1,2-dibromotetrachloroethane: An ozone-friendly reagent for the in situ Ramberga-Baecklund rearrangement and its use in the formal synthesis of E-resveratrol

Article abstract of DOI:10.1021/jo3021852

Dibromotetrachloroethane (C₂Br₂Cl₄) is demonstrated as a halogenating reagent for the one-pot conversion of sulfones to alkenes by way of the Ramberga-Baecklund rearrangement. Dibromotetrachloroethane successfully replaces known ozone depleting agents CCl₄, CBr₂F₂ and C₂Br ₂F₄. A formal synthesis of E-resveratrol is demonstrated using C₂Br₂Cl₄.

Full text of DOI:10.1021/jo3021852

Note
pubs.acs.org/joc
1,2-Dibromotetrachloroethane: An Ozone-Friendly Reagent for the
̈
in Situ Ramberg−Backlund Rearrangement and Its Use in the Formal
Synthesis of E‑Resveratrol
Stefan C. Soderman and Adrian L. Schwan*
̈
Department of Chemistry, University of Guelph, Guelph, Ontario N1G 2W1, Canada
S
* Supporting Information
ABSTRACT: Dibromotetrachloroethane (C2Br2Cl4) is demonstrated as a
halogenating reagent for the one-pot conversion of sulfones to alkenes by way of
the Ramberg−Backlund rearrangement. Dibromotetrachloroethane successfully
̈
replaces known ozone depleting agents CCl4, CBr2F2 and C2Br2F4. A formal
synthesis of E-resveratrol is demonstrated using C2Br2Cl4.
Scheme 2. Key Improvements to the Ramberg−Backlund
ince its inception by Swedish chemists in 1940, the
̈
Rearrangement
SRamberg−Backlund rearrangement (RBR) has endured as
̈
a classic carbon−carbon bond forming reaction used time and
time again through the modern history of organic synthesis.1,2
The rearrangement has been applied in the synthesis of
important organic building blocks,3−5 natural products and
several stilbenoid anticancer agents.6−11 The RBR is the base
promoted conversion of an α-halosulfone into an episulfone
followed by the loss of SO2 to give an alkene through
connection of the sulfone’s two α-carbons. (Scheme 1).1 In the
beginning the transformation was a two-pot process; the
halogenation of the sulfone was followed by the base induced
rearrangement.2
poor yields using Chan’s conditions.15 Low yields were
attributed to loss of the low boiling CF2Br2 when reactions
required increased temperatures. Franck solved this problem by
trading relatively low boiling CF2Br2 (23 °C) for its higher
boiling homologue dibromotetrafluoroethane (C2Br2F4, 47
°C).15 Using Chan’s system with C2Br2F4, in place of CF2Br2,
Franck was able to achieve the in situ RBR on some otherwise
stubborn glycolipid precursors to give the corresponding
alkenes in good yields.15
Scheme 1. General Ramberg−Backlund Rearrangement
̈
An important breakthrough came when Meyers discovered a
one-pot RBR with in situ halogenation of the sulfone followed
by rearrangement and alkene formation.12 This was achieved
for benzyl sulfone using a carbon tetrachloride (CCl4),
potassium hydroxide (KOH) and t-butyl alcohol reaction
system (Scheme 2).12 For benzyl sulfone, the chemistry worked
very well, giving quantitative yield of exclusively E-stilbene.
However, Meyers’ method is plagued by polyhalogenation and
carbene-alkene insertion for dialkyl sulfone systems often giving
complex mixtures of products.12 Many of these problems were
remedied by Chan’s modification, which employed alumina-
supported KOH (KOH-Al2O3), dibromodifluoromethane
(CF2Br2), and tert-butanol.13,14 Chan’s protocol gave excellent
yields and moderate selectivities for dialkyl systems without any
significant carbene insertion or polyhalogenation. Although
Chan’s modification was a significant breakthrough for the in
situ RBR reaction, there existed examples of sulfones that
required higher temperatures to undergo the RBR and provided
Although there is no disputing the efficacy of the
halogenating agents in the aforementioned in situ RBR
protocols, significant economic and environmental drawbacks
do exist. One problem with using these reagents is that they are
relatively expensive. The other major problem is that CCl4,
CF2Br2 and C2Br2F4 are all listed as ozone depleting substances
(ODS) in North America and are being actively phased out.16
In fact, to our knowledge in the US, only one supplier provides
CF2Br2 and C2Br2F4. However, these materials could not be
shipped to Canada because of federal regulations.17 Hence,
these practical limitations to the common in situ halogenating
reagents for the RBR create a demand for a new halogenating
agent devoid of such restrictions. After a literature search, it was
discovered that the non-ODS, hexachloroethane (C2Cl6), had
Received: October 4, 2012
Published: November 12, 2012
© 2012 American Chemical Society
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The Journal of Organic Chemistry
Note
been attempted before for the in situ RBR.18 However, the
reaction proved to be highly substrate specific, working only on
activated cyclic systems containing an ethyl ester α to the
sulfonyl group as in the example of Scheme 3.18
and gave an improved conversion of starting material/product
ratio after 24 h of stirring at rt, and increasing the C2Br2Cl4 to
1.5 equiv advanced the conversion further (entries 2 and 3,
Table 1). In a parallel result, increasing the temperature to
reflux for 12 h gave an improved conversion to 90% E-stilbene
(entry 4, Table 1). Next, in entry 5, the amounts of both KOH-
Al2O3 and C2Br2Cl4 were increased and the mixture was
refluxed for 12 h. Gratifyingly, increasing the amounts of both
reagents brought about full substrate conversion to E-stilbene
Scheme 3. RBR Using Hexachloroethane
1
as analyzed by H NMR and an eventual 95% isolated yield.
