Synthesis of highly functionalized [3]dendralenes and their Diels-Alder reactions displaying unexpected regioselectivity

Article abstract of DOI:10.1039/c6ra01729k

Acyclic tetrasubstituted [3]dendralenes stable towards D-A cyclodimerization were prepared by the double olefination of substituted dienyl phosphonates with dimethylsulfonium methylide, followed by H-W-E olefination of the formed butadienylphosphonoacetates with aldehydes. The X-ray structure of a [3]dendralene with a 4-position benzyl substitution revealed that an electron-rich diene exists in the s-trans conformation, leading to the stability. This structural preference of dendralenes leads to an unusual regioselectivity in the D-A reaction, wherein a deactivated diene participated in the process and displayed endo selectivity. The steric bulk of the groups at the 2 and 4 positions govern the regioselectivity and dominates the electronic effects. For the dendralenes possessing a 4-methyl substituent, the electronically rich diene participated in the D-A reaction. These D-A adducts failed to undergo further cycloaddition owing to steric crowding, which resulted in gauche conformation of the diene, as evidenced by X-ray structures of the adducts.

Full text of DOI:10.1039/c6ra01729k

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Synthesis of highly functionalized [3]dendralenes and their Diels-
Alder reaction displaying unexpected regioselectivity
Gonna Somu Naidua, Rekha Singha, Mukesh Kumarb and Sunil K. Ghosh*a
a Bio-Organic Division
bSolid State Physics Division
Bhabha Atomic Research Centre, Trombay, Mumbai 400085, India
*Corresponding author
Tel: +91-22-25595012; Fax: +91-22-25505151
E-mail: ghsunil@barc.gov.in
Abstract
Acyclic tetrasubstituted [3]dendralenes stable towards D-A cyclodimerization have been
prepared by double olefination of substituted dienyl phosphonates with dimethylsulfonium
methylide followed by H-W-E olefination of the formed butadienylphosphonoacetates with
aldehydes. X-ray structure of a [3]dendralene with 4-position benzyl substitution reveals that
electron rich diene exists in s-trans conformation leading to stability. This structural preference
of dendralenes leads to an unusual regioselectivity in the D-A reaction wherein deactivated diene
participated in the process displaying endo selectivity. The steric bulk of the groups at 2 and 4
positions governs the regioselectivity and dominates the electronic effects. For dendralenes
possessing 4-methyl substituent, the electronically rich diene participated in D-A reaction. These
1

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D-A adducts failed to undergo further cycloaddition owing to steric crowding which results in
gauche conformation of the diene as evidenced by X-ray structures of the adducts.
Introduction
Depending upon the type of atom connectivity (unbranched or branched, cyclic or acyclic), four
fundamental hydrocarbon families of oligoalkene structures are possible as presented in Fig.1.
Dendralenes are the first family of the branched oligoalkenes which feature cross conjugation.1-6
They did not receive proper attention primarily due to their unpredictable stability and lability for
Diels-Alder (D-A) cyclodimerization or oligomerization. Recently they have gained popularity
as they display unique properties different from normal oligoenes.7-16 This created interest in
various fields such as polymer chemistry,7-10 electro chemistry,11-13 material chemistry14,15 and
theoretical chemistry.16 For synthetic chemists, dendralenes are fascinating molecules because
they own a huge potential that can be harnessed by subjecting them to tandem D-A reactions also
known as diene-transmissive D-A (DTDA)17 sequences for quick generation of complex
multicyclic scaffolds from simple acyclic substrates in an atom economical manner. Also several
bioactive natural products18-21 possess dendralenes as core structures.
n
n
Linear polyene
Cyclic annulene
Dendralene
Radialene
3
1
2
4
Fig. 1 Fundamental classes of alkenic hydrocarbons
2

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Early synthetic methods of dendralenes comprised of various classical approaches of
olefin synthesis viz. pyrolysis,22-24 Mitsunobu dehydration,25 β-elimination26 and thermal
decomposition of vinyl sulfolenes27,28 which often involved harsh reaction conditions. Of late
many groups have reported the synthesis of dendralenes mediated by various transition metals.29-
47
Majority of these methods lead to unsubstituted or scantly substituted dendralenes. Some of
the approaches lead to [3]dendralenes functionalized in cyclic systems.34-36 Only a handful of
methods yield amply substituted acyclic [3]dendralenes such as dimerization of allenes,37,38
elimination of 1,3-dienic allylic carbonates39 and enyne metathesis.40-42
Earlier we had reported48 a novel olefination methodology using Corey-Chaykovsky
dimethylsulfonium methylide (DMSM) 549 with various activated olefins providing interesting
products.50-57 Later this methodology was augmented for sequential double olefination of vinyl
phosphonates to provide substituted 1,3-dienes with high regio- and stereo-selectivity.51,52
Subsequently, we employed this methodology for the intended synthesis of 1,5-diaryl-2-
alkoxycarbonyl [3]dendralenes
6
from dienyl phosphonates
7
via 1,3-butadien-2-
ylphosphonoacetate intermediate 8 as depicted in Scheme 1.58 Unfortunately the desired
[3]dendralenes could not be isolated owing to their high reactivity. Under the reaction
conditions, these functionalized [3]dendralenes underwent an in situ D-A cyclodimerization to
provide highly functionalized cyclohexenes 9 with excellent regio- and stereo-control. Since
then, we were in the process of optimizing59 the substituents on the [3]dendralene skeleton which
would enhance their stability thus granting them at our disposal for isolation, characterization
and reactivity studies especially for D-A reaction. Herein we report the aforementioned
sequential double olefination process on appropriately substituted dienyl phosphonates for the
synthesis of highly functionalized [3]dendralenes that are stable against D-A cyclodimerization
3

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under ambient conditions and their D-A reaction with N-methylmaleimide (NMM) as a
representative dienophile.
CO2Et
Ph
P(O)(OCH2CF3)2
7
Me2S=CH2
5
3'
1. NaH
5
1
2. ArCHO
2
CO2Et
4
Ph
3
Ar
Ph
Ref. 58
CO2Et
P(O)(OCH2CF3)2
8
6
1. NaH
2. HCHO
Self D-A
dimerization
CO2Et
Ph
Ar
Ph
Ph
CO2Et
CO2Et
10
Ar
Short lived
9
Scheme 1 Synthesis of [3]dendralenes
Results and Discussion
Lately, Sherburn and coworkers have reported the studies pertaining to the stability and
reactivity of various thinly substituted dendralenes.60,61 Their findings reveal that odd
dendralenes are more reactive in comparison to their even counterparts. The observation has also
been corroborated by DFT calculations which suggest that odd dendralenes prefer D-A reactive
s-cis conformation whereas even dendralenes predominantly remain in D-A unreactive s-trans
conformation. The study also divulges that the conjugating terminal substituents (at C1 or C5)
accelerate the rate of D-A cyclodimerisation of [3]dendralenes contrary to the substituents at C2,
C3 and C4 which have little effect on the dimerisation reactivity.60
4

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In cognizance with the above facts to accomplish our goal of synthesizing functionalized
and stable [3]dendralenes, we decided to exclude one of the terminal substituent on our earlier
reported58 [3]dendralenes 6 to obtain 2,5-disubstituted [3]dendralenes. The corresponding
[3]dendralene 10 was synthesized from dienic phosphonate 7 via 1,3-butadien-2-
ylphosphonoacetate 8 intermediate and formaldehyde was used as the aldehyde component
(Scheme 1). Interestingly, the [3]dendralene 10, although short lived, could be isolated and
characterized by 1H NMR. This exemplified the dramatic effect of substituent on the reactivity
and stability of the [3]dendralenes akin to Sherburn’s observation.
For further enhancement of the stability of [3]dendralenes, we decided to add a
substituent at 4-postion of our earlier reported58 [3]dendralenes 6 which would bestow 1,2,4,5-
tetrasubstituted [3]dendralenes 11. At the outset, we decided to introduce a benzyl substituent at
4-position of the reported [3]dendralenes 6. For this, p-anisaldehyde was reacted with 3-
phenylpropanal in the presence of catalytic amount of pyrrolidine and propionic acid62 which
provided α,β unsaturated aldehyde 14a (Scheme 2). Piperidinium benzoate catalysed
Knoevenagel condensation of 14a with ethyl bis-(2,2,2-trifluroethyl)-phosphonoacetate
furnished the desired dienyl phosphonate 13a as an inseparable 1/1 mixture of two geometrical
1
isomers of the double bond attached to phosphonate group as judged from H NMR. When this
phosphonate 13a was reacted with DMSM 5 generated using Me3SI and n-BuLi in THF, the
desired olefination took place to give the appropriately substituted butadien-2-
ylphosphonoacetate 12a. The phosphonoacetate 12a was then reacted with sodium hydride
followed by benzaldehyde in THF which provided the 1,2,4,5-tetrasubstituted [3]dendralene 11a.
