A triflate hydrodeoxygenation route to resveratrol from syringaldehyde

Full text of DOI:10.1080/00304948.2013.798567

This article was downloaded by: [Temple University Libraries]
On: 10 July 2013, At: 13:51
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Organic Preparations and Procedures
International: The New Journal for
Organic Synthesis
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/uopp20
A Triflate Hydrodeoxygenation Route to
Resveratrol from Syringaldehyde
Matthew C. Davis a , Damon A. Parrish b & Benjamin G. Harvey a
a Chemistry & Materials Division, Michelson Laboratory , Naval Air
Warfare Center , China Lake , CA , 93555 , USA
b Laboratory for the Structure of Matter Code 6910 , Naval Research
Laboratory , Washington , D.C. , 20375 , USA
Published online: 24 Jun 2013.
To cite this article: Matthew C. Davis , Damon A. Parrish & Benjamin G. Harvey (2013) A
Triflate Hydrodeoxygenation Route to Resveratrol from Syringaldehyde, Organic Preparations
and Procedures International: The New Journal for Organic Synthesis, 45:4, 304-313, DOI:
10.1080/00304948.2013.798567
To link to this article: http://dx.doi.org/10.1080/00304948.2013.798567
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the
“Content”) contained in the publications on our platform. However, Taylor & Francis,
our agents, and our licensors make no representations or warranties whatsoever as to
the accuracy, completeness, or suitability for any purpose of the Content. Any opinions
and views expressed in this publication are the opinions and views of the authors,
and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content
should not be relied upon and should be independently verified with primary sources
of information. Taylor and Francis shall not be liable for any losses, actions, claims,
proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or
howsoever caused arising directly or indirectly in connection with, in relation to or arising
out of the use of the Content.
This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,
systematic supply, or distribution in any form to anyone is expressly forbidden. Terms &

Conditions of access and use can be found at http://www.tandfonline.com/page/terms-
and-conditions

Organic Preparations and Procedures International, 45:304–313, 2013
ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2013.798567
OPPI BRIEF
A Triflate Hydrodeoxygenation Route to Resveratrol
from Syringaldehyde
Matthew C. Davis,1 Damon A. Parrish,2 and Benjamin G. Harvey1
1Chemistry & Materials Division, Michelson Laboratory, Naval Air Warfare
Center, China Lake, CA 93555, USA
2Laboratory for the Structure of Matter Code 6910, Naval Research Laboratory,
Washington, D.C. 20375, USA
When a starting material is being contemplated for the synthesis of an active pharmaceutical
ingredient or a building block for polymers, natural products are the green alternatives to
petroleum feedstocks.1,2 Plant metabolites are an excellent source for aromatic compounds
but are invariably oxygenated.3–5 In certain cases, the hydroxy groups of the natural products
are ideally located and can be simply built upon or protected to allow for chemical modifica-
tion elsewhere in the molecule. More often, the natural product has too many hydroxy groups
or it would be preferable to replace one or more of them with some other group. This paper
describes an investigation in the hydrodeoxygenation of some phenolic compounds (Ph-OH
to Ph-H) by reduction of the corresponding trifluoromethanesulfonates (triflates)6–10 in an
effort to synthesize the natural polyphenol resveratrol (trans-3,4ꢀ,5-trihydroxystilbene), a
compound which may have biological activity in mammals.11,12
The spent liquor from paper processing mills contains variable amounts of aro-
matic aldehydes vanillin (3-methoxy-4-hydroxybenzaldehyde, 1a) and syringaldehyde
(3,5-dimethoxy-4-hydroxybenzaldehyde, 1b) depending on the source of wood (conifer
or deciduous).13,14 Syringaldehyde is very close in structure to one of the typical starting
materials for the synthesis of resveratrol, namely 3,5-dimethoxybenzaldehyde (3b).15–18
The triflates of vanillin (2a)18,19 and syringaldehyde (2b)20,21 were obtained by reaction
with trifluoromethanesulfonic anhydride using pyridine as base in methylene chloride in
high yields (Scheme 1). Triflate 2a was isolated as an oil and yet even after distillation
gave unsatisfactory combustion analysis. The reduction procedure employed was based
on the homogeneous method established by Cacchi et al.22 using palladium acetate and a
phosphine ligand along with a reducing agent in dimethylformamide as solvent. However,
with the formic acid salt of triethylamine as the hydrogen donor and triphenylphosphine
Submitted by November 19, 2012.