To achieve the RBR on more sensitive substrates, it was felt
that a lower reaction temperature should be sought. By visual
inspection, the solubility of benzyl sulfone in tBuOH was rather
low, which may have been a cause for the long reaction times at
rt. To combat solubility issues, THF was added initially to a
flask charged with benzyl sulfone to ensure full solubility. Upon
1,2-Dibromotetrachloroethane (C2Br2Cl4) is a common
brominating reagent in organic synthesis and has been used
numerous times to this end.19−23 The compound has several
attractive properties compared with the aforementioned RBR
reagents. As a solid, it is practical to use quantitative molar
equivalents that can be measured and introduced with ease.
CBr2F2, on the other hand, has a boiling point of 23 °C, and
challenges may arise for its quantitation. Indeed, some papers
report the use of 755 and even >100024 molar equivalents of
CBr2F2 under the Chan conditions. As noted, 1,2-dibromote-
trachloroethane is relatively inexpensive, and it is not listed as
an ODS. To our knowledge, C2Br2Cl4 has never been used as a
reagent for the α-bromination of sulfones or in an in situ RBR,
although there is a literature report of the reagent being used to
halogenate a cyclic sultone.23 Given this lack of literature
precedent and its superior price,25 the plan was to evaluate
C2Br2Cl4 as a general reagent for the in situ RBR on
unactivated substrates.
t
complete dissolution of benzyl sulfone in THF at rt, BuOH
was added. Next, KOH-Al2O3 was added followed immediately
by the dropwise addition of a solution of C2Br2Cl4 in THF.
Evaluation of a 1H NMR spectrum of the crude reaction
mixture showed complete conversion to E-stilbene after 4 h of
stirring at rt without any detection of the Z isomer. Purification
by filtration through a silica plug and subsequent flash
chromatography gave exclusively E-stilbene in excellent yield
(Table 1, entry 6).
Using the optimized reaction protocol, an exploration of the
scope the reaction to other substrates was undertaken (Table
2). This was initially done by evaluating the chemistry of a
series of stilbenoid derivatives (entries 2−9). Substituted 3-
nitro and 3-bromo benzyl sulfones also gave excellent yields
and complete stereoselectivities (entries 2 and 3). As expected,
the 2-naphthyl substituted sulfone gave excellent yield and
complete E stereoselectivity (entry 9).
Indeed all the stilbenoid substrates gave yields of ≥82% with
complete E selectivity, including a 2-pyridyl based system,
which was generated from the corresponding sulfone in 92%
yield (entry 5). A 2,6-disubstituted pyridine disulfone substrate
was also attempted and yielded the corresponding E,E-bis(2-
styryl)pyridine with complete selectivity in moderate yield
(entry 10).
These RBR conditions also worked reasonably well for a
primary dialkyl system (Table 2, entry 11), which can be
plagued with polyhalogenation and carbene insertion by-
products (for CCl4).2 The dioctyl sulfone gave the correspond-
ing alkene in moderate yield and a selectivity comparable to
that garnered by Chan’s protocol without any detection of
polyhalogenated byproducts.13 Unfortunately, dicyclopentyl
sulfone did not undergo the in situ RBR with the C2Br2Cl4
system. Even with prolonged heating, increased equivalents or
microwave irradiation, starting material remained without any
observed evidence of alkene formation (Table 2, entries 14 and
15). This result contrasts Chan’s conditions, which can bring
about the conversion of dicyclopentyl sulfone to the
corresponding alkene. The difference in reactivity could be
attributed to steric factors of the brominating agent; C2Br2Cl4 is
a bulkier reagent than Chan’s CBr2F2 and may be unable to
brominate an already sterically hindered sulfonyl α-anion of
dicyclopentyl sulfone. It is anticipated that CBr2F2 also has
reduced entropic requirements in the transition state for the
release of a Br to a nucleophile.
Benzyl sulfone was chosen as the substrate to begin initial
investigations using C2Br2Cl4 as the halogenating agent,
because this substrate is known to undergo the in situ RBR
with excellent yields and selectivity using Meyers’ condi-
tions.2,12 In the first attempt, benzyl sulfone was dissolved in a
t
mixture of BuOH:H2O (5:1) and stirred at room temperature
(rt). Potassium hydroxide (KOH) was added followed by
C2Br2Cl4. The reaction was sluggish, and after 3 days of stirring
at rt, NMR analysis revealed only 10% conversion of starting
material to exclusively the E-stilbene product (entry 1, Table
1). In hopes of improving the reaction rate, the base
component of Chan’s reagent (KOH-Al2O3) was evaluated
Table 1. Optimization of in Situ RBR with C2Br2Cl4 as the
Halogenating Agent
base
(equiv)
equiv of
C2Br2Cl4
conv.
