Exploring the Labile Nature of 2,4,6-Trimethoxyphenyl Moiety in Allylic Systems under Acidic Conditions

Article abstract of DOI:10.1002/ejoc.202000631

An investigation of the unexpected lability of the C_sp3–C_sp2 bond connecting 2,4,6-trimethoxyphenyl group and an allylic moiety is carried out. We observed that the catalytic presence of either Lewis or Br?nsted acid can render such 2,4,6-trimethoxyphenyl group labile. Several nucleophiles were found to substitute the labile C–C bond in mild reaction conditions resulting in very good yields of the allylated products. Even in the absence of a nucleophile, intramolecular cyclization of the parent substrate under acidic activation caused the labile C–C bond to cleave. A major motivation of this study is to understand the lability of electron-rich aryl group in acidic medium, employing 2,4,6-trimethoxyphenyl moiety as a case study. A plausible mechanism is proposed after carrying out several control reactions as well as UV/Vis and ¹H NMR spectroscopic studies. This work provides an insight into the activation of electron-rich arenes as a labile entity in acidic medium while also adding a conceptually novel C–C bond breaking approach to the vast literature of allylation of arenes.

Full text of DOI:10.1002/ejoc.202000631

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Exploring the Labile Nature of 2,4,6-Trimethoxyphenyl Moiety in
Allylic Systems under Acidic Conditions
Authors: Dipankar Paul and Paresh Nath Chatterjee
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000631
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01/2020

10.1002/ejoc.202000631
European Journal of Organic Chemistry
Exploring the Labile Nature of 2,4,6-Trimethoxyphenyl Moiety in Allylic Systems under
Acidic Conditions
Dipankar Paul and Dr. Paresh Nath Chatterjee*
Department of Chemistry, National Institute of Technology Meghalaya, Bijni Complex,
Laitumkhrah, Shillong 793003, Meghalaya, INDIA
*Corresponding author Email: paresh.chatterjee@nitm.ac.in
Abstract
An investigation of the unexpected lability of the Csp3-Csp2 bond connecting 2,4,6-
trimethoxyphenyl group and an allylic moiety is carried out. We observed that the catalytic
presence of either Lewis or Brønsted acid can render such 2,4,6-trimethoxyphenyl group
labile. Several nucleophiles were found to substitute the labile C-C bond in mild reaction
conditions resulting in very good yields of the allylated products. Even in the absence of a
nucleophile, intramolecular cyclization of the parent substrate under acidic activation caused
the labile C-C bond to cleave. A major motivation of this study is to understand the lability of
electron-rich aryl group in acidic medium, employing 2,4,6-trimethoxyphenyl moiety as a
case study. A plausible mechanism is proposed after carrying out several control reactions as
1
well as UV-Vis and H NMR spectroscopic studies. This work provides an insight into the
activation of electron-rich arenes as a labile entity in acidic medium while also adding a
conceptually novel C-C bond breaking approach to the vast literature of allylation of arenes.
Keywords
C-C bond activation, allylation of arene, 1,3,5-trimethoxybenzne, carbon-based leaving
group, acidic labilization of arene.
1
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Graphical Abstract
Key Topic: C-C bond activation
Table of Contents text: A study aimed to comprehand the labile behavior of electron-rich
aryl groups connected to allylic framework under acidic medium. Reveresible protonation
and deprotonation at the ipso-carbon was found to be a driving factor in the C-C bond
breaking reaction
2
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Introduction
High thermodynamic stability of the C-C bond has not only made it ubiquitous but
has also narrowed the avenue of the literature that explores the cleavage of C-C bonds.
Generally, the small pool of C-C bond breaking reactions present in the literature exploits one
or more of these three susceptibilities: i) release of ring strain; ii) chelation assistance; iii)
cleavage of stable functional fragments such as allyl, carbonyl, cyano etc.[1] Recently a lot of
interests have been focussed on the cleavage of stable carbon-based fragments for application
in organic syntheses. In this regard, several 1,3-dicarbonyl species, as well as electron-rich
arene such as 1,3,5-trimethoxybenzene (TMB) have been reported to act as carbon-based
leaving groups (Figure 1).[2]
Figure 1: Molecules that cleave as stable fragments in C-C bond breaking reaction.