Address correspondence to Matthew C. Davis, Chemistry & Materials Division, Michelson Lab-
oratory, Naval Air Warfare Center, China Lake, CA 93555, USA. E-mail: matthew.davis@navy.mil

Triflate Hydrodeoxygenation Route to Resveratrol
305
Scheme 1
as ligand, only starting material was recovered after the reaction. The careful studies of
Cabri et al.23 later established the critical role bidentate phosphine ligands plays in the
reaction.24,25 The reduction proceeded very smoothly to give the aldehydes 3a and 3b in
high yield using 1,1ꢀ-bis(diphenylphosphino)ferrocene (DPPF) all else being the same. The
selectivity in reduction of triflate 2a is noteworthy since Clauss and Jensen26 only obtained
3-methoxybenzyl alcohol by reduction of the mesylate of vanillin, although under rather
different conditions (H2/palladium on charcoal/MeOH/triethylamine).
Although expensive due to the price of Tf2O, this rapid preparation of aldehyde 3b
may be attractive for laboratory scale natural product synthesis. Otherwise, the compound is
made by a five-step route starting from benzoic acid, the last step of which is a stoichiome-
tric, heavy metal-mediated oxidation to the carboxaldehyde which can be capricious.27–29
Rather than repeat the conversion of 3b to resveratrol, an attempt was made to expand
the scope of this triflate reduction (Scheme 2). Perkin condensation30 of syringaldehyde
(1b) with 4-methoxyphenyl-acetic acid (4) gave, after hydrolysis of the intermediate
Scheme 2

306
Davis et al.
acetate ester,31,32 a good yield of the previously unreported 2-arylcinnamic acid 5. Be-
cause the alkene hydrogen of 5 appeared downfield (δ 7.66), it was believed to be the trans
regioisomer,33–36 a fact confirmed by X-ray crystallographic analysis.37 Rather than the
conventional method of copper and quinoline for the decarboxylation of 5,15,38,39 the inter-
esting conditions using ionic liquids reported by Sharma et al. were adopted.40 Microwave
irradiation, however, was not necessary and simple heating of 5 to ∼130◦C in the melt of
the protic ionic liquid, 1-methylimidazolium p-toluenesulfonate,41 gave an excellent yield
of stilbene 6, mp. 110–112◦C. Incidentally, Sharma et al.42 described the preparation of 6
by the Heck reaction between 2,6-dimethoxy-4-vinylphenol and 4-iodoanisole. They indi-
3
cated the trans geometry for their product melting at 96–98◦C, although the J coupling
constant of the alkene protons could not be observed due to overlapping signals. Using
DMSO as NMR solvent for 6, the alkene vicinal coupling of 16 Hz is clearly visible which
is typical for trans geometry.43 So these conditions not only brought about decarboxylation
but, fortuitously, isomerized the stilbene to the thermodynamically favored trans isomer
presumably by way of a quinone-type resonance contributor.33,44,45
The hydrodeoxygenation of 6 was carried out in the same manner as previously de-
scribed for 1a and 1b. Triflate 7 underwent reduction to the stilbene 8 (resveratrol trimethyl
ether) without concomitant reduction of the double bond. This result was surprising since
several groups have reduced stilbenes to bibenzyls by catalytic transfer hydrogenation
using formate salts and homogeneous or heterogeneous palladium catalyst.46,47 However,
Brunel did report the failure of alkene reduction when bidentate phosphine ligands were
employed.48,49 The synthesis of resveratrol was completed by refluxing a mixture of 8
in the molten salt pyridine hydrochloride.50 Although this reagent is convenient to work
with, the yield of the dealkylation was poor which, based on other work,51 is most likely
caused by oligomerization and there are better reagents to accomplish this step cleanly
(such as BBr3 or BCl3).52 Since 6 (DMU-291)53 is the putative active metabolite of the
anticancer compound DMU-212 (9),54,55 the latter was prepared by simple methylation of
6, using potassium tert-butoxide and iodomethane (Scheme 3), and the product was fully
characterized adding further value to the synthetic pathway described here.
Scheme 3
In conclusion, the triflates of hydroxybenzaldehydes undergo palladium-catalyzed
deoxygenation without reduction of the carbonyl group. Syringaldehyde, which can be
obtained from the spent liquor of paper processing, was converted into resveratrol in five
steps in 12% overall yield (unoptimized).

Triflate Hydrodeoxygenation Route to Resveratrol
Experimental Section
307
The melting points were acquired on a Meltemp II electrothermal capillary melting point
apparatus (Laboratory Devices, Holliston, MA) and are not corrected. All NMR data were
obtained on a Bruker Avance II 300 MHz spectrometer (1H at 300 MHz, 13C at 75 MHz,
19F at 282 MHz). NMR data (free induction decay signals) were processed using NUTS
1
software from Acorn NMR (Livermore, CA). All H, 13C and 19F spectra are referenced
to solvent, tetramethylsilane or fluorotrichloromethane. In all cases, thin-layer chromatog-
raphy (TLC) was carried out on aluminum foil backed, silica gel plates eluting with a
mixture of hexanes/EtOAc. Trifluoromethanesulfonic anhydride (Tf2O), syringaldehyde
(1b), vanillin (1a), 4-methoxyphenylacetic acid (4), anhydrous N,N-dimethylformamide
(DMF), 1,1ꢀ-bis(diphenylphosphino)ferrocene (DPPF) and all other reagents were obtained
commercially.
