Stereoselective synthesis of hydroxy stilbenoids and styrenes by atom-efficient olefination with thiophthalides

Article abstract of DOI:10.1039/c2ob06991a

The synthesis of stilbenoids and styryl carboxylic acids is accomplished with high E-stereoselectivity by olefination of aldehydes with thiophthalides under basic conditions. The olefination is highly atom-efficient as it only loses elemental sulfur during the reaction. This olefination, in conjunction with retro Kolbe-Schmitt reaction, allows facile synthesis of E-hydroxystilbenoids with minimal employment of protecting groups. This study also discloses two important findings: formation of i) 4-methylsulfanyl isocoumarins and ii) an 2-arylindenone. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2ob06991a

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PAPER
Stereoselective synthesis of hydroxy stilbenoids and styrenes by atom-efficient
olefination with thiophthalides†
Prithiba Mitra, Brateen Shome, Saroj Ranjan De, Anindya Sarkar and Dipakranjan Mal*
Received 26th November 2011, Accepted 7th January 2012
DOI: 10.1039/c2ob06991a
The synthesis of stilbenoids and styryl carboxylic acids is accomplished with high E-stereoselectivity by
olefination of aldehydes with thiophthalides under basic conditions. The olefination is highly atom-
efficient as it only loses elemental sulfur during the reaction. This olefination, in conjunction with retro
Kolbe–Schmitt reaction, allows facile synthesis of E-hydroxystilbenoids with minimal employment of
protecting groups. This study also discloses two important findings: formation of i) 4-methylsulfanyl
isocoumarins and ii) an 2-arylindenone.
ii) Horner–Wadsworth–Emmons27 (HWE) iii) Heck28 iv)
Introduction
Ramberg–Bäcklund29 v) Julia30 vi) Wittig–Heck31 and vii)
Perkin32 reactions etc. The majority of them suffer from low
Hydroxystilbenes and stilbenoids are a well-known class of
natural products, and occur in a wide variety of structures.1
E-stereoselectivity and atom economy. High E-stereoselectivity
can be achieved by the use of olefin cross metathesis33 reaction
Many members of this class display beneficial biological activi-
ties. The activities encompass therapeutic potential in cancers,2
but formation of the homoproducts is a serious impediment. The
cardiovascular diseases,3 viral infections,4 diabetes,5 Alzhei-
application of the Wittig, HWE or Heck reaction necessitates
mer’s disease,6 dementia7 and also radical scavenging activity.8
protection of the active hydrogens throughout a synthesis. Phe-
Hydroxystilbenoids, resveratrol9 (Res 1) (Fig. 1), piceatannol10
nolic groups are almost always protected, because of their sus-
(2) and oxyresveratrol11 (3) have gained prominence as synthetic
targets due to their remarkable physiological activities. The stil-
benoids and styryl acids are also found as structural motifs in
many other important bioactive natural products (Fig. 1) namely,
pyriculol12 (e.g. 4), resorcyclic acid lactones13 (RALs, e.g. 5),
hydroxy flavonoids,14 chromones,15 and varitriols16 (e.g. 6).
Trans-stilbenoids also form the backbones of organic probes17
for cation sensing, photovoltaic solar cells,18 light emitting
diodes19 (LEDs), organogels20 and recognition probes21 of disac-
charides. Additionally, they serve as the precursors for 3,4-di-
hydroisocoumarins,22 substituted phthalides23 and oligo-
resveratrols.24
ceptibility to oxidation.34 These issues have been recently
addressed by the McNulty group35 and the Wittig reaction has
been modified to render it more adaptable for the
hydroxystilbenoids.
However, efficient and trans-selective olefinations remain to
be innovated. This necessity prompted us to initiate a thorough
reinvestigation of our preliminary report on an uncommon olefi-
nation.36 Toluates (e.g. 7 Scheme 1), which can be converted
readily to thiophthalides37 (e.g. 8) in two steps, were found to
react with aromatic and aliphatic aldehydes 9 to give trans-stilbe-
noids and styryl acids 11 respectively. The reaction was proposed
Commercially, Res (1) is produced from the roots of Poly-
gonum cuspidatum, a Chinese plant used in folk medicine.
Nevertheless, the large scale production from the natural sources
is not viable due to low yield.25 Consequently, the synthesis of
stilbenoids has generated a great deal of interest among research-
ers and a large number of synthetic methods are reported in the
literature. Traditionally, the strategies rely upon i) Wittig26
Department of Chemistry, Indian Institute of Technology, Kharagpur,
West Bengal, India. E-mail: dmal@chem.iitkgp.ernet.in;
Fax: (+) 913222-282252; Tel: +91-3222-283318
†Electronic supplementary information (ESI) available: 1H and 13C
spectra of synthesized compounds. CCDC 855857 and 855858. For ESI
and crystallographic data in CIF or other electronic format See DOI:
10.1039/c2ob06991a
Fig. 1 Stilbenoids and styryl acids decorated natural products.
2742 | Org. Biomol. Chem., 2012, 10, 2742–2752
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Table 2 Base screening studies on olefination with aliphatic aldehydes
Scheme 1 Mechanism of the olefination with thiophthalides.36
Entry
Substrates
Base (2 equiv)–solvent
Productb
% yielda
Table 1 Base screening studies in the olefination with aromatic
aldehydes
1
2
3
4
5
6
7
8 and 14
8 and 14
8 and 14
8 and 14
8 and 14
8 and 14
8 and 14
LTB –THF
KTB–THF
NaH–DMF
LDA–THF
LiHMDS–THF
KHMDS–THF
NaNH2–THF
(E)-15
(E)-15
(E)-15
(E)-15
(E)-15
(E)-15
(E)-15
45c
35
Intractable
10
Intractable
Intractable
22
a The yields refer to that over two steps: olefination and methyl
esterification. b The Z-isomers could not be detected. c The reaction
product was accompanied by 26% of isocoumarin 16.
