On the synthesis and biological properties of isocombretastatins: A case of ketone homologation during Wittig reaction attempts

Article abstract of DOI:10.1039/c2ra22391k

New isocombretastatins were synthesized by reacting the corresponding phenstatin analogs with CH₃PPh₃Br in presence of tBuOK. These new derivatives showed significant activities against cellular proliferation and tubulin polymerization. In particular, monomethoxylated derivatives of phenstatin and isoCA-4 exhibit similar activities to those of parent phenstatin. Attempts of the Wittig reaction on 2- (or 4-) methoxy-4′-nitrobenzophenones in the same conditions do not lead to the expected isocombretastatins but to methyleneketones with the exclusion of triphenylphosphine. A mechanism for this new ketone homologation was proposed.

Full text of DOI:10.1039/c2ra22391k

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PAPER
On the synthesis and biological properties of
isocombretastatins: a case of ketone homologation
Cite this: RSC Advances, 2013, 3,
3683
during Wittig reaction attempts
ac
Vivien Stocker,ab Alina Ghinet,*ab Marie Leman,ab Benoˆıt Rigo,ab Regis Millet,
´
e
e
af
Amaury Farce,ad Deborah Desravines, Joelle Dubois, Christophe Waterlot
´
¨
and Philippe Gautret*ab
New isocombretastatins were synthesized by reacting the corresponding phenstatin analogs with
CH3PPh3Br in presence of tBuOK. These new derivatives showed significant activities against cellular
proliferation and tubulin polymerization. In particular, monomethoxylated derivatives of phenstatin and
isoCA-4 exhibit similar activities to those of parent phenstatin. Attempts of the Wittig reaction on 2- (or 4-)
methoxy-49-nitrobenzophenones in the same conditions do not lead to the expected isocombretastatins
but to methyleneketones with the exclusion of triphenylphosphine. A mechanism for this new ketone
homologation was proposed.
Received 3rd October 2012,
Accepted 2nd January 2013
DOI: 10.1039/c2ra22391k
www.rsc.org/advances
to the E-isomer which displays
a dramatically reduced
Introduction
activity.8c It has been recently described that a new family of
substituted 1,1-diarylethylenes, called isocombretastatins, also
displays a potent inhibition of tubulin polymerization while
retaining excellent cytotoxicity (in the case of phenstatin (4a)
and its derivatives which also contain a non-isomerizable
bridge, a lower cytotoxicity is often observed)9 (Fig. 1). Four
main routes have been described for the synthesis of
isocombretastatins; they are based on modification of thioa-
cetals,10 dehydration of 1,1-diarylethanol,9c palladium-cata-
lyzed coupling of N-tosylhydrazones9b or Wittig olefination of
the corresponding phenstatins.9a,c In this paper, we describe
the synthesis of new isocombretastatins by using the Wittig
The microtubule system, formed of a- and b-tubulin hetero-
dimers, is involved in many essential cell functions1 and is
recognized as an attractive pharmacological target for antic-
ancer drugs.2 The discovery of natural substances capable of
interfering with the dynamics of microtubules has attracted
the attention of medicinal chemists for the rational design of
antitubulin agents.3 Most of the antimitotic drugs in clinical
use or in development, bind at three major sites on tubulin:
the vinca, taxane and colchicine sites.4 Combretastatin A-4 (1a)
binds to tubulin in the colchicine binding site,5 and exhibits
very strong inhibition against a variety of human cancer cell
lines;6 several derivatives, such as CA-4P7a,e,f (fosbretabulin 1b,
Fig. 1) and AVE80627b,g (ombrabulin 2, Fig. 1) have undergone
clinical trials. The trimethoxyphenyl unit and the cisoid
disposition of the two aromatic rings are both essential for
the activity of these compounds (Fig. 1).7 However, these
compounds are prone to double-bond isomerization, leading
aUniv. Lille Nord de France, F-59000 Lille, France. E-mail: alina.ghinet@hei.fr;
philippe.gautret@hei.fr
bUCLille, EA GRIIOT (4481), Laboratoire de pharmacochimie, HEI, 13 rue de Toul, F-
59046 Lille, France
c
´
Institut de Chimie Pharmaceutique Albert Lespagnol, Universite de Lille 2, EA
GRIIOT (4481), 3 rue du Professeur Laguesse, 59006 Lille, France
dInstitut de Chimie Pharmaceutique Albert Lespagnol, EA 4481, IFR114, 3 rue du
Professeur Laguesse, 59006 Lille, France
eInstitut de Chimie des Substances Naturelles, UPR2301 CNRS, Centre de Recherches
de Gif, Avenue de la Terrasse, F-91198 Gif-sur-Yvette Cedex, France
f
´
´
UCLille, Groupe ISA, Equipe Sols et Environnement, Laboratoire Genie Civil et geo
Environnement (LGCgE) Lille Nord de France (EA 4515), 48 Boulevard Vauban, F-
59046 Lille, France
Fig. 1 Structure of combretastatin A-4 (1a) and its prodrugs fosbretabulin (1b),
ombrabulin (2) and of isocombretastatin A-4 (3a) and phenstatin (4a).
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Scheme 1 Reagents and conditions: (i) Friedel–Crafts condensation: (Z = Cl) AlCl3 (3–5 equiv.), CH2Cl2, rt for compounds 4c,h–i,k; (Z = OH) BF3?Et2O (6 equiv.), TFAA (6
equiv.), 1,2-dichloroethane, reflux for compound 4f; (Z = OH) Eaton’s reagent (4 equiv. w/w), 60 uC for derivatives 4b,m–n,p,r, 10–18 h; (ii) AcONa?3H2O, MeOH,
reflux, 1 h; (iii) Me2SO4, K2CO3, acetone, reflux, 18 h.
olefination process and also some ketone homologations
observed during Wittig reaction attempts.
analogs 4b and 4n,p were synthesized using the same
method.11b
Cleavage of the chloroacetyl protecting group of ketones
4b,c,n,p was realized with sodium acetate in methanol by
heating at reflux,7c leading to phenstatin analogs 4a,d,o–q in
medium to good yields. Methylation of phenols 4d,f,i,k using
dimethyl sulfate in the presence of potassium carbonate in
refluxing acetone gave products 4e,g,j,l.
The Friedel–Crafts reaction of acid chloride 5b with 1,3-
dimethoxybenzene (6f), catalyzed by aluminium trichloride,
led to phenstatin analog 4i in a low 28% yield at rt (in the
presence of Eaton’s reagent, AlCl3 or BF3?Et2O, demethylation
of ortho-methoxyketones or of ortho-dimethoxybenzene is
frequently observed).16,23 Of note, heating the reaction mixture
did not increase the yield but also furnished ketones 4s and 4t
as additional products (Scheme 2).
Chemistry
As part of a project on tubulin polymerization inhibitors,11 we
planned to use the Wittig reaction to synthesize new
isocombretastatins with the aim to explore other aspects of
their structure–activity relationships. Thus, their precursors –
phenstatins 4 described in Scheme 1 – were synthesized.
In particular, compounds 4d–e,g,i,j,l were selected because
the 3-hydroxyl group on the B-ring of tubulin inhibitors is not
always essential for potent activity,8b,12 and compounds 4o–q
(R4, R6 = OMe, R5 = OH) were chosen because we found that
the 1,3-dimethoxy-2-hydroxy substitution in the B-ring could
enhance the biological activities of the parent phenstatin.11b
Besides, in order to strongly modify the substitution pattern,
the para-fluorobenzophenone 4r (R4, R7 = OMe, R6 = F) was
synthesized. So, as to put later an amino group in position 4
(substituent R6) of the B-ring,13 the ketone 4h (R4, R7 = OMe,
R2 = NO2) substituted with a nitro group in the para position
was selected.
A para-demethylation of the ketone 4r was observed during
its formation in Eaton’s conditions (Scheme 3).16
The Wittig reaction, involving a phosphorus ylide, is
probably the most widely recognized method for carbonyl
olefination.17 However, it is known that this reaction is
generally slow and gives poor yields with sterically hindered
ketones, such as benzophenones.