3-Methoxy-4-(trifluoromethanesulfonyloxy)benzaldehyde (2a)
To a round-bottomed flask equipped with magnetic stir bar was charged 1a (3.0 g, 20 mmol),
pyridine (4.7 g, 59 mmol, 3 equiv) and CH2Cl2 (25 mL). The mixture was cooled in a Dry
Ice-acetone bath and Tf2O (6.6 mL, 11.1 g, 39 mmol, 2 equiv) was added dropwise over
30 min. Afterwards, the mixture was stirred at rt for 2 h. The reaction mixture was washed
with H2O (25 mL × 2) followed by brine (25 mL). The organic phase was separated, dried
over anhydrous MgSO4 and evaporated in vacuo leaving a brownish oil (5.12 g, 90%).
Although the crude material could be further purified by short-path distillation at reduced
pressure (0.1 torr) to give the product as colorless oil, it appears to be heat sensitive as there
1
was a significant decomposition residue in the distillation pot. H NMR (CDCl3): δ 9.98
(s, 1H), 7.56 (d, J = 1.7 Hz, 1H), 7.51 (dd, J = 8.2 and 1.8 Hz, 1H), 7.40 (d, J = 8.0 Hz,
1H), 3.99 (s, 3H); 13C NMR (CDCl3): δ 190.53, 152.49, 142.97, 137.06, 124.27, 123.45,
13
121.06, 118.92 (q, 1JCF = 321.5 Hz), 112.06, 56.75; 19F { C} NMR (CDCl3): δ -74.2. The
product was used in the synthesis of compound 3a without purification.
3,5-Dimethoxy-4-(trifluoromethanesulfonyloxy)benzaldehyde (2b)
To a round-bottomed flask (100 mL) equipped with magnetic stir bar and addition funnel
(10 mL) was added 1b (3.0 g, 16.5 mmol), CH2Cl2 (50 mL) and triethylamine (3.3 g,
33 mmol, 2 equiv). The mixture was cooled to 0◦C in an ice bath. The funnel was charged
with Tf2O (6.9 g, 4.18 mL, 24.8 mmol, 1.5 equiv) which was added dropwise over 1 h. After
several hours at 0◦C, the mixture was allowed to warm up to rt and washed with H2O. The
organic phase was washed with brine (25 mL), separated and dried over anhydrous MgSO4.
The organic phase was treated with decolorizing charcoal, filtered and evaporated in vacuo.
Compound 2b was obtained as colorless crystals by recrystallization from hexanes (4.5 g,
87%), mp. 105–107◦C, lit.21 108–110◦C. 1H NMR (CDCl3): δ 9.95 (s, 1H), 7.17 (s, 2H),
1
3.99 (s, 6H); 13C NMR (CDCl3): δ 190.65, 153.45, 136.13, 132.25, 118.85 (q, JCF
=
13
321.2 Hz), 106.15, 56.89; 19F { C} NMR (CDCl3): δ –74.08.
Anal. Calcd for C10H9F3O6S: C, 38.22; H, 2.89. Found: C, 38.43; H, 2.89.

308
Davis et al.
3-Methoxybenzaldehyde (3a)
To a round-bottomed flask equipped with magnetic stirring bar charged with DMF (5 mL)
and triethylamine (2.81 g, 27.8 mmol), 98% formic acid (1.28 g, 27.8 mmol) was added
dropwise over 1 min. Then, 2a (1 g, 3.5 mmol) was added followed by Pd(OAc)2 (30 mg,
0.13 mmol) and DPPF (150 mg, 0.27 mmol); all the solids dissolved to give a clear orange
solution. It was then heated to 80◦C and after about 15 min a yellow solid precipitated.
The mixture was cooled to rt and filtered to remove the solid. The filtrate was partitioned
between Et2O (25 mL) and H2O (25 mL). The organic layer was further washed with
H2O (25 mL) followed by brine. The organic phase was dried over anhydrous MgSO4 and
evaporated in vacuo to a brown oil. Distillation under reduced pressure (0.1 torr) gave 3a a
colorless, mobile liquid (400 mg, 85%), lit.56 bp. 121◦C /14 torr. 1H NMR (CDCl3): δ 9.97
(s, 1H), 7.47–7.42 (m, 2H), 7.39–7.37 (m, 1H), 7.20–7.14 (m, 1H), 3.86 (s, 3H); 13C NMR
(CDCl3): δ 192.29, 160.38, 138.03, 130.22, 123.71, 121.70, 112.28, 55.67.
Anal. Calcd for C8H8O2: C, 70.57; H, 5.92. Found: C, 70.27; H, 5.95.