While different research groups have explored the chemistry of 1,3-dicarbonyl species
as the cleaving fragment, we continue our role in exploring the cleavage of 1,3,5-
trimethoxybenzene. In our previous works, we have revealed the leaving ability of the 2,4,6-
trimethoxyphenyl moiety from benzylic systems to synthesize triarylmethanes.[2o-p] Herein,
we investigate the labile nature of the 2,4,6-trimethoxyphenyl group in allylic systems using
conventional and spectroscopic techniques. We have observed that the 2,4,6-
trimethoxyphenyl group can readily be replaced from the allylic systems by various
nucleophiles through the cleavage of the Csp3-Csp2 bond (Scheme 1). Nucleophiles such as
indoles, 2-methylfuran, 2-methylthiophene, 4-hydroxycoumarin, 4-methoxythiophenol etc.
reacts smoothly to generate the corresponding derivatives in good yields while generating
TMB as the by-product. We have also noted that TMB is eliminated even in the absence of a
nucleophile via a C-C bond cleavage as a result of intramolecular cyclization in substrate 1
under acidic conditions. The C-C bond breaking reaction takes place in mild conditions in the
presence of a Lewis or Brønsted acid. We have examined the lability of 2,4,6-
trimethoxyphenyl group under various reaction conditions and in several structurally diverse
substrates. Additionally, we have focussed our efforts to understand the mechanistic pathway
involved in the activation of the electron-rich arene. In this regard, we have carried out
3
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1
various control reactions as well as UV-Vis and H NMR spectroscopic studies. The
spectroscopic experiments suggested that the reversible protonation of the 2,4,6-
trimethoxyphenyl group of 1a in acidic medium may drive the C-C bond breaking reaction.
While exploring the lability of TMB, the results of this study also offer a viable
approach of inducing lability to electron-rich aryl groups in general. As per our knowledge,
there are no reports in the literature focussed at studying the labilization of such arenes in
allylic systems. As a result, few reports that observed the labile nature of electron-rich arenes
in acidic medium termed it unexpected.[3] We believe that the findings of this work offer an
explanation to this seemingly unexpected cleavage of electron-rich arenes. The preliminary
understanding revealed through this report may trigger more research directed at exploring
various possible applications borne out of acidic labilization of electron-rich arene.
Moreover, the C-C bond breaking reaction may be applied for the allylation of various arenes
as represented in Table 2 where mild metal-free reaction conditions generate good yields of
the products in short reaction times. This method of allylation of arenes via C-C bond
cleavage adds a conceptually novel approach to the vast existing literature.[4]
Scheme 1: Seemingly robust C-C bond turns labile in acidic medium.
Results and Discussion
With the relevant knowledge of activation of 2,4,6-trimethoxyphenyl group in acidic
medium, we have reacted (E)-(3-(2,4,6-trimethoxyphenyl)prop-1-ene-1,3-diyl)dibenzene 1a
with model nucleophile 5-nitroindole 2a in various conditions (Table 1). Lewis acidic metal
triflates such as AgOTf, Sn(OTf)2 and Cu(OTf)2, activated the 2,4,6-trimethoxyphenyl group
efficiently and led to the substitution product 3a in more than 80% yields (Table 1, entries 1,
3-4). Although Sc(OTf)3 was previously shown to interact strongly with 1,3,5-
trimethoxybenzene,[5] it did not prove to be efficient in the C-C bond breaking reaction
producing only moderate yield of the desired product (Table 1, entry 2). In benzylic systems
FeCl3 was demonstrated to best activate the 2,4,6-trimethoxyphenyl group but the catalyst’s
4
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European Journal of Organic Chemistry
supremacy does not extend to allylic systems as modest 73% yield of the substitution product
3a is formed leaving some 1a unreacted (Table 1, entry 6).[2o-p] But analogous to benzylic
systems, ZnCl2 fails to activate the 2,4,6-trimethoxyphenyl group in allylic systems as 1a and
2a remains unreacted in the reaction medium (Table 1, entry 7).[2p] When we tried Brønsted
acids, we found that p-toluenesulfonic acid (PTSA) generates 91% yield of the substitution
product 3a by rendering the 2,4,6-trimethoxyphenyl group extremely labile (Table 1, entry
10). However, a stronger acid such as triflic acid (TfOH) produces a messy reaction profile
(Table 1, entry 11). Other acids such as HCl and trifluoroacetic acid can also activate the
electron-rich arene to moderate extent (Table 1, entries 12-13). Although both Lewis acids
and Brønsted acids are comparably effective in activating the labile Csp3-Csp2 bond, we have
chosen PTSA for all the future studies. On examining the effect of various solvents
employing PTSA as the catalyst, we found that both polar aprotic and non-polar aprotic
solvents serve as good medium for the activation of the arene (Table 1, entries 10, 14-17).