Benzophenones 4v (R2, R6 = OMe), 4w (R2 = OMe, R6 = NO2),
4x (R6 = NO2) are commercially available and, as described in
Scheme 1, ketones 4c,f,h–i,k were obtained by aluminum
trichloride or boron trifluoride etherate catalyzed reaction of
4-nitrobenzoic acid chloride 5b with methoxy aromatic
derivatives 6d,e–g or chloroacetyl protected methoxyphenols
6a. Ketones 4m,r were obtained by the Friedel–Crafts
condensation, using Eaton’s reagent,11b of benzoic acids
5a,c–d with aromatic derivatives 6a–c,e. The known phenstatin
According to literature, a thio-Wittig reaction, managed
with a thioketone in place of a ketone, can increase the
efficiency of olefination.18 We obtained effectively the diphe-
nylethene 3b in a better yield by reacting methylenepho-
sphorane, prepared from methyltriphenylphosphonium iodide
and potassium tert-butoxide, with the thioketone 7a than with
the ketone 4v (80% vs. 73%) (Scheme 4). However, the
thioketone 7a was synthesized in 89% yield by treating 4v
with P4S10 and hexamethyldisiloxane (HMDO) in refluxing
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Scheme 2 Reagents and conditions: (i) AlCl3 (4 equiv.), CH2Cl2, rt, 15 h; (ii) AlCl3 (4 equiv.), CH2Cl2, reflux, 15 h.
toluene,19 furnishing only 3b in a 71% global yield from the
ketone 4v (73% by the one-step Wittig reaction). Plus, we
observed that the thioketone 7a underwent a partial reversion
toward the initial compound 4v.20
with CH2LPPh3 under the same conditions (Table 1, entries 1
and 6).
In the literature, it has been reported that some ylide
reagents can react with aldehydes or ketones to generate
epoxides with the recovery of the ylide precursors.31 Moreover,
several base-promoted isomerizations of epoxides were
described leading to methylene ketones.32 However, the
ketone homologation of nitrobenzophenones 4e,g–h,j,w
observed in our reaction conditions probably does not involve
the formation of the epoxide intermediate 9 (Scheme 6): its
rearrangement would implicate the migration of an electron-
deficient aryl group (nitrophenyl group) and not of the
electron-rich aryl group (mono- or dimethoxyphenyl group),
and then the electron deficiency in the transition state would
be less stabilized.33
The mechanism of this reaction needs to explain the
influence of the methoxy and nitro groups. A possible pathway
is proposed in Scheme 6.34a The donating effect of the free
electron pair of the 2- (or 4-) methoxy group decrease the
electrophilic properties of the carbonyl group, and thus
disfavored the formation of the classical Wittig oxapho-
sphetane. However, the withdrawing nitro group allowed an
ipso attack of the methylene anion in the para position of the
nitrophenyl ring. Such an ipso reaction was already observed
during nucleophilic attack of a sulfur ylide on p-nitrobenzal-
dehyde.34b,c Then, formation of the oxaphospholane B from
intermediate A, favored by the donating effect of the free
electron pair of the 2- (or 4-) methoxy group, is followed by a
concerted rearrangement into the homologated ketones 8.
No reaction is observed with 4-nitrobenzophenone (4x) in
our experimental conditions. It is probably due to the absence
of free electron pair group in its ring A: the intermediate B can
not be formed. The lack of reactivity of trimethoxyphenyl
ketone 4l could be explained by the steric hindrance of the two
ortho methoxy groups which modifies the relative orientation
Based on these results, we envisaged to methylenate
directly the benzophenones
4 with the Wittig reagent
CH2LPPh3 (Scheme 5 and Table 1). By this method, isocom-
bretastatins 3b,d,f (Table 1, entries 9, 11 and 12) were isolated
in moderate to good yields (41–73%). However, probably due
to steric or electronic effects, compound 3e was obtained in
only 14% yield (Table 1, entry 10).
In the case of ketone 4h (R2 = NO2; R4, R7 = OMe) (Table 1,
entry 3), the Wittig reaction attempted in the same conditions
did not furnish the corresponding isocombretastatin. Actually,
we only isolated the methyleneketone 8a (Table 1, entry 3) in a
low 15% yield (NOESY correlations confirmed the structure of
this product) accompanied by exclusion of triphenylphosphine
(Scheme 4).
To the best of our knowledge, such a ketone homologation
with a Wittig reagent has never been described. In order to
evaluate the scope and limitations of this novel reaction, the
effect of the benzophenone substituents was examined. Thus
nitrobenzophenones 4e,g–h,j,l (Table 1, entries 3–7), as well as
commercially available ketones 4w or 4x (Table 1, entries 1 and
2), were submitted to CH2LPPh3 in the same conditions.
Among the different benzophenones tested, we observed a
methylene insertion only when a methoxy group is present in
position 2 (substituent R4) or 4 (substituent R6) of the ring B
and a nitro group in the para position of the ring A
(substituent R2), giving products 8a–e (Table 1, entries 2–5)
in a 12–51% yield. In contrast, replacement of the NO2
withdrawing group with a CF3 led to the isocombretastatin 3c
in 44% yield according to a classical Wittig reaction (Table 1,
entry 8); in addition, ketones 4x and 4l proved to be unreactive
Scheme 3 Reagents and conditions: (i) Eaton’s reagent (4 equiv. w/w), 60 uC, 2 h.
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Scheme 4 Reagents and conditions: (i) P4S10 (0.8 equiv.), HMDO (2 equiv.), toluene, reflux, 15 h, (ii) CH3PPh3Br (2 equiv.), tBuOK (5 equiv.), THF, rt, 18 h.
Due to the important activity of the phenstatin metabolite
4q synthesized by Ghinet et al.11b which, compared to the
parent compound, possesses a supplementary methoxy group,
it was interesting to synthesize and evaluate the tubulin
polymerization inhibition of the isocombretastatin analog 3f.
Like its ketone precursor 4q, 3f showed a good antitubulin
activity, with an IC50 value in the low micromolar range but
less potent than 4q. Both exhibited a more potent inhibitory
effect (3f: 1.9 mM; 4q: 1.2 mM) compared to phenstatin (4a: 3.4
mM) in our testing conditions. The replacement of the
trimethoxy unit by a mono-para-methoxylated moiety in 4o
abolished the activity on tubulin polymerization. The mod-
ification of ring-B substitution by a 4-fluoro-2,5-dimethoxy-
phenyl unit in compound 4r led to a significant decrease of the
of the aryl rings, and then disfavors the intramolecular ipso
attack.
Some aspects of the reactivity of 2-hydroxybenzophenones
with Corey–Chaykovsky reagent could also be explained by this
mechanism, in particular the position of the methylene
insertion during ketone homologation.35
Biological evaluation
Tubulin polymerization inhibition and in vitro cell growth
inhibitory activity. The activity of some compounds was
evaluated on the tubulin polymerization inhibition. The
results were summarized in Tables 1 and 2. As seen in
Table 1, the homologated ketones and their parent com-
pounds are rather inactive.
Scheme 5 Reagents and conditions: CH3PPh3Br (2 equiv.), tBuOK (5 equiv.), THF, rt, 18 h for compounds 3b–c, 8a–e or toluene, reflux, 18 h for compounds 3d,e,f.
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Table 1
Entry
1
Starting ketone
% ITPa
N.T.b
Product
N.R.b
Yield (%)
—
% ITPa
N.T.
4x
2
3
N.T.
N.T.
12
15
N.T.
N.T.
4w
8e22
4h23
8a24
4
5
N.T.
32
51
22
18
4j22
8c22
25
4e25
8d26
6
7
2
N.R.
—
32
—
25
4l27
36
4g28
8b
8
9
30
44
73
13
4m29
3c
N.T.
N.T.