3,5-Dimethoxybenzaldehyde (3b)
To a round-bottomed flask (100 mL) equipped with magnetic stir bar and reflux condenser
charged with DMF (3 mL) and triethylamine (1.29 g, 13 mmol), was added dropwise 98%
formic acid (0.588 g, 13 mmol). Then, 2b (500 mg, 1.6 mmol) was added followed by
Pd(OAc)2 (35 mg, 0.15 mmol) and DPPF (177 mg, 0.3 mmol). All the solids dissolved re-
sulting in a clear orange solution. The solution was heated to 80◦C under an N2 atmosphere;
shortly after heating began, a yellow solid precipitated. After 1 h, the reaction mixture was
cooled to rt and filtered through medium filter paper to remove the solid. The filtrate was
partitioned between Et2O (50 mL) and H2O (50 mL). The organic layer was separated and
washed with H2O (25 mL) followed by brine (25 mL). The organic phase was separated
and dried over anhydrous MgSO4 and evaporated in vacuo leaving a yellowish solid which
was essentially pure 3b (260 mg, 90%), mp. 42–44◦C, lit.57 45–46◦C. 1H NMR (CDCl3):
δ 9.92 (s, 1H), 7.02 (d, J = 2.2 Hz, 2H), 6.71 (t, J = 2.2 Hz, 1H), 3.85 (s, 6H); 13C NMR
(CDCl3): δ 192.14, 161.49, 138.64, 107.41, 107.36, 55.88.
Anal. Calcd for C9H10O3: C, 65.05; H, 6.07. Found: C, 65.39; H, 5.97.
trans-2-(4-Methoxyphenyl)-3-(3,5-dimethoxy-4-hydroxyphenyl)acrylic Acid (5)
To a round-bottomed flask (500 mL) equipped with magnetic stir bar and reflux condenser
was added 1b (9.1 g, 50 mmol), 4 (8.3 g, 50 mmol), Ac2O (50 mL) and, lastly, triethylamine
(10 g, 100 mmol, 2 equiv). The mixture was refluxed for 18 h. and then the hot reaction
mixture was poured into vigorously stirred H2O (300 mL). The precipitate formed was
collected on a coarse porosity fritted glass filter was dissolved in 0.83 M NaOH (300 mL,
5 equiv). The solution was filtered through a medium glass frit to remove a small amount
of brown insoluble matter. The filtrate was then stirred and slowly acidified to pH 5 with
conc. HCl. The tan precipitate formed was collected and dried in vacuo (10 torr, 40◦C) to
give compound 5 as a tan powder (13.19 g, 79%) which upon crystallization from ethanol
gave pale yellow plates, mp. 228–230◦C. 1H NMR (DMSO): δ 12.43 (bs, CO2H), 8.83 (bs,
OH), 7.66 (s, 1H), 7.11 (d, J = 8.6 Hz, 2H), 6.99 (d, J = 8.6 Hz, 2H), 6.39 (s, 2H), 3.76 (s,

Triflate Hydrodeoxygenation Route to Resveratrol
309
3H), 3.47 (s, 6H); 13C NMR (DMSO): δ 168.78, 158.66, 147.32, 139.69, 137.03, 130.94,
129.82, 129.07, 124.56, 114.12, 108.37, 55.41, 55.19.
Anal. Calcd for C18H18O6: C, 65.45; H, 5.49. Found: C, 65.18; H, 5.60.
1-Methylimidazolium p-Toluenesulfonate
To a round-bottomed flask (50 mL) equipped with magnetic stir bar was added p-
toluenesulfonic acid monohydrate (4.3 g, 23 mmol) followed by 1-methylimidazole (1.86 g,
23 mmol, 1 equiv); the mixture became warm as all the solids dissolved. After dissolution,
water was removed in vacuo (10 torr to 1 torr, 60◦C) to give a crude white solid which
upon recrystallization from EtOAc/MeCN, gave the salt as a white microcrystalline pow-
der (4.0 g, 69%), mp. 83–85◦C, lit.41 90–91◦C. 1H NMR (CDCl3): δ 9.09 (s, 1H), 7.76 (d,
J = 8.3 Hz, 2H), 7.31 (s, 1H), 7.20 (s, 1H), 7.15 (d, J = 7.9 Hz, 2H), 3.88 (s, 3H), 2.34 (s,
3H); 13C NMR (CDCl3): δ 142.73, 140.24, 136.24, 129.05, 125.92, 122.92, 120.36, 36.05,
21.41.