i
However, protic solvents such as EtOH and PrOH stop the C-C bond breaking reaction
altogether (Table 1, entries 18-19). This may be understood as extremely rapid proton-
exchange between protons of the 2,4,6-trimethoxyphenyl group and the protic solvent may
not allow time for a nucleophile to participate in the reaction.[5] We have also found that the
reaction rate depends on temperature, as only 56% yield of 3a is isolated after 10 h of
reaction at room temperature. Gradual increase in the temperature increases the rate of the
reaction as evident from Table 1 entries 10, 20-22. A 10 mol% loading of the catalyst PTSA
has provided maximum amount of the substitution product, higher catalyst loading generates
an unclean reaction profile while lower loading makes the reaction considerably sluggish
(Table 1, entries 10, 23-24).
Table 1: Lability of 2,4,6-trimethoxyphenyl group under various reaction conditions.a
Entry
Catalyst
AgOTf
Solvent
MeNO2
MeNO2
MeNO2
Temp. (°C)
Yield (%)b
1
2
3
80
80
80
81
55
86
Sc(OTf)3
Sn(OTf)2
5
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4
5
Cu(OTf)2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeCN
Toluene
DCE
80
80
85
22
73
-
Yb(OTf)3
FeCl3
6
80
7
ZnCl2
80
8
SnCl2.H2O
BiCl3
80
48
51
91
75
32
54
81
85
87
32
-
9
80
10
11
12
13
14
15
16
17
18
19
20
21c
22
23d
24e
PTSA
TfOH
80
80
HCl
80
CF3COOH
PTSA
PTSA
PTSA
PTSA
PTSA
PTSA
PTSA
PTSA
PTSA
PTSA
PTSA
80
80
80
80
THF
reflux
reflux
80
EtOH
iPrOH
-
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
25
15
56
72
84
70
25
50
80
80
aReaction conditions: 1a (0.55 mmol), 2a (0.5 mmol), solvent 2 mL, catalyst (10 mol%),
temp. 80 °C, time 1 h; bIsolated yields; ctime 10 h; dcatalyst (5 mol%); ecatalyst (20 mol%).