(%)
yield
(%)
a
b
c
#
solvent
temp
rt
time
3 d
1
KOH (1.0)
1.1
1.1
1.5
1.2
1.8
1.8
TBA/H2O
(5/1)
10
nd
nd
nd
nd
95
91
2
3
4
5
6
KOH-Al2O3
(15.1)
TBA
TBA
TBA
TBA
rt
24 h
24 h
12 h
12 h
4 h
72
KOH-Al2O3
(15.1)
rt
77
KOH-Al2O3
(15.1)
reflux
reflux
rt
90
KOH-Al2O3
(18.9)
100
100
KOH-Al2O3
(18.9)
TBA/THF
(3/1)
Cyclic sulfones have proved to be quite acquiescent to in situ
RBR. As such N-Boc protected 1,4-thiazine S,S-dioxide was
exposed to the RBR conditions, which delivered the
a
b
c
TBA = tBuOH. % Reaction conversion estimated by NMR. The E/
Z ratio was 100:0 in all cases (NMR).
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Note
10%, inseparable by flash chromatography, detectable by GC−
MS), as a consequence of dihalogenation of the sulfone
substrate. This result can be explained by differences in the
relative basicities of the α-protons on the benzylic and hexyl
sides of the sulfone. The benzylic protons are more acidic
(lower pKa ∼ 23.4)27 than the alkyl α-protons (pKa ∼ 31.0).27
Therefore, assuming kinetic deprotonation mirrors thermody-
namic pKa values, the benzylic carbon is more readily
deprotonated and subsequently brominated than the hexyl α-
carbon. Consequently, dibromination could occur at the
benzylic site in competition with anion formation at the α-
carbon on the hexyl side of the molecule. If two bromines are
incorporated at the benzyl site, eventual formation of the α-
sulfonyl anion on the hexyl side of the molecule leads to the
formation of a brominated episulfone. Fast extrusion of SO2
would yield a brominated alkene byproduct. Indeed, an analysis
of the 1H NMR spectrum of the reaction mixture indicated that
the minor products of this 2-pentylstyrene-forming mixture
possessed triplets for their lone vinylic resonance, fully
consistent with bromine incorporation at the benzylic site
and not the 2 position of the 2-pentylstyrene byproducts (vide
supra). Substantial effort was expended to adapt the reaction
conditions to reduce the amount of monobromoalkene, but
improvements were minimal.
Table 2. Scope of the C2Br2Cl4 Mediated Ramberg−
Backlund Rearrangement
̈
The RBR chemistry of benzyl hexyl sulfone and particularly
the presence of a monobrominated alkene allow some
conclusions about the reaction chemistry of the electrophile
with α-sulfonyl anions. Although there is an instance of
C2Br2Cl4 acting as a source of electrophilic chlorine in the
literature,23 GC−MS analysis of the benzyl hexyl sulfone RBR
mixture did not reveal any evidence in support of chlorine
incorporation. On the basis of this example, C2Br2Cl4 delivers
only bromine atoms to the sulfones.
In addition to the preference for bromination and the steric
arguments noted above, the observed chemistry permits
additional comments about the bromination chemistry of
C2Br2Cl4, particularly in relation to that of CF2Br2. Since the
RBR with both reagent systems occurs with the same solid
phase base, the dehydrohalogenation step of the RBR under
each set of conditions might be expected to be comparable,
particularly since the two conditions share related solvent
systems. If this is true, then differences in observed chemistry
should be based on bromine incorporation. One difference has
already been noted for steric effects. The chemistry of benzyl
hexyl sulfone suggests that the bromination chemistry using
C2Br2Cl4 may be faster than with CF2Br2, presumably since the
reagent at hand brominates with concurrent E2 chemistry as
a
b
Isolated yield of pure material unless otherwise indicated. Obtained
c
as an E:Z isomeric ratio of 72:28. Products were obtained 91% pure.
Contaminants were monobrominated congeners. Mixture was heated
at 79 °C. Reaction performed under microwave conditions (300 W
instrument) at 78 °C.
d
e
corresponding Boc protected 3-pyrroline in 52% isolated yield
(Table 2, entry 12), a value similar to other 5-membered cyclic
alkenes prepared under RBR conditions.2,5,26 Finally, the RBR
protocol was evaluated for the olefination of benzyl hexyl
sulfone, a reaction which gave the corresponding alkene with
complete E-stereoselectivity and 64% yield by NMR analysis.
However, there was significant formation of brominated alkene
byproducts, assigned to be E- and Z-PhBrCCHC5H11 (ca.
Scheme 4. Formal Synthesis of Resveratrol
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The Journal of Organic Chemistry
Note
× 0.25 mm × 0.25 μm thickness). Spectra of 1H NMR and 13C NMR
are presented for all purified novel compounds and for alkene products
(Supporting Information).
opposed to carbanion or carbene formation. Chan evaluated
CF2Br2 with benzyl hexyl sulfone in the original paper, and
there is no mention of additional bromination,13 whereas the
C2Br2Cl4 system delivered some minor brominated impurities
as outlined above. For comparison, there are several examples
of CCl4 delivering unwanted chlorines.2 It would appear that
the balance between bromination and dehydrobromination is
ideal for the Chan reagent, and minor problems arise in the
current work with benzyl alkyl sulfones.