Anal. Calcd for C11H14N2O3S · 1/2 H2O: C, 50.18; H, 5.74; N, 10.64. Found: C, 50.16;
H, 5.52; N, 11.06.
trans-3,4ꢀ,5-Trimethoxy-4-hydroxystilbene (6)
To a round-bottomed flask (500 mL) equipped with magnetic stir bar and reflux condenser
was added 1-methylimidazolium p-toluenesulfonate (34.8 g, 137 mmol, 5 equiv.) and 5
(9.1 g, 27.6 mmol). The mixture was stirred and heated to 130◦C (internal temperature)
using a heating mantle. As the mixture reached 130◦C, the solids dissolved to a brownish
colored solution with concurrent gas evolution (CO2). At 10 min intervals, a small aliquot
of the reaction mixture was removed, dissolved in H2O and extracted with Et2O for TLC
analysis. After heating for ∼30 min, the mixture had a purplish color and TLC showed the
reaction was complete. The mixture was cooled to ∼90◦C and diluted with H2O (300 mL)
whereupon a pinkish-tan colored solid precipitated. The precipitate was collected on a
medium porosity fritted glass filter (7.57 g, 95%) and was purified by recrystallization from
MeOH to afford compound 6 as rose colored needles, mp. 110–112◦C, lit.42 96–98◦C. 1H
NMR (CDCl3): δ 7.43 (d, J = 8.7 Hz, 2H), 6.93–6.86 (m, 4H), 6.73 (s, 2H), 5.56 (bs,
1
OH), 3.94 (s, 6H), 3.82 (s, 3H); H NMR (DMSO): δ 8.47 (s, OH), 7.49 (d, J = 8.8 Hz,
2H), 7.07 (d, J = 16.5 Hz, 1H), 6.97 (d, J = 16.4 Hz, 1H), 6.93 (d, J = 8.6 Hz, 2H),
6.85 (s, 2H), 3.81 (s, 6H), 3.76 (s, 3H); 13C NMR (CDCl3): δ 159.18, 147.38, 134.69,
130.37, 129.37, 127.56, 126.88, 126.48, 114.25, 103.28, 56.39, 55.41; 13C NMR (DMSO):
δ 158.55, 148.12, 135.40, 130.14, 127.92, 127.27, 126.78, 125.39, 114.15, 103.92, 55.98,
55.09.
Anal. Calcd for C17H18O4: C, 71.31; H, 6.34. Found: C, 71.11; H, 6.17.
trans-3,4ꢀ,5-Trimethoxy-4-(trifluoromethanesulfonyloxy)stilbene (7)
To a round-bottomed flask (50 mL) equipped with magnetic stir bar and N2 bubbler was
added 6 (600 mg, 2 mmol), pyridine (332 mg, 4 mmol, 2 equiv) and CH2Cl2 (20 mL).

310
Davis et al.
The mixture was cooled in an ice bath before Tf2O (888 mg, 3 mmol, 1.5 equiv) was
added dropwise over 20 min, during which time the color changed from deep red to
pale orange. Afterwards, the ice bath was removed and the reaction mixture was stirred
at rt overnight. A work-up similar to that used in the preparation of 1a and 2a gave
an oil that slowly crystallized during drying in vacuo (790 mg, 90%). Recrystallization
from heptanes/EtOAc gave compound 7 as clear, tan needles, mp. 104–106◦C (dec.).
1H NMR (CDCl3): δ 7.46 (d, J = 8.7 Hz, 2H), 7.03 (d, Jab = 16.1 Hz, 1H), 6.91
(d, J = 8.7 Hz, 2H), 6.89 (d, Jab = 16.3 Hz, 1H), 6.72 (s, 2H), 3.93 (s, 6H), 3.84
(s, 3H); 13C NMR (CDCl3): δ 160.00, 152.69, 138.64, 130.35, 129.59, 128.21, 125.75,
13
118.92 (q, 1JCF = 321.3 Hz), 114.49, 102.94, 56.49, 55.58; 19F { C} NMR (CDCl3): δ –
74.11.
Anal. Calcd for C18H17F3O6S: C, 51.67; H, 4.10. Found: C, 51.84; H, 3.97.
trans-3,4ꢀ,5-Trimethoxystilbene (8)
To a round-bottomed flask (100 mL) equipped with magnetic stir bar charged with anhy-
drous DMF (6 mL) and triethylamine (960 mg, 9.5 mmol, 5 equiv), was added dropwise,
98% formic acid (437 mg, 9.5 mmol, 5 equiv) was added over 10 min. (exotherm). After
the mixture was allowed to cool to rt, a solution of 7 (790 mg, 2 mmol) in anhydrous
DMF (3 mL) was added in one portion followed by Pd(OAc)2 (21 mg, 0.09 mmol) and
DPPF (105 mg, 0.18 mmol). A reflux condenser was attached and the reaction mixture was
heated under N2 to an internal temperature of 80◦C. After 20 min., the reaction mixture
had become dark and was complete as indicated by TLC analysis. The mixture was cooled
to rt and partitioned between H2O (50 mL) and Et2O (50 mL). A rag layer formed and
the mixture was filtered through medium filter paper. The organic layer was separated and
washed with H2O (50 mL) and then brine (50 mL). After drying over anhydrous MgSO4,
the organic phase was evaporated in vacuo to give a pale brown oil that slowly crystallized
1
(470 mg, 91%), mp. 55–57◦C, lit.58 56–57◦C. H NMR (CDCl3): δ 7.45 (d, J = 8.9 Hz,
2H), 7.05 (d, J = 16 Hz, 1H), 6.90 (d, J = 16 Hz, 1H), 6.89 (d, J = 8.6 Hz, 2H), 6.65 (d,
J = 2.2 Hz, 2H), 6.38 (t, J = 2.5 Hz, 1H), 3.83 (s, 9H); 13C NMR (CDCl3): 161.20, 139.93,
130.16, 128.96, 128.02, 126.81, 114.37, 104.57, 99.86, 55.57, 55.53.
