The synthesis of some novel stilbene dimers incorporating diamide tethers: Studies in single electron transfer oxidation (FeCl3)

Article abstract of DOI:10.1039/c7ra12534h

The FeCl₃ oxidative cascade reaction of the acetamido stilbene 1 which we reported some years ago produced the first atropodiastereomeric indolostilbene hybrid 3. By contrast, recent investigation of the oxidation of the stilbene succinamide di

Full text of DOI:10.1039/c7ra12534h

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The synthesis of some novel stilbene dimers
incorporating diamide tethers: studies in single
Cite this: RSC Adv., 2018, 8, 2506
electron transfer oxidation (FeCl )†
3
a
a
b
Maryam Sadat Alehashem, * Azhar Ariffin,* Amjad Ayad Qatran Al-Khdhairawi
and Noel F. Thomas*a
Received 17th November 2017
Accepted 25th December 2017
The FeCl
produced the first atropodiastereomeric indolostilbene hybrid 3. By contrast, recent investigation of the
oxidation of the stilbene succinamide dimer 72 (FeCl /CH Cl ) appears, on the basis of spectroscopic
evidence, to have produced the bridged macrocyclic indoline 73.
3
oxidative cascade reaction of the acetamido stilbene 1 which we reported some years ago
DOI: 10.1039/c7ra12534h
3
2
2
rsc.li/rsc-advances
Some years earlier in a fascinating exploration of the radical-
mediated transannular/Diels Alder reaction, Jones reported
1
. Introduction
8
Some years ago we discovered that the 3,5-dimethoxy that treatment of 7 with tributyltin hydride/AIBN gave rise to the
substituted acetamido stilbene, 1 when exposed to FeCl
CH Cl proceeded in a mechanistically complex reaction to
yield four products, one of which was, unprecedented.
3
in tricycle 11 via 13-endo dig and Diels Alder reactions (Scheme 3).
By contrast, when Pattenden et al. treated the iodopropyl
furan derivative 12 with tributyltin hydride, the intermediate
2
2
1
This atropodiastereoselective transformation gave rise to formed by 12-endo dig ring closure underwent furan cleavage 14
a product 3 incorporating a stilbene, an indole, a chlor- followed by 5-exo trig ring closure 15 to yield the tetracyclic
odimethoxyphenyl substituent, two stereogenic axes and an ketone 16, Scheme 4.
intramolecular hydrogen bond resulting in a 14-membered
The Pattenden syntheses above generated macrocyclic
pseudomacrocycle in the conformation shown, 3 (Scheme 1). intermediates which are an efficient means to the desired ends
This development raises the question of the effect of methoxy that is, the macrocycles are not the nal products. By contrast in
substitution since completely different products are obtained the next few examples, the macrocycles are the intended targets.
when the substitution pattern was changed from 3,5 to 3,4- For example in the synthesis by Endo, the macrocyclic nal
2
9
dimethoxy. The above transformation raises the intriguing products incorporate diamide tethers. Endo, linked two
possibility that a macrocyclic variant of this reaction may be molecules of L-cysteine 19 by means of adipoyl chloride 18. The
a realistic possibility. To the best of our knowledge, macrocyclic corresponding diester diamide was exposed O
synthesis via oxidatively generated tethered amino stilbene 25 C to yield the bisdisulphide macrocycle, 21 (Scheme 5).
in Et N/DMF at
2
3
ꢀ
radical cations, has not previously been reported. To put this
development into a wider context, Boger reported a powerful the work of Mizuno. Parabromobenzaldehyde 22 was exposed
The concept of the tethered stilbene has been illustrated by
10
and versatile Pd(0) mediated indole macrocyclisation that to TiCl
4
/Zn to yield the paradibromo stilbene 23 by McMurry
3
resulted in the synthesis of chloropentin/DEF molecules
coupling. Treatment of 23 with t-BuLi gave the dilithiated
(Scheme 2).
species (24) which then reacted with 1,3-bis[(chlor-
The Boger group noted that free radical and peptide coupling odimethylsilyl)methyl]benzene 25 to produce the trans,trans
3
strategies failed to deliver the macrocycles 5 and 6. For other stilbenophane 26. Photoreaction of 26 gave rise to the tethered
10
examples of palladium mediated heterocyclic/macrocyclic cyclobutane macrocycles 27 and 28. Again to the best of our
4
5
6
construction see the work of Harrowven, Ohno, Martin and knowledge, no stilbene dimers incorporating diamide ethers
7
Parker.
based on succinamide or adipoylamide have been reported and
studied from the point of view of FeCl promoted cyclisations.
