One-step synthesis of isocoumarins and 3-benzylidenephthalides via ligandless pd-catalyzed oxidative coupling of benzoic acids and vinylarenes

Article abstract of DOI:10.1021/jo400174w

A straightforward synthetic method for the preparation of isocoumarins and 3-benzylidenephthalides via C-H olefination and oxidative coupling of readily available benzoic acids and vinylarenes was developed. The directing effect of the substituents on the benzoic acid allows for the synthesis of both types of lactone in pure form.

Full text of DOI:10.1021/jo400174w

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Note
One-step Synthesis of Isocoumarins and 3-
Benzylidenephthalides via Ligandless Pd–catalyzed
Oxidative Coupling of Benzoic Acids and Vinylarenes
Debkumar Nandi, Debalina Ghosh, Shih-Ji Chen, Bing-Chiuan Kuo, Nancy M. Wang, and Hon Man Lee
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo400174w • Publication Date (Web): 18 Mar 2013
Downloaded from http://pubs.acs.org on March 18, 2013
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The Journal of Organic Chemistry
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One-step Synthesis of Isocoumarins and 3-Benzylidenephthalides via Ligandless Pd–catalyzed Oxidative
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Coupling of Benzoic Acids and Vinylarenes
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Debkumar Nandi, Debalina Ghosh, ShihꢀJi Chen, BingꢀChiuan Kuo, Nancy M. Wang, and Hon Man Lee*
Department of Chemistry, National Changhua University of Education, Changhua 50058, Taiwan, R.O.C.
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*Eꢀmail: leehm@cc.ncue.edu.tw
Abstract
A straightꢀforward synthetic method for the preparation of isocoumarins and 3ꢀbenzylidenephthalides via
C–H olefination and oxidative coupling of readily available benzoic acids and vinylarenes was developed. The
directing effect of the substituents on the benzoic acid allows for the synthesis of both types of lactone in pure
form.
Isocoumarins1ꢀ6 and 3ꢀbenzylidenephthalides4ꢀ7 are naturally occurring lactones which exhibit a broad range
of biological activities. They are also important in medicinal chemistry as building blocks for the synthesis of
bioactive compounds.8,9 Because of their wideꢀrange of biological activities, a number of methods have been
developed for the construction of isocoumarins10ꢀ12 and 3ꢀbenzylidenephthalide frameworks.3,13 For isocoumarins,
the most popular method is based on the catalytic cyclization of in situ14ꢀ18 or preformed19ꢀ24 oꢀalkynylbenzoic acid
derivatives. For instance, Youn recently reported the oxidative cyclization of 2ꢀalkynylbenzaldehyde catalyzed by
Nꢀheterocyclic carbene (Scheme 1a).18 Synthetic methods avoiding alkyneꢀbased substrates have also been
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developed, including cyclization of 2ꢀalkenyl or 2ꢀallylbenzoic acid derivatives,3,25,26 microwaveꢀassisted reaction
of homophthalic acid with acid chlorides or esters,27 Cu(I)ꢀcatalyzed intramolecular sequential C–C coupling and
rearrangement of 1ꢀ(2ꢀhalophenyl)ꢀ1,3ꢀdiones,28 and Cu(I)ꢀcatalyzed intermolecular domino reactions from
2ꢀhalobenzoic acids or 2ꢀhalobenzoic acid derivatives with 1,3ꢀdiketones.29ꢀ31 Despite the efficiency of these
synthetic strategies for isocoumarins, they are significantly limited by substrate availability. Most often, these
methods involve multistep sequences, harsh conditions, or expensive catalysts and ligands. Also in some of these
syntheses, mixtures of isocoumarin and 3ꢀbenzylidenephthalide are obtained.14,18 Comparatively, the synthesis of
3ꢀbenzylidenephthalides has received less attention and reported procedures generally require multistep synthesis
via 5ꢀexo cyclization of oꢀalkynylbenzoic acids.3
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Recently, Yu reported the tandem Pdꢀcatalyzed hydroxylꢀdirected C–H olefination reaction/oxidative
cyclization.32 In his study, monoꢀNꢀprotected amino acid ligands effectively promoted C–H olefination and the
olefinated intermediates of electronꢀdeficient alkenes underwent Pd(II)ꢀcatalyzed intramolecular oxidative
cyclization to give pyrans (Scheme 1b). Since ortho C–H activation directed by a carboxylate group is wellꢀknown,
33ꢀ36 we envisioned the feasibility of a similar Pdꢀcatalyzed C–H olefination between benzoic acid and vinylarene
(Scheme 1c).37ꢀ40 A subsequent Pdꢀcatalyzed intramolecular ringꢀclosing process via attack of the carboxylate O
atom on the olefin moiety should give isocoumarins or 3ꢀbenzylidenephthalides. This strategy is challenging
because kinetically significant aryl C–H activation is involved. Desirably, extra synthetic steps to remove the
directing group would not be required since it is part of the product.32
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Scheme 1. Lactone and Benzopyran Synthesis
Herein, we report a straightꢀforward strategy to selectively obtain isocoumarins and 3ꢀbenzylidenephthalides.
Unlike aforementioned syntheses, our method based on Pdꢀcatalyzed tandem C–H olefination and oxidative
cyclization is a simple oneꢀstep procedure that avoids lengthy prefunctionalization of substrates since both benzoic
acid and vinylarenes are cheap and widely accessible. The practicability of this method is further manifested by
the ligandless and mild reaction conditions.
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The reaction between benzoic acid and styrene yielding isocoumarins 1a was chosen for the optimization of
conditions (Table 1). The best solvent was determined to be DMF (entries 1–3). The optimal temperature was 110
°C (entries 4–6), as higher temperature resulted in an inferior yield. A moderate 5 mol% Pd loading was necessary
to give the product in reasonable yield (entries 5 and 7). Theoretically four H atoms were released and therefore
1–2 equiv of Ag2O were required. Thus, reducing Ag2O to subꢀstoichiometric amount lowered the yield. However,
excess Ag2O also decreased the yield drastically (entries 5 and 9–11). Oxidants other than Ag salts were not
effective (entries 12–13). Since 1 equiv of water also formed in the reaction, the addition of 4 Å molecular sieves
improved the yield (entry 5 vs. 8).
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Table 1. Reaction Optimizationa
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entry
Pd mol%
Oxidant
/additive
solvent
temp.