3b30
4v
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Table 1 (Continued)
Entry
10
Starting ketone
% ITPa
Product
Yield (%)
14
% ITPa
40
.50c,10b
4o11b
3e
3f
11
12
98c
41
44
91c
4q11b
77c
39
4r
3d
a
b
c
IPT: Inhibition of tubulin polymerization at a 100 mM concentration. N.T.: Not tested, N.R.: No reaction. See Table 2
antitubulin activity, its isocombretastatin analog 3f, deleting
all the activity. Finally, the presence of a para-trifluoromethyl
group on the B-ring did not lead to a potential inhibitor of the
biological target.
obtained with compound 4o, its isocombretastatin analog 3e
was not retained by the NCI for biological evaluation.
As benzophenone precursor 4q, the isocombretastatin 3f
showed significant cytotoxicity against melanoma cell lines,
notably against MDA-MB-435 cell line, but was generally less
potent than its precursor.
Fluorinated compounds 3d and 4m present slightly lower
activities than the phenolic compounds. As previously seen on
3f and 4q, the ketone precursor 4r was more active than the
isocombretastatin 3d. Both showed good cytotoxicity against
colon cancer and melanoma cell lines. 4r also exhibited very
potent anti-proliferative activity against leukemia cell lines
K-562 and SR. Compared to 4r, 3d was not so potent on these
lines, but revealed a strong activity against the non-small cell
lung cancer A549/ATCC cell line.
The cytotoxicities of compounds 3c, 3d, 3f, 4m, 4o, 4q, 4r
and 4u were evaluated against a panel of 60 human cancer cell
lines by the National Cancer Institute (NCI). The representative
results are presented in Table 2. Only compounds with a
trimethoxylated ring displayed some interesting cellular
activities. This is in accordance with the literature,8a and it
is confirmed by the modest cell growth inhibitory activity (at
1025 molar concentration) of compounds 4o (substituted by a
para-methoxy group on the A-ring), 4u (para-demethylated
derivative of 4r), 4m and 4c (two derivatives with a 2,5-
dimethoxybenzene as B-ring). Considering the results
Scheme 6 Proposed mechanism for ketone homologation of 4w.
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Fig. 2 Superimposition of the lowest-energy docked models of compounds 3d (A), 3f (B), 4r (C) and 4q (D) over combretastatin A-4 (1a, atoms colored in orange) in
the tubulin binding site. The hydrogen bond between combretastatin A-4 (1a) or 4q and Vala181 are shown as dashed yellow lines.
favourable contacts to supplement its hydrophobic interac-
tions with tubulin. Compound 4q (Fig. 2D) solutions split in
three clusters of unequal size. The largest is also associated
with the highest scores and adopts a conformation very similar
to that of combretastatin A-4 (1a), with the major difference of
the orientation of the trimethoxylated ring. The shorter tensor
of compound 4q hinders its placement and creates a 1-carbon
rotation of the substitution pattern in respect with the tensor
position of combretastatin A-4 (1a). Still, its other ring bears its
hydroxyl in a correct position to form a hydrogen bond with
the nitrogen of Vala181, as combretastatin A-4 (1a) does.
Molecular modeling
Docking studies were realized in the colchicine binding site of
tubulin, on compounds that presented a biological potential
(3d, 3f, 4q and 4r) (Fig. 2).
Compound 3d (Fig. 2A) adopts a slightly more common
conformation of somewhat higher than average score in which
it lies upright on the side of the pocket normally accommodat-
ing the trimethoxylated cycle of combretastatin A-4 (1a) and is
stabilised only by hydrophobic contacts. Compound 3f
(Fig. 2B) fares little better, with about the same proportion
of conformations of slightly better than average score forming
a close cluster of solutions. Although it occupies the pocket in
the same global position as combretastatin A-4 (1a), the tensor
is inverted when compared to the reference molecule; pointing
its double bond toward the surface of the binding site instead
of toward the middle of the pocket. It is again stabilised only
by hydrophobic contacts.
Conclusion
We have synthesized new isocombretastatins by reacting
phenstatin analogs with CH3PPh3Br in the presence of
tBuOK. These new derivatives showed significant activities
against cellular proliferation and tubulin polymerization. In
particular, 3f and 4q, the monomethoxy derivatives of
phenstatin (4a) and isoCA-4 (3a) exhibit similar activities to
Compound 4r (Fig. 2C) displays nearly a single solution,
with a single conformation but a position less well defined in
the pocket, as it lacks any hydrogen bond to anchor it. It is
quite close to 3d, but apparently forms more electrostatically
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(s, 2H, OCOCH2Cl), 6.88 (d, J = 8.8 Hz, 1H, ArH), 6.93 (d, J = 9.3
Hz, 2H, ArH), 7.32 (d, J = 8.8 Hz, 1H, ArH), 7.82 (d, J = 9.3 Hz,
2H, ArH). The physico-chemical properties are in accordance
with the literature.11b
2,6-Dimethoxy-3-(3,4,5-trimethoxybenzoyl)phenyl chloroace-
tate (4p). This product was synthesized following the general
procedure using Eaton’s reagent. 1H NMR (CDCl3) d (ppm)
3.68 (s, 3H, OCH3), 3.86 (s, 6H, 2OCH3), 3.91 (s, 3H, OCH3),
3.93 (s, 3H, OCH3), 4.38 (s, 2H, OCOCH2Cl), 6.81 (d, J = 8.6 Hz,
1H, ArH), 7.10 (s, 2H, ArH), 7.33 (d, J = 8.6 Hz, 1H, ArH). The
physico-chemical properties are in accordance with the
literature.11b
those of phenstatin (4a) on K-562, HCT-116, DU145 and MCF7
cancer cell lines.
In the same time, we have found that attempts of Wittig
reaction on 2- (or 4-) methoxy-49-nitrobenzophenones in the
same conditions do not lead to the expected isocombretasta-
tins but to methyleneketones with the exclusion of triphenyl-
phosphine.
Experimental section
General
(4-Fluoro-2,5-dimethoxyphenyl)(3,4,5-trimethoxyphenyl)methanone
(4r). The general procedure was followed using 2-fluoro-1,4-
dimethoxybenzene 6c (1.0 g, 6.4 mmol), 3,4,5-trimethoxybenzoic
acid 5a (2.0 g, 9.6 mmol) and Eaton’s reagent (0.8 g of P2O5 in 5.4
mL of CH3SO3H) at 60 uC for 2 h. The crude product was purified
by column chromatography on silica gel with EtOAc–n-heptane
(3/7) to give the pure product as a white solid (1.1 g, 51%); mp
(EtOAc–n-heptane) 110–112 uC; Rf (EtOAc–n-heptane (3/7)) = 0.75.
1H NMR (CDCl3) d (ppm) 3.70 (s, 3H, OCH3), 3.85 (s, 6H, 2OCH3),
3.87 (s, 3H, OCH3), 3.94 (s, 3H, OCH3), 6.81 (d, J = 12.0 Hz, 1H,
ArH), 7.03 (d, J = 9.8 Hz, 1H, ArH), 7.07 (s, 2H, ArH). 13C NMR
(CDCl3) d 56.3 (2CH3), 56.5 (CH3), 57.1 (CH3), 60.9 (CH3), 101.6
(CH), 107.4 (2CH), 115.3 (CH), 123.9 (C), 132.8 (C), 141.4 (C),
142.7 (C), 151.9 (C), 152.9 (2C), 155.5 (C), 193.9 (C). 19F NMR
(CDCl3, 376 MHz) d (ppm) 2127.2 (dd, J = 12.2, 9.5 Hz, 1F, ArF).
IR n/cm21: 2944, 1638, 1213, 1126. Calc. for C18H19FO6: C, 61.71;
H, 5.47. Found: C, 61.31; H, 5.21%.
Starting materials were commercially available. Melting points
were measured on a MPA 100 OptiMelt1 apparatus and are
uncorrected. NMR spectra were acquired at 400 MHz for 1H
NMR, at 100 MHz for 13C NMR, and at 376 MHz for 19F NMR
on a Varian 400 MHz Premium Shielded1 spectrometer.