We were gratified to note that the dendralene 11a was stable towards D-A cyclodimerization at
ambient temperature. Subsequently, the butadien-2-ylphosphonoacetate 12a was reacted with a
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few more aldehydes under standard HWE conditions to give the desired 1,2,4,5-tetrasubstituted
[3]dendralenes (11b-e) (Scheme 2) with one of the terminal aryl group (5 position) having an
electron donating substituent (4-OMe) in moderate yields but with high stereoselectivity except
for the product 11e where ethyl glyoxalate was used as the aldehyde component. The dendralene
11e was obtained as a separable mixture of Z and E diastereoisomers (11ea:11eb, 60:40) for the
double bond generated due to H-W-E reaction.
To examine the electronic effect of substitution on terminal aryl rings on the reactivity of
1,2,4,5-tetrasubstituted [3]dendralenes, we decided to have mildly electron withdrawing 3-chloro
substituent at the 5-position aryl ring. To achieve this, 2-benzyl-3-(3-chlorophenyl) prop-2-enal
14b was converted to dienic phosphonate 13b as an inseparable 6:4 mixture of two
diastereoisomers and then to butadien-2-ylphosphonoacetate 12b as shown in Scheme 2. This
phosphonoacetate 12b upon reaction with different aldehydes provided another series of 1,2,4,5-
tetrasubstituted [3]dendralenes (11f-j) in moderate yields with very high selectivity except for
11j which was produced as an inseparable mixture of Z/E diastereoisomers (double bond
substituted with ester groups) in a ratio of 64/36. All these product dendralenes are stable
towards D-A cyclodimerization at ambient temperature.
6

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O
1. NaH, THF
Pyrrolidine,
EtCO2H,
75 oC, 1 d
H
R1
CO2Et
2. R1CHO,
30 oC,1 d
(F3CH2CO)2(O)P
(F3CH2CO)2(O)P
R
CO2Et
H
CO2Et
O
5, THF,
-10 oC, 1 h
R
EtO2C
Ar
P(O)(OCH2CF3)2
R
R
H
piperidinium
benzoate, toluene,
reflux, 2 d
ArCHO
Ar
Ar
13
Ar
R
14
12
11
14a: R = Bn; Ar = 4-MeOC6H4-; 32%
14b: R = Bn; Ar = 3-ClC6H4-; 82%
14c: R = Me; Ar = 4-MeOC6H4-; 75%
13a: R = Bn; Ar = 4-MeOC6H4-; 85%
13b: R = Bn; Ar = 3-ClC6H4-; 65%
13c: R = Me; Ar = 4-MeOC6H4-; 79%
12a: R = Bn; Ar = 4-MeOC6H4-; 87%
12b: R = Bn; Ar = 3-ClC6H4-; 79%
12c: R = Me; Ar = 4-MeOC6H4-; 86%
Br
Cl
Ph
Ph
X
EtO2C
EtO2C
Ph
EtO2C
EtO2C
EtO2C
Ph
Y
Ph
Ph
Ph
MeO
MeO
MeO
MeO
MeO
X = CO2Et, Y = H; 11ea 30%
X = H, Y = CO2Et; 11eb 18%
11a 30%
11b 41%
11c 35%
11d 31%
Br
OMe
Ph
Ph
CO2Et
X
Ph
EtO2C
EtO2C
EtO2C
EtO2C
EtO2C
Me
Y
Cl
Cl
Cl
Cl
Cl
Ph
Ph
Ph
Ph
11i, 27%
Ph
MeO
11g, 47%
11j, 40%
11f, 35%
11h, 15%
11k, 45%
X = CO2Et, Y = H ; 64%
X = H, Y = CO2Et ; 36%
Scheme 2 Synthesis of densely substituted isolable [3]dendralenes
Our next goal was to change the 4-position substituent to a sterically less demanding
substituent like a methyl group instead of benzyl. To achieve this, prop-2-enal 14c was converted
to 4-methyl substituted [3]dendralene 11k via butadien-2-ylphosphonoacetate 12c as depicted in
Scheme 2. Like previous cases, phosphonate 13c was also formed as an inseparable 1/1 mixture
of diastereoisomers and the product dendralene 11k was also stable at room temperature.
The structure of the dendralene 11a was confirmed by single crystal X-ray
crystallography (Fig. 2) which also revealed its interesting conformational preferences in the
solid state. The dienic part encompassing double bonds at 1 and 3 positions are in quasi s-cis
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conformation while the diene component covering double bonds at 3 and 4 positions are in s-
trans conformation. DFT calculations60 have shown that in unsubstituted [3]dendralenes, one
dienic component exists predominantly as s-cis conformation and the other dienic unit as s-trans
conformation. The present X-ray crystal structure of dendralene 11a confirms it for the first time.
Fig. 2 X-Ray structure of 11a
As mentioned earlier the conjugating terminal substituents (at C1 or C5) are known to
have a marked accelerating influence on the cyclodimerisation rate of [3]dendralenes whereas
the substituents at C2, C3 and C4 have little effect on the dimerization reactivity.60,61 In our earlier
attempted [3]dendralenes 6 (Scheme 1),58,59 there were two conjugating terminal substituents at
C1 and C5 and one substituent at C2 position. None of those dendralenes could be isolated
because they were unstable and underwent D-A cyclodimerisation. In the present study, the
[3]dendralene 10 had one conjugating terminal substituent (C5) and one substituent at C2 position
1
which was short lived, but could be isolated and H NMR spectrum could be recorded as a
signature of its formation. Interestingly, [3]dendralenes 11a-11l having two conjugating terminal
substituents at C1 and C5 have been stabilized by the two substituents at C2 and C4 positions.
Thus it can be inferred that the substituents at C2, C4 have a substantial influence on rendering
the stability to [3]dendralenes (Fig. 3).
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Present work
Ar
Ar
Ph
Ar
CO2Et
Ph
Ph
Earlier work( ref. 58,59)
Ph
Ph
Ar
CO2Et
CO2Et
Present work
Ar
CO2Et
Ph
CO2Et
CO2Et
Ph
Ph
CO2Et
Ph
N
Ar
Ph
CO2Et
CO2Et
Ph
Ar
Ph
Ar
Ph
Ph
O
O
Me
CO2Et
Ar
Me
OH
non-isolable
short lived
stable
Stability
Fig. 3 Stability of substituted [3]dendralenes
After accomplishing our goal of obtaining 1,2,4,5-tetrasubstituted [3]dendralenes 11a-k
which are stable towards D-A cyclodimerization, we next aimed to examine their reactivity for
intermolecular D-A reaction with NMM as dienophile. When 1,5-diaryl-2-ethoxycarbonyl-4-
benzyl [3]dendralene 11b was reacted with 1.0 molar equivalent of NMM in refluxing benzene,
it furnished a mixture of stereoisomeric D-A adducts out of which the major stereoisomer 15
(69%) was easily separated from the mixture where as the minor isomers could not be identified
(Scheme 3). This major isomer 15 was found to be endo-isomer as confirmed by X-ray
crystallography (Fig. 4). It is noticeable that the D-A reaction had taken place at the diene ‘A’
incorporating double bonds at 1,3 positions thus indicating that these two double bonds exist in
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s-cis conformation in solution also as was observed in solid state by the X-ray structure (Fig. 2).
It is noteworthy that the electronically rich diene‘B’ encompassing double bonds at 3,4 positions
is unable to participate in the D-A reaction owing to s-trans conformation that was preferred due
to steric bulk of the benzyl group which results in high barrier of s-trans ꢀ s-cis interconversion.
This allowed the electronically deactivated diene to participate in the D-A reaction.
Ph
OH
Me
Br
HA
H
O
HA
R2
4
R1
2
N
MeO
O
O
H
Ar2
Ar1
Me
3
H
H
NMM
NMM
19:
21:
β
α
-HA
-HA
EtO2C
Ph
5
1
A
B
+
11l
11
11b
11g
N Me
Ar2
Ph
O
H
H
H
Regioselectivity
O
HO
N
Me
15: Ar2 = 4-BrC6H4-
16: Ar2 = 3-ClC6H4-
11k
NMM
O
Me
20
MeO
Ph
Ph
CO2Et
H
O
H
H
H
EtO2C
Me
N
Me
H
O
O
Me
H
O
MeO
N
MeO
Me
18
17
Dendralene
Ar1
R1
R2
Ar2
Product from
Diene A
Product from
Diene B
-
4-BrC6H4-
4-BrC6H4-
Ph
CO2Et
CO2Et
CO2Et
CH2OH
Bn
Bn
Me
Me
4-MeOC6H4-
3-ClC6H4-
15 (69%)
16 (62%)
18 (41%)
20 (10%)
11b
11g
11k
11l
-
4-MeOC6H4-
4-MeOC6H4-
17 (48%)
19 (65%) endo
21 (4%) exo
Ph
Scheme 3 Diels–Alder reaction of [3]dendralenes
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Fig.4 X-Ray structures of 15, 16
In order to examine if any stereoelectronic effect is operating from the conjugating aryl
substituents at 1 or 5 positions on the D-A reaction, [3]dendralene 11g was reacted with 1.0
molar equivalent of NMM in refluxing toluene which furnished a mixture of D-A adducts. From
the mixture of products, the major diastereoisomer 16 was obtained in 62% yield (Scheme 3) as
endo-isomer which was confirmed by single crystal X-ray crystallography (Fig. 4). The minor
isomers could not be identified. Once again the DA reaction took place at the diene‘A’
incorporating double bonds at 1,3 positions thus indicating that these two double bonds exist in
s-cis conformation in solution state which is sterically less demanding. The electronic effect of
substituent at 5-position aryl group did not play any role because the diene‘B’ incorporating
double bonds at 3,4 positions comprising this substituent probably preferred s-trans
conformation.