(ºC)
yieldb
(%)
7
8
9
1
2
3
4
5
6
7
8
5
5
Ag2O (1 equiv)
Ag2O (1 equiv)
Ag2O (1 equiv)
Ag2O (1 equiv)
Ag2O (1 equiv)
Ag2O (1 equiv)
Ag2O (1 equiv)
DCE
NMP
DMF
DMF
DMF
DMF
DMF
DMF
100
100
100
60
0
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0
5
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5
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110
130
110
110
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28
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2.5
5
Ag2O (1 equiv)/
MS 4 Å (0.5 g)
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5
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5
5
5
Ag2O (15 mol%)
Ag2O (50 mol%)
Ag2O (2 equiv)
DMF
DMF
DMF
DMF
DMF
110
110
110
110
110
11
26
32
0
10
11
12
13
CuOAc (1 equiv)
PhI(OAc)2 (1 equiv)
0
aReaction conditions: 2.0 mmol benzoic acid, 2.0 mmol vinylarene, 15–200
mol% oxidant/additive, 2.5 or 5 mol% Pd(OAc)2, 5 mL dry solvent, heating, 20
h. bisolated yield.
Using the optimized conditions, the substrate scope of the reaction was investigated (Table 2). In general, the
use of unsubstituted, paraꢀ, and metaꢀsubstituted benzoic acids afforded isocoumarins as single products. Benzoic
acids with electronꢀdonating groups (EDGs) gave higher yields than unsubstituted substrate (1a vs. 4a and 1b vs.
4b). This reactivity pattern, together with the fact that C–H activation is disfavored when an electronꢀwithdrawing
group (EWG) is present on the benzoic acid (vide infra), is consistent with an electrophilic aromatic substitution
mechanism (SEAr). The reactions also went smoothly with EDGs on the vinylarene, producing 4b and 4e, in 70
and 56% yields, respectively. However, attempts to use vinylarenes with EWGs failed. The formation of pure 2a–c
from 3ꢀtoluic acid indicates that C–H cleavage on the benzoic acid ring selectively occurred at the less hindered
ortho site. Sterically hindered 3ꢀmethylstyrene also successfully produced 2c, 3c and 4c in satisfactory yields. The
Xꢀray structure of 2a was obtained (Figure S1 in supporting information).
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Table 2. Synthesis of 3-Substituted Isocoumarinsa,b
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entry
1
R2
ꢀꢀ
product
yieldb (%)
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1a
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8
9
2
3
Me
OMe
1b
1d
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68
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3
4
H
Me
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2b
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70
O
O
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2c
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6
7
H
Me
3a
3b
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72
8
9
ꢀꢀ
ꢀꢀ
3c
4c
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69
10
11
H
Me
4a
4b
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70
12
ꢀꢀ
4e
56
aReaction conditions: 2.0 mmol benzoic acid, 2.0 mmol vinylarene,
1 equiv. Ag2O, 5 mol% Pd(OAc)2, 5 mL DMF, 110 ºC, 20 h, MS 4
Å (0.5 g). bisolated yield.
Pleasingly, the reaction can be extended to other aromatic acids. For instance, 9ꢀanthracenecarboxylic acid (5)
reacted with arylarenes to afford 7ꢀmembered ring lactones 6a, b, and d in 64–68% yields (Scheme 2a). We were
also pleased to find that heteroaromatic carboxylic acids can also be used as substrates. The reaction of
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51 1ꢀmethylꢀ3ꢀindolecarboxylic acid with arylarenes afforded 7a and b in good yields (Scheme 2b). However, the
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reaction between isomeric 1ꢀmethylꢀ2ꢀindolecarboxylic acid and styrene failed perhaps owing to the less acidic
C3H of the indole.
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Scheme 2. Preparation of Lactone Derivatives
When orthoꢀsubstituted benzoic acids were employed in the reaction with vinylarenes under identical
conditions, isomeric (z)ꢀ3ꢀbenzylidenephthalides 8–10 were isolated instead of isocoumarins in 47–80% yields
(Table 3). EDGs on the benzoic acids were essential and the yields also significantly improved if methyl or
methoxyꢀsubstituted styrenes were employed (8b vs. 8a). These results reveals an intriguing directing effect of the
benzene ring substituents on the regioselective nucleophilic attack of the carboxylate O atom on the olefin (vide
infra). Notably, the reactions failed with 4ꢀacetylstyrene bearing a EWG.
Table 3. Synthesis of 3-Benzylidenephthalidea,b
entry
1
R2
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product
yieldb (%)
47
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3
Me
OMe
8b
8d
80
53
3
ꢀꢀ
8c
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5
6
H
Me
9a
9b
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74
7
ꢀꢀ
9c
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8
ꢀꢀ
10e
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aReaction conditions: 2.0 mmol benzoic acid, 2.0 mmol vinylarene,
1 equiv. Ag2O, 5 mol% Pd(OAc)2, 5 mL DMF, 110 ºC, 20 h, MS 4
Å (0.5 g). bisolated yield.
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To confirm the aryl C–H activation via the SEAr mechanism, we carried out reactions between vinylarenes
and benzoic acids with EWGs. Various substrates including 2ꢀacetylbenzoic acid was tested; however, mixtures of
unidentified products resulted. Intriguingly, in the case of 2ꢀnitrobenzoic acid, instead of the formation of lactone
products, decarboxylative Heck coupling reaction occurred, 41,42 affording compounds 11a, b, and d in good yields
(Scheme 3). This reactivity pattern can be explained by the fact that nucleophilic attack of the phenyl ring on Pd(II)
via the SEAr mechanism is strongly disfavored. Thus, instead of ortho aryl C–H activation, decarboxylation
occurred preferentially. A competitive experiment was also performed (Scheme S1 in supporting information). The
reaction of a mixture of oꢀ and pꢀtoluic acids with 3ꢀmethylstyrene revealed a slight preference for the formation
of 3ꢀbenzylidenephthalides. Further mechanistic information was obtained from kinetic isotopic experiments
(Scheme S2 in supporting information), which gave a kH/kD value of 2.8, indicating that aryl C–H activation may
be a rateꢀcontrolling step.
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Scheme 3. Decarboxylative Heck Coupling Reaction
On the basis of the above results, we propose the mechanistic cycle (Scheme 4). Upon coordination to Pd(II),
the carboxylate group directs the ortho C–H bond toward the metal center. A fiveꢀmembered palladacycle was
formed via SEAr. Such palladacycles are common intermediates in Pdꢀcatalyzed C–H functionalization.37,39 Next,
a Heckꢀtype mechanism involving βꢀH elimination at C1 of the vinyl group produces intermediate A with a new
C–C bond formed regioselectively. For orthoꢀsubstituted benzoic acids, intramolecular attack of the coordinated O
60 atom on C1 of the vinyl group affords intermediate B. Subsequently,
βꢀH elimination furnishes the
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3ꢀbenzylidenephathalide. For other benzoic acids, the coordinated O atom in A attacks C2, leading to intermediate
C, which undergoes βꢀH elimination to give isocoumarin. The dependence of the preferential formation of B and
C on ring substitution remains to be elucidated. However, it may be related to the steric effect between the
neighboring ortho substituent and carboxylate group, which restricts O atom from attacking the distant C2 of the
vinyl group. In order to complete the catalytic cycle, Ag(I) is needed to oxidize Pd(0) back to the active Pd(II)
species. The formation of metallic Ag was visually observed on the surface of the molecular sieve after the
reaction.