Chemical shifts (d) are expressed in ppm relative to TMS as
internal standard. Thin layer chromatographies were realized
on Macherey Nagel silica gel plates with a fluorescent indicator
and were visualized with UV-lamp at 254 nm and 366 nm.
Column chromatographies were performed on silica gel (40–60
mm; Macherey–Nagel). Elemental analyses (C, H, N, S) of new
ˆ
´
compounds were determined by Pole Chimie Moleculaire,
´
´
Faculte de Sciences Mirande, Universite de Bourgogne, Dijon,
France.
General procedure for Friedel–Crafts reaction using Eaton’s
reagent
(4-Fluoro-2,5-dimethoxyphenyl)-(4-hydroxy-3,5-dimethoxy-
phenyl)methanone (4u). The general procedure was followed
using 2-fluoro-1,4-dimethoxybenzene 6c (1.0 g, 6.4 mmol),
3,4,5-trimethoxybenzoic acid 5a (2.0 g, 9.6 mmol) and Eaton’s
reagent (0.8 g of P2O5 in 5.4 mL of CH3SO3H) at 60 uC for 2 h.
The crude product was purified by column chromatography on
silica gel with EtOAc–n-heptane (3/7) to give the pure product
as a white solid (0.4 g, 19%); mp (EtOAc–n-heptane) 122–124
uC; Rf (EtOAc–n-heptane (3/7)) = 0.61. 1H NMR (CDCl3) d (ppm)
3.70 (s, 3H, OCH3), 3.87 (s, 3H, OCH3), 3.89 (s, 6H, 2OCH3),
5.98 (s, 1H, ArOH), 6.81 (d, J = 12.8 Hz, 1H, ArH), 7.02 (d, J = 9.5
Hz, 1H, ArH), 7.11 (s, 2H, ArH). 13C NMR (CDCl3) d 56.3
(2CH3), 57.1 (CH3), 60.9 (CH3), 101.6 (CH), 107.4 (2CH), 115.3
(CH), 124.1 (C), 129.1 (C), 139.9 (C), 146.6 (2C), 151.7 (C), 152.8
(C), 155.3 (C), 193.6 (C). 19F NMR (CDCl3, 376 MHz) d (ppm)
2127.7 (dd, J = 12.3, 9.6 Hz, 1F, ArF). Calc. for C17H17FO6: C,
60.71; H, 5.09. Found: C, 60.76; H, 5.00%.
A well-stirred mixture of aromatic derivative (1 equiv.), benzoic
acid (1.1 equiv.) and Eaton’s reagent (P2O5/CH3SO3H mixture
1/10 w/w) (4 equiv. w/w) was heated at 60 uC for 2–18 h. After
cooling to rt, the solution was poured into water, quenched
with
a saturated solution of sodium bicarbonate, then
extracted with dichloromethane and dried on MgSO4.
Volatiles were removed in vacuo to give the crude product.
(2,5-Dimethoxyphenyl)[4-(trifluoromethyl)phenyl]metha-
none (4m). The general procedure was followed using 1,4-
dimethoxybenzene 6e (1.3 g, 9.5 mmol), 4-(trifluoromethyl)
benzoic acid 5d (2.0 g, 10.0 mmol) and Eaton’s reagent (P2O5/
CH3SO3H mixture 1/10 w/w) (0.7 g of phosphorus pentoxide in
4.9 mL of methanesulfonic acid) at 50 uC for 15 h. The pure
product was obtained without further purification as a light
brown solid (2.9 g, 98%). 1H NMR (CDCl3) d (ppm) 3.64 (s, 3H,
OCH3), 3.80 (s, 3H, OCH3), 6.94 (d, J = 9.3 Hz, 1H, ArH), 6.97 (d,
J = 3.2 Hz, 1H, ArH), 7.06 (dd, J = 9.3, 3.2 Hz, 1H, ArH), 7.69 (d,
J = 9.1 Hz, 2H, ArH), 7.90 (d, J = 9.1 Hz, 2H, ArH). 13C NMR
(CDCl3) d 55.8 (CH3), 56.1 (CH3), 113.0 (CH), 114.6 (CH), 118.3
(CH), 125.2 (2CH), 128.4 (C), 129.8 (2CH), 130.6 (C), 140.7 (C),
151.9 (2C), 153.6 (C), 195.1 (C). 19F NMR (CDCl3, 376 MHz) d
(ppm) 263.0 (s, 3F, CF3). IR n/cm21: 2943, 1674, 1492, 1322,
1126. Calc. for C16H13F3O3: C, 61.94; H, 4.22. Found: C, 61.76;
H, 4.33%. The other physico-chemical properties are in
accordance with the literature.29
General procedure for Friedel–Crafts reaction using
aluminium trichloride
A mixture of aromatic derivative (1 equiv.), benzoic acid
chloride (1 equiv.) and aluminium trichloride (3 to 5 equiv.) in
dichloromethane was stirred at rt for 15 h. The solution was
poured into iced water, extracted with dichloromethane and
dried over MgSO4. Volatiles were removed in vacuo to give the
crude product which was recrystallized from pure ethanol or
Et2O or purified by column chromatography on silica gel.
2-Methoxy-5-(4-nitrobenzoyl)phenyl chloroacetate (4c). The
general procedure was followed using 2-methoxyphenyl
2,6-Dimethoxy-3-(4-methoxybenzoyl)phenyl chloroacetate
(4n). This product was synthesized following the general
procedure using Eaton’s reagent. 1H NMR (CDCl3) d (ppm)
3.65 (s, 3H, OCH3), 3.88 (s, 3H, OCH3), 3.89 (s, 3H, OCH3), 4.39
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chloroacetate 6a (5.4 g, 27 mmol), 4-nitrobenzoic acid chloride
5b (5.0 g, 27 mmol) and aluminium trichloride (12.5 g, 94
mmol). The final residue was recrystallized from EtOH to give
the pure product (6.0 g, 64%) as a yellow–white solid; mp
(EtOH) 132–133 uC ; Rf (EtOAc–n-heptane (5/5)) = 0.60. 1H NMR
(CDCl3) d (ppm) 3.94 (s, 3H, OCH3), 4.35 (s, 2H, OCOCH2Cl),
7.08 (d, J = 8.8 Hz, 1H, ArH), 7.61 (d, J = 2.2 Hz, 1H, ArH), 7.75
(dd, J = 8.8, 2.2 Hz, 1H, ArH), 7.89 (d, J = 8.8 Hz, 2H, ArH), 8.35
(d, J = 8.8 Hz, 2H, ArH). 13C NMR (CDCl3) d 40.4 (CH2), 56.3
(CH3), 111.9 (CH), 123.6 (2CH), 124.6 (CH), 130.3 (2CH), 130.6
(CH), 139.2 (C), 143.0 (C), 149.7 (C), 155.4 (C), 165.2 (C), 192.4
(C). IR n/cm21: 2958, 1778, 1654, 1596, 1347, 1099, 729. Calc.
for C16H12ClNO6: C, 54.95; H, 3.46; N, 4.01. Found: C, 54.74; H,
3.39; N, 3.90%.
(3-Hydroxy-4-methoxyphenyl)(4-nitrophenyl)methanone
(4d). A mixture of 2-methoxy-5-(4-nitrobenzoyl)phenyl chlor-
oacetate 4c (3.0 g, 8.5 mmol) and AcONa?3H2O (3.5 g, 25.5
mmol) in MeOH was refluxed for 1 h. The solvent was removed
in vacuo and the crude solid was dissolved in a mixture of
water/dichloromethane. A 10% HCl aqueous solution was
added until precipitation of the pure product as a yellow solid
(2.2 g, 94%); mp (CH2Cl2) 182–184 uC; Rf (EtOAc–n-heptane (5/
5)) = 0.46. 1H NMR (CDCl3) d (ppm) 4.00 (s, 3H, OCH3), 5.94 (br
s, 1H, OH), 6.94 (d, J = 8.0 Hz, 1H, ArH), 7.37 (dd, J = 8.0, 2.4
Hz, 1H, ArH), 7.42 (d, J = 2.4 Hz, 1H, ArH), 7.88 (d, J = 8.6 Hz,
2H, ArH), 8.32 (d, J = 8.6 Hz, 2H, ArH). 13C NMR (CDCl3) d 55.3
(CH3), 56.2 (CH3), 109.9 (CH), 116.0 (CH), 123.4 (2CH), 124.2
(CH), 129.7 (C), 130.3 (2CH), 143.6 (C), 145.6 (C), 145.0 (C),
149.5 (C), 151.1 (C), 193.5 (C). IR n/cm21: 3476, 2956, 1640,
1596, 1351. Calc. for C14H11NO5: C, 61.54; H, 4.06; N, 5.13.