Anal. Calcd for C17H18O3: C, 75.53; H, 6.71. Found: C, 75.53; H, 6.62.
trans-3,4ꢀ,5-Trihydroxystilbene (Resveratrol)
To a 250 mL round-bottom flask equipped with a magnetic stir bar was added 8 (2.7 g,
10 mmol) and pyridine hydrochloride (10.4 g, 90 mmol, 9 equiv). A reflux condenser was
attached and the reaction mixture was refluxed for 2 h under an N2 atmosphere. Afterwards,
the mixture was allowed to cool to ∼90◦C and quenched into H2O (200 mL) whereupon
a purplish colored solid precipitated; the mixture (including the solid) was extracted with
EtOAc (50 mL × 3). The combined extracts were diluted with hexanes (100 mL) and then
filtered through a thin pad of silica gel to remove insoluble dark colored, polar impurities.
The filtrate was evaporated in vacuo leaving an off-white solid. The crude product was
slurried with HOAc and collected to give resveratrol as a tan microcrystalline powder

Triflate Hydrodeoxygenation Route to Resveratrol
311
(450 mg, 20%), mp. 258–261◦C, lit.16 261◦C. 1H NMR (DMSO): δ 9.59 (s, OH), 9.23 (s,
2OH), 7.41 (d, J = 8.9 Hz, 2H), 6.95 (d, Jab = 16.3 Hz, 1H), 6.82 (d, Jab = 16.3 Hz,
1H), 6.76 (d, J = 8.9 Hz, 2H), 6.39 (d, J = 2.0 Hz, 2H), 6.13 (t, J = 2.1 Hz, 1H); 13C
NMR (DMSO): δ 158.58, 157.28, 139.36, 128.15, 127.96, 127.92, 125.74, 115.61, 104.41,
101.87.
Anal. Calcd for C14H12O3: C, 73.67; H, 5.30. Found: C, 73.40; H, 5.44.
trans-3,4,4ꢀ,5-Tetramethoxystilbene (9, DMU-212)
To a round-bottom flask (100 mL) equipped with a magnetic stir bar and reflux condenser
was added 6 (1.16 g, 4.1 mmol) and anhydrous DMF (15 mL). The mixture was stirred until
all the solids had dissolved to give a red solution and then followed by addition of KOtBu
(690 mg, 6.2 mmol, 1.5 equiv) in one portion. The color changed to fluorescent yellow-green
and shortly thereafter copious solids precipitated (potassium salt of 6). Then iodomethane
(1.16 g, 8.2 mmol, 2 equiv) was added to the suspension and the mixture was heated to
80◦C. After 1 h, all the solids had dissolved and the color of the solution had changed
to pale yellow. The mixture was cooled to rt and diluted with H2O (50 mL) whereupon a
white solid precipitated. The solid was collected on a medium porosity fritted glass filter.
The off-white filter cake was air dried on the frit (1.10 g, 89%) and recrystallized from
heptanes/1,2-dichloroethane to afford compound 9 as colorless plates, mp. 148–150◦C,
lit.53 152–153◦C. 1H NMR (DMSO): δ 7.53 (d, J = 8.5 Hz, 2H), 7.17 (d, Jab = 16.1 Hz,
1H), 7.02 (d, Jab = 16.3 Hz, 1H), 6.95 (d, J = 8.5 Hz, 2H), 6.89 (s, 2H), 3.83 (s, 6H),
3.78 (s, 3H), 3.67 (s, 3H); 13C NMR (DMSO): δ 158.87, 153.04, 137.05, 133.12, 129.76,
127.59, 127.44, 126.29, 114.19, 103.61, 60.05, 55.86, 55.12.
Anal. Calcd for C18H20O4: C, 71.98; H, 6.71. Found: C, 71.84; H, 6.61.
Acknowledgments
Financial support of the Strategic Environmental Research and Development Program is
gratefully acknowledged. Thanks to Ann Moorehead and Cyndy Kitchens of the Technical
Library (NAWCWD China Lake) for collecting several of the references.