To quell the steric effect, 4-methyl substituted [3]dendralene 11k was reacted with NMM
which resulted in formation of regioisomeric adducts 17 and 18 (Scheme 3) in a ratio of 54:46,
respectively. This suggests that now the steric hinderence was moderated thus both the dienes
‘A’ and ‘B’ have very similar preference for s-cis conformation and could participate in the D-A
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reaction. The D-A adducts 17 and 18 could not be separated. Thus, their structural analysis was
performed on a 54:46 mixture of the two regioisomers, where most of the signals were clearly
distinguishable. The stereochemistry and regiochemistry of the products 17 and 18 was
ascertained on the basis of COSY and ROESY interactions from the inseparable mixture (for
detail interpretations, see the SI). For isomer 17, a strong ROESY interactions between protons
at δ 3.85 (ArCH) ↔ δ 7.08 (ortho H of Ar), and between δ 6.77 (PhCH) ↔ δ 7.40-7.31 (ortho H
of Ph) (Fig. 5) indicate that diene component comprise of double bonds at 3,4 positions
participated in the D-A reaction. The ROESY interaction between protons at δ 3.85 (ArCH) and
δ 3.17-3.13 (NCOCHCH2) further supports for the endo addition of NMM (Fig. 5). For isomer
18, strong ROESY interactions between protons at δ 4.56 (PhCH) ↔ δ 7.09 (ortho H of Ph) and
between δ 6.27 (ArCH) ↔ δ 7.30-7.18 (ortho H of Ar) indicate that diene component comprising
of double bonds at 1,3 positions participated in D-A reaction and interaction between protons at
δ 4.56 (PhCH) ↔ δ 3.23-3.19 (NCOCHCH2) suggests the endo nature of the product (Fig. 5).
δ
7.40-7.31
6.77
H
CO2Et
H
δ
7.09
Me
H
H
δ
δ
6.27
O
δ
4.56
H
H
H
Me
3.85 H
EtO2C
H
δ
7.30-7.18
H
δ
δ 3.17-3.13
N
O
H
O
N
Me
H
MeO
O
δ
3.23-3.19
MeO
Me
δ
7.08
17
18
Fig. 5 ROESY interactions of 17 and 18
Despite our repeated efforts, these Diels-Alder adducts 15, 16 and the mixture of 17 and
18 did not undergo further D-A reaction with several dienophiles. This failure could be chiefly
attributed to the stereoelectronic effects of substituents to adopt an s-cis conformation of the
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dienic system in the D-A adducts which is a prerequisite for D-A reaction. The X-ray crystal
structures of 15 and 16 also supported this fact where it is clearly seen that the diene component
is in a gauche conformation. To address the electronic effect, the ester functionality in the
dendralene 11k was reduced using DIBAL-H to obtain a new alcoholic [3]dendralene 11l
(Scheme 4).
Ph
Ph
DIBAL-H,
CH2Cl2,
-78oC, 1 h
CO2Et
OH
Me
Me
80%
MeO
MeO
11k
11l
Scheme 4 Preparation of [3]dendralene 11l
When 11l was reacted with 1.0 molar equivalent of NMM in refluxing toluene, it
furnished a mixture of three isomers 19, 20 and 21 in a ratio of 80:14:6 (Scheme 3) respectively
from which all the individual isomers are separated by chromatography. The structure of 19 was
established by single crystal X-ray crystallography (Fig. 6). The structure of 21 was assigned by
1
studying the H NMR of 19 and 21. Both the spectra showed similarity except that ArCH in 21
was a singlet thus suggesting trans relationship of the two protons viz. ArCH and ArCHCH. The
structure of 20 was ascertained on the basis of COSY and ROESY interactions. The positive
ROESY interactions between protons at δ 4.47 (PhCH) ↔ δ 7.36 (ortho H of Ph), between δ
6.48 (ArCH) ↔ δ 7.28 (ortho H of Ar), between δ 4.47 (PhCH) ↔ 4.37(HOCHAHB), and
between δ 4.47 (PhCH) ↔ δ 3.79 (HOCHAHB) are indicative of the depicted regiochemistry
whereas the absence of ROESY interaction between protons at δ 4.47 (PhCH) ↔ δ 2.53-2.45
(NCOCHCH2) suggests exo nature of the product (Fig. 7). The main difference between
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structures 18 (Fig. 5) and 20 (Fig. 7) is the stereochemistry at the ring junction. In case of
compound 18, we could get a positive ROESY peak due to cis disposition of protons at the ring
junction and benzylic proton. Therefore in case of compound 20, on the basis of analogy from
the absence of ROESY peak between protons at δ 4.47 (PhCH) ↔ δ 2.53-2.45 (NCOCHCH2) we
concluded that the protons at ring junction are trans with respect to the benzylic proton. This
apparently exo product 20 probably is not due to exo-mode D-A reaction but due to small amount
of double bond isomerisation during heating which then underwent endo-selective D-A with
NMM. No endo-isomer with this regioselectivity was found in the reaction mixture which
suggests that the diene ‘A’ (Scheme 3) with depicted stereochemistry preferred for s-trans
conformation. Thus the stereoselectivity i.e. endo:exo ratio (19:21) was 93:7, whereas the
regioselectivity (19,21:20) was 86:14. It is interesting to note that diene ‘B’ (Scheme 3)
encompassing double bonds at 3, 4 positions predominantly participated in the D-A reaction
unlike in dendralenes 11k, 11b and 11g. Hence there was a switch over of regioselectivity from
diene ‘A’ to diene ‘B’ (Scheme 3) as the substituents on the [3]dendralenes were changed.
Fig. 6 X-Ray structure of 19
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δ
7.36
H
δ
4.35
H
O
H
H
δ
3.79
H
H
X
HO
N
Me
H
δ
7.28
δ
δ
4.47
H
6.48
O
δ
2.53-2.45
Me
MeO
Fig. 7 ROESY interactions of 20
Conclusions
In conclusion we have achieved our goal of the synthesis of stable and highly functionalized
[3]dendralenes. The present work is a systematic study encompassing synthesis of 1,2,4,5-
tetrasubstituted [3]dendralenes in acyclic systems and study of their reactivity pattern. It is
evident that substituents at 2 and 4 positions of [3]dendralenes drastically diminish its reactivity
for self D-A dimerisation reactions irrespective of their electronic nature (electron donating or
withdrawing) hence imparting stability. This is due to D-A unfavoured s-trans conformation of
the dienic components caused by the substituent at these positions. From the D-A reaction
studies, it became apparent that steric effect outweighs electronic activation or deactivation.
Sterically hindered 4-benzyl substituted [3]dendralene switched the regioselectivity of the D-A
reaction with NMM in favour of electronically deactivated diene component with
ethoxycarbonyl substitution at 2-position. In case of 4-methyl substiuted [3]dendralene, the
electronically rich diene component participated in D-A with NMM. The D-A reactions are
highly endo selective. We were unable to engage the first D-A adduct for DTDA sequence with
reactive dienophiles. This could be attributed to the steric effect of the dense functionalities
which prevent the diene to adopt s-cis conformation which is a prerequisite for its success.
Nonetheless these D-A adducts could be promising candidates for biological studies as many of
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the isoindole derivatives display myriad of biological properties viz. antimicrobial, antiviral,
analgesic, antiinflamatory and antitumor activities.63
Experimental section:
General Information
All reactions were performed in oven-dried (120 °C) or flame-dried glass apparatus under dry N2
or argon atmosphere. Tetrahydrofuran (THF) was dried by distillation from
sodium/benzophenone ketyl. n-BuLi (1.6 M in hexane) was purchased from Aldrich. All the
aldehydes were purchased from Aldrich and were freshly distilled prior to use. TLC was carried
out using Merck silica gel 60 F254 plates. Column chromatography was performed on silica gel
(230–400 mesh). 1H NMR spectra were recorded on 200, 300, 500, 600 MHz, 13C NMR spectra
were recorded with 50, 75, 125, 150 MHz and 31P NMR spectra were recorded on 121.5 MHz
spectrometer using CDCl3, C6D6, CD3COCD3 as the solvents. The spectra were referenced to
residual chloroform (δ 7.25 ppm, 1H; 77.00 ppm, 13C), partially deuterated acetone (δ 2.05 ppm,
1
1H; 29.9, 206.7 ppm, 13C), partially deuterated benzene (δ 7.16 ppm, H; 128.4 ppm, 13C) and
H3PO4 as external reference (δ 0.00 ppm, 31P). IR spectra were carried out on the FT-IR-
spectrometer using NaCl discs, and wave numbers were given in cm-1. Melting points (m.p) were
uncorrected. A high-resolution mass spectrum was obtained using a high-resolution ESI-TOF
mass spectrometer.