Found: C, 61.40; H, 3.89; N, 4.97%.
(2-Hydroxy-3,4-dimethoxyphenyl)(4-nitrophenyl)methanone
(4f). A mixture of 1,2,3-trimethoxybenzene 6d (5.0 g, 30 mmol),
4-nitrobenzoic acid 5b (5.0 g, 30 mmol), boron trifluoride
etherate (22.2 mL, 180 mmol) and trifluoroacetic anhydride
(25.5 mL, 180 mmol) in 1,2-dichloroethane was refluxed for 18
h. After cooling to rt, the solution was poured into water and
extracted with dichloromethane, then dried on MgSO4. The
solvent was removed in vacuo. The crude product was
recrystallized in Et2O to give the pure product as a yellow
solid (2.1 g, 24%); mp (Et2O) 145–147 uC; Rf (EtOAc–n-heptane
(5/5)) = 0.57. 1H NMR (CDCl3) d (ppm) 3.95 (s, 3H, OCH3), 3.96
(s, 3H, OCH3), 6.49 (d, J = 8.4 Hz, 1H, ArH), 7.20 (d, J = 8.4 Hz,
1H, ArH), 7.80 (d, J = 8.4 Hz, 1H, ArH), 8.36 (d, J = 8.4 Hz, 2H,
ArH), 12.11 (s, 1H, OH). 13C NMR (CDCl3) d 56.3 (CH3), 60.8
(CH3), 103.3 (CH), 114.2 (C), 123.6 (2CH), 129.7 (2CH), 129.7
(CH), 136.9 (C), 143.5 (C), 149.4 (C), 158.0 (C), 159.4 (C), 198.2
(C). IR n/cm21: 2942, 1626, 1589, 1345, 1291, 1101. Calc. for
C15H13NO6: C, 59.41; H, 4.32; N, 4.62. Found: C, 59.22; H, 4.16;
N, 4.49%.
pure product was obtained by recrystallization in EtOH and
obtained as a yellow solid (2.8 g, 28%) ; mp (EtOAc–n-heptane)
144–146 uC; Rf (EtOAc–n-heptane (5/5)) = 0.72. 1H NMR (CDCl3)
d (ppm) 3.89 (s, 3H, OCH3), 6.44 (dd, J = 9.0, 2.3 Hz, 1H, ArH),
6.54 (d, J = 2.3 Hz, 1H, ArH), 7.34 (d, J = 9.0 Hz, 1H, ArH), 7.78
(d, J = 8.7 Hz, 2H, ArH), 8.36 (d, J = 8.7 Hz, 2H, ArH), 12.41 (s,
1H, ArOH). 13C NMR (CDCl3) d 55.8 (CH3), 101.3 (CH), 108.2
(CH), 112.7 (C), 123.7 (2CH), 129.6 (2CH), 134.7 (CH), 143.7
(C), 149.3 (C), 166.7 (C), 167.0 (C), 197.6 (C). IR n/cm21: 1741,
1592, 1518, 1340, 1206, 703. Calc. for C14H11NO5: C, 61.54; H,
4.06; N, 5.13. Found: C, 61.65; H, 3.92; N, 5.67%.
(2-Hydroxy-4,6-dimethoxyphenyl)(4-nitrophenyl)methanone
(4k). The general procedure of Friedel–Crafts was followed
using 1,3,5-trimethoxybenzene 6g (1.0 g, 6 mmol), 4-nitroben-
zoic acid chloride 5b (1.1 g, 6 mmol) and aluminium
trichloride (3.6 g, 26 mmol). The crude product was
recrystallized in EtOH to give the pure product as a yellow
solid (0.5 g, 28%). 1H NMR (CDCl3) d (ppm) 3.43 (s, 1H, OCH3),
3.87 (s, 1H, OCH3), 5.91 (d, J = 2.4 Hz, 1H, ArH), 6.18 (d, J = 2.4
Hz, 1H, ArH), 7.61 (d, J = 8.8 Hz, 2H, ArH), 8.25 (d, J = 8.8 Hz,
2H, ArH), 12.43 (s, 1H, OH). The other physico-chemical
properties are in accordance with the literature.27
(3-Hydroxy-2,4-dimethoxyphenyl)(4-methoxyphenyl)metha-
none (4o). This product was synthesized as product 4d. 1H
NMR (CDCl3) d (ppm) 3.75 (s, 3H, OCH3), 3.88 (s, 3H, OCH3),
3.96 (s, 3H, OCH3), 5.72 (s, 1H, ArOH), 6.71 (d, J = 8.6 Hz, 1H,
ArH), 6.92 (d, J = 8.6 Hz, 1H, ArH), 6.93 (d, J = 8.9 Hz, 2H, ArH),
7.83 (d, J = 8.9 Hz, 2H, ArH). The physico-chemical properties
are in accordance with the literature.10b
(3-Hydroxy-2,4-dimethoxyphenyl)(3,4,5-trimethoxyphenyl)methanone
(4q). This product was synthesized as product 4d. 1H NMR
(CDCl3) d (ppm) 3.81 (s, 3H, OCH3), 3.86 (s, 6H, 2OCH3), 3.93
(s, 3H, OCH3), 3.97 (s, 3H, OCH3), 5.74 (s, 1H, ArOH), 6.71 (d,
J = 8.5 Hz, 1H, ArH), 6.93 (d, J = 8.5 Hz, 1H, ArH), 7.10 (s, 2H,
ArH). The physico-chemical properties are in accordance with
the literature.11b
(2,4-Dihydroxyphenyl)(4-nitrophenyl)methanone (4s). The
general procedure was followed using 1,3-dimethoxybenzene
6f (4.9 g, 36 mmol), 4-nitrobenzoic acid chloride 5b (10.0 g, 54
mmol) and aluminium trichloride (19.2 g, 144 mmol) at reflux
for 15 h. The crude product was purified by column
chromatography on silica gel with EtOAc–n-heptane (2/8).
The pure phenol was obtained as a yellow solid (3.25 g, 35%);
mp (EtOAc–n-heptane) 173–174 uC; Rf (EtOAc–n-heptane (5/5))
= 0.57. 1H NMR (CDCl3) d (ppm) 5.60 (s, 1H, ArOH), 6.39 (dd, J
= 8.9, 2.3 Hz, 1H, ArH), 6.50 (d, J = 2.3 Hz, 1H, ArH), 7.36 (d, J =
8.9 Hz, 1H, ArH), 7.79 (d, J = 8.7 Hz, 2H, ArH), 8.37 (d, J = 8.7
Hz, 2H, ArH), 12.31 (s, 1H, ArOH). 13C NMR (CDCl3) d 104.0
(CH), 108.2 (CH), 112.4 (C), 123.7 (2CH), 129.6 (2CH), 135.5
(CH), 139.8 (C), 143.6 (C), 163.3 (C), 166.5 (C), 197.7 (C). IR n/
cm21: 3322, 2921, 1590, 1333, 1233, 840. Calc. for C13H9NO5:
C, 60.24; H, 3.50; N, 5.40. Found: C, 57.36; H, 3.20; N, 5.05%.
3-Hydroxy-4-(4-nitrobenzoyl)phenyl-4-nitrobenzoate (4t).