References
1. J. E. Holladay, J. F. White, J. J. Bozell and D. Johnson, Top Value Added Chemicals from
Biomass, Vol II: Results from Screening for Potential Candidates from Biorefinery Lignin, US
Dept. of Energy PNNL-16983; October 2007.
2. A. J. Ragauskas, C. K. Williams, B. H. Davison, G. Britovsek, J. Cairney, C. A. Eckert, W. J.
Frederick, Jr., J. P. Hallett, D. J. Leak, D. J., C. L. Liotta, J. R. Mielenz, R. Murphy, R. Templer
and T. Tschaplinski, Science, 311, 484 (2006).
3. J. H. P. Tyman, “Studies in Organic Chemistry Vol. 52: Synthetic and Natural Phenols”, Elsevier,
New York, 1996.
4. D. A. Whiting, Nat. Prod. Rep., 18, 583 (2001).
5. S. Quideau, D. Deffieux, C. Douat-Casassus and L. Pouyse´gu, Angew. Chem. Int. Ed., 50, 586
(2011).

312
Davis et al.
6. S. Cacchi, E. Morera and G. Ortar, Org. Synth., 68, 138 (1990).
7. T. Q. Hu, G. R. Cairns and B. R. James, Holzforschung, 54, 127 (2000); Chem. Abstr., 133,
348333 (2000).
8. H. Sajiki, A. Mori, T. Mizusaki, T. Ikawa, T. Maugawa and K. Hirota, Org. Lett., 8, 987
(2006).
9. P. Eklund, A. Lindholm, J.-P. Mikkola, A. Smeds, R. Luhtila¨ and R. Sjo¨holm, Org. Lett., 5, 1509
(2003).
10. P. Ganji and H. Ibrahim, J. Org. Chem., 77, 511 (2012).
11. K. J. Pearson, J. A. Baur, K. N. Lewis, L. Peshkin, N. L. Price, N. Labinsky, W. R. Swindell, D.
Kamara, R. K. Minor, E. Perez, H. A. Jamieson, Y. Zhang, S. R. Dunn, K. Sharma, N. Pleshko,
L. A. Woollett, A. Csiszar, Y. Ikeno, D. Le Couteur, P. J. Elliott, K. G. Becker, P. Navas, D. K.
Ingram, N. S. Wolf, Z. Ungvari, D. A. Sinclair and R. de Cabo, Cell Metab., 8, 157 (2008).
12. G. J. Soleas, E. P. Diamandis and D. M. Goldberg, Clin. Biochem., 30, 91 (1997).
13. M. B. Hocking, J. Chem. Educ., 74, 1055 (1997).
14. Z. Wong, K. Chen and J. Li, BioRes., 5, 1509 (2010).
15. G. Solladie´, Y. Pastural-Jacope´ and J. Maignan, Tetrahedron, 59, 3315 (2003).
16. M. Takaoka, J. Faculty Sci., Hokkaido Imp. Univ., 3(Ser. III), 1 (1940); Chem. Abstr., 34, 51639
(1940).
17. B. Sun, J. Hoshino, K. Jermihov, L. Marler, J. M. Pezzuto, A. D. Mesecar and M. Cushman,
Bioorg. Med. Chem., 18, 5352 (2010).
18. C. S. Dowd, K. Herrick-Davis, C. Egan, A. DuPre, C. Smith, M. Teitler and R. A. Glennon, J.
Med. Chem., 43, 3074 (2000).
19. K. Ishibashi, K. Nakajima, Y. Sugioka, M. Sugiyama, T. Hamada, H. Horikoshi and T. Nishi,
Chem. Pharm. Bull., 47, 226 (1999).
20. S. N. Gurley, Ph.D. Dissertation, The University of Tennessee Health Science Center, 2010;
Chem. Abstr., 156, 401018 (2011).
21. H. Yamakoshi, F. Ikarashi, M. Minami, M. Shibuya, T. Sugahara, N. Kanoh, H. Ohori, H. Shibata
and Y. Iwabuchi, Org. Biomol. Chem., 7, 3772 (2009).
22. S. Cacchi, E. Morera and G. Ortar, Tetrahedron Lett., 25, 4821 (1984).
23. W. Cabri, S. DeBernardinis, F. Francalanci and S. Penco, J. Org. Chem., 55, 350 (1990).
24. Y. Pan and C. P. Holmes, Org. Lett., 3, 2769 (2001).
25. J. M. Saa´, M. Dopico, G. Martorell and A. Garcia-Raso, J. Org. Chem., 55, 991 (1990).
26. K. Clauss and H. Jensen, Angew. Chem. Int. Ed., 12, 918 (1973).
27. A. W. Weston and C. M. Suter, Org. Synth. Coll. Vol. 3, p. 288, John Wiley & Sons: London,
1955.