Entry
Substrates
Base (2 equiv)–solvent
Producta
% yield
1
2
3
4
5
6
7
8 and 12
8 and 12
8 and 12
8 and 12
8 and 12
8 and 12
8 and 12
LTB–THF
KTB–THF
NaH–DMF
LDA–THF
LiHMDS–THF
KHMDS–THF
NaNH2–THF
(E)-13
(E)-13
(E)-13
(E)-13
(E)-13
(E)-13
(E)-13
75
58
45
92
46
10
72
a The Z-isomers could be not detected.
Fig. 3 Structure and ORTEP view of isocoumarin 16.
that the olefination is highly stereoselective and furnished only
the E-isomer 13. The screening study (Table 2) of the bases was
carried out with propionaldehyde 14 as a model aliphatic alde-
hyde. Due to the difficulty in purification of the resulting acid,
the reaction mixture was treated with DBU–CH3I38 and the cor-
responding methyl ester was isolated and characterized. The
yield of the product 15 was not significant, the highest being
observed with lithium tert-butoxide (LTB). It may be noted that
under Julia olefination conditions compound 15 is formed as an
inseparable 1 : 1 mixture of E and Z isomers.39a Evidently, the
efficiency of the olefination with propionaldehyde is inferior to
that with aromatic aldehydes under similar conditions.
This is partly because of an interesting yet competing and
unprecedented side reaction leading to the isocoumarin 16
(Fig. 3), the structure of which was confirmed by the X-ray crys-
tallographic analysis.
Following the optimization studies, we explored the scope of
the olefination for selected aliphatic, aromatic aldehydes and
ketones as shown in Table 3. With butyraldehyde 17 (Table 3),
the yield of the olefination product 18 was slightly higher. The
corresponding isocoumarin product (cf. 16) was not formed. The
reaction of citronellal 19, furnished two products, the desired
styryl ester 20 and isocoumarin 21 in significant yields.
As a model study on the synthesis of varitriol (6), ribosyl alde-
hyde 22,39b prepared in four steps from D-glucose was condensed
Fig. 2 ORTEP view of the acid 13.
to proceed through the formation of episulfide intermediates 10
followed by in situ extrusion of elemental sulfur. But the
promise of the olefination as a synthetic method was seriously
impeded by low yields (30–55%). In this article, we report sig-
nificant improvement of the yields by appropriate choice of
bases, and demonstrate the scope and usefulness of the olefina-
tion in conjunction with retro Kolbe–Schmitt reaction in the syn-
thesis of natural stilbenoids.
Results and discussion
This work began with optimization study of the reaction of
parent thiophthalide 8 with p-anisaldehyde 12. The results are
summarized in Table 1. The structure of product 13 was
confirmed by X-ray structure analysis (Fig. 2). As revealed,
LDA appeared to be the most effective base, giving the product
13 in 92% yield, remarkably better than our earlier report36 on
similar reactions. The outcome with NaNH2, which is cheaper
than the lithium bases, is also encouraging. It is also noteworthy
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Table 3 Substrate scope of the olefination with thiophthalides
Entry
1
Donor
Acceptora
Product
% yield
45b
8
26b
56b
2
3
8
8
35b
29b
4
8
73b
5
6
8
8
68b
72b
7
8
62b
62b
8
9
8
8
38b
71b
10
11
8
8
67c
25c
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Table 3 (Contd.)
Entry
Donor
Acceptora
Product
% yield
52c
8
12
8
8
73c
13
14
67b
65c
15
16
68d
8
35d
42d
17
Intractable
a Unless otherwise stated, all the reactions were carried out using 1.2 equiv of acceptor. b Two equiv of LTB were used. c Two equiv of LDA were
used. d Four equiv of LTB were used.
with thiophthalide 8 in the presence of LTB. The outcome was
sugar appended styryl ester 23. The reaction of acetophenone 24
with thiophthalide 8 under the specified reaction conditions gave
a mixture of products, from which the desired stilbenoids 25
were obtained in 68% yield as an inseparable mixture of the two
geometrical isomers as indicated by the 1H NMR spectrum.
Since the reaction mixture was contaminated with a small
amount of the episulfides 26 (vide Scheme 5), a modified set of
reaction conditions was employed for the olefination of benzo-
phenone 27. In the case of benzophenone 27, the reaction
mixture was refluxed with trimethyl phosphite40 in toluene for
desulfurization of the episulfide intermediate prior to esterifica-
tion (DBU–MeI in acetone) and the corresponding styryl ester
28 was obtained in 72% yield. Similar reaction with cyclopenta-
none 29 afforded corresponding styryl acid 30 in 62% yield
(Table 3). Since it was susceptible to lactonization on standing, it
was only characterized by its NMR spectral data. Instead, the
dihydroisocoumarin derivative 31 was fully characterized by
analyzing NMR spectral and HRMS data. In contrast, the styryl
acid 32, obtained by condensation of thiophthalide 8 with cyclo-
hexanone 33, could be isolated and characterized as it was. In
order to delineate the reactivity of an α,β-unsaturated aldehyde,
perillaldehyde 34 was reacted with parent thiophthalide 8 in the
presence of LTB. Olefination product 35 was the sole product
and isolated in 71% yield. For the olefination of aromatic alde-
hydes, LDA was used since it appeared to give higher yields of
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Scheme 2 Synthesis of 3-hydroxy-5-methoxystilbene-2-carboxylic
acid 54.
the products (Table 1). The reaction of p-nitrobenzaldehyde 36
with thiophthalide 8 expectedly provided styryl acid 37 as the
single isomer in 67% yield. With methyl 2-formylbenzoate 38,
the reaction of the thiophthalide 8 was somewhat unexpected.
2-Arylindenone 40 was unusually formed as the major product
(52% yield) along with the expected diester 39 (25% yield). The
speculative mechanism for the formation of 2-arylindenone 40 is
depicted in Scheme 7. In order to test the feasibility of double
olefination, terephthaldehyde 41 was reacted with the parent
thiophthalide 8 in the similar manner as before. The expected
diolefination product 42 was obtained as the only product in
73% yield. The reaction of furfural 43 in the presence of LTB
was not stereoselective. It provided an inseparable mixture of
geometrical isomers 44 (combined yield of 67%). In addition, a
substantial amount of 2-furoic acid was obtained.