This brings us to the next section where this novel concept is
3
a
Department of Chemistry, Faculty of Science, University of Malaya, 50603 Kuala described (our synthetic plan).
Lumpur, Malaysia. E-mail: maryam.alehashem@yahoo.com; azhar70@um.edu.my;
noelhomas@um.edu.my; noelhomas@yahoo.com
b
2. The synthetic plan
Atta-ur-Rahman Institute for Natural Product Discovery, Faculty of Pharmacy,
Universiti Teknologi MARA Selangor Branch, 42300 Puncak Alam, Selangor, Malaysia
The Mizuno study we have just described (Scheme 6) estab-
lished the principle that two stilbenes could be held together by
†
Electronic supplementary information (ESI) available. See DOI:
0.1039/c7ra12534h
1
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Scheme 1 A radical cation mediated synthesis of an indolo stilbene hybrid.
Scheme 2 Boger's application of the Larock annulation to macrocyclic construction.
11
a silane tether in preparation for cycloaddition. Our condence (A). The literature reveals many elegant applications of the
1
2–17
in viability of our diamide tethered Heck precursor strategy was cation radical Diels Aleder reaction
further encouraged by the report of Parker in which the
(Scheme 7).
11
We believed we could adopt diacid chlorides like 30 to
bicyclo-[4.2.0]-octadiene 29 was prepared in racemic form in prepare our novel dimers as described below. Our basic plan is
seven steps. Treatment of 29 with adipoyl chloride, DMAP, shown in Scheme 8.
CH Cl , gave the two adipoylamide octadiene dimers; a racemic
2
2
modication and the C-2 symmetric compound 31. By way of
illustration, when the racemic compound was exposed to the
3
. Results and discussion
antimony hexachloride complex (a cation radical salt), a penta- Although the iodophenyl malonamide dimer 37 could be
cyclic bislactone macrocycle 34 was obtained. This bis lactone prepared in moderate yields (Scheme 9), for reasons we will
was eventually transformed to the natural product (+)-Kingianin revisit later, the attempted double Heck coupling proved to be
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have been tried. These alternatives notwithstanding, we opted
for a revised strategy. In this approach the amino stilbene
monomer was constructed by the Heck procedure followed by
a double acylation with the appropriate diacid chloride. This
revised procedure is depicted below.
The optimum conditions for the Heck, in contrast to our
19
previous experience with various ortho amido stilbenes, was to
dissolve the iodoaniline 35 in dry CH
3
CN under nitrogen with
N and 2-furyl phos-
ꢀ
heating to 80 C. Palladium acetate, Et
3
20
phine were then added in this order followed by 3,4-dime-
thoxystyrene 40. Reuxing continued until the starting material
was consumed. Similar conditions were exploited by Heck in
the course of a synthesis of a more functionalized version of our
amino stilbene.
Scheme 3 Macrocyclic precursors en route Diels Alder reaction.
The double acylation reaction proved to be much more
challenging. In our early attempts malonyl chloride was added
dropwise to a solution of the amino stilbene in dry CH Cl . This
2 2
led to a complex mixture from which, aer chromatography,
only 22% of the desired product could be isolated. The
complications associated with preparing amides by the acid
chloride procedure are by now well known as the extensive the
peptide and related literature clearly indicate. Ketene formation
and associated side reactions are to be expected. Although many
ingenious methods for tacking these problems by activation of
the corresponding carboxylic acids, have been developed, we
found that when the amino stilbene was added slowly dropwise
ꢀ
to malonyl chloride for 1 h at 0 C, we obtained the best yield of
Scheme 4 Pattenden's radical mediated synthesis of a tetracyclic
ketone via macrocyclic precursors.
the corresponding dimer (65%). By means of this improved
procedure the corresponding dimers incorporating succinyl
(
n ¼ 2), glutaryl (n ¼ 3) and adipoyl amides (n ¼ 4) tethers were
prepared in comparable yields.