General procedure for aldehydes 14a-c: A solution of 3-phenylpropanal (3.2 mL, 24.3 mmol,
1 equiv), 4-methoxybenzaldehyde (29.5 mL, 243 mmol, 10 equiv), pyrrolidine (0.6 mL, 7.3
mmol, 0.3 equiv) and propionic acid (0.55 mL, 7.3 mmol, 0.3 equiv) were heated at 75 ºC for 24
h under argon atmosphere. Excess 4-methoxybenzaldehyde was distilled out and the residue was
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purified by column chromatography (petroleum ether-EtOAc; 95:5) to provide the aldehyde 14a
(1.96 g, 32%) as orange coloured viscous liquid. The same procedure was followed for the
preparation of compounds 14b,c.
(E)-2-Benzyl-3-(4-methoxyphenyl)acrylaldehyde (14a)64: Rf (hexane-EtOAc, 90:10) = 0.35; IR
ν
max: 3058, 3028, 3002, 2954, 2931, 2908, 2836, 2715, 2566, 1683, 1667, 1624, 1592, 1508,
1
1495, 1453, 1305, 1252, 1210, 1175, 1148, 1032, 956, 887, 828, 736, 700 cm-1; H NMR (200
MHz, CDCl3): δ 9.66 (s, 1 H, CHO), 7.46 (d, J = 9.0 Hz, 2 H, Ar), 7.44 (s, 1 H, ArCH), 7.27-
7.19 (m, 5 H, Ph), 6.90 (d, J = 8.8 Hz, 2 H, Ar), 3.97 (s, 2 H, PhCH2), 3.82 (s, 3 H, OCH3); 13C
NMR (50 MHz, CDCl3): δ 194.9, 161.0, 151.5, 138.2, 137.9, 131.8, 128.4, 127.7, 126.9, 126.0,
114.2, 55.1, 30.1.
(E)-2-Benzyl-3-(3-chlrophenyl)acrylaldehyde (14b)64: Following the general procedure, isolated
yield (1.36 g, 82%) as yellow coloured viscous liquid; Rf (hexane-EtOAc, 90:10) = 0.4; IR ν
:
max
3083, 3061, 3027, 2927, 2826, 2717, 1682, 1627, 1599, 1561, 1494, 1474, 1453, 1394, 1206,
1
1142, 1077, 956, 890, 784, 737, 697 cm-1; H NMR (200 MHz, CDCl3): δ 9.68 (s, 1 H, CHO),
7.45-7.11 (m, 10 H, Ar, Ph, C=CH), 3.90 (s, 2 H, PhCH2); 13C NMR (50 MHz, CDCl3): δ 194.7,
149.4, 141.7, 138.0, 136.1, 134.7, 130.0, 129.7, 129.5, 128.6, 127.9, 127.5, 126.3, 30.3.
(E)-3-(4-Methoxyphenyl)-2-methylacrylaldehyde (14c)65: Following the general procedure,
isolated yield (5.2 g, 75%) as yellow coloured viscous liquid; Rf (hexane-EtOAc, 80:20) = 0.48;
IR νmax: 3007, 2961, 2935, 2837, 2716, 1682, 1622, 1598, 1571, 1514, 1443, 1407, 1321, 1304,
1258, 1177, 1116, 1034, 1014, 763, 571, 562, 538 cm-1; 1H NMR (300 MHz, CDCl3): δ 9.54 (s, 1
H, CHO), 7.53 (d, J = 8.4 Hz, 2 H, Ar), 7.19 (s, 1 H, ArCH), 6.97 (d, J = 8.4 Hz, 2 H, Ar), 3.86
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(s, 3 H, OCH3), 2.08 (s, 3 H, C=CCH3); 13C NMR (150 MHz, CDCl3): δ 195.3, 160.6, 149.7,
136.0, 131.9, 127.8, 114.1, 55.2, 10.7.
General procedure for phosphonates 13a-c: A solution of aldehyde 14a (2.4 g, 9.5 mmol, 1
equiv), ethyl bis-(2,2,2-trifluroethyl)-phosphonoacetate (3.6 g, 9.5 mmol, 1 equiv) and
piperdinium benzoate (394 mg, 1.9 mmol, 0.2 equiv) in toluene (25 mL) was heated under reflux
for 2 d in a flask fitted with Dean-Stark apparatus. The reaction mixture was then brought to
room temperature, diluted with water and extracted with ethyl acetate. The organic extract was
concentrated under the reduced pressure and the residue purified by column chromatography
(petroleum ether-EtOAc; 85:15) to give phosphonate 13a as inseparable mixture of two E/Z
isomers (3.15 g, 85%) as brown coloured viscous liquid. The same procedure was followed for
the preparation of compounds 13b,c.
(2E/Z,4E)-Ethyl 4-benzyl-2-[bis(2,2,2-trifluoroethoxy)phosphoryl]-5-(4-methoxyphenyl)penta-
2,4-dienoate (13a): Rf (hexane-EtOAc, 80:20) = 0.29; Found: C, 53.10; H, 4.20. Calc. for
C25H25F6O6P: C, 53.01; H, 4.45%; IR νmax: 3063, 3028, 3002, 2970, 2939, 2907, 1720, 1605,
1
1579, 1508, 1496, 1455, 1419, 1296, 1251, 1175, 1104, 1071, 1032, 962 cm-1; H NMR (600
MHz, CDCl3): δ 7.63 (d, J =25.8 Hz, 1 H, ArC=CCH=C, 2Z), 7.40 (d, J = 25.8 Hz, 1 H,
ArC=CCH=C, 2E), 7.29-7.12 (m, 14 H, Ph, Ar), 6.89 (d, J = 8.4 Hz, 2 H, Ar, 2Z), 6.87 (s, 1 H,
ArCH, 2Z), 6.86 (d, J = 9.0 Hz, 2 H, Ar, 2E), 6.83 (s, 1 H, ArCH, 2E), 4.34-4.08 (m, 8 H, 2 ×
OCH2CF3), 4.24 (q, J = 7.2 Hz, 2 H, OCH2CH3, 2Z), 3.99 (q, J = 7.2 Hz, 2 H, OCH2CH3, 2E),
3.98 (s, 2 H, PhCH2, 2Z), 3.82 (s, 3 H, OCH3, 2Z). 3.80 (s, 3 H, OCH3, 2E), 3.79 (s, 2 H, PhCH2,
2E), 1.28 (d, J = 7.2 Hz, 3 H, OCH2CH3, 2Z), 1.09 (d, J = 7.2 Hz, 3 H, OCH2CH3, 2E); 13C NMR
(150 MHz, CDCl3): δ 164.3 (d, J = 13.9 Hz, 2Z), 163.8 (d, J = 14.8 Hz, 2E), 160.1, 156.1 (d, J =
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6.3 Hz, 2Z), 154.8 (d, J = 7.2 Hz, 2E), 143.1 (2Z), 139.6 (2Z), 138.5 (2E), 138.0 (2Z), 133.5 (d, J
= 19.9 Hz, 2E), 133.2 (d, J = 21.3 Hz, 2Z), 131.4 (2E), 131.1 (2Z), 128.9 (2E), 128.4 (2Z), 128.3
(2E), 128.1 (2Z), 127.8 (2E), 126.5 (2E), 126.3 (2Z), 122.4 (dq, J = 275.8, 9.7 Hz), 120.6 (d, J =
186.4 Hz, 2E), 118.5 (d, J = 184.3 Hz, 2Z), 114.0 (2Z), 113.8 (2E), 62.3 (q, J = 37.9 Hz, 2Z),
62.2 (q, J = 37.9 Hz, 2E), 61.8, 55.1, 41.3 (2E), 34.8 (2Z), 13.6 (2E), 13.3 (2Z).