Scheme 3 Synthesis of 3′,4-dihydroxy-3,5′-dimethoxystilbene 56.
In view of the wide occurrence of phenolic–OH groups in
natural stilbenoids, the reactivity of methoxy substituted
thiophthalide 45 was examined. Its reaction with p-methoxyben-
zaldehyde 46 smoothly furnished styryl ester 47 in 65% yield.
To develop the potential of this method as a protecting-group-
free41 olefination technique, OH-unprotected thiophthalide42 48
was reacted with p-anisaldehyde 46 (Table 3) in the presence of
LTB as base and the corresponding hydroxystilbenoid 49
obtained in 68% yield. In the similar vein, OH-unprotected alde-
hyde i.e. p-hydroxybenzaldehyde 50 was also subjected to the
olefination. The expected hydroxystilbenoid 51 was obtained in
35% yield along with the dihydroisocoumarin derivative 52
(42%), which probably formed during acidic work-up. In order
to accomplish a protecting group free synthesis of pholidotol-
C,43 we attempted to condense thiophthalide 48 with 2,3-dihy-
droxybenzaldehyde 53. However, no definitive product formed
with either LTB or LDA.
Scheme 4 Synthesis of methyl ester of cajaninstilbene acid 59.
dimethoxystilbene 56, isolated from the legume Cassia didymo-
botrya.46 The reaction of thiophthalide 48 with vanillin 57
(Scheme 3) in the presence of LTB furnished styryl acid 58
along with unreacted starting materials 48 and 57. After prelimi-
nary chromatography, the crude acid 58 was dissolved in
minimum volume of methanol and refluxed with 30% aq KOH
for 5 h to effect the retro Kolbe–Schmitt reaction. The hydroxy-
stilbene 56 was obtained in 48% yield.
Synthesis of methyl cajaninstilbene carboxylate (59)
Cajaninstilbene acid47a was isolated from the methanol extract of
the pod surfaces of Cajanus cajan and reported to show strong
antioxidant activity,47b equivalent to that of resveratrol. Retro-
synthesis of 59 revealed the requirement of the prenylated
thiophthalide 60. We attempted its preparation by ortho-selective
prenylation of 5-methoxy-7-hydroxythiophthalide 48 with 1,1-
dimethylallyl alcohol 61 in 1,2-dichloroethane (Scheme 4) in
presence of different Lewis acids. The results were not encoura-
ging although prenylation48 of β-naphthol are reported to
proceed with excellent yields and regioselectivity. The Lewis
acids Sc(OTf)3, SnCl4·5H2O, ZnI2, Cu(OTf)2 and Amberlyst-15
were chosen in line with a previous study.48 All the reactions
were carried out with 1 mmol of the thiophthalide 48, 1.2 mmol
of the alcohol 61 and 20 mol% of the catalyst. In the case of
Amberlyst-15 under reflux, the conversion was maximum
(20%).
Synthesis of 3-hydroxy-5-methoxystilbene-2-carboxylic acid (54)
Hydroxystilbenoid 5444 was isolated from methanolic extracts of
pigeonpea (Cajanus cajan Millsp.) leaves and it was shown to
inhibit lettuce radicle elongation.
For the synthesis of stilbene acid 54, hydroxythiophthalide 48
was submitted to reaction with benzaldehyde 55 (4 equiv) under
the conditions given in Scheme 2. The desired styryl acid 54 was
produced in 68% yield. It is worth noting that protection of the
phenolic-OH in 48 was not necessary.
Synthesis of 3′,4-dihydroxy-3,5′-dimethoxystilbene (56)
In extending the scope of the olefination, decarboxylation of stil-
bene acids was explored under retro-Kolbe–Schmitt con-
ditions.45 We decided to synthesize 3′,4-dihydroxy-3,5′-
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Scheme 6 Mechanism of formation of the isocoumarin 16.
Scheme 5 Trapping of episulfide 26.
The starting thiophthalide was recovered and based on its
recovery the yield of 60 was about 50%. Use of increased pro-
portion of the alcohol, loading of the catalyst, heating the reac-
tion mixture at 120 °C in a pressure tube or even heating the
thiophthalide 48 in the neat alcohol 61 was of no avail in
increasing the yield of the reaction. Reaction of the prenylated
thiophthalide 60 with excess benzaldehyde 55 (3 equiv) in the
presence of excess LTB (Scheme 4) resulted in the formation of
the acid 62. DBU promoted methylation of the crude acid 62
furnished methyl ester of cajaninstilbene acid 59 in good yield.
Mechanistic study
Scheme 7 Proposed mechanism for the formation of 2-arylindenone
40.
A) Trapping of episulfide 26
In order to provide an acceptable evidence for the proposed
episulfide intermediate 26, the reaction between thiophthalide 8
and acetophenone 24 was chosen (Table 3). The H NMR study
1
(using ORCA software) of the syn analogue 66b indicates that
the dihedral angle between the S–C–C and C–C–O planes is
about 55°, which is inadequate for intramolecular lactone ring
opening to furnish the episulfide (cf. 10). However, for the pro-
posed elimination of LiH leading to 68, the dihedral angle
between Li–S–C and S–C–H of 180° is achievable by single
bond rotation. Treatment with DBU–MeI in acetone results in
the formation of isocoumarin derivative 16 (Scheme 6). The
usual anti diastereomer 66a possesses a dihedral angle of about
171° between the planes S–C–C and C–C–O. It suits intramole-
cular lactone opening resulting in the formation of the episulfide
intermediate 67.