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Scheme 4. A Proposed Catalytic Cycle
Thunberginol F is a naturally occurring 3ꢀbenzylideꢀnephthalide isolated from Hydrangea macrophylla var.
thunbergii.6 Thunberginol F 7ꢀOꢀ
β
ꢀDꢀglucopyranoside was also isolated from the roots of Scorzonera judaica.7
The natural product exhibits antiallergic,5,6 antimicrobial, and other biological activities,6 and has been synthesized
in threeꢀsteps from N,Nꢀdiethylꢀ2ꢀmethoxyꢀbenzamide in an overall 9% yield.5 We applied our methodology to the
ligandless twoꢀstep preparation of thunberginol F (Scheme 5). Commercially available 2ꢀmethoxybenzolic acid
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and 3,4ꢀdimethoxystyrene reacted to give 9e. Deprotection of the OH groups afforded pure thunberginol F in an
overall 58% yield. The Xꢀray structure of 9e was established (Figure S2 in supporting information). Our
preliminary biological studies showed that thunberginol F exhibited similar cytotoxicity effect as paclitaxel. It can
inhibit growth of human cancer cells above 75% at 30 ꢀM (Figure S3 in supporting information).
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Scheme 5. Total Synthesis of Thunberginol F
In summary, we have developed a straightforward synthetic method for the preparation of isocoumarins and
3ꢀbenzylidenephthalides via C–H olefination and oxidative coupling of aromatic carboxylic acids and vinylarenes.
The directing effect of the substituents on benzoic acids allows the preparation of both types of lactones in pure
forms. Based on easily available substrates and a simple oneꢀstep procedure, this method should receive interest in
natural product synthesis and medicinal chemistry.
Experimental Section
All manipulations were performed under a dry nitrogen atmosphere using standard Schlenk techniques. Solvents
were dried with standard procedures. Starting chemicals were purchased from commercial source and used as
received. 1H and 13C{1H} NMR spectra were recorded at 300.13 and 75.48 MHz, respectively. HRMS was carried
out on a sector field mass spectrometer.
Typical Procedure for the Preparation of Coupling Products. To a 50 mL flask fitted with magnetic stirrer
arene carboxylic acid (2.0 mmol), Ag2O (2.0 mmol), Pd(OAc)2 (0.023 g, 0.1 mmol) (5 mol%) and oven activated
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molecular sieves 4 Å (0.5 g) were added under nitrogen. Styrene (2.00 mmol) and dry DMF (5 mL) were then
added to it. The reaction mixture was stirred at 110 ºC for 20 h and then was allowed to cool at room temperature
and filtered through celite bed and mother liquor was collected. After dilution with 20 mL of distilled water, the
solution was extracted with ethyl acetate (3x15 mL). The organic layer was separated washed with saturated
NaHCO3 solution and dried over anhydrous MgSO4. Removal of the solvent resulted in a residual mass which was
subjected to column chromatography over silica gel using hexane and an increasing proportion of ethyl acetate as
eluent to provide the corresponding products.
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3-Phenyl-1H-isochromen-1-one (1a).43 Yellow solid (249 mg, 56% yield); Rf = 0.43 (9:1 hexane: EtOAc), synthesized
following the general procedure from benzoic acid (244 mg, 2.0 mmol) and styrene (208 mg, 2.0 mmol); mp = 82.2 ºC;
1H NMR (CDCl3, 300 MHz): δ 8.26 (d, J = 7.5 Hz, 1H), 7.83 (dd, J = 7.8, 1.5 Hz, 2H), 7.67 (td, J = 7.5, 1.1 Hz, 1H),
13
7.47ꢀ6.90 (m, 5H), 6.91 (s, 1H); C NMR (CDCl3, 75 MHz): δ 162.3, 153.5, 137.5, 134.9, 131.9, 129.9, 129.6, 128.8,
128.1, 126.0, 125.2, 120.5, 101.8; HRMS (ESI): m/z [M]+ calcd for C15H10O2 222.0680, found 222.0683.
3-p-Tolyl-1H-isochromen-1-one (1b).43 White solid (307 mg, 65% yield); Rf = 0.66 (8:2 hexane: EtOAc),
synthesized following the general procedure from benzoic acid (244 mg, 2.0 mmol) and 1ꢀmethylꢀ4ꢀvinylbenzene (236
mg, 2.0 mmol); mp = 109.1 ºC; 1H NMR (CDCl3, 300 MHz): δ 8.24 (d, J = 8.1 Hz, 1H), 7.73ꢀ7.68 (m, 2H), 7.64 (d,
13
J = 7.5 Hz, 1H), 7.45ꢀ7.40 (m, 2H), 7.21(d, J = 8.4 Hz, 2H), 6.84 (s, 1H), 2.36 (s, 3H); C NMR (75 MHz): δ
162.5, 153.7, 140.3, 137.7, 134.8, 130.1, 129.5, 129.1, 127.9, 125.9, 125.1, 120.3, 101.1, 21.4; HRMS (ESI) m/z
[M]+ calcd for C16H12O2 236.0837, found 236.0835.
3-(4-Methoxyphenyl)-1H-isochromen-1-one (1d).44 Pale yellow solid (343 mg, 68% yield); Rf = 0.25 (9:1
hexane: EtOAc), synthesized following the general procedure from benzoic acid (244 mg, 2.0 mmol) and
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1ꢀmethoxyꢀ4ꢀvinylbenzene (268 mg, 2.0 mmol); mp = 109.1 ºC. 1H NMR (CDCl3, 300 MHz): δ 8.24 (d, J = 8.2 Hz,
1H), 7.76 (d, J = 9.0 Hz, 2H), 7.64 (m, 1H), 7.41 (td, J = 5.6 Hz, 3.0 Hz, 2H), 6.92 (d, J = 9.0 Hz, 2H), 6.77 (s,
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1H), 3.82 (s, 3H); C NMR (CDCl3, 75 MHz): δ 164.5, 161.1, 153.7, 137.9, 134.8, 129.5, 127.6, 126.3, 125.7,
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124.5, 120.1, 144.2, 100.2, 55.4. HRMS (ESI) m/z calcd for C16H12O3 [M]+ 252.0786, found 252.0783.