Given the success of this RBR method for the synthesis of
stilbenoids, the total synthesis of E-resveratrol, a naturally
occurring phenolic stilbenoid found in the skins of red grapes,
was attempted. Currently E-resveratrol is the subject of
numerous biological studies for several properties including
antioxidant, cardiovascular, anti-inflammatory and antiaging
properties.28 The synthesis of E-resveratrol has been achieved
before using an in situ RBR protocol employing the ODS,
CCl4, as the halogenating reagent.9 The synthesis began with a
thioetherification reaction between thiol 1 and 3,5-dimethox-
ybenzyl bromide, which gave the resulting crude sulfide (2) in
96% yield (Scheme 4). Next, crude sulfide 2 was oxidized to
sulfone 3 with mCPBA in good yield. The sulfone (3) was then
exposed to the in situ RBR protocol to give O-permethylated E-
resveratrol 4 with complete stereoselectivity and excellent yield,
concluding the formal synthesis of E-resveratrol. Subsequent
demethylation with boron tribromide to give the phenolic E-
resveratrol is well established chemistry, and in one example has
been reported in 84% yield.9
General Procedure for Preparation of Benzyl Sulfanes.
Starting thiol (3.2−12.9 mmol) was placed under a N2 atmosphere
and dissolved in dry THF (5−10 mL [25 mL for hexanethiol]). The
solution was chilled to 0 °C, solid 95% NaH (1.0−1.3 equiv) was
added, and the mixture was stirred for 10 min. The coreacting bromide
(1.05−1.2 equiv [0.5 equiv for {bromomethyl}benzotrifluoride and
bis{bromomethyl}pyridine]) in THF (2−4 mL) was added dropwise,
and the mixture was stirred overnight. The reaction was quenched by
the addition of water, and the mixture was extracted with ethyl acetate
(3 × 10 mL). The organic layer was washed successively with a 10%
NaOH (aq.) solution (2 × 15 mL), H2O (15 mL), and then brine (15
mL). The organic layer was dried over MgSO4, filtered and
concentrated under reduced pressure to yield the crude sulfide of
sufficient purity for the next step. 2.1 equiv of NaH was employed
when 2-(bromomethyl)pyridine hydrobromide was the electrophile.
Crude yields: 77, 88−99%. Except for the three noted below, all benzyl
sulfanes have been previously reported, and characterization data
(NMR and/or MP) matched that of the literature.9,29−34 Dicyclopen-
tyl sulfane,35 di(n-octyl) sulfane36 and N-Boc thiomorpholine37 were
prepared according to literature procedures.
General Procedure for MCPBA Oxidation of Sulfanes. The
crude sulfane (2.8−14 mmol) was dissolved in DCM (60−75 mL) and
stirred at 0 °C. MCPBA (calibrated to 77 or 83%, 2.5−3.5 equiv; 4
equiv for 2,6-bis[benzylsulfanylmethyl]pyridine) was added, and the
reaction was stirred for 8 h at rt. The crude reaction mixture was
washed with saturated Na2S2O3 (aq.), NaHCO3 (aq.), H2O and brine.
The organic layer was dried over MgSO4 and filtered, and the solvent
was removed in vacuo. The crude product was purified by flash
chromatography using EtOAc/hexanes as the eluent. Yields were 37,
53−89%. The characterization data (NMR and/or MP) for known
sulfones matched literature data.9,29,31,37−41
Data for New Sulfones. 3-Bromobenzyl benzyl sulfone. Crude
3-bromobenzyl benzyl sulfane (98% yield, 1H NMR (400 MHz,
CDCl3) δ = 7.53 (s, 1H), 7.41−7.30 (m, 6H), 7.27−7.13 (m, 2H),
3.59 (s, 2H), 3.53 (s, 2H); 13C NMR (101 MHz, CDCl3) δ = 140.6,
137.8, 132.0, 130.1, 130.0, 129.0, 128.6, 127.7, 127.2, 122.5, 35.7, 35.0)
was subjected to oxidation as above to provide 3-bromobenzyl benzyl
sulfone as a white solid (63%): mp 134−135 °C; 1H NMR (400 MHz,
CDCl3) δ = 7.53 (td, J = 1.6, 7.8 Hz, 1H), 7.48 (t, J = 1.6 Hz, 1H),
7.45−7.35 (m, 5H), 7.35−7.31 (m, 1H), 7.28 (t, J = 7.7 Hz, 1H), 4.17
(s, 2H), 4.06 (s, 2H); 13C NMR (101 MHz, CDCl3) δ = 133.8, 132.2,
130.8, 130.5, 129.5, 129.5, 129.2, 129.1, 127.3, 122.8, 58.6, 57.1; IR
(neat) cm−1 3064, 3033, 2987, 2941, 1643, 1633, 1412, 1302, 1277,
1116, 1072, 793. Analysis calc’d for C14H13BrO2S: C, 51.70; H, 4.03.
Found: C, 51.79; H, 4.19.
In conclusion, C2Br2Cl4 has proven to be an effective reagent
for the in situ RBR of dibenzylic, primary dialkyl and cyclic alkyl
sulfones. The principal drawbacks occur for highly hindered
alkyl sulfones and when pKa differences of the groups on the
sulfones are the largest. The reagent system is clearly a greener,
more pactical and more economical alternative to the ozone-
depleting reagents that have been successfully used in the
recent past for in situ RBRs. As such, the C2Br2Cl4 reagent
system is recommended for future syntheses requiring a
Ramberg−Backlund protocol.