of the reaction mixture indicated the formation of both 63 and
26. Two singlets40 at δ 4.74 and 4.71 were diagnostic of the two
isomers of the latter. Attempts for the isolation of 26 were
without success. It is to be noted that isolable episulfides are rare
in the literature. Refluxing the reaction mixture in toluene in the
presence of trimethyl phosphite ensured sulfur extrusion. For
derivatization, the mixture was submitted to methylation with
DBU–CH3I in acetone. Quite unexpectedly, the reaction furn-
ished phthalide 64 (Scheme 5) in 40% yield, besides the ester 25
in 27% yield. Formation of 64 indirectly proved the formation of
49
26. Treatment of 64 with NiCl2–NaBH4 followed by DBU–
CH3I in acetone afforded the ester 25 in 60% yield. Treatment of
C) Formation of 2-arylindenone 40
the mixture with diazomethane in ether furnished two insepar-
1
able esters 25 and 65. Two singlets at δ 4.83 and 4.80 in the H
The intermediate 69 formed during the course of the reaction
might have followed intramolecular cyclization path-A and path-
B (Scheme 7). The thiirane intermediate 70 formed in path-A
undergoes desulfurization to give styryl acid 71, which after
O-methylation furnishes the diester 39. The path-B provides
thiolactone 72 which undergoes LTB mediated lateral lithiation
to result in lithio species 73. This intermediate 73 then under-
goes intramolecular nucleophilic rearrangement through 74 to
give episulfide intermediate 75. Sulfur extrusion from 75 fol-
lowed by acidic work-up yields the acid 76. This was character-
ized as its ester derivative 40. The structure of this unusual 40
was established by analysis of NMR spectral data.
NMR spectrum indicated the presence of two thiirane esters
(mixture of cis and trans isomer of 65).
B) Formation of the isocoumarin co-products
The formation of isocoumarin 16 is unprecedented and tenta-
tively formulated as in Scheme 6. It is proposed that both dihy-
droisocoumarins 66a and 66b are formed in appreciable
amounts. The intermediate 66a, in which S− and lactone ‘O’ are
trans to each other collapses to the desired 15 derivative via the
episulfide intermediate 67. The energy minimized structure
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dried (Na2SO4) and concentrated. The residue was purified by
column chromatography on silica gel to afford the corresponding
pure ester.
Conclusions
The olefination of aldehydes with thiophthalides for the syn-
thesis of stilbenoids and styryl carboxylic acids is found to be
highly stereoselective and atom-efficient. It is shown to proceed
through episulfide intermediates followed by sulfur extrusion.
Protection of labile phenolic hydroxyl groups could be avoided
during some synthesis. The olefination is applied in the synthesis
of three natural hydroxystilbenoids. This study also discloses that
the carboxylic acid group ortho to the phenolic OH group under-
goes retro Kolbe–Schmitt reaction. The unusual formations of
isocoumarin and indenone could be further elaborated.
2-[2-(4-Methoxy-phenyl)-vinyl]benzoic acid50 (13)
1H NMR (400 MHz, [D6]-DMSO): δ = 12.97 (brs, 1H),
7.82–7.74 (m, 3H), 7.55–7.47 (m, 3H), 7.33 (t, 1H, J = 7.6 Hz),
7.11 (d, 1H, J = 16.4 Hz), 6.95 (d, 1H, J = 8.4 Hz), 3.80 (s, 3H);
13C NMR (100 MHz, [D6]-DMSO): δ = 169.2, 159.7, 138.6,
132.3, 130.8, 136.3, 130.0, 128.4, 127.4, 126.8, 125.2, 114.7,
55.5.
Experimental section
Methyl 2-but-1-enylbenzoate (15)39a
Typical olefination procedure with LTB (Method A)
1H NMR (400 MHz, CDCl3): δ = 7.84 (d, 1H, J = 7.6 Hz), 7.54
(d, 1H, J = 8 Hz), 7.43 (t, 1H, J = 7.2 Hz), 7.25 (t, 1H, J = 7.2
Hz), 7.13 (d, 1H, J = 15.6 Hz), 6.20–6.16 (m, 1H), 3.90 (s, 3H),
2.32–2.19 (m, 2H), 1.13–1.09 (t, 3H, 3J = 7.6); 13C NMR
(100 MHz, CDCl3): δ = 168.3, 139.9, 135.7, 132.1, 130.5,
128.3, 127.6, 127.4, 126.6, 52.2, 26.5, 13.8.
A solution of thiophthalide (1 mmol) in dry THF (5 mL) was
added to a suspension of LTB (2 mmol) in dry THF (10 mL) at
−60 °C under an inert atmosphere. The resulting solution was
stirred at −60 °C for 30 min after which a solution of an alde-
hyde or ketone (1.2 mmol) in dry THF (5 mL) was added to it.
The cooling bath was removed after about 30 min at −60 °C and
the reaction mixture was brought to room temperature and
further stirred for 12–16 h. The reaction was then quenched with
6 N HCl and THF removed under reduced pressure. The residue
was then extracted with ethyl acetate (3 × 50 mL). The combined
extracts were washed with brine (3 × 1/3 vol.), dried (Na2SO4)
and concentrated to provide the crude product. This was then
purified by column chromatography on silica gel or by crystalli-
zation or by subjecting to methylation (DBU–CH3I) followed by
column chromatography on silica gel.
3-Ethyl-4-methylsulfanylisochromen-1-one (16)
1H NMR (400 MHz, CDCl3): δ = 8.29 (d, J = 8 Hz, 1H), 8.09
(d, J = 8 Hz, 1H), 7.80 (t, J = 7.2 Hz, 1H), 7.50 (t, J = 7.6 Hz,
1H), 3.05–3.0 (m, 2H), 2.26 (s, 3H), 1.31 (t, J = 7.6 Hz, 3H);
13C NMR (100 MHz, CDCl3): δ = 164.0, 162.1, 148.0, 145.3,
140.0, 128.0, 125.0, 120.7, 109.4, 26.2, 19.2, 12.7; IR (KBr,
cm−1): ν˜ = 1727, 1606, 1461, 1409, 1180, 1072, 765, 692;
HRMS (ESI+): required for C12H14O2S+ ([MH]+) m/z =
221.0636, found m/z = 221.0630.