Mechanistic hypotheses/predictions dependent on radical
cation reactive conformations
3
In Scheme 8, we indicated that 38 when exposed to FeCl would
be expected to undergo polycyclisation/macrocyclisation. The
text “carbon-centred free radicals and radical cations” edited by
21
Forbes in worthy of careful study. We have described the
chemistry of radical cations in a review entitled: the radical
cation mediated cleavage of catharanthine leading to the
vinblastine type alkaloids: implications for total synthesis and
22
drug design. Radical cation/intact olen and diradical cation
pathways (assuming oxidation of both olenic bonds) need to
be considered (Scheme 10).
Scheme 5 Exploitation of adipoyl tethered cysteines in macrocyclic
disulphide synthesis.
In the rst proposed pathway, the stilbene 43 has undergone
single electron transfer oxidation of one of the olenic bonds to
disappointing. We surmised that the coupling of the palladium yield the monoradical cation 44. Intramolecular nucleophilic
reagent to the two amide carbonyls to give a six membered attack by the NH 44 will give rise to the indolyl radical 46 which
0
00
chelate inhibited the oxidative insertion step in the Heck reac- subsequently attacks the intact olen at the C-7 position to
0
0
tion. To the extent that the presence of two NH'S contributes to yield the C-7 macrocyclic radical 47 which undergoes oxidation
this problem, protection of both amide nitrogen by the SEM to the corresponding benzylic carbocation and a second intra-
protecting group in addition to changing both the palladium molecular capture should result in the bisindoline 49,
reagent and the inclusion of a ligand would improve the effi- Scheme 11.
ciency of the Heck coupling probably by promotion of the all
Our speculation regarding diverse pathways for our tethered
important oxidative insertion into the aryl indole bond. An stilbene radical cation continues in Scheme 12. The key inter-
18
alternative reagent combination Pd
2
(dba)
3
/Pd(t-Bu
3
P)
2
could mediate in this case the diradical cation 50 resulting from
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Scheme 6 Stilbenophanes (generated by the McMurry reaction) transannular precursors of the cyclobutane macrocycles.
oxidation of both olenic bonds. In intermolecular variants of formation of the diradical cation 50 (Scheme 12) radical
amino stilbene (or amido stilbene) oxidative dimerisation combination (assumed to precede cyclisation) would give rise to
under electrochemical conditions, a high concentration of the the dication species 51. Double intramolecular capture of the
stilbene radical cation is believed to be present on the electrode dication will yield either the mesobisindoline 52 from the
23,24
surface.
radical cation intact olen dimerisations would appear to be 55 via the threo dicationic intermediate 54 (Scheme 12).
reasonable given the presumption that the radical cation is in Continuing our mechanistic speculation, we see in Scheme
Under conditions of ferric chloride oxidation, erythro intermediate 51 or alternatively, the racemic bisindoline
a low concentration although this is not a hard and fast rule. In 13 the intramolecular example of crossover nucleophilic
any event we are in this report dealing with tethered stilbenes capture, the intermolecular variant of which we have described
25
and therefore it would prudent to keep an open mind. With the previously. The tethered dication must adopt a reactive
Scheme 7 Parker's use of an adipoyl tether for an intramolecular cation radical Diels Alder reaction.
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Scheme 10 Heck coupling/double acylation.
delocalisation and subsequently biaryl coupling 63. By contrast
Scheme 8 Our synthetic plan for the preparation of diamide tethered
stilbenes.
0
0
(Scheme 16), the C(7 ) radical undergoes rapid oxidation [67 to
68] to yield the carbocationic intermediate 68 which undergoes
intramolecular electrophilic aromatic substitution 68 and
rearomatisation leading to 70.
conformation that prohibits direct nucleophilic capture on the
benzylic carbenium ions 56 of the type described in Scheme 12.
The “macrocyclic” bisisoquinolines with cis ring fusion 57
would be the result (Scheme 14).
Preliminary reections on the FeCl promoted cascade
3
reactions
In Scheme 14, we see another example of radical cation
intact olen dimerisation. Intramolecular attack by the radical
When the aminostilbene succinamide 72 was exposed to FeCl3
5
6
8 on the intact olen results in a second benzylic radical [59 to
0] aer intramolecular capture of the benzylic carbocation 59
(in a 1 : 1 molar ratio) in CH Cl , 73 was obtained as the major
2 2
product. A comparison of the NMR spectroscopic features of
starting material and this product is intriguing.