7-Methyl-3-phenyl-1H-isochromen-1-one (2a).43 White solid (273 mg, 58% yield); Rf = 0.44 (9:1 hexane:
EtOAc), synthesized following the general procedure from mꢀtoluic acid (272 mg, 2.0 mmol) and styrene (208 mg, 2.0
mmol); mp = 143.7 ºC; 1H NMR (CDCl3, 300 MHz): δ 8.07 (s, 1H), 7.83 (dd, J = 8.1, 1.5 Hz, 2H), 7.49 (d, J = 9.0
Hz, 1H), 7.42ꢀ7.35 (m, 4H), 6.89 (s, 1H), 2.43 (s, 3H); 13C NMR (CDCl3, 75 MHz): δ 162.5, 152.6, 138.4, 136.1,
134.9, 130.0, 129.7, 129.2, 128.7, 125.9, 125.0, 120.3, 101.7, 21.4; HRMS (ESI) m/z calcd for C16H12O2 [M]+
236.0837, found 236.0838.
7-Methyl-3-p-tolyl-1H-isochromen-1-one (2b).43 White solid (350 mg, 70% yield); Rf = 0.91 (8:2 hexane:
EtOAc); synthesized following the general procedure from 3ꢀmethylbenzoic acid (272 mg, 2.0 mmol) and
1ꢀmethylꢀ4ꢀvinylbenzene (236 mg, 2.0 mmol); mp = 159.2 ºC; 1H NMR (CDCl3, 300 MHz): δ 8.04 (s, 1H), 7.70 (d,
J = 8.4 Hz, 2H), 7.46 (dd, J = 7.5, 1.5 Hz, 1H), 7.31 (d, J = 8.1 Hz, 1H), 7.20 (d, J = 8.1 Hz, 2H), 6.81 (s, 1H),
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2.41 (s, 3H), 2.36 (s, 3H); C NMR (CDCl3, 75 MHz): δ 162.9, 153.0, 140.0, 138.2, 136.1, 136.2, 135.2, 129.5,
129.3, 129.3, 125.0, 120.3, 101.0, 21.4; HRMS (ESI) m/z calcd for C17H14O2 [M]+ 250.0993, found 250.0997.
7-Methyl-3-m-tolyl-1H-isochromen-1-one (2c). Offꢀwhite solid (380 mg, 76% yield); Rf = 0.53 (9:1 hexane:
EtOAc); synthesized following the general procedure from 3ꢀmethylbenzoic acid (272 mg, 2.0 mmol) and
1ꢀmethylꢀ3ꢀvinylbenzene (236 mg, 2.0 mmol); mp = 125.4 ºC; 1H NMR (CDCl3, 300 MHz): δ 8.06 (s, 1H), 7.66 (s,
1H), 7.60 (d, J = 7.8 Hz, 1H), 7.48 (dd, J = 7.9, 1.6 Hz, 1H), 7.36ꢀ7.32 (m, 1H), 7.28 (d, J = 7.5, 1H), 7.18 (d, J =
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7.5, 1H), 6.87 (s, 1H), 2.42 (s, 3H), 2.38 (s, 3H); 13C NMR (CDCl3, 75 MHz): δ 162.7, 152.3, 136.6, 136.2, 135.1,
130.6, 129.3, 128.7, 125.9, 125.7, 122.2, 120.3, 115.0, 101.7, 21.5, 21.4. HRMS (ESI) m/z calcd for C17H14O2
[M]+ 250.0993, found: 250.1003.
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6-Methyl-3-phenyl-1H-isochromen-1-one (3a).18 White solid (240 mg, 51% yield); Rf = 0.67 (8:2 hexane: EtOAc);
synthesized following the general procedure from 4ꢀmethylbenzoic acid (272 mg, 2.0 mmol) and styrene (208 mg, 2.0
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mmol); mp = 102.5 ºC; H NMR (CDCl3, 300 MHz): δ 8.17 (d, J = 7.8 Hz, 1H), 7.86 (dd, J = 8.1, 1.8 Hz, 2H),
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7.46ꢀ7.41 (m, 3H), 7.41ꢀ7.31 (m, 2H), 6.88 (s, 1H), 2.47 (s, 3H); C NMR (CDCl3, 75 MHz): δ 153.6, 150.5, 147.0,
137.6, 132.0, 129.9, 129.6, 129.6, 128.8, 125.9, 125.2, 118.1, 101.8, 29.7; HRMS (ESI) m/z calcd for C16H12O2 [M]+
236.0837, found 236.0837.
6-Methyl-3-p-tolyl-1H-isochromen-1-one (3b). White solid (360 mg, 72% yield); Rf = 0.51 (9:1 hexane: EtOAc);
synthesized following the general procedure from 4ꢀmethylbenzoic acid (272 mg, 2.0 mmol) and
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1ꢀmethylꢀ4ꢀvinylbenzene (236 mg, 2.0 mmol); mp = 155.4 ºC; H NMR (CDCl3, 300 MHz): δ 8.16 (d, J = 8.1 Hz,
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1H), 7.75 (d, J = 8.4 Hz, 2H), 7.28ꢀ7.23 (m, 4H), 6.81 (s, 1H), 2.47 (s, 3H), 2.40 (s, 3H); C NMR (CDCl3, 75
MHz): δ 162.5, 153.8, 145.9, 140.1, 137.8, 130.1, 129.5, 129.3, 129.3, 125.8, 125.1, 118.0, 101.0, 22.0, 21.4;
HRMS (ESI) m/z calcd for C17H14O2 [M]+ 250.0993, found 250.0997.
6-Methyl-3-m-tolyl-1H-isochromen-1-one (3c). Off white solid (360 mg, 72% yield); Rf = 0.57 (9:1 hexane:
EtOAc); synthesized following the general procedure from 4ꢀmethylbenzoic acid (272 mg, 2.0 mmol) and
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1ꢀmethylꢀ3ꢀvinylbenzene (236 mg, 2.0 mmol); mp = 112.5 ºC; H NMR (CDCl3, 300 MHz): δ 8.14 (d, J = 6.0 Hz,
1H), 7.67 (s, 1H), 7.62 (d, J = 9.0 Hz, 1H), 7.33ꢀ7.30 (m, 1H), 7.28 (d, J = 3.0 Hz, 1H), 7.24ꢀ7.18 (m, 2H), 6.83 (s,
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1H), 2.44 (s, 3H), 2.39 (s, 3H); C NMR (CDCl3, 75 MHz): δ 162.5, 153.8, 147.0, 138.6, 137.7, 131.9, 130.7,
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129.5, 128.7, 126.0, 126.0, 125.8, 122.3, 118.1, 101.7, 22.0, 21.5. HRMS (ESI) m/z calcd for C17H14O2 [M]+
250.0993, found: 250.0995.