The general procedure was followed using 1,3-dimethoxyben-
zene 6f (4.9 g, 36 mmol), 4-nitrobenzoic acid chloride 5b (10.0
g, 54 mmol) and aluminium trichloride (19.2 g, 144 mmol) at
reflux for 15 h. The pure product was obtained as a beige solid
(1.9 g, 13%); mp (EtOAc–n-heptane) 148–150 uC; Rf (EtOAc–
(2,5-Dimethoxyphenyl)(4-nitrophenyl)methanone (4h). This
product was synthesized following the general procedure using
aluminium trichloride. The physico-chemical properties are in
accordance with the literature.23
(2-Hydroxy-4-methoxyphenyl)(4-nitrophenyl)methanone (4i).
The general procedure was followed using 1,3-dimethoxyben-
zene 6f (5.0 g, 36 mmol), 4-nitrobenzoic acid chloride 5b (6.7 g,
36 mmol) and aluminium trichloride (16.9 g, 126 mmol). The
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n-heptane (5/5)) = 0.73. H NMR (CDCl3) d (ppm) 6.84 (dd, J =
8.8, 2.2 Hz, 1H, ArH), 7.04 (d, J = 2.2 Hz, 1H, ArH), 7.57 (d, J =
8.8 Hz, 1H, ArH), 7.86 (d, J = 8.7 Hz, 2H, ArH), 8.38 (s, 4H,
ArH), 8.40 (d, J = 8.7 Hz, 2H, ArH), 12.05 (s, 1H, ArOH). 13C
NMR (CDCl3) d 111.7 (CH), 113.0 (CH), 117.0 (C), 123.8 (2CH),
123.9 (2CH), 129.9 (2CH), 131.5 (2CH), 134.1 (C), 134.5 (CH),
142.9 (C), 149.7 (C), 151.2 (C), 157.0 (C), 162.1 (C), 162.4 (C),
198.7 (C). IR n/cm21: 1741, 1593, 1347, 1242, 849. Calc. for
C20H12N2O8: C, 58.83; H, 2.96; N, 6.86. Found: C, 58.71; H,
2.61; N, 6.64%.
phorus pentasulfide (1.5 g, 6.6 mmol) and HMDO (3.5 mL,
16.5 mmol) in toluene was stirred at reflux for 15 h. The
solvent was removed in vacuo. The crude reaction mixture was
dissolved in dichloromethane, washed with water and dried on
MgSO4. Volatiles were removed in vacuo and the crude product
was purified by column chromatography on silica gel with
EtOAc–n-heptane (3/7) to give the pure thione as a dark blue
1
solid (1.9 g, 89%). H (CDCl3, 400 MHz) d (ppm) 3.88 (s, 6H,
2OCH3), 6.88 (d, J = 8.8 Hz, 4H, ArH), 7.73 (d, J = 8.8 Hz, 4H,
ArH). The physico-chemical properties are in accordance with
the literature.39
General procedure for methylation of phenols
General procedure for Wittig reaction
A mixture of phenol (1 equiv.), dimethyl sulfate (1.5 equiv.)
and potassium carbonate (2.5 equiv.) in acetone was refluxed
during 18 h. After cooling to rt, the excess of dimethyl sulfate
was quenched by triethylamine, then the solution was poured
into water, extracted with dichloromethane and dried on
MgSO4. The solvent was removed in vacuo to give the crude
product.
A mixture of potassium tert-butoxide (5 equiv.) and methyl-
triphenylphosphonium bromide (2 equiv.) in tetrahydrofuran
or toluene was stirred at rt or 80 uC for 1 h. The benzophenone
(1 equiv.) dissolved in tetrahydrofuran or toluene was added
and the mixture was stirred at rt or 80 uC for 15 h. The solution
was poured into water, then extracted in dichloromethane and
dried (MgSO4). The solvent was removed in vacuo. The crude
product was purified by column chromatography on silica gel
to obtain the Wittig compound or the inserted carbon product.
1-Methoxy-4-[1-(4-methoxyphenyl)vinyl]benzene (3b).30 From
bis(4-methoxyphenyl)methanone (4v) directly. The general pro-
cedure for Wittig reaction was followed using commercially
available bis(4-methoxyphenyl)methanone 4v (0.5 g, 2.1
mmol), potassium tert-butoxide (1.2 g, 10.3 mmol) and
methyltriphenylphosphonium bromide (1.5 g, 4.1 mmol) in
tetrahydrofuran at rt. The crude product was purified by
column chromatography on silica gel with EtOAc–n-heptane
(15/85). The pure Wittig product was obtained as a white solid
(0.4 g, 73%).
(3,4-Dimethoxyphenyl)(4-nitrophenyl)methanone (4e). This
product was synthesized following the general procedure for
1
the methylation of phenols. H NMR (CDCl3) d (ppm) 3.96 (s,
3H, OCH3), 3.98 (s, 3H, OCH3), 6.90 (d, J = 7.7 Hz, 1H, ArH),
7.29 (dd, J = 7.7, 1.6 Hz, 1H, ArH), 7.51 (d, J = 1.6 Hz, 1H, ArH),
7.89 (d, J = 8.8 Hz, 2H, ArH), 8.34 (d, J = 8.8 Hz, 2H, ArH). The
physico-chemical properties are in accordance with the
literature.25
(4-Nitrophenyl)(2,3,4-trimethoxyphenyl)methanone (4g).
The general procedure for the methylation of phenols was
followed using (2-hydroxy-3,4-dimethoxyphenyl)(4-nitrophe-
nyl)methanone 4d (1.5 g, 5.0 mmol), dimethyl sulfate (0.72
mL, 7.5 mmol) and potassium carbonate (1.6 g, 12 mmol). The
product was obtained as a yellow solid (1.5 g, 97%); mp
Via bis(4-methoxyphenyl)methanethione (7a). The general
procedure for Wittig reaction was followed using bis(4-
methoxyphenyl)methanethione (0.5 g, 1.9 mmol), potassium
tert-butoxide (1.1 g, 9.7 mmol) and methyltriphenylphospho-
nium bromide (1.4 g, 3.9 mmol) in tetrahydrofuran at rt. The
crude product was purified by column chromatography on
silica gel with EtOAc–n-heptane (15/85). The pure Wittig
product was obtained as a white solid (0.36 g, 80%); mp
(EtOAc–n-heptane) 140–141 uC; Rf (EtOAc–n-heptane (5/5)) =
0.74. 1H NMR (CDCl3) d (ppm) 3.83 (s, 6H, 2OCH3), 5.29 (s, 2H,
CH2), 6.86 (d, J = 8.8 Hz, 4H, ArH), 7.28 (d, J = 8.8 Hz, 4H, ArH).
13C NMR (CDCl3) d 55.3 (2CH3), 111.7 (CH2), 113.5 (4CH),
129.4 (4CH), 134.3 (2C), 149.0 (C), 159.3 (2C). Calc. for
1
(CH2Cl2) 93–95 uC; Rf (EtOAc–n-heptane (5/5)) = 0.65. H NMR
(CDCl3) d (ppm) 3.68 (s, 3H, OCH3), 3.88 (s, 3H, OCH3), 3.95 (s,
3H, OCH3), 6.77 (d, J = 8.8 Hz, 1H, ArH), 7.26 (d, J = 8.8 Hz, 1H,
ArH), 7.89 (d, J = 8.8 Hz, 2H, ArH), 8.29 (d, J = 8.8 Hz, 2H, ArH).
13C NMR (CDCl3) d 56.2 (CH3), 61.0 (CH3), 61.6 (CH3), 107.1
(CH), 123.3 (2CH), 124.9 (C), 125.8 (CH), 130.0 (2CH), 141.9
(C), 144.0 (C), 149.7 (C), 153.0 (C), 157.4 (C), 193.7 (C). IR n/
cm21: 2945, 1650, 1589, 1352, 1098. Calc. for C16H15NO6: C,
60.57; H, 4.77; N, 4.41. Found: C, 60.28; H, 4.81; N, 4.37%.