(Scheme 14). Further oxidation and deprotonation would
proceed to yield the indolostilbene hybrid 61. Any strain
inherent in such a structure would be alleviated for higher
values of n (e.g. 3, 4 etc.). A different reactive conformation is
depicted in Scheme 15 [compare 62 (Scheme 15) with 58
In examining the aromatic region of 400 MHz NMR spec-
trum of the proposed structure 73 (Scheme 17) we note that the
overlapping pair of doublets, integrating for three protons, at
6.48 ppm correlate with triplets at 7.18 and 7.3 ppm according
(
Scheme 14)]. In this alternative the radical cation, through the
to the COSY spectrum. The J value of 10.32 Hz is consistent with
0
of the C-7 radical, attacks the intact olen. This sets up the
000
000
000
000
the ortho coupled C(3 ) C(4 ) and C(6 ) and C(5 ) protons of
0
0
a biaryl link as a result of delocalisation C(7 ) radical (not
shown) (Scheme 15). Oxidation and deprotonation gives rise to
the bridged fused 8 : 10 ring system incorporating an indoline
moiety 65.
0
the A ring. The J value of 10.3 Hz is slightly outside the normal
range for such protons it is interesting to note that the C(6 )
and C(3 ) protons of the A 73 have experienced much greater
shielding compared to the starting succinamide 72 and the
corresponding protons of the A ring of the dimer. This is
000
000
0
The cascade sequence depicted Scheme 16 is in contrast to
0
Scheme 15. In the earlier scheme the C(7 ) radical 62 underwent
000
because the C(6 ) proton experiences a repulsive interaction
Scheme 9 Attempted double acylation/double Heck.
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Scheme 11 Intramolecular attack of a radical cation on an intact olefin.
000
with the C(7 ) methine proton (as the physical model reveals) normal values). This is consistent with a less crowded envi-
000
and the C(3 ) proton is in close proximity to the methylene ronment for the A ring system. Overall these correspond to the
protons of the succinamide tether (Fig. 1). On the other hand doublet–triplet–triplet–doublet pattern represented by the A
0
the physical model indicates a more congested environment for and A ortho substituted aniline ring systems. We believe that
0
this A ring system compared with the A ring system (and the correlating doublets at 6.45 and 6.75 ppm correspond to the
0
0
0
compared to the starting stilbene succinamide dimer 72) which protons on the B ring system i.e. C(5 ) H and C(6 ) H (a classic
0
00
000
accounts for the unusual shielding of the C(6 ) and C(5 ) AB pattern). It is worth noting that there are three broad
protons. In the case of the latter, we observe a second set of aromatic singlets at 6.78 and 6.94 ppm with one more hidden
doublets at 6.85 and 6.9d which also correlate with the set of under the broad doublet at 6.5 ppm which integrates for 3
triplets in the region 7.27 to 7.4d. These peaks are more protons. By of comparison, the starting stilbene succinamide
deshielded with coupling constants of 7.24 and 7.28 Hz (more dimer 72 has a doublet at 6.87 ppm corresponding to C(2)–H. By
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Scheme 12 Formation of meso and racemic bisindolines via 51 and threo 54 dicationic intermediates.
contrast for the product 73 there are two broad singlets (at 6.94 of the starting aminostilbene malonamide 72 where the four
and 6.78 ppm) with the third singlet we believe to be hidden methoxymethyl carbons overlap to a degree. It is interesting that
under the broad doublet at 6.48 ppm. These singlets correspond we have two distinctive singlets at 4.2 and 3.4 ppm. We believe
0
000
00
to C(2)–H, C(5)–H and C(2 )–H. We now examine the aliphatic that these singlets correspond to the C(7 )–H and C(7 )–H
region of the spectrum. The four methoxy singlets that cover the protons located at two of the four contiguous asymmetric
region 3.77 to 3.96 ppm indicate the disruption of symmetry in centres. The virtually orthogonal relationship of the protons at
0
0
000
0
the product 73 compared to the starting material 72 (Scheme C(7 )–H, C(7 )–H and C(7 )–H accounts for the appearance of
7). It is noteworthy that in the C spectrum of 73, the four CH
carbons) are clearly visible and partially overlapping at 55.05, the C(7 )–H and C(7)–H protons to appear as doublets. We
1
3
000
0
00
1
3
the C(7 )–H and C(7 )–H protons as singlets. We would expect
(
5
5.99, 55.86 and 55.93 ppm. From an examination of the HMQC suspect that these protons are subsumed under the broad peak
1
3
and C DEPT spectrum. This suggests a disruption of symmetry at 2.06 ppm. This broad peak partly masks a small impurity.
which is all the more evident the C data is compared with that These features are consistent with our proposed structure and
1
3
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Scheme 13 Double intramolecular (cross over capture) of dicationic species 56.