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6-Methoxy-3-phenyl-1H-isochromen-1-one (4a).45 White solid (304 mg, 60% yield); Rf = 0.30 (9:1 hexane:
EtOAc); synthesized following the general procedure from 4ꢀmethoxybenzoic acid (304 mg, 2.0 mmol) and styrene
(208 mg, 2.0 mmol); mp = 133.1 ºC; 1H NMR (CDCl3, 300 MHz): δ 8.19 (d, J = 9.0 Hz, 1H), 7.84 (dd, J = 7.6, 1.6
Hz, 2H), 7.42 (d, J = 7.2 Hz, 3H), 6.99 (dd, J = 7.5, 2.4 Hz, 1H), 6.86 (s, 1H), 6.84 (d, J = 3.0 Hz, 1H), 3.90 (s,
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3H); C NMR (CDCl3, 75 MHz): δ 164.7, 154.1, 139.8, 132.0, 131.8, 130.1, 130.0, 128.8, 125.3, 116.5, 113.6,
107.9, 101.8, 55.8; HRMS (ESI) m/z calcd for C16H12O3 [M]+ 252.0786, found 252.0789.
6-Methoxy-3-p-tolyl-1H-isochromen-1-one (4b). White solid (372 mg, 70% yield); Rf = 0.60 (8:2 hexane:
EtOAc); synthesized following the general procedure from 4ꢀmethoxybenzoic acid (304 mg, 2.0 mmol) and
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1ꢀmethylꢀ4ꢀvinylbenzene (236 mg, 2.0 mmol); mp = 148.3 ºC; H NMR (CDCl3, 300 MHz): δ 8.21 (d, J = 8.7 Hz,
1H), 7.78 (s, 1H), 7.75 (s, 1H), 1.26 (d, J = 8.7 Hz, 2H), 7.01 (dd, J = 8.7, 2.4 Hz, 1H), 6.86 (d, J = 3.0 Hz, 1H),
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6.84 (s, 1H), 3.93 (s, 3H), 2.41 (s, 3H); C NMR (CDCl3, 75 MHz): δ 164.7, 162.3, 140.3, 140.1, 131.8, 129.5,
129.2 125.2, 116.4, 113.6, 107.8, 101.2, 55.7, 21.4; HRMS (ESI) m/z calcd for C17H14O3 [M]+ 266.0942, found
266.0948.
6-Methoxy-3-m-tolyl-1H-isochromen-1-one (4c). White solid (370 mg, 69% yield); Rf = 0.59 (8:2 hexane:
EtOAc); synthesized following the general procedure from 4ꢀmethoxybenzoic acid (304 mg, 2.0 mmol) and
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1ꢀmethylꢀ3ꢀvinylbenzene (236 mg, 2.0 mmol); mp = 136.7 ºC; H NMR (CDCl3, 300 MHz): δ 8.18 (d, J = 9.0 Hz,
1H), 7.68 (s, 1H), 7.63ꢀ7.60 (m, 1H), 7.30ꢀ7.21 (m, 2H), 6.98 (dd, J = 8.9, 2.6 Hz, 1H), 6.84 (s, 1H), 6.83 (d, J =
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2.4 Hz, 1H), 3.89 (s, 3H), 2.38 (s, 3H); C NMR (CDCl3, 75 MHz): δ 164.8, 152.3, 139.9, 138.6, 131.9, 130.8,
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128.7, 126.0, 122.4, 116.5, 113.7, 107.9, 102.6, 101.8, 56.7, 21.5. HRMS (ESI) m/z calcd for C17H14O3 [M]+
266.0942, found: 266.0946.
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3-(3,4-Dimethoxyphenyl)-6-methoxy-1H-isochromen-1-one (4e). White solid (350 mg, 56% yield); Rf = 0.41
(7:3 hexane: EtOAc); synthesized following the general procedure from 4ꢀmethoxybenzoic acid (304 mg, 2.0 mmol)
and 1,2ꢀdimethoxyꢀ4ꢀvinylbenzene (328 mg, 2.0 mmol); mp = 118.2 ºC; 1H NMR (CDCl3, 300 MHz): δ 8.16 (d, J =
8.7 Hz, 1H), 7.42 (dd, J = 8.5, 1.9 Hz, 1H), 7.33 (d, J = 2.1 Hz, 1H), 6.96 (dd, J = 8.8, 2.2 Hz, 1H), 6.91ꢀ6.88 (m,
1H), 6.81 (d, J = 2.4 Hz, 1H), 6.75 (s, 1H), 3.96 (s, 3H), 3.91 (s, 3H), 3.89 (s, 3H); 13C NMR (CDCl3, 75 MHz): δ
164.8, 162.3, 158.7, 154.2, 150.7, 149.1, 140.1, 131.8, 124.9, 118.5, 116.3, 111.1, 108.1, 107.6, 100.7, 56.1, 56.0,
55.7. HRMS (ESI) m/z calcd for C18H16O5 [M]+ 312.0997, found: 312.1003.
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(Z)-3-Phenyl-1H-anthra[9,1-cd]oxepin-1-one (6a). Red solid (412 mg, 64% yield); Rf = 0.71 (8:2 hexane:
EtOAc); synthesized following the general procedure from anthraceneꢀ9ꢀcarboxylic acid (444 mg, 2.0 mmol) and
styrene (208 mg, 2.0 mmol); mp = 195.9 ºC; 1H NMR (CDCl3, 300 MHz): δ 9.65 (d, J = 9.0 Hz, 1H), 8.60 (s, 1H),
7.97ꢀ7.94 (m, 3H), 7.91 (d, J = 2.7 Hz, 1H), 7.75ꢀ7.69 (m, 1H), 7.57ꢀ7.50 (m, 2H), 7.47ꢀ7.41 (m, 3H), 7.31ꢀ7.29
(m, 1H), 6.49 (s, 1H); 13C NMR (CDCl3, 75 MHz): δ 160.2, 146.8, 143.8, 138.5, 135.6, 134.4, 132.4, 130.2, 129.8,
129.8, 128.8, 128.7, 127.5, 126.7, 126.5, 125.7, 124.9, 121.9, 112.9, 108.1; HRMS (ESI) m/z calcd for C23H14O2
[M]+ 322.0993, found 322.0996.
(Z)-3-p-Tolyl-1H-anthra[9,1-cd]oxepin-1-one (6b). Red solid (457 mg, 68% yield); Rf = 0.40 (9:1 hexane:
EtOAc); synthesized following the general procedure from anthraceneꢀ9ꢀcarboxylic acid (444 mg, 2.0 mmol) and
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1ꢀmethylꢀ4ꢀvinylbenzene (236 mg, 2.0 mmol); mp = 150.8 ºC; H NMR (CDCl3, 300 MHz): δ 9.63 (d, J = 9.0 Hz,
1H), 8.54 (s, 1H), 7.93 (d, J = 7.2 Hz, 1H), 7.88 (d, J = 1.8 Hz, 1H), 7.86ꢀ7.83 (m, 3H), 7.73ꢀ7.67 (m, 1H), 7.54
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(dd, J = 6.8, 1.4 Hz, 1H), 7.50ꢀ7.44 (m, 1H), 7.25 (m, 1H), 7.22 (s, 1H), 6.44 (s, 1H), 2.39 (s, 3H); 13C NMR
(CDCl3, 75 MHz): δ 160.3, 146.2, 137.5, 135.5, 132.0, 131.6, 130.0, 129.7, 129.4, 129.2, 128.5, 126.7, 126.4,
125.7, 125.1, 124.9, 121.6, 112.9, 108.1, 21.4; HRMS (ESI) m/z calcd for C24H16O2 [M]+ 336.1150, found
336.1153.