Typical olefination procedure with LDA (Method B)
LDA (2 mmol) was prepared by adding n-BuLi (2 mmol, 1.6 M
in hexane) to a solution of diisopropylamine (2 mmol) in THF
(10 mL) at −78 °C under an inert atmosphere. After 30 min at
−78 °C, an appropriate thiophthalide (1 mmol) in THF (5 mL)
was added dropwise over 10 min. The reaction mixture was
stirred at −78 °C for 30 min and then a solution of appropriate
aldehyde (1.2 mmol) in THF (5 mL) was added dropwise over
15 min at −78 °C. The reaction mixture was further stirred at
−78 °C for 30 min and then allowed to warm at room tempera-
ture and stirred for 12–16 h. The crude product was then purified
by column chromatography on silica gel, or by crystallization or
by directly subjecting to esterification and then it was purified by
column chromatography on silica gel.
Methyl 2-pent-1-enylbenzoate (18)
1H NMR (400 MHz, CDCl3): δ = 7.84 (d, J = 7.6 Hz, 1H), 7.54
(d, J = 7.6 Hz, 1H), 7.43 (t, J = 7.2 Hz, 1H), 7.24 (t, J = 7.6 Hz,
1H), 7.14 (d, J = 16.6 Hz, 1H), 6.18–6.10 (m, 1H), 3.89 (s, 3H),
2.23 (q, J = 7.2 Hz, J = 10 Hz, 2H), 1.57–1.48 (m, 2H), 0.97
(t, J = 8 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ = 168.3,
149.8, 144.0, 142.0, 140.4, 128.7, 128.3, 127.4, 126.6, 52.2,
35.4, 22.6, 14.9; HRMS (ESI+): required for C13H16O2Na+
([M + Na]+) m/z = 227.1048, found m/z = 227.1041.
Methyl 2-(4,8-dimethylnona-1,7-dienyl)benzoate (20)
1H NMR (400 MHz, CDCl3): δ = 7.85 (dd, J = 1.6 Hz, J = 8
Hz, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.46–7.42 (m, 1H), 7.27–7.23
(m, 1H), 7.11 (d, J = 15.6 Hz, 1H), 6.15–6.08 (m, 1H),
5.12–5.09 (m, 1H), 3.89 (s, 3H), 2.31–1.97 (m, 4H), 1.69
(s, 3H), 1.68 (s, 3H), 1.46–1.38 (m, 1H), 1.25–1.16 (m, 2H),
0.95 (d, J = 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ =
168.3, 139.7, 132.6, 131.9, 131.2, 130.3, 129.7, 128.2, 127.3,
126.5, 124.8, 52.0, 40.6, 36.8, 32.9, 25.7, 25.6, 19.5, 17.7;
HRMS (ESI+): required for C19H26O2Na+ ([M + Na]+) m/z =
309.1830, found m/z = 309.1823.
Typical esterification procedure with DBU
DBU (2 mmol) was added to a stirred solution of a crude acid
(1 mmol) in dry acetone (5 mL) at rt and the reaction was stirred
for 15 min. Iodomethane (5 mmol) was added to the mixture
over a period of 5–10 min, and stirring was continued for 3–4 h
at rt. The reaction mixture was concentrated and diluted with
ethyl acetate (50 mL). The resulting solution was washed succes-
sively with water (10 mL), saturated aqueous solution of sodium
thiosulfate (5 mL), and brine (10 mL). The organic layer was
2748 | Org. Biomol. Chem., 2012, 10, 2742–2752
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3-(2,6-Dimethylhept-5-enyl)-4-methylsulfanylisochromen-1-one
(21)
148.3, 141.1, 142.5, 141.3, 140.0, 127.7, 125.9, 119.8, 35.1,
31.1, 30.0, 25.7.
1H NMR (400 MHz, CDCl3): δ = 8.29 (d, J = 7.6 Hz, 1H), 8.08
(d, J = 8 Hz, 1H), 7.80 (t, J = 7.6 Hz, 1H), 7.50 (t, J = 7.2 Hz,
1H), 5.08 (t, J = 6.8 Hz, 1H), 2.97–2.81 (m, 2H), 2.23 (s, 3H),
2.12–1.96 (m, 3H), 1.67 (s, 3H), 1.59 (s, 3H), 1.47–1.38 (m,
1H), 1.33–1.24 (m, 1H), 0.96 (d, J = 6.8 Hz, 3H); 13C NMR
(100 MHz, CDCl3): δ = 161.9, 161.9, 147.7, 145.1, 141.5,
129.8, 127.8, 124.9, 124.3, 120.5, 110.6, 39.5, 36.8, 31.8, 25.7,
25.5, 19.3, 18.7, 17.7; HRMS (ESI+): required for
C19H24O2SNa+ ([M + Na]+) m/z = 339.1495, found m/z =
339.1495.
Spiro[3H-2-benzopyran-3,1′-cyclopentan]-1(4H)-one52 (31)
1H NMR (400 MHz, CDCl3): δ = 8.06 (d, J = 7.6 Hz, 1H), 7.51
(t, J = 7.2 Hz, 1H), 7.36 (t, J = 7.6 Hz, 1H), 7.22 (d, J = 7.6 Hz,
1H), 3.09 (s, 2H), 2.02–1.92 (m, 4H), 1.68–1.67 (m, 4H); 13C
NMR (100 MHz, CDCl3): δ = 165.5, 148.8, 143.5, 140.0, 127.6,
127.4, 125.2, 91.4, 38.5, 37.6, 23.8; HRMS (ESI+): required for
C13H15O2+ ([M + H]+) m/z = 203.1072, found m/z = 203.1067.
2-(Cyclohexylidenemethyl)benzoic acid (32)
1H NMR (400 MHz, CDCl3): δ = 8.07 (d, J = 8 Hz, 1H), 7.50
(t, J = 7.6 Hz, 1H), 7.31 (t, J = 8 Hz, 1H), 7.25 (d, J = 7.6 Hz,
1H), 6.66 (s, 1H), 2.32 (t, J = 6 Hz, 2H), 2.19 (t, J = 5.6 Hz,
2H), 1.74–1.54 (m, 6H); 13C NMR (100 MHz, CDCl3): δ =
173.0, 142.8, 140.5, 142.2, 141.4, 141.1, 128.3, 126.1, 121.5,
37.4, 29.7, 28.5, 27.9, 26.6; HRMS (ESI+): required for
C14H17O2+ ([M + H]+) m/z = 217.1229, found m/z = 217.1226.