(2E/Z,4E)-Ethyl 4-benzyl-2-[bis(2,2,2-trifluoroethoxy)phosphoryl]-5-(3-chlorophenyl)penta-
2,4-dienoate (13b): Following the general procedure, inseparable mixture 60:40 of two E/Z
isomers were isolated, yield (1.42 g, 65%) as brown coloured viscous liquid; Rf (hexane-EtOAc,
80:20) = 0.45; Found: C, 50.37; H, 3.59. Calc. for C24H22ClF6O5P: C, 50.50; H, 3.88%; IR ν
:
max
1
3064, 2982, 1723, 1594, 1495, 1454, 1419, 1374, 1173, 1070, 963, 879 cm-1; H NMR (300
MHz, CDCl3): δ 7.55 (dd, J = 25.5, 1.5 Hz, 1 H, ArCHCCH=C, 2Z), 7.36 (dd, J = 25.8, 1.2 Hz, 1
H, ArCHCCH=C, 2E), 7.30-7.05 (m, 18 H, Ar, Ph), 7.04 (s, 1 H, ArCH, 2E), 6.65 (s, 1 H, ArCH,
2Z), 4.35-4.12 (m, 10 H, 2 × OCH2CF3, OCH2CH3, 2Z), 4.08 (q, J = 7.2 Hz, 2 H, OCH2CH3, 2E),
3.91 (s, 2 H, PhCH2, 2E), 3.76 (s, 2 H, PhCH2, 2Z), 1.27 (t, J = 7.2 Hz, 3 H, OCH2CH3, 2Z), 1.15
(t, J = 7.2 Hz, 3 H, OCH2CH3, 2E); 13C NMR (75 MHz, CDCl3): δ 164.1 (d, J = 13.6, 2E), 163.4
(d, J = 14.8, 2Z), 155.2 (d, J = 6.5, 2E), 154.7 (d, J = 6.8, 2Z), 139.0 (2E), 137.8 (2E), 137.6
(2Z), 137.4 (2E), 137.1 (2Z), 136.6 (d, J = 21.0, 2E), 135.0 (2Z), 134.4 (d, J = 19.1, 2Z), 129.9
(2E), 129.7 (2Z), 129.3, 129.1, 128.6, 128.3, 127.6 (2Z), 127.1 (2E), 126.9 (2Z), 126.7 (2E),
123.3 (d, J = 185.6, 2Z), 122.4 (dq, J = 266.6, 9.3), 121.3 (d, J = 183.6, 2E), 62.4 (q, J = 37.7),
62.1, 42.0 (2Z), 35.3 (2E), 13.7 (2Z), 13.6 (2E).
(2E/Z,4E)-Ethyl 2-[bis(2,2,2-trifluoroethoxy)phosphoryl]-5-(4-methoxyphenyl)-4-methylpenta-
2,4-dienoate (13c): Following the general procedure, inseparable mixture 1:1 of two E/Z isomers
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were isolated, yield (6.14 g, 79%) as brown coloured viscous liquid; Rf (hexane-EtOAc, 80:20) =
0.25; Found: C, 46.48; H, 3.98. Calc. for C19H21F6O6P: C, 46.54; H, 4.32%; IR νmax : 2965, 2937,
1
2909, 1720, 1606, 1578, 1509, 1305, 1258, 1175, 1101, 1071, 960 cm-1; H NMR (600 MHz,
CDCl3): δ 7.63 (d, J = 26.4 Hz, 1 H, ArC=CCH=C, 2Z), 7.39 (d, J = 25.8 Hz, 1 H, ArC=CCH=C,
2E), 7.34 (d, J = 9.0 Hz, 2 H, Ar, 2E), 7.15 (d, J = 8.4 Hz, 2 H, Ar, 2Z), 6.94 (s, 1 H, ArCH, 2E),
6.92 (d, J = 9.0 Hz, 2 H, Ar, 2E), 6.89 (d, J = 8.4 Hz, 2 H, Ar, 2Z), 6.87 (s, 1 H, ArCH, 2Z),
4.46-4.37 (m, 8 H, 2 × OCH2CF3), 4.30 (q, J = 7.2 Hz, 4 H, OCH2CH3), 3.84 (s, 3 H, OCH3, 2E),
3.82 (s, 3 H, OCH3, 2Z), 2.04 (s, 3 H, C=CCH3, 2E), 2.03 (s, 3 H, C=CCH3, 2Z), 1.33 (t, J = 7.2
13
Hz, 6 H, OCH2CH3); C NMR (125 MHz, CDCl3): δ 165.1 (d, J = 13.2 Hz, 2E), 164.7 (d, J =
16.2 Hz, 2Z), 160.1, 156.6 (d, J = 7.2 Hz, 2E), 152.1 (d, J = 7.1 Hz, 2Z), 144.3 (2E), 140.7 (2Z),
131.7, 131.6 (2Z), 131.3 (2E), 128.5 (2Z), 128.3 (2E), 122.5 (dq, J = 266.4, 9.5 Hz), 120.0 (d, J =
189.9 Hz, 2Z), 116.7 (d, J = 187.5 Hz, 2E), 114.0, 62.5 (dq, J = 39.2, 3.6 Hz), 62.0, 55.2, 21.4,
15.6, 13.7.
General procedure for butadien-2-ylphosphonoacetate 12a-c: n-BuLi (0.89 mL, 1.6 M, 1.43
mmol, 3 equiv) was added drop wise to a stirred suspension of trimethylsulfonium iodide (292
mg, 1.43 mmol, 3 equiv) in THF (10 mL) at -10 ºC under argon atmosphere and stirred for 20
min at the same temperature. Later, a solution of dienic phosphonate 13a (270 mg, 0.47 mmol, 1
equiv) in THF (5 mL) was cannulated into the reaction mixture and stirred for 1 h. The
temperature of the reaction mixture was allowed to rise slowly to room temperature followed by
dilution of the reaction mixture with water and extraction with ethyl acetate. The organic layer
was concentrated and column chromatography (petroleum ether-EtOAc; 85:15) was done to
obtain the diene 12a (0.24 g, 87%) as pale yellow liquid. The same procedure was followed for
the preparation of compounds 12b,c.
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(4E)-Ethyl
4-benzyl-2-[bis(2,2,2-trifluoroethoxy)phosphoryl]-5-(4-methoxyphenyl)-3-
methylene-4-pentenoate 12a: Rf (hexane-EtOAc, 80:20) = 0.34; Found: C, 53.98; H, 4.93. Calc.
for C26H27F6O6P: C, 53.80; H, 4.69%; IR νmax: 3058, 3024, 2969, 2938, 2911, 2840, 1729, 1649,
1602, 1574, 1542, 1510, 1456, 1417, 1369, 1299, 1258, 1173, 1104, 1070, 1032, 965, 878, 844,
1
699, 660 cm-1; H NMR (600 MHz, CDCl3): δ 7.30-7.27 (m, 2 H, Ph), 7.21-7.20 (m, 5 H, Ph,
Ar), 6.94 (s, 1 H, ArCH), 6.83 (d, J = 8.4 Hz, 2 H, Ar), 5.57 (d, J = 4.8 Hz, 1 H, C=CHAHB),
5.51 (d, J = 4.8 Hz, 1 H, C=CHAHB), 4.48-4.36 (m, 4 H, 2 × OCH2CF3), 4.34 (d, J = 24 Hz, 1 H,
POCH), 4.17 (q, J = 7.2 Hz, 2 H, OCH2CH3), 3.95 (d, J = 16.8 Hz, 1 H, PhCHAHB), 3.88 (d, J =
13
16.8 Hz, 1 H, PhCHAHB), 3.79 (s, 3 H, OCH3), 1.22 (t, J = 7.2 Hz, 3 H, OCH2CH3); C NMR
(125 MHz, CDCl3): δ 167.1, 158.9, 139.2, 137.7, 135.6, 130.8, 129.9, 129.2 (d, J = 9.4 Hz),
128.5, 128.0, 126.0, 122.8 (dq, J = 181.3, 9.1 Hz), 119.8 (d, J = 8.5 Hz), 113.8, 63.5-62.0 (m),
62.3, 55.1, 48.1 (d, J = 145.3 Hz), 34.6, 13.7; 31P NMR (121.5 MHz, CDCl3): δ 23.4.
(4E)-Ethyl 4-benzyl-2-[bis(2,2,2-trifluoroethoxy)phosphoryl]-5-(3-chlorophenyl)-3-methylene-
4-pentenoate (12b): Following the general procedure, isolated yield (0.18 g, 79%) as pale yellow
liquid; Rf (hexane-EtOAc, 80:20) = 0.25; Found: C, 51.37; H, 4.39. Calc. for C25H24ClF6O5P: C,
51.34; H, 4.14%; IR νmax: 3063, 3028, 2968, 2932, 2878, 1734, 1718, 1603, 1594, 1560, 1497,
1472, 1456, 1417, 1297, 1264, 1170, 1100, 1070, 962 cm-1; 1H NMR (200 MHz, CDCl3): δ 7.30-
7.15 (m, 9 H, Ar, Ph), 6.92 (s, 1 H, ArCH), 5.64 (d, J = 4.8 Hz, 1 H, C=CHAHB), 5.58 (d, J = 5
Hz, 1 H, C=CHAHB), 4.50-4.06 (m, 5 H, 2 × OCH2CF3, POCH), 4.17 (q, J = 7.2 Hz, 2 H,
OCH2CH3), 3.93 (d, J = 16.6 Hz, 1 H, PhCHAHB), 3.82 (d, J = 16.4 Hz, 1 H, PhCHAHB), 1.22 (t,
J = 7.2 Hz, 3 H, OCH2CH3); 13C NMR (50 MHz, CDCl3): δ 167.0 (d, J = 1.5 Hz), 138.8 (d, J = 6
Hz), 138.7, 138.6, 137.4(d, J = 8 Hz), 134.2, 129.8, 129.7, 128.7, 128.6, 128.0, 127.5, 126.5,
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126.3, 120.4 (dq, J = 276, 8 Hz) 121.2 (d, J = 9 Hz), 62.8, (dq, J = 32, 6 Hz), 62.5, 48.3 (d, J =