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3-(4-Methoxyphenyl)-1H-anthra[9,1-cd]oxepin-1-one (6d). Red solid (457 mg, 65% yield); Rf = 0.64 (8:2
hexane: EtOAc); synthesized following the general procedure from anthraceneꢀ9ꢀcarboxylic acid (444 mg, 2.0 mmol)
and 1ꢀmethoxyꢀ4ꢀvinylbenzene (268 mg, 2.0mmol); mp = 174.5 ºC; 1H NMR (CDCl3, 300 MHz): δ 9.74 (d, J = 8.7
Hz, 1H), 8.71 (s, 1H), 8.06 (d, J = 8.4 Hz, 1H), 8.01ꢀ7.94 (m, 3H), 7.78 (dd, J = 6.6, 1.5 Hz, 1H), 7.60ꢀ7.55 (m,
2H), 7.28 (s, 1H), 7.01 (d, J = 9.0 Hz, 2H), 6.53 (s, 1H), 3.89 (s, 3H); 13C NMR (CDCl3, 75 MHz): δ 165.0, 159.0,
145.4, 135.5, 132.2, 131.2, 130.1, 129.6, 129.2, 128.2, 127.3, 126.7, 126.4, 125.8, 121.3, 114.1, 113.9, 113.6,
107.9, 55.3. HRMS (ESI) m/z calcd for C24H16O3 [M]+ 352.1099, found 352.1092.
5-Methyl-3-phenylpyrano[4,3-b]indol-1(5H)-one (7a). Pale yellow solid (364 mg, 66% yield); Rf = 0.33 (8:2
hexane: EtOAc); synthesized following the general procedure from 1ꢀmethylꢀ1Hꢀindoleꢀ3ꢀcarboxylic acid (350 mg,
2.0 mmol) and styrene (208 mg, 2.0 mmol); mp = 217.1 ºC; 1H NMR (CDCl3, 300 MHz): δ 8.16 (d, J = 3.6 Hz, 1H),
7.86ꢀ7.83 (m, 2H), 7.43ꢀ7.39 (m, 3H), 7.31ꢀ7.25 (m, 3H), 6.84 (s, 1H), 3.73 (s, 3H); 13C NMR (CDCl3, 75 MHz):
δ 158.3, 146.2, 139.1, 132.2, 130.3, 128.8, 125.6, 124.6, 124.1, 122.59, 121.1, 109.33, 99.8, 90.8, 29.8; HRMS
(ESI) m/z calcd for C18H13NO2 [M]+ 275.0946, found 275.0942.
5-Methyl-3-p-tolylpyrano[4,3-b]indol-1(5H)-one (7b). Pale yellow solid (398 mg, 69% yield); Rf = 0.41(8:2
hexane: EtOAc); synthesized following the general procedure from 1ꢀmethylꢀ1Hꢀindoleꢀ3ꢀcarboxylic acid (350 mg,
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2.0 mmol) and 1ꢀmethylꢀ4ꢀvinylbenzene (236 mg, 2.0 mmol); mp = 205.8 ºC; H NMR (CDCl3, 300 MHz): δ 8.14
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(dd, J = 7.5, 2.1 Hz, 1H), 7.72 (d, J = 8.4 Hz, 2H), 7.30ꢀ7.25 (m, 3H), 7.18 (d, J = 8.1 Hz, 2H), 6.78 (s, 1H), 3.72
(s, 3H), 2.36 (s, 3H); 13C NMR (CDCl3, 75 MHz): δ 159.2, 158.5, 140.7, 139.1, 129.5, 129.5, 129.4, 125.5, 125.5,
124.5, 124.2, 122.5, 121.1, 109.3, 90.0, 29.8, 21.4.; HRMS (ESI) m/z calcd for C19H15NO2 [M]+ 289.1103, found
289.1107.
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(Z)-3-Benzylidene-7-methylisobenzofuran-1(3H)-one (8a). White solid (222 mg, 47% yield); Rf = 0.64 (9:1
hexane: EtOAc); synthesized following the general procedure from oꢀtoluic acid (272 mg, 2.0 mmol) and styrene (208
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mg, 2.0 mmol); mp = 125.2 ºC; H NMR (CDCl3, 300 MHz): δ 7.79 (d, J = 9.0 Hz, 2H), 7.54 (m, 2H), 7.43ꢀ7.36
(m, 2H), 7.31ꢀ7.25 (m, 2H), 6.35 (s, 1H), 2.69 (s, 3H); 13C NMR (CDCl3, 75 MHz): δ 167.2, 149.1, 144.5, 141.0,
139.6, 134.1, 133.3, 131,3, 130.0, 128.7, 128.2, 121.1, 117.2, 106.2, 17.5; HRMS (ESI) m/z calcd for C16H12O2
[M]+ 236.0837, found 236.0831.
(Z)-7-Methyl-3-(4-methylbenzylidene)isobenzofuran-1(3H)-one (8b). White solid (401 mg, 80% yield); Rf =
0.68 (9:1 hexane: EtOAc); synthesized following the general procedure from 2ꢀmethylbenzoic acid (272 mg, 2.0
mmol) and 1ꢀmethylꢀ4ꢀvinylbenzene (236 mg, 2.0 mmol); mp = 153.7 ºC; 1H NMR (CDCl3, 300 MHz): δ 7.72 (d, J
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= 8.1 Hz, 2H), 7.52 (d, J = 5.7 Hz, 2H), 7.25ꢀ7.19 (m, 3H), 6.32 (s, 1H), 2.69 (s, 3H), 2.39 (s, 3H); C NMR
(CDCl3, 75 MHz): δ 167.3, 143.9, 141.1, 139.5, 138.3, 134.1, 131.1, 130.5, 130.0, 129.4, 121.0, 117.1, 106.4, 21.4,
17.5; HRMS (ESI) m/z calcd for C17H14O2 [M]+ 250.0993, found 250.0990.