Methyl 2-[2-(6-allyloxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]
dioxol-5-yl)-vinyl]benzoate (23)
1H NMR (400 MHz, CDCl3): δ = 7.88 (d, J = 7.6 Hz, 1H), 7.61
(d, J = 8 Hz, 1H), 7.54 (d, J = 16.4 Hz, 1H), 7.47 (t, J = 7.6 Hz,
1H), 7.32 (t, J = 7.6 Hz, 1H), 6.25 (dd, J = 8 Hz, 16 Hz, 1H),
5.98 (d, J = 3.6 Hz, 1H), 5.88–5.81 (m, 1H), 5.27 (d, J = 17.2
Hz, 1H), 5.17 (d, J = 10.4 Hz, 1H), 4.84 (dd, J = 2.8 Hz, 8 Hz,
1H), 4.62 (d, J = 3.6 Hz, 1H), 4.14–4.01 (m, 2H), 3.92–3.89
(m, 4H), 1.55 (s, 3H), 1.34 (s, 3H); 13C NMR (100 MHz,
CDCl3): δ = 167.6, 138.3, 134.0, 132.7, 132.2, 130.4, 128.6,
127.6, 127.5, 126.4, 117.3, 111.5, 104.9, 83.9, 83.1, 81.5, 71.3,
52.1, 26.8, 26.2; HRMS (ESI+): required for C20H25O6
([M + H]+) m/z = 361.1651, found m/z = 361.1648.
2-[2-(4-Isopropenylcyclohex-1-yl)vinyl]benzoic acid (35)
1H NMR (400 MHz, CDCl3): δ = 8.03 (d, J = 7.6 Hz, 1H), 7.63
(d, J = 7.6 Hz, 1H), 7.51 (t, J = 7.6 Hz, 1H), 7.39 (d, J = 16 Hz,
1H), 7.29 (t, J = 7.6 Hz, 1H), 6.72 (d, J = 16 Hz, 1H), 5.96 (s,
1H), 4.75 (s, 2H), 2.53–2.48 (m, 1H), 2.35–2.12 (m, 4H),
1.98–1.94 (m, 1H), 1.76 (s, 3 H), 1.61–1.50 (m, 1H); 13C NMR
(50 MHz, CDCl3): δ = 173.5, 149.7, 140.8, 136.1, 135.2, 133.0,
132.4, 131.6, 131.2, 127.0, 126.6, 124.1, 108.9, 41.2, 31.7,
27.5, 25.1, 20.9; HRMS (ESI+): required for C18H20O2Na+
([M + Na]+) m/z = 291.1361, found m/z = 291.1357.
Methyl 2-(2-phenylpropenyl)benzoate (25)
1H NMR (400 MHz, CDCl3): δ = 8.02 (d, J = 7.6 Hz, trans-
isomer), 7.88 (d, J = 7.6 Hz, cis-isomer), 7.62 (d, J = 7.6 Hz,
trans-isomer), 7.53 (t, J = 7.6 Hz, trans-isomer), 7.47–7.29
(m, cis and trans isomer), 7.17–7.09 (m, cis and trans isomer),
6.98 (s, cis isomer), 6.87 (d, J = 6.8 Hz, cis isomer), 3.92 (s, cis
isomer), 3.90 (s, trans isomer), 2.29 (s, cis isomer), 2.13
(s, trans isomer); 13C NMR (100 MHz, CDCl3): (mixture of cis
and trans) δ = 167.9, 143.7, 140.2, 136.2, 132.6, 132.2, 131.8,
131.3, 130.8, 129.7, 128.9, 128.5, 127.7, 127.4, 126.8, 126.2,
52.2, 17.3; HRMS (ESI+): required for C17H16O2Na+
([M + Na]+) m/z = 275.1048, found m/z = 275.1053.
2-[2-(2-Nitrophenyl)vinyl]benzoic acid (37)
1H NMR (400 MHz, CDCl3) δ = 8.14 (d, J = 7.6 Hz, 1H),
8.05–7.99 (m, 2H), 7.85 (d, J = 7.6 Hz, 1H), 7.79 (d, J = 7.6
Hz, 1H), 7.62 (t, J = 7.6 Hz, 2H), 7.52–7.41 (m, 3H); 13C NMR
(100 MHz, CDCl3): δ = 171.7, 148.2, 149.8, 143.7, 143.5,
143.4, 143.0, 141.9, 129.1, 128.5, 128.4, 127.5, 126.9, 125.0
(one signal is perhaps overlapped); HRMS (ESI+): required for
C15H11NO4Na+ ([M + Na]+) m/z = 292.0586, found m/z =
292.0582.
Methyl 2-(2,2-diphenylvinyl)benzoate51 (28)
Dimethyl bis-2,2′-(1,2-ethenediyl)benzoate53 (39)
1H NMR (400 MHz, CDCl3): δ = 7.89 (d, 1H, J = 2.4), 7.43
(s, 1H), 7.37–7.28 (m, 5H), 7.20–7.13 (m, 5H), 7.10–7.08 (m,
2H), 6.96–6.94 (m, 1H); 13C NMR (100 MHz, CDCl3): δ =
167.79, 143.13, 143.06, 139.98, 139.76, 131.62, 131.33, 131.01,
130.17, 129.88, 128.18, 128.16, 128.03, 127.86, 127.56, 127.14,
126.44, 52.09.
1H NMR (400 MHz, CDCl3): δ = 7.94 (d, 1H, J = 8 Hz), 7.88
(s, 1H), 7.82 (d, 1H, J = 8 Hz), 7.53 (t, 1H, J = 7.4 Hz), 7.33
(t, 1H, J = 7.2 Hz), 3.90 (s, 3H); 13C NMR (100 MHz, CDCl3):
δ = 168.0, 139.7, 132.5, 130.8, 130.4, 128.7, 127.8, 127.5, 52.3.