28. A. P. Monte, M. S. Kabir, M. A. Rott, W. R. Schwan, J. M. Cook, III and J. A. Miskowski, US
Pat. Appl. 20110092578 A1, 2010; Chem. Abstr., 154, 486200 (2011).
29. F. Raul, Y. Schneider, R. Brouillard, A. Fougerousse, P. Chabert and E. Gonzalez, PCT Int. Appl.
WO 2002-FR-3492 (2002); Chem. Abstr., 138, 321056 (2003).
30. M. Crawford and G. W. Moore, J. Chem. Soc., 3445 (1955).

Triflate Hydrodeoxygenation Route to Resveratrol
313
31. A. Karube and R. Onoda, Nippon Kagaku Kaishi, 2166 (1973); Chem. Abstr., 80, 47605 (1974).
32. S. Ogawa, Bull. Chem. Soc. Jpn, 2, 20 (1927).
33. C. F. Xiao, Y. Zou, J.-L. Du, H.-Y. Sun and X.-K. Liu, Synth. Commun., 42, 1243 (2012).
34. J.-L. Mao, X.-K. Ran, J.-Z. Tian, B. Jiao, H.-L. Zhou, L. Chen and Z.-G. Wang, Bioorg. Med.
Chem. Lett., 21, 1549 (2011).
35. R. Rotta, A. C. Neto, D. P. de Lima, A. Beatriz and G. V. J. da Silva, J. Mol. Struct., 975, 59
(2010).
36. K. Gaukroger, J. H. Hadfield, L. A. Hepworth, N. J. Lawrence and A. T. McGown, J. Org. Chem.,
66, 8135 (2001).
37. Crystallographic data (without structure factors) for compound 5 has been deposited with Cam-
bridge Crystallographic Data Centre as supplementary publication CCDC 888230.
38. T. Cohen and R. A. Schambach, J. Am. Chem. Soc., 92, 3189 (1970).
39. R. E. Buckles and N. G. Wheeler, Org. Synth. Coll. 4, 857, John Wiley & Sons: London, 1963.
40. A. Sharma, R. Kumar, N. Sharma, V. Kumar and A. K. Sinha, Adv. Synth. Catal., 350, 2910
(2008).
41. E. J. Ka¨rkka¨inen, Ph.D. Dissertation, University of Oulu, 2007; Chem. Abstr., 149, 53579 (2008)
42. A. Sharma, N. Sharma, R. Kumar, A. Shard and A. K. Sinha, Chem. Comm., 3283 (2010).
43. E. Breitmaier, “Structure Elucidation by NMR in Organic Chemistry: A Practical Guide” 3rd
rev. ed., Wiley, Chichester, 2002.
44. V. Kumar, A. Sharma, A. Sharma and A. K. Sinha, Tetrahedron, 63, 7640 (2007).
45. A. Sinha, V. Kumar, A. Sharma, A. Sharma and R. Kumar, Tetrahedron, 63, 11070 (2007).
46. J. R. Wier, B. A. Patel and R. F. Heck, J. Org. Chem., 45, 4926 (1980).
47. H. Berthold, T. Schotten and H. Ho¨nig, Synthesis, 1607 (2002).
48. J. M. Brunel, Synlett, 330 (2007).
49. J. Ko¨ve´r and S. Z. Antus, Naturforsch., 60b, 792 (2005).
50. M. Wang, Y. Jin and C.-T. Ho, J. Agric. Food Chem., 47, 3974 (1999).
51. E. Alesso, R. Torviso, M. Erlich, L. Finkielsztein, B. Lantan˜o, G. Moltrasio, J. Aguirre, R.
Va´zquez, L. Pizzio, C. Ca´ceres, M. Blanco and H. Thomas, Synth. Commun., 32, 3803 (2002).
52. T. Jeffery and B. Ferber, Tetrahedron Lett., 44, 193 (2003).
53. V. P. Androutsopoulos, K. C. Ruparelia, A. Papakyriaou, H. Filippakis, A. M. Tsatsakis and
D. A. Spandidos, Eur. J. Med. Chem., 46, 2586 (2011).
54. S. Sale, R. D. Verschoyle, D. Boocock, D. J. L. Jone, N. Wilshir, K. C. Ruparelia, G. A. Potter,
P. B. Farmer, W. P. Steward and A. J. Gescher, Br. J. Cancer, 90, 736 (2004).
55. M. Cushman, D. Nagarathnam, D. Gopal, H.-M. He, C. M. Lin and E. Hamel, J. Med. Chem.,
35, 2293 (1992).
56. M. Asano and S. Huziwara, Yakugaku Zasshi, 59, 141 (1939); Chem. Abstr., 33, 41340 (1939).
57. R. Adams, S. MacKenzie, Jr. and S. Loewe, J. Am. Chem. Soc., 70, 664 (1948).
58. E. Spa¨th and K. Kromp, Ber., 74, 189 (1941).