(Z)-7-Methyl-3-(3-methylbenzylidene)isobenzofuran-1(3H)-one (8c). Off white solid (310 mg, 62% yield); Rf =
0.48 (9:1 hexane: EtOAc); synthesized following the general procedure from 2ꢀmethylbenzoic acid (272 mg, 2.0
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mmol) and 1ꢀmethylꢀ3ꢀvinylbenzene (236 mg, 2.0 mmol); mp = 168.4 ºC; H NMR (CDCl3, 300 MHz): δ 7.64 (s,
1H), 7.62 (s, 1H), 7.54 (s, 1H), 7.52 (s, 1H), 7.30ꢀ7.24 (m, 2H), 7.10 (d, J = 6.0 Hz, 1H), 6.32 (s, 1H), 2.68 (s, 3H),
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2.38 (s, 3H); C NMR (CDCl3, 75 MHz): δ 167.4, 144.4, 141.1, 139.6, 138.3, 134.1, 133.2, 131.4, 130.6, 129.1,
128.7, 127.3, 117.2, 106.5, 21.5, 17.6. HRMS (ESI) m/z calcd for C17H14O2 [M]+ 250.0993, found: 250.0985.
(Z)-3-(4-Methoxybenzylidene)-7-methylisobenzofuran-1(3H)-one (8d). Light yellow solid (280 mg, 53% yield);
Rf = 0.61 (8:2 hexane: EtOAc); synthesized following the general procedure from 2ꢀmethylbenzoic acid (272 mg, 2.0
mmol) and 1ꢀmethoxyꢀ4ꢀvinylbenzene (268 mg, 2.0 mmol); mp = 137.1 ºC; 1H NMR (CDCl3, 300 MHz): δ 7.76 (d,
J = 9.0 Hz, 2H), 7.51 (d, J = 3 Hz, 1H), 7.50 (s, 1H), 7.23ꢀ7.22 (m, 1H), 6.91 (d, J = 9.0 Hz, 2H), 6.30 (s, 1H),
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3.82 (s, 3H), 2.67 (s, 3H); C NMR (CDCl3, 75 MHz): δ 167.5, 159.6, 143.0, 139.6, 134.1, 131.5, 130.9, 126.1,
123.1, 116.9, 114.3, 113.7, 106.2, 55.3, 17.6. HRMS (ESI) m/z calcd for C17H14O3 [M]+ 266.0942, found:
266.0934.
(Z)-3-Benzylidene-7-methoxyisobenzofuran-1(3H)-one (9a). Pale yellow solid (312 mg, 62% yield); Rf = 0.33
(8:2 hexane: EtOAc); synthesized following the general procedure from 2ꢀmethoxybenzoic acid (304 mg, 2.0 mmol)
and styrene (208 mg, 2.0 mmol); mp = 144.2°C; 1H NMR (CDCl3, 300 MHz): δ 7.79 (d, J = 9.0 Hz, 2H), 7.59 (t, J
= 9.0 Hz, 1H) 7.38ꢀ7.33 (m, 2H), 7.29ꢀ7.27 (m, 2H), 6.87 (d, J = 9.0 Hz, 1H), 6.33 (s, 1H), 3.96 (s, 3H); 13C NMR
(CDCl3, 75 MHz): δ 166.1, 158.4, 144.2, 142.9, 136.6, 133.1, 130.1, 128.7, 128.3, 111.6, 111.1, 110.8, 107.0, 56.1;
HRMS (ESI) m/z calcd for C16H12O3 [M]+ 252.0786, found 252.0783.
(Z)-7-Methoxy-3-(4-methylbenzylidene)isobenzofuran-1(3H)-one (9b). White solid (393 mg, 74% yield); Rf =
0.54 (8:2 hexane: EtOAc); synthesized following the general procedure from 2ꢀmethoxybenzoic acid (304 mg, 2.0
mmol) and 1ꢀmethylꢀ4ꢀvinylbenzene (236 mg, 2.0 mmol); mp = 188.1 ºC; 1H NMR (CDCl3, 300 MHz): δ 7.72 (d, J
= 6.6 Hz, 2H), 7.61 (td, J = 8.2, 3.0 Hz, 1H), 7.25 (dd, J = 7.9, 1.6 Hz, 1H), 7.18 (d, J = 7.2 Hz, 2H), 6.88 (dd, J =
8.1, 1.5 Hz, 1H), 6.33 (s, 1H), 3.98 (s, 3H), 2.38 (s, 3H); 13C NMR (CDCl3, 75 MHz): δ 165.3, 158.5, 143.6, 143.1,
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138.6, 136.5, 130.4, 130.2, 129.5, 115.0, 111.5, 110.9, 110.7, 107.2, 56.1, 21.5; HRMS (ESI) m/z calcd for
C17H14O3 [M]+ 266.0942, found 266.0945.
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(Z)-7-Methoxy-3-(3-methylbenzylidene)isobenzofuran-1(3H)-one (9c). Light yellow solid (310 mg, 59% yield);
Rf = 0.55 (8:2 hexane: EtOAc); synthesized following the general procedure from 2ꢀmethoxybenzoic acid (304 mg,
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2.0 mmol) and 1ꢀmethylꢀ3ꢀvinylbenzene (236 mg, 2.0 mmol); mp = 196.3 ºC; H NMR (CDCl3, 300 MHz): δ
7.65ꢀ7.60 (m, 3H), 7.28 (d, J = 8.1 Hz, 2H), 7.11 (d, J = 6.0 Hz, 1H), 6.92 (d, J = 9.0 Hz, 1H), 6.34 (s, 1H), 4.00 (s,
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3H), 2.38 (s, 3H); C NMR (CDCl3, 75 MHz): δ 165.3, 158.6, 144.1, 143.1, 138.4, 136.6, 133.1, 130.7, 129.3,
128.7, 127.4, 111.6, 111.1, 107.3, 56.2, 21.5. HRMS (ESI) m/z calcd for C17H14O3 [M]+ 266.0942, found:
266.0937.
(Z)-3-(3,4-Dimethoxybenzylidene)-7-methoxyisobenzofuran-1(3H)-one (9e).46 Yellow solid (370 mg, 60%
yield); Rf = 0.48 (1:1 hexane: EtOAc); synthesized following the general procedure from 2ꢀmethoxybenzoic acid (304
mg, 2.0 mmol) and 1,2ꢀdimethoxyꢀ4ꢀvinylbenzene (328 mg, 2.0 mmol); mp = 118.8 ºC; 1H NMR (CDCl3, 300 MHz):
δ 7.58 (t, J = 3.9 Hz, 1H), 7.41 (d, J = 2.1 Hz, 1H), 7.33 (dd, J = 8.4, 2.1 Hz, 1H), 7.24 (d, J = 7.8 Hz, 1H), 6.85
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(dd, J = 8.2, 5.5 Hz, 2H), 6.29 (s, 1H), 3.98 (s, 3H), 3.93 (s, 3H), 3.89 (s, 3H); C NMR (CDCl3, 75 MHz): δ
165.2, 158.5, 149.4, 148.9, 143.2, 142.9, 136.5, 123.3, 123.8, 122.2, 112.6, 111.4, 111.1, 110.7, 107.1, 56.1, 56.0,