Methyl 2-(1-oxo-1H-inden-2-yl)benzoate (40)
2-(Cyclopentylidenemethyl)benzoic acid (30)
1H NMR (400 MHz, CDCl3): δ = 8.41 (s, 1H), 8.07 (d, J = 8
Hz, 2H), 7.86 (d, J = 8 Hz, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.68
(t, J = 7.2 Hz, 1H), 7.63–7.59 (m, 1H), 7.52 (t, J = 7.6 Hz, 1H),
7.43 (t, J = 7.6 Hz, 1H), 3.91 (s, 3H); 13C NMR (100 MHz,
1H NMR (200 MHz, CDCl3): δ = 8.5 (d, J = 7.4 Hz, 1H),
7.53–7.47 (m, 2H), 7.34–7.27 (m, 1H), 7.0 (brs, 1H), 2.57–2.46
(m, 4H), 1.75 (brs, 4H); 13C NMR (50 MHz, CDCl3): δ = 173.8,
This journal is © The Royal Society of Chemistry 2012
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CDCl3): δ = 193.6, 167.0, 144.0, 147.5, 143.8, 143.5, 143.1,
142.5, 141.1, 140.2, 129.2, 129.0, 128.4, 124.8, 123.5, 121.4,
52.3; IR (KBr, cm−1): ν˜ = 2950, 1698, 1689, 1479, 1268, 1079,
(d, J = 16 Hz, 1H), 6.84 (d, J = 8.8 Hz, 2H), 3.94 (s, 3H); 13C
NMR (100 MHz, CDCl3,): δ 168.6, 166.0, 149.8, 142.4, 141.3,
140.8, 140.3, 128.5, 128.2, 127.0, 126.9, 125.2, 116.8, 52.5; IR
(KBr, cm−1): ν˜ = 3355, 1702, 1600, 1438, 1241, 1078, 966,
819, 651; HRMS (ESI+): required for C16H14O3Na ([M + Na]+)
m/z = 277.0841, found m/z = 277.0838.
+
952, 885, 757, 700; HRMS (ESI+): required for C17H12O3
([M]+) m/z = 264.0786, found m/z = 264.0776.
Dimethyl 2,2′-(1,4-phenylenedi-2,1-ethenediyl)bisbenzoate (42)
3-(4-Hydroxyphenyl)isochroman-1-one (52)
1H NMR (400 MHz, CDCl3): δ = 8.02 (d, J = 16.4 Hz, 1H),
7.94 (d, J = 7.6 Hz, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.55 (s, 2H),
7.51 (t, J = 7.2 Hz, 1H), 7.32 (t, J = 7.6 Hz, 1H), 7.02 (d, J = 16
Hz, 1H), 3.94 (s, 3H); 13C NMR (100 MHz, CDCl3): δ = 167.9,
149.2, 147.1, 142.2, 141.1, 140.8, 128.6, 127.4, 127.2, 126.9,
52.2 (perhaps one signal is overlapped); HRMS (ESI+): required
for C26H22O4Na+ ([M + Na]+) m/z = 421.1416, found m/z =
421.1408.
1H NMR (400 MHz, CDCl3): δ = 8.15 (d, J = 7.6 Hz, 1H), 7.58
(t, J = 7.2 Hz, 1H), 7.43 (t, J = 7.6 Hz, 1H), 7.34–7.28 (m, 4H),
6.88 (d, J = 8.4 Hz, 2H), 5.50 (dd, J = 2.8 Hz, J = 12 Hz, 1H),
3.36 (dd, J = 12.4 Hz, J = 16.4 Hz, 1H), 3.12 (dd, J = 2.8 Hz,
J = 16.4 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ = 166.8,
156.8, 139.4, 134.3, 130.5, 130.0, 128.2, 128.1, 127.7, 125.0,
116.3, 80.5, 35.3; IR (KBr, cm−1): ν˜ = 3303, 1693, 1602, 1282,
831; HRMS (ESI+): required for C16H15O3 ([M + H]+) m/z =
+
255.1021, found m/z = 255.1019.
Methyl 2-(furan-2-yl-vinyl)benzoate39a (44)
1H NMR (400 MHz, CDCl3): δ = 8.01 (d, J = 8 Hz, cis isomer),
7.91–7.84 (m, cis and trans isomer), 7.65 (d, J = 7.6 Hz, trans
isomer), 7.56–7.42 (m, cis and trans isomer), 7.38–7.28 (m, cis
and trans), 7.20 (s, cis isomer), 6.90 (d, J = 12.4 Hz, cis
isomer), 6.83 (d, J = 16.4 Hz, trans isomer), 6.46–6.40 (m, cis
and trans isomer), 6.23 (d, J = 1.6 Hz, cis isomer), 5.92 (d, J =
3.2 Hz, cis isomer), 3.93 (s, trans isomer), 3.85 (s, cis isomer);
13C NMR (100 MHz, CDCl3): mixture of cis and trans δ =
167.8, 153.2, 142.4, 141.4, 139.5, 138.6, 132.0, 131.8, 130.0,
130.6, 130.4, 128.6, 128.0, 127.2, 127.0, 126.4, 125.5, 114.1,
117.7, 117.6, 111.5, 111.0, 109.5, 109.1, 52.1, 51.9.
2-Hydroxy-4-methoxy-6-styrylbenzoic acid (54)
1H NMR: (200 MHz, CDCl3): δ = 12.47 (s, 1H), 7.93 (d, J = 16
Hz, 1H), 7.50 (d, J = 7.0 Hz, 2H), 7.40–7.26 (m, 3H), 6.82 (d, J
= 16 Hz, 1H), 6.65 (d, J = 2.6 Hz, 1H), 6.43 (d, J = 2.6 Hz, 1H),
3.87 (s, 3H); 13C NMR (50 MHz, CDCl3): δ = 173.7, 165.6,
163.9, 143.2, 137.4, 130.5, 130.2, 128.6, 127.6, 126.7, 107.1,
104.2, 100.2, 55.4.