̈
EXPERIMENTAL SECTION
■
General Methods. Melting points are uncorrected. Infrared (IR)
spectra were obtained on a FT-IR spectrometer as a neat film. NMR
1
spectra for H NMR and 13C NMR were recorded at 600 and 150.9
4-Trifluoromethylbenzyl benzyl sulfone. Crude 4-trifluoromethyl-
MHz or 400 and 100.6 MHz, respectively, in CDCl3 unless otherwise
noted. 1H NMR and 13C NMR chemical shifts are referenced to
CHCl3 or tetramethylsilane and are recorded in parts per million
(ppm). Tetrahydrofuran (THF) was freshly distilled from benzophe-
none and sodium. All chemicals including benzyl bromides, benzyl
thiols and benzyl sulfane were obtained from commercial sources
unless otherwise noted. m-CPBA was obtained commercially and was
dried and calibrated with benzyl sulfide before use. All air and water
sensitive reagents were transferred via oven-dried nitrogen-purged
syringes into flame-dried flasks under an inert nitrogen atmosphere.
Flash chromatography was performed on 200−450 mesh Type 60 Å
silica gel. Analytical thin-layer chromatography (TLC) was performed
using 0.25 mm, extra hard layer, 60 Å F254 glass-backed silica gel plates.
Microwave reactions were carried out in a CEM Discover S-class
reactor. Microwave reactions were carried out in vessels equipped with
a Teflon cap. The temperature of the reaction mixture was monitored
using a surface sensor. The dynamic method with maximum power
300W, 250 psi setting for maximum pressure and without powermax
option was used. (Caution! Cardiac pacemakers require magnets to
control their operation during checkout. Some danger exists if a pacemaker
is positioned in close proximity to the instrument cavity.) GC−MS
experiments were performed using a Factor Four column (30 m length
1
benzyl benzyl sulfane (89% yield, H NMR (400 MHz, CDCl3) δ =
7.55 (d, J = 8.0 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 7.33−7.29 (m, 5H),
3.61 (s, 2H), 3.59 (s, 2H); 13C NMR (101 MHz, CDCl3) δ = 142.4,
137.7, 129.3 (q, J = 32.3 Hz), 129.3, 129.0, 128.6, 127.2, 125.4 (q, J =
3.7 Hz), 122.2 (q, 272.3 Hz), 35.7, 35.1) was subjected to oxidation as
above to provide 4-trifluoromethylbenzyl benzyl sulfone as a white
solid (82%): mp 146−147 °C; 1H NMR (400 MHz, CDCl3) δ = 7.65
(d, J = 8.0 Hz, 2H), 7.49 (d, J = 8.0 Hz, 2H), 7.45−7.36 (m, 5H), 4.20
(s, 2H), 4.15 (s, 2H); 13C NMR (101 MHz, CDCl3) δ = 131.6, 131.3,
131.2 (q, J = 31.4 Hz), 130.8, 129.3, 129.2, 127.4, 125.9 (q, J = 3.8
Hz), 123.9 (q, J = 271.6 Hz), 58.9, 57.2; IR (neat) cm−1 3048, 2982,
2938, 1636, 1417, 1332, 1298, 1155, 1120, 858. Analysis calc’d for
C15H13F3O2S: C, 57.32; H, 4.17. Found: C, 57.31; H, 4.30.
2,6-Bis[benzylsulfonylmethyl]pyridine. Obtained as a white solid
(82%): mp 228−229 °C; 1H NMR (400 MHz,DMSO-d6) δ = 7.93 (t,
J = 7.6 Hz, 1H), 7.53 (d, J = 7.6 Hz, 2H), 7.46−7.42 (m, 4H), 7.40−
7.36 (m, 6H), 4.66 (s, 4H), 4.63 (s, 4H); 13C NMR (101 MHz,
CDCl3) δ = 149.6, 138.1, 131.3, 128.4, 128.4, 128.3, 125.7, 58.9, 57.8;
IR (nujol mull) cm−1 3084, 3063, 3004, 2853, 1589, 1299, 1284, 1126,
774, 694. Analysis calc’d for C21H21NO4S2: C, 60.70; H, 5.09. Found:
C, 60.59; H, 5.16.
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Note
Benzyl 3,5-dimethoxybenzyl sulfone. Crude benzyl 3,5-dimethox-
ybenzyl sulfane (96% yield, H NMR (400 MHz, CDCl3) δ = 7.34−
[lit.45 63−64 °C]; 1H NMR (400 MHz, CDCl3) δ = 8.60 (dd, J = 0.9,
4.8 Hz, 1H), 7.67−7.60 (m, 2H), 7.60−7.55 (m, 2H), 7.42−7.33 (m,
3H), 7.32−7.23 (m, 1H), 7.17 (d, J = 16.1 Hz, 1H), 7.12 (ddd, J = 1.0,
4.8, 7.5 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ = 155.6, 149.7,
136.7, 136.6, 132.7, 128.8, 128.4, 128.0, 127.1, 122.1, 122.1.
E-4-Methoxyphenyl-3′,5′-dimethoxyphenylethene. See details for
compound 4 below.
1
7.23 (m, 5H), 6.46−6.44 (m, 2H), 6.35−6.34 (m, 1H), 3.78 (s, 6H),
3.62 (s, 2H), 3.54 (s, 2H); 13C NMR (101 MHz, CDCl3) δ = 160.8,
140.5, 138.1, 129.1, 128.5, 127.0, 106.9, 99.2, 55.3, 35.8, 35.7) was
subjected to oxidation as above to provide benzyl 3,5-dimethoxybenzyl
1
sulfone as a white solid (71%): mp 94−95 °C; H NMR (400 MHz,
1
CDCl3) δ = 7.39 (m, 5H), 6.56−6.52 (m, 2H), 6.47 (m, 1H), 4.14 (s,
2H), 4.06 (s, 2H), 3.79 (s, 6H); 13C NMR (101 MHz, CDCl3) δ =
161.0, 130.9, 129.6, 129.0, 129.0, 127.5, 108.8, 101.0, 58.3, 57.9, 55.5;
IR (neat) cm−1 3063, 3004, 2967, 2937, 2839, 1597, 1457, 1431, 1312,
1206, 1154, 1116, 1064, 932. Analysis calc’d for C16H18O4S: C, 62.72;
H, 5.92. Found: C, 62.72; H, 5.81.