55.9. HRMS (ESI) m/z calcd for C18H16O5 [M]+ 312.0997, found 312.0994.
(Z)-3-(3,4-Dimethoxybenzylidene)-5,7-dimethoxyisobenzofurane-1(3H)-one (10e).46 Yellow solid (349 mg,
51% yield); Rf = 0.39 (3:7 hexane: EtOAc); synthesized following the general procedure from 2,4ꢀdimethoxybenzoic
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acid (364 mg, 2.0 mmol) and 1,2ꢀdimethoxyꢀ4ꢀvinylbenzene (328 mg, 2.0 mmol); mp = 118.4 ºC; H NMR (CDCl3,
300 MHz): δ 7.41 (d, J = 1.8 Hz, 1H), 7.33 (dd, J = 8.4, 1.8 Hz, 1H), 6.85 (d, J = 8.4 Hz, 1H), 6.67 (d, J = 1.8 Hz,
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1H), 6.39 (s, 1H), 6.25 (s, 1H), 3.94 (s, 3H), 3.93 (s, 3H), 3.91 (s, 3H), 3.89 (s, 3H); 13C NMR (CDCl3, 75 MHz):
δ 166.9, 149.3, 148.9, 145.0, 143.1, 126.3, 123.7, 112.6, 111.0, 106.7, 104.3, 99.7, 94.4, 56.0, 57.0, 56.8. HRMS
(ESI) m/z calcd for C19H18O6 [M]+ 342.1103, found 342.1106.
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(E)-1-Nitro-2-styrylbenzene (11a).47 Orange oil (364 mg, 81% yield); Rf = 0.66 (9:1 hexane: EtOAc); synthesized
following the general procedure from 2ꢀnitrobenzoic acid (334 mg, 2.0 mmol) and styrene (208 mg, 2.0 mmol); 1H
NMR (CDCl3, 300 MHz): δ 7.92 (d, J = 7.8 Hz, 1H), 7.72 (d, J = 7.8 Hz, 1H), 7.61ꢀ7.51 (m, 4H), 7.40ꢀ7.31 (m,
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4H), 7.06(d, J = 16.2 Hz, 1H); C NMR (CDCl3, 75 MHz): δ 147.9, 136.5, 133.8, 133.2, 132.9, 128.8, 128.6,
128.1, 130.0, 127.1, 124.8, 123.4; HRMS (ESI) m/z calcd for C14H11NO2 [M]+ 225.0789, found 225.0786.
(E)-1-(2-Nitrostyryl)-4-methylbenzene (11b).48 Orange oil (325 mg, 78% yield); Rf = 0.68 (9:1 hexane: EtOAc);
synthesized following the general procedure from 2ꢀ nitrobenzoic acid (334 mg, 2.0 mmol) and
1ꢀmethylꢀ4ꢀvinylbenzene (236 mg, 2.0 mmol); 1H NMR (CDCl3, 300 MHz): δ 7.92 (dd, J = 8.1, 1.2 Hz, 1H), 7.73
(dd, J = 7.9, 1.1 Hz, 1H), 7.59ꢀ7.51 (m, 2H), 7.42 (d, J = 8.1 Hz, 2H), 7.38ꢀ7.33 (m, 1H), 7.17(d, J = 8.1 Hz, 2H),
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7.05(d, J = 16.2 Hz, 1H), 2.36 (s, 3H); C NMR (CDCl3, 75 MHz): δ 148.0, 138.7, 133.9, 133.8, 133.2, 138.1,
129.6, 128.1, 127.8, 127.1, 124.8, 122.4, 21.4; HRMS (ESI) m/z calcd for C15H13NO2 [M]+ 239.0946, found
239.0943.
(E)-1-(4-Methoxystyryl)-2-nitrobenzene (11d).49 Orange solid (357 mg, 70% yield); Rf = 0.48 (9:1 hexane:
EtOAc); synthesized following the general procedure from 2ꢀ nitrobenzoic acid (334 mg, 2.0 mmol) and
1ꢀmethoxyꢀ4ꢀvinylbenzene (268 mg, 2.0mmol); mp = 69.9 ºC; 1H NMR (CDCl3, 300 MHz): δ 7.91 (dd, J = 8.1, 1.2
Hz, 1H), 7.72 (dd, J = 7.9, 1.5 Hz, 1H ), 7.55 (t, J = 7.5 Hz, 1H), 7.48ꢀ7.43 (m, 3H), 7.35 (d, J = 9 Hz, 1H), 7.04
(d, J = 16.2, 1H), 6.90 (d, J = 9.0 Hz, 2H), 3.82 (s, 3H); 13C NMR (CDCl3, 75 MHz): δ 160.1, 147.9, 133.5, 133.3,
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133.0, 129.3, 128.5, 127.9, 127.5, 124.8, 121.1, 114.3, 56.4; HRMS (ESI) m/z calcd for C15H13NO3 [M]+
255.08954, found 255.08951.
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Thunberginol F.50 Compound 9e (100 mg, 0.32 mmol) of was taken in 2 mL of dry DCM in a 50 mL of reaction
flask and the temperature of the reaction flask was allowed to cool down at ꢀ60º C. Then a 1M DCM solution of
BBr3 (5.2 equiv., 1.66 mL, 1.66 mmol) was dropewise added to it under nitrogen. The temperature of the reaction
mixture slowly increased to room temperature and allowed to stir for another 2 h. The solution was then poured to
ice cold water (20 mL), and the mixture was extracted with EtOAc (4×15 mL). The organic extract was washed
with brine solution and dried over MgSO4 and concentered under reduced pressure. The crude mass was washed
several times with DCM to give the pure compound as light yellow solid (0.084g, 97%); Rf = 0.78 (100% EtOAc);
mp = 208.9 ºC; 1H NMR (DMSOꢀd6, 300 MHz): δ 7.76 (t, J = 8.0 Hz, 1H), 7.57 (d, J = 7.5 Hz, 1H), 7.39 (d, J =
3.0 Hz, 1H), 7.13 (d, J = 8.1 Hz, 1H), 7.05 (m, 1H), 6.79 (dd, J = 7.8, 2.1, 1H), 6.68 (s, 1H); 13C NMR (DMSOꢀd6,
75 MHz): δ 164.6, 158.4, 147.0, 145.9, 143.2, 141.6, 137.6, 126.5, 125.2, 123.1, 117.1, 116.3, 112.3, 111.8, 108.1;
HRMS (ESI) m/z calcd for C15H10O5 [M]+ 270.0528, found 270.0526.
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Acknowledgements. We are grateful to the National Science Council of Taiwan for financial support of this work.
Supporting Information. Crystallographic data, additional experimental details, and NMR spectra for all
products. This material is available free of cost via the Internet at http://pubs.acs.org.
Notes. The authors declare no competing financial interest
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