(2,4-Dimethoxyphenyl)(4-nitrophenyl)methanone (4j). This
product was synthesized following the general procedure for
the methylation of phenols. 1H (CDCl3) d (ppm) 3.65 (s, 3H,
OCH3), 3.90 (s, 3H, OCH3), 6.50 (d, J = 2.1 Hz, 1H, ArH), 6.61
(dd, J = 8.6, 2.1 Hz, 1H, ArH), 7.55 (d, J = 8.6 Hz, 1H, ArH), 7.86
(d, J = 8.8 Hz, 2H, ArH), 8.26 (d, J = 8.8 Hz, 2H, ArH). The
physico-chemical properties are in accordance with the
literature.22
C
16H16O2: C, 79.97; H, 6.71. Found: C, 79.80; H, 6.82%.
1,4-Dimethoxy-2-(1-[4-(trifluoromethyl)phenyl]vinyl)benzene
(3c). The general procedure for Wittig reaction was followed
using (2,5-dimethoxyphenyl)[4-(trifluoromethyl)phenyl]metha-
none 4m (2.0 g, 6.5 mmol), potassium tert-butoxide (3.6 g, 32.5
mmol) and methyltriphenylphosphonium bromide (4.6 g, 13.0
mmol) in tetrahydrofuran at rt. The product was obtained
without purification as a yellow oil (0.9 g, 44%); Rf (EtOAc–
(4-Nitrophenyl)(2,4,6-trimethoxyphenyl)methanone (4l).
This product was synthesized following the general procedure
1
for the methylation of phenols. H NMR (CDCl3) d (ppm) 3.69
1
(s, 6H, 2OCH3), 3.88 (s, 3H, OCH3), 6.17 (s, 2H, ArH), 7.95 (d, J
= 8.8 Hz, 2H, ArH), 8.25 (d, J = 8.8 Hz, 2H, ArH). The physico-
chemical properties are in accordance with the literature.27
n-heptane (5/5)) = 0.74. H NMR (CDCl3) d (ppm) 3.56 (s, 3H,
OCH3), 3.79 (s, 3H, OCH3), 5.43 (d, J = 1.1 Hz, 1H, CH2), 5.75
(d, J = 1.1 Hz, 1H, CH2), 6.84 (d, J = 8.9 Hz, 1H, ArH), 6.85 (dd, J
= 2.8, 1H, ArH), 6.88 (d, J = 8.9, 2.8 Hz, 1H, ArH), 7.39 (d, J = 8.2
Hz, 1H, ArH), 7.52 (d, J = 8.2 Hz, 1H, ArH). 13C NMR (CDCl3) d
Bis(4-methoxyphenyl)methanethione (7a).
A mixture of
bis(4-methoxyphenyl)methanone (2.0 g, 8.3 mmol), phos-
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55.2 (CH3), 55.7 (CH3), 112.1 (CH), 113.2 (CH), 116.6 (CH2),
116.8 (CH), 124.4 (2C), 126.05 (2CH), 127.9 (CH), 130.6 (C),
133.3 (C), 143.9 (CH), 145.4 (C), 150.6 (C), 153.1 (C). 19F NMR
(CDCl3, 376 MHz) d (ppm) 262.4 (s, 3F, CF3). IR n/cm21: 2950,
1615, 1114. Calc. for C17H15F3O2: C, 66.23; H, 4.90. Found: C,
66.62; H, 4.83%.
(d, J = 1.6 Hz, 1H, CH2), 6.51 (s, 2H, ArH), 6.72 (d, J = 12.8 Hz,
1H, ArH), 6.87 (d, J = 9.4 Hz, 1H, ArH). 13C NMR (CDCl3) d 54.1
(C), 56.1 (2CH3), 56.5 (CH3), 57.2 (CH3), 60.9 (CH3), 101.3 (CH),
101.5 (C), 103.8 (2CH), 115.4 (CH2), 117.1 (CH), 136.5 (C), 137.8
(C), 141.1 (C), 145.9 (C), 151.1 (C), 152.9 (2C). IR n/cm21: 3503,
2934, 1576, 1340. Calc. for C19H22O6: C, 65.88; H, 6.40. Found:
C, 65.55; H, 6.76%.
5-[1-(4-Fluoro-2,5-dimethoxyphenyl)ethenyl]-1,2,3-trimethox-
ybenzene (3d). The general procedure for Wittig reaction was
followed using (4-fluoro-2,5-dimethoxyphenyl)(3,4,5-trimethox-
yphenyl)methanone 4r (0.5 g, 1.4 mmol), potassium tert-
butoxide (0.8 g, 7.1 mmol) and methyltriphenylphosphonium
bromide (1.0 g, 2.8 mmol) in toluene at 80 uC. The crude
product was purified by column chromatography on silica gel
with EtOAc–n-heptane (5/5) to give the pure Wittig by-product
as a white solid (0.2 g, 44%); mp (EtOAc–n-heptane) 77–79 uC;
Rf (EtOAc–n-heptane (4/6)) = 0.54. 1H NMR (CDCl3) d (ppm)
3.64 (s, 3H, OCH3), 3.80 (s, 6H, 2OCH3), 3.85 (s, 3H, OCH3),
3.93 (s, 3H, OCH3), 5.32 (d, J = 1.8 Hz, 1H, CH2), 5.59 (d, J = 1.8
Hz, 1H, CH2), 6.54 (s, 2H, ArH), 6.66 (d, J = 8.6 Hz, 1H, ArH),
6.74 (d, J = 8.6 Hz, 1H, ArH). 13C NMR (CDCl3) d 55.9 (2CH3),
56.2 (CH3), 60.5 (CH3), 60.9 (CH3), 104.2 (2CH), 106.2 (CH),
115.1 (CH2), 121.1 (CH), 128.1 (C), 137.8 (C), 138.4 (C), 145.0
(C), 146.5 (C), 147.5 (C), 152.8 (C), 154.8 (C). 19F NMR (CDCl3,
376 MHz) d (ppm) 2132.71 (dd, J = 11.2, 9.5 Hz, 1F, ArF). IR n/
cm21: 2927, 1574, 1124. Calc. for C19H21FO5: C, 65.51; H, 6.08.
Found: C, 65.09; H, 6.51%.
1-(2,5-Dimethoxyphenyl)-2-(4-nitrophenyl)ethanone (8a).
The general procedure for Wittig reaction was followed using
(2,5-dimethoxyphenyl)(4-nitrophenyl)methanone 4h (1.0 g, 3.5
mmol), potassium tert-butoxide (1.9 g, 17.4 mmol) and
methyltriphenylphosphonium bromide (2.5 g, 7.0 mmol) in
tetrahydrofuran at rt. The crude product was purified by
column chromatography on silica gel with EtOAc–n-heptane
(5/95) to give the pure insertion product as a white solid (0.15
g, 15%); mp (EtOAc–n-heptane) 95–98 uC; Rf (EtOAc–n-heptane
(5/5)) = 0.59. 1H NMR (CDCl3) d (ppm) 3.78 (s, 3H, OCH3), 3.90
(s, 3H, OCH3), 4.42 (s, 2H, CH2), 7.28 (d, J = 3.2 Hz, 1H, ArH),
7.40 (d, J = 8.9 Hz, 2H, ArH), 8.18 (d, J = 8.9 Hz, 2H, ArH). 13C
NMR (CDCl3) d 49.8 (CH2), 55.8 (CH3), 56.0 (CH3), 113.1 (CH),
114.2 (CH), 121.0 (CH), 123.5 (2CH), 127.4 (C), 130.6 (2CH),
143.0 (C), 146.9 (C), 153.2 (C), 153.6 (C), 197.6 (C). Calc. for
C16H15NO5: C, 63.78; H, 5.02; N, 4.65. Found: C, 63.59; H, 5.02;
N, 4.62%.
2-(4-Nitrophenyl)-1-(2,3,4-trimethoxyphenyl)ethanone (8b).