4-Methoxystilbene. No Z-isomer was detected in the H NMR of
the crude reaction mixture. The crude product was purified by flash
chromatography using EtOAc/hexanes (2:98) as the eluent to give
exclusively the E-isomer as a white solid (86 mg, 95%): mp = 134−137
°C [lit.46 130−133 °C];1H NMR (400 MHz, CDCl3) δ = 7.50−7.44
(m, 4H), 7.34 (t, J = 7.6 Hz, 2H), 7.25−7.21 (m, 1H), 7.07 (d, J = 16.4
Hz, 1H), 6.97 (d, J = 16.4 Hz, 1H), 6.90 (m, 2H), 3.83 (s, 3H); 13C
NMR (101 MHz, CDCl3) δ = 159.3, 137.7, 130.2, 128.7, 128.2, 127.7,
127.2, 126.6, 126.3, 114.1, 55.3.
Benzyl 4-methoxybenzyl sulfone. Obtained as a white solid (75%):
1
mp 126−127 °C; H NMR (400 MHz, CDCl3) δ = 7.41−7.37 (m,
5H), 7.29 (d, J = 8.8 Hz, 2H), 6.92 (d, J = 8.8 Hz, 2H), 4.11 (s, 2H),
4.07 (s, 2H), 3.82 (s, 3H); 13C NMR (101 MHz, CDCl3) δ = 160.2,
132.1, 130.9, 129.0, 127.7, 119.3, 114.5, 57.8, 57.4, 55.4; IR (neat)
cm−1 3003, 2979, 2961, 2935, 2837, 1638, 1611, 1586, 1306, 1285,
1249, 1142, 1127, 1033, 832. Analysis calc’d for C15H16O3S: C, 65.19;
H, 5.84. Found: C, 65.40; H, 5.81.
3,5-Dimethoxystilbene. No Z-isomer was detected in the 1H NMR
of the crude reaction mixture. Recrystallization of the residue from
hexanes gave the pure E-alkene as a white solid (86 mg, 87%): mp =
53−54 °C [lit.47 53−55 °C];1H NMR (400 MHz, CDCl3) δ = 7.52−
7.49 (m, 2H), 7.37−7.33 (m, 2H), 7.28−7.24 (m, 1H), 7.09 (d, J =
16.4 Hz, 1H), 7.03 (d, J = 16.4 Hz, 1H), 6.67 (m, 2H), 6.40 (t, J = 2
Hz, 1H), 3.83 (s, 6H); 13C NMR (101 MHz, CDCl3) δ = 161.0, 139.4,
137.2, 129.2, 128.7, 128.7, 127.8, 126.6, 104.6, 100.0, 55.4.
General One-Pot RBR Procedure for Preparation of Alkenes.
The sulfone (100−120 mg, 0.307−0.510 mmol) was dissolved in
THF/tBuOH (2.5 mL/7.5 mL) and stirred at rt. Next, KOH-Al2O3
(19 equiv) was added to the reaction mixture. Immediately following
base addition, a solution of 1,2-dibromotetrachloroethane (equivalents
indicated in Table 2) in THF (2 mL) was added slowly dropwise via a
syringe. The reaction mixture was stirred for 2−48 h (see Table 2 for
precise times) at rt. Upon sulfone consumption (TLC monitoring),
the reaction mixture was flushed through a silica plug with EtOAc to
remove inorganic components. Fractions were combined and
concentrated. Purification by flash chromatography gave pure material.
See Table 2 for yields.
1
E-2-Naphthyl styrene. No Z-isomer was detected in the H NMR
of the crude reaction mixture. The crude product was recrystallized
from hexanes to give exclusively the E-isomer as clear colorless crystals
(67 mg, 87%): mp 145−147 °C [lit.47 144−146 °C];1H NMR (400
MHz, CDCl3) δ = 7.88−7.76 (m, 4H), 7.73 (dd, J = 1.7, 8.5 Hz, 1H),
7.59−7.52 (m, 2H), 7.49−7.40 (m, 2H), 7.40−7.33 (m, 1H), 7.31−
7.18 (m, 3H); 13C NMR (101 MHz, CDCl3) δ = 137.4, 134.9, 133.7,
133.1, 129.1, 128.8, 128.8, 128.4, 128.0, 127.8, 126.7, 126.6, 126.4,
126.0, 123.5.
E-Stilbene. No Z-isomer was detected in the 1H NMR of the crude
reaction mixture. Purification by flash chromatography eluting with
hexanes gave E-stilbene as a white solid (66 mg, 91%): mp 122−123
1
2,6-Bis(E-2-styryl) pyridine. No Z-isomer was detected in the H
NMR of the crude reaction mixture. The crude product was
recrystallized from hexanes/EtOAc to give exclusively the E-isomer
as a white solid (33 mg, 49%): mp 164−165 °C [lit.46 165−166
°C];1H NMR (400 MHz, CDCl3) δ = 7.71 (d, J = 16.0 Hz, 2H),
7.66−7.61 (m, 5H), 7.41−7.37 (m, 4H), 7.32−7.25 (m, 4H), 7.21 (d, J
= 16.0 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ = 155.4, 137.0, 136.8,
132.9, 128.7, 128.3, 127.2, 120.5.