0
Scheme 14 12-endo trig (for n ¼ 1) cyclisation of the C(7 ) radical culminating in the indolostilbene 61.
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0
Scheme 15 11-endo trig for (n ¼ 1) cyclisation of the C(7 ) radical biaryl formation.
account for the at rst surprising upeld shi of these features among others are a consequence of conformational
1
3
protons. We now turn our attention to the C spectrum with effects inherent in the bridged macrocyclic super structure.
0
00
respect to the methine carbons corresponding to C(7 ) and
We ruled out a structure to 57 (Scheme 13) as this is clearly
00
C(7 ). There carbons in the HMQC are found at 47 and 50 ppm a symmetrical structure which would yield two distinctive
respectively. These peaks relate to the proton spectrum where methoxy singlets which would not t the NMR data for our
0
0
000
00
C(7 ) is at 4.2 and C(7 ) at 3.4 ppm. C(7 ) is clearly more macrocycle. The structure 61 (Scheme 14) was also ruled out as
deshielded because of the electron withdrawing effect of the B apart from the methylenes of the succinyl moiety, only two
0
and B aromatic rings. The other two methine carbons can be aliphatic CH signals would be expected (methoxy signals
found under the region 26 to 28 ppm and are thus related to excluded). A physical model demonstrated that 65 (Scheme 15)
the corresponding protons under the broad peak at 2.06 ppm would be two highly strained and this was subsequently ruled
(
from the HMQC) (the carbon 13 peaks are admittedly weak out. Notice that alternative structures 52 and 55 (Scheme 12)
and impurities in that region complicate matters but the can also be excluded as either of these should give rise to only
HMQC places these methine carbons at about 27 ppm). It is two methoxy signals in the NMR spectrum (Fig. 2 and 3).
0
signicant that the C(7) and C(7 ) methine protons are in more
sterically congested environments due on the one hand, to the
0
environment of the succinamide moiety and the A ring and on
4
. Conclusion
0
the other, the B ring in a pseudo 1,3-diaxial interaction with
0
the C(7 ) proton (there is of course another pseudo 1,3-diaxial
Although the evidence presented is not, at this stage incontro-
vertible, we believe the proposed structure 73 is the best t for
the spectroscopic evidence and the evidence of the physical
model. Therefore in the circumstances in which we nd
ourselves, we are compelled to present these signicant results
which suggest that we have here the rst example of a macro-
cyclic bridged indoline generated by exposure of a hitherto
unknown bis amino stilbene succinamide 72 to the single
0
interaction between the C(7) proton and the A ring). This
explains the upeld shi of these methine protons in the
proton spectrum. Notice that the broad peak we have
mentioned at 2.06 ppm most likely includes the N–H which is
more shielded compared to other systems we have studied.
The succinyl protons that appeared as a sharp peak (singlet)
integrating for four protons at 2.87 ppm in the starting stil-
bene succinamide dimer, now appear as a broad multiplet at
electron oxidant FeCl . We hope, in more favourable circum-
stances, to present the results of a more comprehensive inves-
tigation in the future.
3
3
.18 in 73. The broad peak at 2.06 ppm integrates for three
protons (the C(7), C(7 ) and NH protons). These intriguing
0
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Scheme 16 11-endo trig (n ¼ 1) ring closer, oxidation, electrophilic aromatic substitution leading to 70.
Fig. 1 Two views of the physical model of 73.
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1
Fig. 2 H NMR (CDCl
3
, 400 MHz) spectrum of compound bis(2((E)-(3,4-dimethoxystyryl)phenyl)succinamide).
1
Fig. 3 H NMR (CDCl
3
, 400 MHz) spectrum of compound (73) Scheme 17.
in Hz. Mass spectra were measured using Agilent 6530 Accurate
Mass Q-TOFLC/MS system.