145 Hz), 34.6, 13.8; 31P NMR (121.5 MHz, CDCl3): δ 23.1.
(4E)-Ethyl
2-[bis(2,2,2-trifluoroethoxy)phosphoryl]-5-(4-methoxyphenyl)-4-methyl-3-
methylene-4-pentenoate (12c): Following the general procedure, isolated yield (700 mg, 86%)
as pale yellow liquid; Rf (hexane-EtOAc, 80:20) = 0.3; Found: C, 47.79; H, 4.85. Calc. for
C20H23F6O6P: C, 47.63; H, 4.60%; IR νmax: 2971, 2938, 2914, 2838, 1730, 1609, 1509, 1460,
1
1415, 1371, 1302, 1161, 1068, 1033, 960 cm-1; H NMR (600 MHz, CDCl3): δ 7.21 (d, J = 8.4
Hz, 2 H, Ar), 6.89 (d, J = 8.4 Hz, 2 H, Ar), 6.64 (s, 1 H, ArCH), 5.60 (d, J = 4.8 Hz, 1 H,
C=CHAHB), 5.59 (d, J = 6.0 Hz, 1 H, C=CHAHB), 4.51-4.35 (m, 4 H, 2 × OCH2CF3), 4.38 (d, J =
24 Hz, 1 H, POCH), 4.25 (q, J = 7.2 Hz, 1 H, OCHAHBCH3), 4.24 (q, J = 7.2 Hz, 1 H,
OCHAHBCH3), 3.82 (s, 3 H, OCH3), 2.04 (s, 3 H, C=CCH3), 1.28 (t, J = 7.2 Hz, 3 H, OCH2CH3);
13C NMR (125 MHz, CDCl3): δ 167.3, 158.5, 139.4 (d, J = 8.2 Hz,), 134.2, 130.5, 129.8, 128.0,
122.4 (dq, J = 270, 28 Hz), 118.0 (d, J = 8.2 Hz), 113.5, 62.6 (dq, J = 8.6, 24.7 Hz), 62.4, 55.1,
48.1 (d, J = 144.4 Hz), 16.1, 13.8; 31P NMR (121.5 MHz, C6D6): δ 23.7.
(E)-Ethyl 2,3-dimethylene-5-phenylpent-4-enoate (10): A solution of diene 8 (0.29 g, 0.63
mmol), in THF (6 mL) was cannulated to a suspension of NaH (0.028 g, 55% in oil, 0.63 mmol)
in THF (1 mL) at 0 ºC. After 15 min, formaldehyde gas was bubbled through this reaction
mixture for 5 min and 10 min. The reaction mixture was diluted with water and extracted with
20% EtOAc in hexanes. The organic extract was concentrated under reduced pressure to give 10.
Attempt to purify this material by chromatography was not successful due to degradation by
dimerization and polymerization. Rf (hexane-EtOAc, 95:5) = 0.5; 1H NMR (200 MHz, CDCl3): δ
7.40-7.18 (m, 5H, Ph), 6.89 (d, J = 16.2 Hz, 1 H, PhCH), 6.38 (d, J = 1.2 Hz, 1 H,
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EtCO2C=CHAHB), 6.36 (d, J = 16.2 Hz, 1 H, PhCH=CH), 5.75 (d, J = 1.2 Hz, 1H,
EtCO2C=CHAHB), 5.38 (s, 1 H, PhCH=CHC=CHAHB), 5.23 (s, 1 H, PhCH=CHC=CHAHB), 4.23
(q, J = 7.2 Hz, 2 H, OCH2), 1.28 (t, J = 7.2 Hz, 3 H, OCH2CH3).
General procedure for [3]dendralenes 11a-k: A solution of butadien-2-ylphosphonoacetate
12a (190 mg, 0.33 mmol, 1 equiv) in THF (5 mL) was cannulated to a suspension of sodium
hydride (15 mg, 55% in oil, 0.33 mmol, 1 equiv) in THF (1 mL) under argon atmosphere and
stirred for 5 min. Then freshly distilled benzaldehyde (34 µL, 0.33 mmol, 1 equiv) was added
and stirred at room temperature for 24 h. The reaction mixture was diluted with water and
extracted with ethyl acetate. The organic layer was concentrated under the reduced pressure and
purified by column chromatography (petroleum ether-EtOAc; 95:5) to obtain the dendralene 11a
(42 mg, 30%) as white solid. The same procedure was followed for the preparation of
dendralenes 11b-k.
(2Z,4E)-Ethyl 4-benzyl-2-benzylidene-5-(4-methoxyphenyl)-3-methylenepent-4-enoate (11a):
Rf (Benzene) = 0.85; mp 92-93 ºC; Found: C, 82.26; H, 6.83. Calc. for C29H28O3: C, 82.05; H,
6.65%; IR νmax: 3081, 2959, 2923, 2855, 1715, 1604, 1573, 1508, 1494, 1463, 1455, 1370, 1304,
1256, 1210, 1175, 1095, 1029 cm-1; 1H NMR (600 MHz, CDCl3): δ 7.35-7.23 (m, 12 H, Ar, 2 ×
Ph), 6.90 (s, 1 H, PhCH), 6.84 (s, 1 H, ArCH), 6.84 (d, J = 9.0 Hz, 2 H, Ar), 5.27 (s, 1 H,
C=CHAHB), 5.24 (s, 1 H, C=CHAHB), 4.19 (q, 2 H, J = 7.2 Hz, OCH2CH3), 3.94 (s, 2 H, PhCH2),
3.79 (s, 3 H, OCH3), 1.16 (t, J = 7.2 Hz, 3 H, OCH2CH3); 13C NMR (150 MHz, CDCl3): δ 169.0,
158.9, 148.7, 139.8, 136.4, 135.8, 135.7, 134.9, 132.4, 130.1, 129.8, 128.7, 128.6, 128.5, 128.4,
126.1, 117.1, 113.9, 61.1, 55.4, 35.5, 14.0. Recrystalization of compound 11a from ethyl
acetate/hexane gave crystals suitable for single crystal X-ray analysis.
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(2Z,4E)-Ethyl
2-(4-bromobenzylidene)-4-benzyl-5-(4-methoxyphenyl)-3-methylenepent-4-
enoate (11b): Following the general procedure, isolated yield (43 mg, 41%) as pale yellow
liquid; Rf (Benzene) = 0.75; Found: C, 69.14; H, 5.57. Calc. for C29H27BrO3: C, 69.19; H, 5.41%;
IR νmax: 2956, 2923, 2853, 1715, 1698, 1649, 1607, 1555, 1538, 1508, 1487, 1457, 1369, 1275,
1247, 1179, 1106, 1070, 1036 cm-1; 1H NMR (200 MHz, CDCl3): δ 7.46 (d, 2 H, J = 8.4 Hz, Ar),
7.31-7.19 (m, 9 H, Ar, Ph), 6.85 (s, 1 H, 4-BrC6H4CH), 6.83 (d, J = 8.8 Hz, 2 H, Ar), 6.73 (s, 1
H, 4-CH3OC6H4CH), 5.25 (s, 1 H, C=CHAHB), 5.24 (s, 1 H, C=CHAHB), 4.18 (q, J = 7.2 Hz, 2
H, OCH2CH3), 3.91 (s, 2 H, PhCH2), 3.79 (s, 3 H, OCH3), 1.17 (t, J = 7.2 Hz, 3 H, OCH2CH3);
13C NMR (150 MHz, CDCl3): δ 168.6, 158.9, 148.6, 139.7, 136.6, 136.3, 134.6, 133.6, 132.5,
131.5, 130.2, 130.1, 129.7, 128.6, 128.5, 126.1, 122.5, 117.4, 113.9, 61.2, 55.3, 35.5, 14.1.
(2Z,4E)-Ethyl
2-(3-chlorobenzylidene)-4-benzyl-5-(4-methoxyphenyl)-3-methylenepent-4-
enoate (11c): Following the general procedure, isolated yield (57 mg, 35%) as pale yellow
liquid; Rf: (hexane-EtOAc, 95:5) = 0.4; Found: C, 75.91; H, 5.93. Calc. for C29H27ClO3: C,
75.89; H, 5.93%; IR νmax: 3065, 2924, 2866, 2833, 1717, 1605, 1562, 1510, 1495, 1464, 1453,
1
1371, 1366, 1336, 1304, 1255, 1206, 1177, 1089, 1034 cm-1; H NMR (600 MHz, CDCl3): δ
7.38-7.19 (m, 11 H, Ar), 6.87 (s, 1 H, 3-ClPhCH), 6.84 (d, J = 9.0 Hz, 2 H, 4-OCH3Ph), 6.76 (s,
1 H, 4-OCH3PhCH), 5.27 (s, 1 H, C=CHAHB), 5.26 (s, 1 H, C=CHAHB), 4.20 (q, J = 7.2 Hz, 2 H,
OCH2CH3), 3.93 (s, 2 H, PhCH2), 3.79 (s, 3 H, OCH3), 1.18 (t, J = 7.2 Hz, 3 H, OCH2CH3); 13C
NMR (150 MHz, CDCl3): δ 168.5 158.9, 148.4, 139.7, 137.5, 137.3, 136.2, 134.3, 133.2, 132.5,
130.2, 129.7, 129.6, 128.6, 128.5, 128.3, 126.7, 126.1, 117.5, 113.9, 61.3, 55.4, 35.5, 14.0.