°C [lit.42 123.9−124.6 °C]; H NMR (400 MHz, CDCl3) δ = 7.52−
1
7.49 (m, 4H), 7.51−7.33 (m, 4H), 7.28−7.24 (m, 2H), 7.11 (s, 2H);
13C NMR (101 MHz, CDCl3) δ = 137.4, 128.7, 127.7, 126.6.
E-2-(3-Bromophenyl) styrene. No Z-isomer was detected in the 1H
NMR of the crude reaction mixture. The crude product was
recrystallized from hexanes to give exclusively the E-isomer as a
white solid (72 mg, 90%): mp 88−89 °C [lit.43 89−90 °C]; 1H NMR
(400 MHz, CDCl3) δ = 7.66 (t, J = 1.8 Hz, 1H), 7.53−7.47 (m, 1H),
7.44−7.32 (m, 4H), 7.28 (tt, J = 1.0, 7.3 Hz, 1H), 7.25−7.18 (m, 1H),
7.10 (d, J = 16.4 Hz, 1H), 7.01 (d, J = 16.4 Hz, 1H); 13C NMR (101
MHz, CDCl3) δ = 139.5, 136.8, 130.4, 130.2, 129.3, 128.8, 128.1,
127.1, 126.7, 125.2, 122.9.
E,Z-Diheptylethene. The crude product was purified by flash
chromatography (100% hexanes). Fractions were combined and
concentrated to give product as a clear colorless oil13 (39 mg, 51%,
1
E:Z = 72:28 by NMR integration). E-alkene: H NMR (600 MHz,
CDCl3) δ = 5.38 (m, 2H), 1.96 (m, 4H), 1.35−1.23 (m, 20H), 0.88 (t,
J = 6.0 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ = 130.5, 31.9, 29.7,
29.2, 29.1, 27.2, 22.7, 14.1; GC−MS m/z 224 [M+] (1), 221 (6), 139
1
E-2-(3-Nitrophenyl) styrene. No Z-isomer was detected in the H
1
(17), 125 (53), 111 (100), 109 (18). Z-alkene: H NMR (600 MHz,
NMR of the crude reaction mixture. The crude product was
recrystallized from hexanes to give exclusively the E-isomer as a
white solid (68 mg, 88%): mp 96−97 °C [lit.44 92−95 °C]; 1H NMR
(400 MHz, CDCl3) δ = 8.34 (s, 1H), 8.07 (dd, J = 8.0, 1.2 Hz, 1H),
7.77 (d, J = 8.0 Hz, 1H), 7.54−7.48 (m, 3H), 7.39 (t, J = 7.2 Hz, 2H),
7.33−7.29 (m, 1H), 7.21 (d, J = 16.4 Hz, 1H), 7.11 (d, J = 16.4 Hz,
1H); 13C NMR (101 MHz, CDCl3) δ = 148.7, 139.2, 136.3, 132.3,
131.8, 129.6, 128.9, 128.6, 126.9, 126.1, 122.0, 120.9.
CDCl3) δ = 5.35 (m, 2H), 2.01 (m, 4H), 1.35−1.23 (m, 20H), 0.87
(m, 6H); 13C NMR (100 MHz, CDCl3) δ = 129.9, 32.6, 29.8, 29.3,
29.2, 27.2, 22.7, 14.1; GC−MS m/z 224 [M+] (2), 221 (3), 153 (9),
139 (17), 125 (56), 111 (100), 109 (14).
N-Boc-3-pyrroline. The crude product, as a clear, colorless oil was
1
1
pure by H NMR. (45 mg, 52%): H NMR (400 MHz, CDCl3) δ =
5.77 (m, 2H), 4.11 (m, 4H), 1.48 (s, 9H); 13C NMR (101 MHz,
CDCl3) δ = 154.3, 125.9, 125.8, 79.3, 53.1, 52.8, 28.5 (rotamers).48
E-1-Phenyl-1-heptene.49 An inseparable mixture of E-1-phenyl-1-
heptene and two isomeric 1-bromo-1-phenyl-1-heptenes were
obtained, and the desired product as a clear liquid (53 mg;
E-2-(4-Trifluoromethylphenyl) styrene. No Z-isomer was detected
in the 1H NMR of the crude reaction mixture. The crude product was
recrystallized from hexanes to give exclusively the E-isomer as a clear
colorless needles (64 mg, 82%): mp 131−132 °C [lit.42 132.1−133.4
°C]; 1H NMR (400 MHz, CDCl3) δ = 7.61−7.56 (m, 4H), 7.53 (d, J
= 7.2 Hz, 2H), 7.38 (t, J = 5.5 Hz, 2H), 7.32−7.28 (m, 1H), 7.19 (d, J
= 16.4 Hz, 1H), 7.11 (d, J = 16.4 Hz, 1H); 13C NMR (150.9 MHz,
CDCl3) δ = 140.8, 136.7, 132.2, 129.3 (q, J = 32.4 Hz), 128.8, 128.3,
127.1, 126.8, 126.6, 125.7 (q, J = 3.7 Hz), 124.3 (q, J = 272.6 Hz).