5
. Experimental
General remarks
Unless otherwise noted, materials were purchased from
commercial suppliers and used without purication. Column
chromatography was performed using Merck silica gel (0.040–
Phase I: preparation of (E)-2-(3,4-dimethoxystyryl)aniline (71)
(see Table 1)
In a dry, two necked ask, the desired 2-iodo aniline (1 g,
0.063). IR spectra were recorded on a perkinElmer spectrum 400
ꢂ3
4
.56 ꢁ 10 mol) was dissolved in dry CH
3
CN (8 ml) and stirred
FTIR/FT-FIRspectrophotometer were used; for centrifugal
chromatography, Merck silica gel 60 PF254 containing gypsum
were used. Nuclear magnetic resonance (NMR) spectra were
obtained on a JEOL FT-NMR BRUKER AVN 400 and JEOL FT-
NMR LA400 spectra are reported in units of ppm on the scale,
relative to chloroform and the coupling constants are given
ꢀ
under nitrogen. The solution was heated at 80 C and reuxed
for
a
few minutes. Palladium(II) acetate (0.0102 g,
ꢂ5
4
4
3
.56 ꢁ 10 mol) was added, followed by triethylamine (2.5 ml,
ꢂ3
ꢂ4
.56 ꢁ 10 mol) and 2-furyl phosphine (0.042 g, 1.82 ꢁ 10 mol).
ꢂ3
-4 Dimethoxystyrene (0.93 g, 5.9802 ꢁ 10 ) was then added
to the reaction ask. The reaction mixture was heated under
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Scheme 17 A bridged macrocyclic indoline diamide.
reux for 3 h and stirring continued overnight at room. When the Phase III: preparation of bis(2((E)-(3,4-dimethoxystyryl)
TLC indicated the complete consumption of starting material, the phenyl)succinamide) (72) (see Table 1)
mixture was extracted with ethyl acetate (3 ꢁ 30 ml) and
ꢂ4
To a stirred solution of the succinyl chloride (0.030 g, 1.95 ꢁ 10
washed distilled water (3 ꢁ 30 ml). The resulting organic extracts
were combined and solvent was removed under reduced pressure
to yield crude product. Purication by column chromatography
ꢂ4
mol) and DMAP (0.052 g, 4.3 ꢁ 10 mol) in CH Cl (4 ml) was
2
2
ꢂ4
ꢀ
added amino stilbene (0.1 g, 3.9 ꢁ 10 mol) drop wise at 0 C.
The stirring was continued overnight and the reaction allowed to
warm to room temperature. When the TLC indicated the
complete consumption of starting material, the reaction mixture
was extracted with ethyl acetate (2 ꢁ 30 ml) and the washed with
distilled water (2 ꢁ 30 ml). The resulting organic extracts were
combined and evaporated under reduced pressure to yield crude
product. Purication by column chromatography (7 : 3 hex-
(
7 : 3 hexane : ethyl acetate) afforded the desired product (71%
yield).
E)-2-(3,4-Dimethoxystyryl)aniline. H NMR (CDCl
MHz) d 3.90 (3H, s), 3.93 (3H, s), 6.72, (1H, d, J ¼ 7.8 Hz), 6.81
1H, t, J ¼ 7.8 Hz), 6.86 (2H, d, J ¼ 8.2 Hz), 6.94 (1H, d, J ¼ 16.0
Hz), 7.03 (1H, d, J ¼ 16.0 Hz), 7.09 (1H, t, J ¼ 7.8 Hz), 7.04 (2H, d,
1
(
3
, 400
(
1
3
1
J ¼ 8.2 Hz), and 7.38 (1H, d, J ¼ 7.6 Hz); C{ H} NMR (CDCl
3
,
ane : ethyl acetate) afforded the desired product (67% yield).
1
00 MHz) d 55.93, 55.98, 108.9, 111.04, 116.2, 117.73, 128.5,
27.29.5, 124.15, 127.2, 128.39, 130.21, 130.81, 143.81, 148.9.
1
((E)-2-(3,4-Dimethoxystyryl)phenyl)succinamide.