(2Z,4E)-Ethyl
2-[(E)-3-benzyl-4-(4-methoxyphenyl)buta-1,3-dien-2-yl]-5-phenylpenta-2,4-
dienoate (11d): Following the general procedure, isolated yield (43 mg, 31%) as yellow liquid;
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Rf (hexane-EtOAc, 90:10) = 0.53; Found: C, 82.63; H, 6.72. Calc. for C31H30O3: C, 82.64; H,
6.71%; IR νmax: 3062, 3024, 2956, 2928, 2839, 1702, 1609, 1592, 1508, 1495, 1453, 1369, 1301,
1246, 1217, 1175, 1149, 1036, 976 cm-1; 1H NMR (500 MHz, CDCl3): δ 7.86 (dd, J = 15.5, 11.5
Hz, 1 H, PhCH=CHCH=C), 7.51 (d, J = 7.0 Hz, 2 H, Ar), 7.38-7.17(m, 10 H, 2 × Ph), 6.81 (d, J
= 9.0 Hz, 2 H, Ar), 6.80 (d, J = 15.5 Hz, 1 H, PhCH ), 6.76 (s, 1 H, ArCH), 6.71 (d, J = 11.5 Hz,
1 H, PhCH=CHCH=C), 5.24 (s, 1 H, C=CHAHB), 5.17 (s, 1 H, C=CHAHB), 4.26 (q, J = 7 Hz, 2
H, OCH2CH3), 3.93 (s, 2 H, PhCH2), 3.78 (s, 3 H, OCH3), 1.29 (t, J = 7 Hz, 3 H, OCH2CH3); 13C
NMR (125 MHz, CDCl3): δ 167.1, 158.7, 149.0, 141.0, 140.0, 139.7, 136.6, 132.8, 131.6, 129.9,
129.8, 128.6, 128.5, 128.3, 128.2, 127.2, 125.8, 125.5, 116.3, 113.7, 60.5, 55.1, 34.8, 14.2.
Synthesis of 11ea/eb: Following the general procedure, a 6:4 mixture of Z/E isomers (1H NMR)
were isolated as colourless liquid. The individual isomers were separated by chromatography.
Diethyl 2-[(E)-3-benzyl-4-(4-methoxyphenyl)buta-1,3-dien-2-yl]maleate (11ea): Isolated yield
(55 mg, 30%); Rf (hexane-EtOAc, 80:20) = 0.54; Found: C, 74.08; H, 6.82. Calc. for C26H28O5:
C, 74.26; H, 6.71%; IR νmax: 3059, 2980, 2960, 2932, 2835, 1720, 1610, 1510, 1500, 1453, 1396,
1364, 1333, 1254, 1176, 1092, 1035 cm-1; 1H NMR (500 MHz, CDCl3): δ 7.29-7.25 (m, 4 H, Ar,
Ph), 7.21-7.18 (m, 3 H, Ph), 6.86 (d, J = 9.0 Hz, 2 H, Ar), 6.77 (s, 1 H, ArCH), 6.00 (s, 1 H,
CHCO2Et), 5.30 (s, 1 H, C=CHAHB), 5.27 (s, 1 H, C=CHAHB), 4.31 (q, J = 7.0 Hz, 2 H,
OCH2CH3), 4.22 (q, J = 7.0 Hz, 2 H, OCH2CH3), 3.85 (s, 2 H, PhCH2), 3.80 (s, 3 H, OCH3),
13
1.31 (t, 3 H, J = 7.0 Hz), 1.30 (t, J = 7.0 Hz, 3 H, OCH2CH3); C NMR (125 MHz, CDCl3): δ
167.3, 164.9, 158.9, 148.7, 146.0, 139.0, 135.5, 133.0, 129.9, 129.1, 128.4, 126.0, 121.0, 120.1,
113.8, 61.5, 60.9, 55.2, 35.5, 14.0, 13.9.
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Diethyl 2-((E)-3-benzyl-4-(4-methoxyphenyl)buta-1,3-dien-2-yl)fumarate (11eb): Isolated yield
(33 mg, 18%); Rf (hexane-EtOAc, 80:20) = 0.52; IR νmax: 3061, 2981, 2837, 1722, 1607, 1510,
1495, 1391, 1250, 1032 cm-1; 1H NMR (200 MHz, CDCl3): δ 7.28-7.18 (m, 7 H, Ar, Ph), 6.77 (d,
J = 8.8 Hz, 2 H, Ar), 6.41 (s, 1 H, ArCH), 5.93 (s, 1 H, CHCO2Et), 5.39 (s, 1 H, C=CHAHB),
5.02 (s, 1 H, C=CHAHB), 4.37 (q, J = 7.0 Hz, 2 H, OCH2CH3), 4.16 (q, J = 7.2 Hz, 2 H,
OCH2CH3), 3.76 (s, 3 H, OCH3), 3.52 (s, 2 H, PhCH2), 1.37 (t, J = 7.0 Hz, 3 H, OCH2CH3), 1.25
(t, J = 7.2 Hz, 3 H, OCH2CH3); 13C NMR (50 MHz, CDCl3): δ 167.6, 165.2, 158.8, 147.1, 143.0,
138.7, 135.9, 129.9, 129.8, 129.4, 128.6, 128.3, 126.4, 123.7, 118.3, 113.7, 61.6, 60.9, 55.2, 45.6,
14.0.
(2Z,4E)-Ethyl 4-benzyl-2-benzylidene-5-(3-chlorophenyl)-3-methylenepent-4-enoate (11f):
Following the general procedure, isolated yield (54 mg, 35%) as colourless liquid; Rf (hexane-
EtOAc, 95:5) = 0.5; Found: C, 78.62; H, 6.12. Calc. for C28H25ClO2: C, 78.40; H, 5.87%; IR
ν
max: 3060, 3026, 2981, 2959, 2871, 1716, 1636, 1589, 1556, 1490, 1476, 1453, 1373, 1213,
1
1095 cm-1; H NMR (300 MHz, CDCl3): δ 7.35-7.18 (m, 14 H, Ar, 2×Ph), 6.88 (s, 1 H, PhCH),
6.83 (s, 1 H, ArCH), 5.33 (s, 1 H, C=CHAHB), 5.29 (s, 1 H, C=CHAHB), 4.21 (q, J = 7.2 Hz, 2 H,
OCH2CH3), 3.90 (s, 2 H, PhCH2), 1.17 (t, J = 7.2 Hz, 3 H, OCH2CH3); 13C NMR (75 MHz,
CDCl3): δ 168.7, 148.0, 139.6, 139.3, 139.0, 135.5, 135.3, 135.0, 134.2, 131.1, 129.6, 128.8,
128.5, 128.4, 128.3, 127.2, 126.6, 126.2, 118.0, 61.1, 35.4, 13.9.
(2Z,4E)-Ethyl
2-(4-bromobenzylidene)-4-benzyl-5-(3-chlorophenyl)-3-methylenepent-4-
enoate (11g): Following the general procedure, isolated yield (240 mg, 47%) as pale yellow
liquid; Rf (hexane-EtOAc, 90:10) = 0.75; Found: C, 66.50; H, 4.92. Calc. for C28H24BrClO2: C,
66.22; H, 4.76%; IR νmax: 3061, 3026, 2979, 2926, 1720, 1591, 1561, 1486, 1453, 1371, 1343,
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1302, 1276, 1211, 1073, 1046, 1010 cm-1; 1H NMR (200 MHz, CDCl3): δ 7.47 (d, J = 8.6 Hz, 2
H, Ar), 7.36-7.15 (m, 11 H, Ar, Ph), 6.82 (s, 1 H, ArCH), 6.70 (s, 1 H, ArCH), 5.29 (s, 1 H,
C=CHAHB), 5.28 (s, 1 H, C=CHAHB), 4.18 (q, J = 7 Hz, 2 H, OCH2CH3), 3.87 (s, 2 H, PhCH2),
13
1.17 (t, J = 7 Hz, 3 H, OCH2CH3); C NMR (50 MHz, CDCl3): δ 168.4, 147.9, 139.4, 139.1,
138.9, 136.0, 134.4, 134.2, 133.7, 131.5, 131.1, 130.1, 129.6, 128.8, 128.5, 128.4, 127.3, 126.6,
126.2, 122.5, 118.2, 61.2, 35.4, 13.9.