3′,4-Dihydroxy-3,5′-dimethoxystilbene (56)
1H NMR (400 MHz, [D6]-acetone): δ = 8.38 (s, 1H), 7.76
(s, 1H), 7.23 (d, J = 1.6 Hz, 1H), 7.09 (d, J = 16 Hz, 1H),
7.04–6.95 (m, 2H), 6.82 (d, J = 8 Hz, 1H), 6.64 (s, 2H), 6.32
(t, J = 2 Hz, 1H), 3.89 (s, 3H), 3.77 (s, 3H); 13C NMR
(100 MHz, [D6]-acetone): δ = 162.4, 159.9, 148.9, 147.9, 141.2,
130.7, 130.1, 127.2, 121.6, 116.3, 110.4, 107.0, 104.2, 101.7,
56.6, 55.8.
Methyl 2-methoxy-6-[2-(4-methoxyphenyl)ethenyl]benzoate (47)
1H NMR: (400 MHz, CDCl3): δ = 7.41 (d, J = 8.8 Hz, 2H),
7.35–7.28 (m, 2H), 7.04 (d, J = 16 Hz, 1H), 6.93–6.88 (m, 3H),
6.81 (d, J = 8 Hz, 1H), 3.96 (s, 3H), 3.84 (s, 3H), 3.81 (s, 3H);
13C NMR (100 MHz, CDCl3): δ = 168.9, 169.8, 166.7, 146.6,
141.5, 140.6, 129.9, 128.2, 122.8, 122.7, 117.6, 114.3, 109.6,
56.1, 55.4, 52.6; HRMS (ESI+): required for ([M + Na]+) m/z =
321.1103, found m/z = 321.1101.
7-Hydroxy-5-methoxy-6-(3-methylbut-2-enyl)-3H-benzo[c]
thiophen-1-one (60)
1H NMR (200 MHz, CDCl3): δ = 9.47 (s, 1H), 6.39 (s, 1H),
5.03 (t, J = 5.8 Hz, 1H), 4.26 (s, 2H), 3.86 (s, 3H), 3.27 (d, J =
6.8 Hz, 2H), 1.76 (s, 3H), 1.68 (s, 3H); 13C NMR (50 MHz,
CDCl3): δ = 200.8, 163.8, 156.7, 146.4, 132.6, 121.3, 119.5,
114.3, 97.8, 56.4, 34.2, 25.9, 24.4, 18.0; HRMS (ESI+): required
for C14H16O3SNa+ ([M + Na]+) m/z = 287.0718, found m/z =
287.0711.
2-Hydroxy-4-methoxy-6-[2-(4-methoxyphenyl)vinyl]benzoic acid
(49)
1
m.p. = 162 °C–168 °C; H NMR (400 MHz, [D6]-acetone): δ =
7.83 (d, J = 16 Hz, 1H), 7.50 (d, J = 8.4 Hz, 2H), 6.93 (d, J =
8.8 Hz, 2H), 6.92 (d, J = 16 Hz, 1H), 6.71 (d, J = 2.4 Hz, 1H),
6.41 (d, J = 2.4 Hz, 1H), 3.87 (s, 3H), 3.81 (s, 3H); 13C NMR
(100 MHz, [D6]-acetone): δ = 174.2, 167.0, 165.6, 161.0, 144.9,
141.8, 141.5, 129.3, 128.6, 116.3, 107.8, 104.8, 101.1, 56.3,
Methyl 2-hydroxy-4-methoxy-3-(3-methylbut-2-enyl)-6-
styrylbenzoate (59)
+
56.0; HRMS (ESI+): required for C17H17O5 ([M + H]+) m/z =
301.1076 found m/z = 301.1073.
1H NMR (400 MHz, CDCl3): δ = 11.04 (s, 1H), 7.19 (d, J = 7.2
Hz, 2H), 7.01 (t, J = 7.2 Hz, 2H), 6.94–6.90 (m, 2H), 6.10
(s, 1H), 5.95 (d, J = 16.4 Hz, 1H), 4.72 (t, J = 6.8 Hz, 1H), 3.51
(s, 3H), 3.45 (s, 3H), 2.97 (d, J = 6.4 Hz, 2H), 1.32 (s, 3H), 1.22
(s, 3H); 13C NMR (100 MHz, CDCl3) δ = 172.2, 162.9, 162.8,
141.2, 137.9, 131.8, 131.1, 128.9, 128.5, 127.6, 126.4, 123.8,
Methyl [2-(4-hydroxyphenyl)vinyl]benzoate (51)
1H NMR (400 MHz, CDCl3): δ = 7.92 (d, J = 7.6 Hz, 1H), 7.83
(d, J = 16 Hz, 1H), 7.70 (d, J = 8 Hz, 1H), 7.50 (t, J = 7.6 Hz,
1H), 7.40 (d, J = 7.6 Hz, 2H), 7.30 (t, J = 7.6 Hz, 1H), 6.96
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121.8, 104.8, 98.4, 55.9, 52.4, 26.3, 26.0, 18.4; IR (KBr, cm−1):
373; (f) M. Isaka, C. Suyarnsestakorn and M. Tanticharoen, J. Org.
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14 M. Cuendet, O. Potterat and K. Hostettmann, Phytochemistry, 2001, 56,
631.
ν˜ = 1698, 1589, 1479, 1268, 1079, 952, 887, 757; HRMS
(ESI+): required for C22H25O4 ([M + H]+) m/z = 353.1747,
+
found m/z = 353.1748.
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17 H. A. Behanna and S. I. Stupp, Chem. Commun., 2005, 4845.
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Acknowledgements
We thank CSIR, New Delhi for the financial support of the
project. P. M. thanks UGC, New Delhi. B. S. and S. R. D. thank
CSIR, New Delhi for their research fellowships. We are also
thankful to Debakar Dev for solving the crystal structures and
Subhajit Mandal for energy minimizations.
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