The general procedure for Wittig reaction was followed using
(4-nitrophenyl)(2,3,4-trimethoxyphenyl)methanone 4g (1.0 g,
3.2 mmol), potassium tert-butoxide (1.8 g, 16.0 mmol) and
methyltriphenylphosphonium bromide (2.3 g, 6.3 mmol) in
tetrahydrofuran at rt. The crude product was purified by flash
chromatography on silica gel with EtOAc–n-heptane gradient
to give the pure insertion product as an orange solid (0.3 g,
32%); mp (EtOAc–n-heptane) 88–89 uC; Rf (EtOAc–n-heptane
(5/5)) = 0.55. 1H NMR (CDCl3) d (ppm) 3.88 (s, 3H, OCH3), 3.92
(s, 3H, OCH3), 3.99 (s, 3H, OCH3), 4.39 (s, 2H, CH2), 6.72 (d, J =
8.8 Hz, 1H, ArH), 7.41 (d, J = 8.8 Hz, 2H, ArH), 7.51 (d, J = 8.8
Hz, 1H, ArH), 8.18 (d, J = 8.8 Hz, 1H, ArH). 13C NMR (CDCl3) d
49.0 (CH2), 56.1 (CH3), 60.9 (CH3), 61.5 (CH3), 107.3 (CH),
123.5 (2CH), 124.9 (C), 126.0 (CH), 130.6 (2CH), 141.9 (C),
2,6-Dimethoxy-3-[1-(4-methoxyphenyl)vinyl]phenol (3e). The
general procedure for Wittig reaction was followed using (3-
hydroxy-2,4-dimethoxyphenyl)(4-methoxyphenyl)methanone
4o (0.4 g, 1.2 mmol), potassium tert-butoxide (0.7 g, 6.3 mmol)
and methyltriphenylphosphonium bromide (0.9 g, 2.5 mmol)
in tetrahydrofuran at rt. The crude product was purified by
column chromatography on silica gel with EtOAc–n-heptane
(2/8). The pure Wittig product was obtained as a beige solid
(0.05 g, 14%); mp (EtOAc–n-heptane) 111–113 uC; Rf (EtOAc–
1
n-heptane (5/5)) = 0.58. H NMR (CDCl3) d (ppm) 3.61 (s, 3H,
OCH3), 3.80 (s, 3H, OCH3), 3.92 (s, 3H, OCH3), 5.22 (d, J = 1.5
Hz, 1H, CH2), 5.57 (d, J = 1.5 Hz, 1H, CH2), 5.63 (s, 1H, ArOH),
6.66 (d, J = 8.4 Hz, 1H, ArH), 6.74 (d, J = 8.4 Hz, 1H, ArH), 6.83
(dd, J = 9.0, 2.3 Hz, 2H, ArH), 7.26 (dd, J = 9.0, 2.3 Hz, 2H, ArH).
13C NMR (CDCl3) d 55.3 (CH3), 56.2 (CH3), 60.5 (CH3), 106.4
(CH), 113.5 (2CH), 121.1 (CH2), 127.9 (2CH), 128.4 (C), 133.9
(C), 138.4 (C), 145.0 (C), 146.0 (C), 147.4 (C), 159.8 (C). IR n/
cm21: 3409, 2921, 2849, 1605, 1492, 1454, 1244, 1088, 827.
Calc. for C17H18O4, 1/3 n-C7H16: C, 72.63; H, 7.36. Found: C,
72.95; H, 7.58%.
143.0 (C), 146.9 (C), 154.0 (C), 157.9 (C), 196.4 (C). IR n/cm21
:
2937, 1659, 1583, 1333, 1093. Calc. for C17H17NO6, 1/10
n-C7H16: C, 62.28; H, 5.49; N, 4.10. Found: C, 62.26; H, 5.47;
N, 4.10%.
1-(2,4-Dimethoxyphenyl)-2-(4-nitrophenyl)ethanone (8c).
The general procedure for Wittig reaction was followed using
(2,4-dimethoxyphenyl)-(4-nitrophenyl)methanone 4j (1.5 g, 5.2
mmol), potassium tert-butoxide (2.9 g, 26.0 mmol) and
methyltriphenylphosphonium bromide (3.7 g, 10.4 mmol) in
tetrahydrofuran at rt. The crude product was purified by flash
chromatography on silica gel with EtOAc–n-heptane gradient
to give the pure insertion product as an orange solid (0.5 g,
32%). 1H NMR (CDCl3) d (ppm) 3.86 (s, 3H, OCH3), 3.91 (s, 3H,
OCH3), 4.38 (s, 2H, CH2), 6.46 (d, J = 2.2 Hz, 1H, ArH), 6.55 (dd
J = 8.6, 2.2 Hz, 1H, ArH), 7.38 (d, J = 8.8 Hz, 2H, ArH), 7.85 (d, J
= 8.6 Hz, 1H, ArH), 8.17 (d, J = 8.8 Hz, 2H, ArH). The physico-
chemical properties are in accordance with the literature.22
1-(3,4-Dimethoxyphenyl)-2-(4-nitrophenyl)ethanone (8d).
The general procedure for Wittig reaction was followed using
2,6-Dimethoxy-3-[1-(3,4,5-trimethoxyphenyl)vinyl]phenol
(3f). The general procedure for Wittig reaction was followed
using (3-hydroxy-2,4-dimethoxyphenyl)(3,4,5-trimethoxyphe-
nyl)methanone 4q (1.0 g, 2.6 mmol), potassium tert-butoxide
(1.5 g, 13.0 mmol) and methyltriphenylphosphonium bromide
(1.9 g, 5.2 mmol) in toluene at 80 uC. The crude product was
purified by column chromatography on silica gel with EtOAc–
n-heptane (5/5). The pure Wittig product was obtained as a
beige solid (0.4 g, 41%); mp (EtOAc–n-heptane) 82–84 uC; Rf
1
(EtOAc–n-heptane (4/6)) = 0.34. H NMR (CDCl3) d (ppm) 3.62
(s, 3H, OCH3), 3.80 (s, 6H, 2OCH3), 3.85 (s, 3H, OCH3), 3.86 (s,
3H, OCH3), 3.98 (s, 1H, OH), 5.28 (d, J = 1.6 Hz, 1H, CH2), 5.68
3694 | RSC Adv., 2013, 3, 3683–3696
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(3,4-dimethoxyphenyl)(4-nitrophenyl)methanone 4e (1.0 g, 3.5
mmol), potassium tert-butoxide (1.9 g, 17.4 mmol) and
methyltriphenylphosphonium bromide (2.5 g, 7.0 mmol) in
tetrahydrofuran at rt. The crude product was purified by flash
chromatography on silica gel with EtOAc–n-heptane gradient
to give the pure insertion product as an orange solid (0.5 g,
51%). 1H NMR (CDCl3) d (ppm) 3.93 (s, 3H, OCH3), 3.96 (s, 3H,
OCH3), 4.36 (s, 2H, CH2), 6.91 (d, J = 8.8 Hz, 1H, ArH), 7.43 (d, J
= 8.8 Hz, 2H, ArH), 7.55 (d, J = 2.4 Hz, 1H, ArH), 7.65 (dd, J =
8.8, 2.4 Hz, 1H, ArH), 8.20 (d, J = 8.8 Hz, 1H, ArH). The physico-
chemical properties are in accordance with the literature.26
1-(4-Methoxyphenyl)-2-(4-nitrophenyl)ethanone (8e). The
general procedure for Wittig reaction was followed using
commercially available (4-methoxyphenyl)(4-nitrophenyl)-
methanone 4w (2.0 g, 7.8 mmol), potassium tert-butoxide
(5.5 g, 15.5 mmol), and methyltriphenylphosphonium bro-
mide (4.4 g, 38.8 mmol) in tetrahydrofuran at rt. The crude
product was purified by flash chromatography on silica gel
with EtOAc–n-heptane gradient to give the pure insertion
product as an orange solid (0.25 g, 12%). The physico-chemical
properties are in accordance with the literature.22
Acknowledgements
´
The authors gratefully acknowledge the ‘Conseil Regional
Nord-Pas-de-Calais’ for the V.S.’s PhD scholarship and the NCI
(National Cancer Institute) for the biological evaluation of the
compounds on their 60-cell panel.
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3696 | RSC Adv., 2013, 3, 3683–3696
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