H NMR
1
(CDCl
3
, 400 MHz) d ppm 6.86 (s), 6.76 (d, J ¼ 8.2 Hz), 6.92 (d, J ¼
8
.2 Hz), 6.89 (d, J ¼ 16 Hz), 7.02 (d, J ¼ 7.8 Hz), 7.31 (t, J ¼
7
.8 Hz), 7.28 (t, J ¼ 7.8 Hz), 7.64 (d, J ¼ 7.8 Hz), 6.56 (d, J ¼ 16
Phase II: preparation of bis (2-(E)-(3,4-dimethoxystyryl)phenyl)
malonamide (42) (see Table 1)
13
Hz), 2.87 (d, J ¼ 6.68 Hz), 3.82 (S), 3.83 (S). C NMR (CDCl
3
, 100
MHz) d ppm: 135.6, 109.8, 149.0, 111.2, 119.8, 128.8, 128.9,
To a stirred solution of the malonyl chloride (0.027 g, 1.95 ꢁ 128.5, 128.2, 129.7, 127.0, 172.3, 28.68, 55.98.
ꢂ4
ꢂ4
1
0
mol) prepared as above, and DMAP (0.052 g, 4.3 ꢁ 10
mol) in CH Cl (4 ml), was added slowly dropwise amino
2
2
ꢂ4
ꢀ
Phase 4: preparation of bis(2((E)-(3,4-dimethoxystyryl)phenyl)
glutaramide) (74) (see Table 1)
stilbene (0.1 g, 3.9 ꢁ 10 mol) at 0 C. The stirring was
continued overnight and the reaction allowed warm to room
temperature when TLC indicated complete consumption was To a stirred solution of the glutaryl chloride (0.030 g, 1.95 ꢁ
ꢂ4
ꢂ4
extracted with ethyl acetate (2 ꢁ 30 ml) and the washed with 10 mol) and DMAP (0.052 g, 4.3 ꢁ 10 mol) in CH
2
Cl
2
(4 ml)
ꢂ4
distilled water (2 ꢁ 30 ml). The resulting organic extracts were was added slowly dropwise amino stilbene (0.1 g, 3.9 ꢁ 10
ꢀ
combined and evaporated under reduced pressure to yield mol) drop wise at 0 C. The stirring was continued overnight
crude product. Purication by column chromatography (7 : 3 and the reaction allowed to warm to room temperature. When
hexane : ethyl acetate) afforded the desired product (65% the TLC indicated the complete consumption of starting
yield).
material, the reaction mixture was extracted with ethyl acetate
1
(
(E)-2-(3,4-Dimethoxystyryl)phenyl)malonamide.
H
NMR (2 ꢁ 30 ml) and then washed with distilled water (2 ꢁ 30 ml).
(CDCl
3
, 400 MHz) d ppm: 7.04 (s), 6.69 (d, J ¼ 8.2 Hz), 6.93 (d, J ¼ The resulting organic extracts were combined and evaporated
8
.2 Hz), 7.05 (d, J ¼ 16 Hz), 7.52 (d, J ¼ 7.8 Hz), 7.19 (t, J ¼ 7.8 under reduced pressure to yield crude product. Purication by
Hz), 7.23 (t, J ¼ 7.8 Hz), 7.75 (d, J ¼ 7.8 Hz), 6.84 (d, J ¼ 16 Hz). column chromatography (7 : 3 hexane : ethyl acetate) afforded
1
3
C NMR (CDCl , 100 MHz) d ppm: 133.7, 108.6, 140.0, 141.9, the desired product (62% yield).
3
1
1
1
20.57, 120.34, 130.02, 130.04, 124.21, 126.16, 127.7, 130.04,
31.12, 165.62, 44.83, 55.69, 55.87.
((E)-2-(3,4-Dimethoxystyryl)phenyl)glutaramide.
H
NMR
(CDCl
3
, 400 MHz) d 6.92 (S), 6.83 (d, J ¼ 8.2 Hz), 6.96 (d, J ¼
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.2 Hz), 6.93 (d, J ¼ 16 Hz), 7.03 (d, J ¼ 7.7 Hz), 7.32 (t, J ¼ 7.7
RSC Advances
8
Acknowledgements
Hz), 7.37 (t, J ¼ 7.7 Hz), 7.68 (d, J ¼ 7.7 Hz), 6.62 (d, J ¼ 16 Hz),
1
3
1
2
.84 (t, J ¼ 6.52 Hz), 3.87 (S), 3.90 (S), C{ H} NMR (CDCl , 100 The authors would like to thank University Malaya for the
3
MHz) d 135.6, 109.6, 149.0, 149.2, 111.3, 121.1, 130.2, 128.8, Postgraduate Research Grant (PPP)-Research PG178-2015A,
1
3
28.9, 129.17, 129.01, 129.01, 128.19, 126.74, 123.6, 172.3, Fundamental Research Grant Scheme (FRGS) FP044-2015A
3.14, 27.5, 55.94, 55.98.
and the Ministry of Higher Education (MOHE) Malaysia (HIR-
05) for nancial support.
