¼1.4 Hz and 3J¼11.5 Hz, 4J¼1.5 Hz, re-
spectively, trans/cis 5:1 in the order given), 6.56 and 6.40 (each d,
total 1H, 4J¼2.7 Hz and 4J¼2.8 Hz, respectively, trans/cis 5:1 in the
order given), 6.35 and 6.33 (each d, total 1H, 4J¼2.7 Hz and
4J¼2.8 Hz, respectively, trans/cis 5:1 in the order given), 6.17 and
5.85 (each dt, total 1H, 3J¼16.2, 7.1 Hz and 3J¼11.5, 7.4 Hz, trans/cis
5:1 in the order given), 3.77 and 3.76 (each s, total 3H, cis/trans 1:5
in the order given), 3.71 and 3.69 (each s, total 3H, trans/cis 5:1 in
the order given), 3.28 and 3.26 (each dd, total 2H, 3J¼7.4 Hz,
4J¼1.5 Hz and 3J¼7.1 Hz, 4J¼1.4 Hz, respectively, cis/trans 1:5 in the
order given),1.09e0.91 (m,18H), 0.83e0.65 (m,12H) ppm; 13C NMR
8. Iwamoto, H.; Takuwa, A.; Hamada, K.; Fujiwara, R. J. Chem. Soc., Perkin Trans. 1
1999, 575e581.
9. Parker, K. A.; Mindt, T. L. Org. Lett. 2002, 4, 4265e4268.
10. We also found that addition of base (Et3N, DIPEA, K2CO3) and oxidizing agents
(DDQ, O2), intended to accelerate the enolization step or to recycle hydroqui-
none side products in-situ, led to rapid degradation of substrates and/or in-
termediates in each case even at low temperature.
11. We note the resemblance of this phosphine oxide promoted isomerization to
the acid-catalyzed oxa-6pi electrocyclization observed by Jurd and studied in
detail by Bishop, et al. See (a) Jurd, L. Tetrahedron 1977, 33, 163e168; (b) Bishop,
L. M.; Winkler, M.; Houk, K. N.; Bergman, R. G.; Trauner, D. Chem.dEur. J. 2008,
14, 5405e5408.
12. A related enolization/electrocyclization has been suggested as the mechanism
of the thermal isomerization of 2-demethylplastoquinone-3 to 7-
demethylplastichromenol-2, see: Muckensturm, B.; Diyani, F.; Reduron, J.-P.;
Hildenbrand, M. Phytochemistry 1997, 45, 549e550.
13. For a relevant review see: Ferreira, S. B.; da Silva, F. de C.; Pinto, A. C.; Gonzaga,
D. T. G.; Ferreira, V. F. J. Heterocycl. Chem. 2009, 46, 1080e1097.
14. For recent reviews on multicatalysis, see: (a) Ambrosini, L. M.; Lambert, T. H.
ChemCatChem 2010, 2, 1373e1380; (b) Ramachary, D. B.; Jain, S. Org. Biomol.
Chem. 2011, 9, 1277e1300; (c) Walji, A. M.; MacMillan, D. W. C. Synlett 2007,
1477e1489; (d) Chapman, C. J.; Frost, C. G. Synthesis 2007, 1e21; (e) Wasilke, J.-
C.; Obrey, S. J.; Baker, R. T.; Bazan, G. C. Chem. Rev. 2005, 105, 1001e1020.
15. The circular arrow notation in Scheme 4 is a convention introduced by Lam-
bert; see: Cernak, T. A.; Lambert, T. H. J. Am. Chem. Soc. 2009, 131, 3124e3125
and Ref. 14a. It is similar to notations for multicatalysis used in Refs. 14cee.
16. Ellis, G. P. Chemistry of Heterocyclic Compounds ‘Chromenes, Chromanones and
Chromones’; John: New York, NY, 1977; Vol. 31; 11e141.
(CD2Cl2)
d 172.6, 172.4, 151.8, 150.2, 149.8, 148.9, 138.2, 137.9, 129.3,
129.2, 129.1, 128.9, 124.0, 122.6, 112.3, 108.4, 104.5, 104.4, 56.5, 55.7,
52.2, 52.0, 39.0, 34.7, 7.2, 7.1, 6.1, 5.6 ppm; LRFAB-MS:
[MþNa]þ¼489 (calcd for C24H42O5Si2Na: 489).
4.3.17. 1,3,4-Trimethoxyphenyl butenoate 12. From 2-bromo-1,3,4-
trimethoxybenzene (11)32 (151 mg, 0.61 mmol) and vinyl stannane
2 (mixture of cis/trans isomers) according to general procedure 2;
reaction time: 18 h. Pale yellow oil (84 mg, 52%, mixture of trans/cis
isomers 3:1): IR (neat)
n
2951, 2837, 1738, 1483, 1257, 1164, 1100,
6.82 and 6.78 (each d, total 1H,
796 cmꢂ1 1H NMR (CD2Cl2)
;
d
3J¼9.0 Hz, cis/trans 1:3 in the order given), 6.79e6.64 (m, 1.75H),
6.59 (d, 0.75H, 3J¼9.0 Hz, trans-isomer), 6.40 (dt, 0.25H, 3J¼11.3 Hz,
4J¼1.6 Hz, cis-isomer), 5.97 (dt, 0.25H, 3J¼11.3, 7.2 Hz, cis-isomer),
3.80, 3.79, 3.78, 3.76, 3.72, 3.69, 3.66 and 3.65 (each s, total 12H),
3.26 (d, 1.5H, 3J¼6.2 Hz, trans-isomer), 3.01 (dd, 0.5H, 3J¼7.2 Hz,
17. Takanashi, S.-I.; Mori, K. Liebigs Ann./Recl. 1997, 825e838.
4J¼1.6 Hz, cis-isomer) ppm; 13C NMR (CD2Cl2)
d 172.8, 172.7, 152.8,
18. Guzikowski, A. P.; Cai, S. X.; Espitia, S. A.; Hawkinson, J. E.; Huettner, J. E.;
Nogales, D. F.; Tran, M.; Woodward, R. M.; Weber, E.; Keana, J. F. W. J. Med.
Chem. 1996, 39, 4643e4653.
151.9,148.6,148.1,147.8,147.7,120.6, 127.5,126.6, 124.6, 123.5, 120.4,
112.3,111.9,106.4,106.1. 40.3, 35.5, 60.6, 56.72, 56.70, 56.4, 56.2, 52.2,
52.0 ppm; LRFAB-MS: [MþNa]þ¼289 (calcd for C14H18O5Na: 289).
19. Zhu, J.; Beugelmans, R.; Bigot, A.; Singh, G. P.; Bois-Choussy, M. Tetrahedron Lett.
1993, 34, 7401e7404.
20. For a similar system, Bishop et al. (Ref. 11b) calculated a
the oxa-6 rearrangement in the gas phase
D
Gz of 19.8 kcal/mol for
p
Acknowledgements
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This work was supported by the National Institutes of Health
(CA-87503 and GM 74776) and a fellowship of the Graduate As-
sistance in Areas of National Need program of the U.S. Department
of Education. We thank Dr. Tun Li Shen (Brown University) for mass
spectroscopic measurements and Dr. Fernando Raineri and Dr.
Jonathan G. Rudick (Stony Brook University) for valuable
discussions.

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K.A. Parker, T.L. Mindt / Tetrahedron 67 (2011) 9779e9786
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