1
brominated:desired (91:9) by H NMR; ca. 64% of desired alkene).
No Z-isomer of E-1-phenyl-1-heptene was detected in the 1H NMR or
GC−MS of the reaction mixture. E-1-Phenyl-1-heptene: 1H NMR
(400 MHz, CDCl3) δ = 7.34−7.25 (m, 4H), 7.21−7.15 (m, 1H), 6.37
(d, J = 15.6 Hz, 1H), 6.22 (dt, J = 15.6, 6.8 Hz, 1H), 2.19 (q, J = 6.9
Hz, 2H), 1.50−1.43 (m, 2H), 1.38−1.29 (m, 4H), 0.91 (t, J = 7.0 Hz,
3H); 13C NMR (101 MHz, CDCl3) δ = 138.00, 131.3, 129.7, 128.5,
126.9, 125.9, 32.6, 31.6, 29.1, 22.6, 14.1; GC−MS m/z 174 [M+]
(100), 175 (63), 173 (43), 161 (10), 143 (9), 117 (21), 105 (14).
1
E-2-Pyridyl styrene. No Z-isomer was detected in the H NMR of
the crude reaction mixture. The crude product was purified by flash
chromatography using EtOAc/hexanes (2:98) as the eluent to give
exclusively the E-isomer as a white solid (66 mg, 92%): mp 61−62 °C
10982
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The Journal of Organic Chemistry
Note
Minor, inseparable components. 1-Bromo-1-phenyl-1-heptene 1:
GC−MS m/z 252 [M+] (63), 254 (62), 197 (14), 195 (15), 171 (18),
143 (9), 131 (10), 117 (36), 105 (100). 1-Bromo-1-phenyl-1-heptene
2: GC−MS m/z 252 [M+] (100), 254 (98), 197 (14), 195 (15), 173
(78), 171 (33), 157 (11), 143 (17), 129 (10), 117 (42), 105 (89).
Specific Protocols for Preparation of Trimethyl Resveratrol
(4). 4-Methoxyphenyl-3′,5′-dimethoxyphenyl sulfone (3). 4-Methox-
yphenylmethanethiol (1, 1.87 mL, 12.9 mmol) was dissolved in dry
THF (5 mL) under a nitrogen atmosphere. The solution was chilled to
0 °C, solid 95% NaH (0.326 g, 13.6 mmol) was added, and the
mixture was stirred for ∼10 min. A solution of 1-(bromomethyl)-3,5-
dimethoxybenzene (3.15 g, 13.6 mmol) in THF (2 mL) was added
dropwise, and the mixture was stirred overnight. The reaction was
quenched by the addition of water, and the mixture was extracted with
ethyl acetate (3 × 10 mL). The organic layer was washed successively
with a 10% NaOH (aq.) solution (2 × 15 mL), H2O (15 mL) and
brine (15 mL). The organic layer was dried over MgSO4, filtered, and
concentrated under reduced pressure to yield crude sulfide 2 as a clear
yellow oil (3.42 g, 96%): 1H NMR (400 MHz, CDCl3) δ = 7.21 (d, J =
8.8 Hz, 2H), 6.84 (d, J = 8.8 Hz, 2H), 6.45−6.44 (m, 2H), 6.35−6.34
(m, 1H), 3.80 (s, 3H), 3.78 (s, 6H), 3.58 (s, 2H), 3.53 (s, 2H); 13C
NMR (101 MHz, CDCl3) δ = 160.8, 158.6, 140.6, 130.1, 130.1, 113.9,
106.9, 99.1, 55.3, 55.3, 35.8, 35.1. Crude sulfide 2 (3.30 g, 10.8 mmol)
was dissolved in DCM (70 mL) and stirred at 0 °C. To this solution
was added MCPBA (ca. ∼77%, 5.61 g, 25.0 mmol), and the reaction
was stirred for 8 h at rt. The crude reaction mixture was washed with
saturated Na2S2O3 (aq.), NaHCO3 (aq.), H2O and brine. After these
successive washes the organic layer was dried over MgSO4, filtered,
and the solvent was removed in vacuo. The crude product was purified
by flash chromatography using EtOAc/hexanes as the eluent to yield
sulfone 3 as a white solid (2.85 g, 78%): mp 95−96 °C; 1H NMR (400
MHz, CDCl3) δ = 7.29 (d, J = 8.7 Hz, 2H), 6.91 (d, J = 8.7 Hz, 2H),
6.52 (d, J = 2.2 Hz, 2H), 6.47 (t, J = 2.2 Hz, 1H), 4.11−4.07 (m, 2H),
4.06−4.01 (m, 2H), 3.80 (s, 3H), 3.78 (s, 6H); 13C NMR (101 MHz,
CDCl3) δ = 161.0, 160.2, 132.2, 129.7, 119.2, 114.4, 108.8, 100.9, 58.1,
57.3, 55.4, 55.3. The 1H NMR and 13C NMR were in good agreement
with literature data.9
ACKNOWLEDGMENTS
■
The authors thank NSERC of Canada for funding this research.
S.C.S. thanks NSERC for a graduate scholarship.
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ASSOCIATED CONTENT
■
S
* Supporting Information
1H NMR and 13C NMR spectra of alkenes and of new sulfones.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: schwan@uoguelph.ca.
Notes
The authors declare no competing financial interest.
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