(2Z,4E)-Ethyl
2-(4-methoxybenzylidene)-4-benzyl-5-(3-chlorophenyl)-3-methylenepent-4-
enoate (11h): Following the general procedure, isolated yield (28 mg, 15%) as colourless liquid;
Rf (hexane-EtOAc, 95:5) = 0.28; IR νmax: 3061, 3029, 2956, 2930, 2838, 1714, 1709, 1601, 1565,
1507, 1453, 1376, 1295, 1255, 1201, 1178, 1097, 962 cm-1; 1H NMR (300 MHz, CDCl3): δ 7.34-
7.17 (m, 11 H, Ar, Ph), 6.88 (d, J = 8.7 Hz, 2 H, Ar), 6.86 (s, 1 H, ArCH), 6.75 (s, 1 H, ArCH),
5.29 (s, 1 H, C=CHAHB), 5.26 (s, 1 H, C=CHAHB), 4.23 (q, J = 7.2 Hz, 2 H, OCH2CH3), 3.89 (s,
13
2 H, PhCH2), 3.84 (s, 3 H, OCH3), 1.21 (t, J = 7.2 Hz, 3 H, OCH2CH3 ); C NMR (75 MHz,
CDCl3): δ 169.0, 159.8, 148.4, 139.7, 139.3, 139.1, 134.8, 134.2, 133.1, 132.2, 140.0, 130.3,
129.6, 128.8, 128.5, 128.4, 127.2, 126.6, 126.1, 117.6, 113.8, 61.0, 55.3, 35.4, 14.0; HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C29H28ClO3 459.1721; Found 459.1723.
(2Z,4E)-Ethyl
2-[(E)-3-benzyl-4-(3-chlorophenyl)buta-1,3-dien-2-yl]-5-phenylpenta-2,4-
dienoate (11i): Following the general procedure, isolated yield (37 mg, 27%) as yellow liquid; Rf
(hexane-EtOAc, 95:5) = 0.54; Found: C, 79.25; H, 5.80. Calc. for C30H27ClO2: C, 79.19; H,
5.98%; IR νmax: 3058, 3027, 2979, 2929, 2869, 1705, 1615, 1592, 1561, 1496, 1476, 1447, 1367,
1
1317, 1304, 1221, 1206, 1159, 1150, 1096, 1045, 1033 cm-1; H NMR (300 MHz, CDCl3): δ
7.86 (dd, J = 15.6, 11.4 Hz, 1 H, PhCH=CHCH), 7.53-7.50 (m, 2 H, Ar), 7.39-7.11 (m, 12 H, Ar,
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2 × Ph), 6.82 (d, J = 15.6 Hz, 1 H, PhCH=CHCH ), 6.73 (s, 1 H, ArCH), 6.70 (dd, J = 11.4, 0.9
Hz, 1 H, PhCH=CHCH=C), 5.31 (s, 1 H, C=CHAHB), 5.23 (s, 1 H, C=CHAHB), 4.27 (q, J = 7.2
13
Hz, 2 H, OCH2CH3), 3.89 (s, 2 H, PhCH2), 1.31 (t, J = 7.2 Hz, 3 H, OCH2CH3); C NMR (75
MHz, CDCl3): δ 167.0, 148.6, 141.5, 140.2, 139.8, 139.6, 139.2, 136.6, 134.2, 132.3, 130.4,
129.5, 128.8, 128.5, 128.2, 127.3, 127.1, 126.6, 126.1, 125.4, 117.7, 60.7, 34.8, 14.3.
Diethyl 2-[(E)-3-benzyl-4-(3-chlorophenyl)buta-1,3-dien-2-yl]maleate (11j): Following the
general procedure, isolated yield (54 mg, 40%) as colourless liquid. The product was
contaminated with 36% of diethyl 2-[(E)-3-benzyl-4-(3-chlorophenyl)buta-1,3-dien-2-
yl]fumarate and could not be separated. Rf (hexane-EtOAc, 95:5) = 0.26; Found: C, 70.80; H,
5.98. Calc. for C25H25ClO4: C, 70.67; H, 5.93%; IR νmax: 3063, 3026, 2979, 2934, 2906, 2871,
1723, 1615, 1591, 1562, 1241, 1182, 1100, 1027 cm-1; 1H NMR (500 MHz, CDCl3): δ 7.34-7.14
(m, 18 H, Ar, Ph), 6.75 (s, 1 H, ArCH, Z), 6.40 (s, 1 H, ArCH, E), 5.99 (s, 1 H, CHCO2Et, Z),
5.91 (s, 1 H, CHCO2Et, E), 5.44 (s, 1 H, C=CHAHB, E), 5.35 (s, 1 H, C=CHAHB, Z), 5.30 (s, 1 H,
C=CHAHB, Z), 5.06 (s, 1 H, C=CHAHB, E), 4.40 (q, J = 7.0 Hz, 2 H, OCH2CH3, E), 4.33 (q, J =
7.0 Hz, 2 H, OCH2CH3, Z), 4.24 (q, J = 7.0Hz, 2 H, OCH2CH3, Z), 4.19 (q, J = 7.0 Hz, 2 H,
OCH2CH3, E), 3.81 (s, 2 H, PhCH2, Z), 3.58 (s, 2 H, PhCH2, E), 1.39 (t, J = 7.0 Hz, 3 H,
OCH2CH3, E), 1.33 (t, J = 7.0 Hz, 3 H, OCH2CH3, Z), 1.32 (t, J = 7.0 Hz, 3 H, OCH2CH3, Z),
13
1.28 (t, J = 7.0 Hz, 3 H, OCH2CH3, E); C NMR (125 MHz, CDCl3): δ 167.3 (E), 167.2 (Z),
164.9 (E), 164.8 (Z), 148.3 (Z), 146.9 (E), 145.4 (Z), 142.4 (E), 139.9 (E), 138.9 (Z), 138.5 (Z),
138.4 (Z), 138.0 (E), 137.7 (E), 134.3 (Z), 134.1 (E), 131.8 (Z), 129.6 (E), 129.4 (Z), 128.9 (E),
128.8 (Z), 128.6 (E), 128.5, 127.4 (Z), 127.2 (E), 126.6 (Z), 126.5 (E), 126.3 (Z), 123.9 (E), 121.1
(Z), 121.0 (E), 118.5 (E), 61.6, 61.0, 45.5 (E), 35.6 (Z), 14.1, 14.0.
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(2Z,4E)-Ethyl 2-benzylidene-5-(4-methoxyphenyl)-4-methyl-3-methylenepent-4-enoate (11k):
Following the general procedure, isolated yield (100 mg, 45%) as colourless liquid; Rf (hexane-
EtOAc, 95:5) = 0.42; Found: C, 79.52; H, 6.89. Calc. for C23H24O3: C, 79.28; H, 6.94%; IR ν
:
max
1
3070, 3036, 2364, 2326, 1962, 1812, 1717, 1611, 1509, 1479, 1251, 1214, 1177, 1036 cm-1; H
NMR (300 MHz, CDCl3) : δ 7.36-7.26 (m, 7 H, Ar, Ph), 6.91 (d, J = 8.4 Hz, 2 H, Ar), 6.85 (s, 1
H, PhCH), 6.62 (s, 1 H, ArCH), 5.37 (s, 1 H, C=CHAHB), 5.32 (s, 1 H, C=CHAHB), 4.22 (q, J =
6.9 Hz, 2 H, OCH2CH3), 3.84 (s, 3 H, OCH3), 2.13 (s, 3 H, C=CCH3), 1.17 (t, J = 6.9 Hz, 3 H,
OCH2CH3); 13C NMR (75 MHz, CDCl3): δ 169.1, 158.3, 150.5, 135.6, 135.5, 134.7, 130.4,
129.7, 128.5, 128.3, 115.3, 113.6, 61.0, 55.3, 17.0, 13.9.
(2Z,4E)-2-Benzylidene-5-(4-methoxyphenyl)-4-methyl-3-methylenepent-4-en-1-ol (11l): To a
solution of dendralene 11k (151 mg, 0.43 mmol) in dichloromethane (10 mL), DIBAL-H (1.74
mL, 1.0 M in cyclohexane, 1.73 mmol) was added at -78°C under the argon atmosphere and the
solution was stirred for 1 h at the same temperature. The temperature of the reaction mixture was
raised to 0 ºC, stirred for another 1 h and finally allowed to attain room temperature. The reaction
mixture was quenched with dil HCl and extracted with dichloromethane. The organic layer was
concentrated under reduced pressure and the residue was purified by column chromatography
(petroleum ether-EtOAc; 90:10) to obtain the dendralene 11l (105 mg, 80%) as colourless liquid.
Rf (hexane-EtOAc, 80:20) = 0.4; Found: C, 82.15; H, 7.32. Calc. for C21H22O2: C, 82.32; H,
7.24%; IR νmax: 3426, 3058, 3034, 2951, 2933, 2838, 1607, 1511, 1480, 1441, 1303, 1248, 1177,
1034 cm-1; 1H NMR (300 MHz, CD3COCD3): δ 7.49 (d, J = 7.5 Hz, 2 H, Ph), 7.37-7.25 (m, 5 H,
Ar, Ph), 6.90 (d, J = 8.7 Hz, 2 H, Ar), 6.64 (s, 1 H, PhCH), 6.53 (s, 1 H, ArCH), 5.27 (s, 1 H,
C=CHAHB), 5.24 (s, 1 H, C=CHAHB), 4.36 (d, J = 5.4 Hz, 2 H, CH2OH), 3.89 (t, J = 5.4 Hz, 1 H,
29