0
Preparation of bis(2((E)-(3,4-dimethoxystyryl)phenyl)
adipamide) (75) (see Table 1)
References
ꢂ4
To a stirred solution of adipoyl chloride (0.030 g, 1.95 ꢁ 10
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2
2
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4
5
6
(7 : 3 hexane : ethyl acetate) afforded the desired product (63%
yield).
1
(
E)-2-(3,4-Dimethoxystyryl)adipamide amides.
H
NMR
(
CDCl
3
, 400 MHz) 7.06 (S), 6.87 (d, J ¼ 8.2 Hz), 7.06 (d, J ¼ 8.2
Hz), 6.91 (d, J ¼ 16 Hz), 7.48 (d, J ¼ 7.8 Hz), 7.17 (t, J ¼ 7.8 Hz),
7
.28 (t, J ¼ 7.8 Hz), 7.82 (d, J ¼ 7.8 Hz), 7.0 (d, J ¼ 16 Hz), 2.37 (d,
1
3
1
J ¼ 6.56 Hz), 2.42 (d, J ¼ 84 Hz), 3.91 (S), 3.94 (S). C{ H} NMR
7
8
9
(CDCl , 100 MHz) d 138.2, 121.69, 149.0, 150.0, 111.33, 119.89,
3
1
3
32.53, 130.3, 133.7, 126.91, 125.46, 123.98, 132.53, 172.3,
3.93, 25.17, 25.17, 55.98, 55.99.
7
847–7850.
3
The FeCl promoted oxidative cascade reactions of the
aminostilbene succinamide dimer (73)
1
0 H. Maeda, K.-i. Nishimura, K. Mizuno, M. Yamaji,
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9
701.
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01.
ꢂ4
1
(
.58 ꢁ 10 mol) was dissolved in CH Cl (25 ml). FeCl $6H O
2
2
3
2
1
1
1
1
1
1
1
1
1
ꢂ4
0.042 g, 1.58 ꢁ 10 mol) was added to the mixture under
4
nitrogen. The mixture was stirred at room temperature and
monitored by TLC. Aer the consumption of the starting
malenal, saturated ammonium chloride was added to the
reaction mixture followed by extracted with ethyl acetate (3 ꢁ
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2
5 ml). The combined organic fractions were dried over
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matography (7 : 3 hexane : ethyl acetate) gave rise to a major
5
66.
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7
product in 61% yield.
1
Aminostilbene succinamide dimer (73). H NMR (CDCl
3
, 400
1
MHz) 6.94 (S), 6.40 (d, J ¼ 7.80 Hz), 6.71 (d, J ¼ 7.80 Hz), 7.38 (d,
J ¼ 7.64 Hz), 6.78 (d, J ¼ 7.64 Hz), 7.15 (t, J ¼ 7.64 Hz), 7.26 (t, J ¼
1
1
3
1
7
(
.64 Hz), 6.87 (d, J ¼ 7.64 Hz), 6.85 (S), 6.48 (S). C{ H} NMR
3
CDCl , 100 MHz) d 176.3, 132.6, 132.44, 130.28, 129.9, 129.5,
2
1
5
28.6, 128.3, 127.9, 126.8, 122.0, 122.8, 112.8, 110.7, 109.9, 55.0,
5.9, 55.8, 55.9, 51.8, 49.7, 37.1, 37.1, 33.9.
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5
660.
Conflicts of interest
2
0 C. B. Ziegler Jr and R. F. Heck, J. Org. Chem., 1978, 43, 2941–
There are no conicts to declare.
2946.
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24 E. Steckhan, J. Am. Chem. Soc., 1978, 100, 3526–3533.
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2520 | RSC Adv., 2018, 8, 2506–2520
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