After defining the reaction conditions that best activates the 2,4,6-trimethoxyphenyl
group, we set out to study the effect of various nucleophiles on the C-C bond breaking
reaction. Initially, we investigated various derivatives of indoles 2a-e as nucleophiles and
isolated good to very good yields of the corresponding products 3a-e (Table 2, entries 1-5). 5-
membered heteroarenes such as 2-methylfuran 2f and 2-methylthiophene 2g also gave the
desired reaction smoothly (Table 2, entries 6-7). Labile 2,4,6-trimethoxyphenyl group was
also readily substituted by 4-hydroxycoumarin 2h and 1,3-dimethoxybenzene 2i yielding the
desired products 3h and 3i in 92% and 78%, respectively (Table 2, entries 8-9). In all cases,
the leaving TMB 4, generated by the Csp3-Csp2 bond cleavage, was also recovered during
chromatographic purification of the reaction mixtures. A measure of the lability of the C-C
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bond under study may be grasped from the reaction of 4-methoxythiophenol 2j with 1a where
a new C-S bond replaces a C-C bond (Table 2, entry 10). The unlikely exchange of a usually
strong C-C bond by a weaker C-S bond is made feasible under acidic activation of the
electron-rich arene as suggested by the studies presented later. When we treated substrate 1a
with allyltrimethylsilane 2k, we obtained a moderate 64% yield of the desired product 3k
while 3-phenyl-1H-indene 5 was formed as a side-product via intramolecular cyclization
(Table 2, entry 11). The formation of indene 5 is further explained in Scheme 2B. We have
also studied if the allylic backbone connected to the 2,4,6-trimethoxyphenyl group plays any
crucial role in determining the lability of the C-C bond. To postpone the question of
regioselectivity, initially we have chosen symmetric substituents on the allylic backbone as
shown in substrate 1a-1e (Table 2). We have noticed that the lability of the 2,4,6-
trimethoxyphenyl group does not differ significantly when aromatic or heteroaromatic
substituents are present symmetrically in the allylic backbone as very good yields after C-C
bond cleavage were observed (Table 2, entries 12-15). It needs to be pointed out that in all
the reactions presented in Table 2, the trans-configuration of the double bond in the allylic
backbone was preserved.
Table 2: Effect of nucleophile and the allylic moiety on the C-C bond breaking reaction.a
Yield of
Entry
1
Ar-, 1
Nu-H 2
Product 3
3 (%)b
Ph-, 1a
91
2
Ph-, 1a
84
7
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3
4
5
Ph-, 1a
Ph-, 1a
Ph-, 1a
85
76
81
6
7
Ph-, 1a
Ph-, 1a
89
83
8
Ph-, 1a
92
9
Ph-, 1a
Ph-, 1a
78
81
10
8
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11
12
Ph-, 1a
64
4-MeC6H4-, 1b
87
88
87
13
14
4-ClC6H4-, 1c
1-Napthyl-, 1d
15
2-Thienyl-, 1e
83
aReaction conditions: 1 (0.55 mmol), 2 (0.5 mmol), PTSA (10 mol%), MeNO2 2 mL, temp.
80 °C, time 1 h. bIsolated yields.
When substrate 1 was unsymmetrically substituted, the reaction with nucleophile 2a
resulted in the formation of a single isomer in very high yield (Table 3). The reaction of
substrate 1f and 1g produced 3p and 3q respectively, where the nucleophile attacked the less
hindered terminus of the allylic moiety. Moreover, the reaction of 1h which generated 3r in
very high yield also hints at α-selectivity of the C-C bond breaking reaction as no γ-selective
product was obtained. With the reaction suggesting of being α-selective, we proceeded to
investigate the mechanism of the C-C bond breaking reaction.
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Table 3: Regioselectivity of the C-C bond breaking reaction.a
Entry
1
Substrate 1
Product 3
Yield of 3 (%)b
86
2
93
3
90
aReaction conditions: 1 (0.55 mmol), 2 (0.5 mmol), PTSA (10 mol%), MeNO2 2 mL, temp.
80 °C, time 1 h. bIsolated yields.
Few control reactions as outlined in Scheme 2 were carried out to understand the
mechanistic intricacy involved in the reaction. We noted that when weaker nucleophiles, such
as mesitylene 2l or pentamethylbenzene 2m, were used, the expected substitution reaction did
not take place (Scheme 2A). Instead, we observed that 3-phenyl-1H-indene 5 was formed and
TMB was eliminated as a by-product while the nucleophiles 2l/2m remained unreacted. We
understand that when suitable nucleophile is absent, compound 5 is formed via
intramolecular cyclization and subsequent rearrangement from substrate 1a as outlined in
Scheme 2B. The rearrangement of presumably formed 1-phenyl-1H-indene to a more stable
isomer 3-phenyl-1H-indene 5 under acidic medium at elevated temperature is well studied.[6]
In absence of any nucleophile, few unidentifiable compounds in small amounts were also
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European Journal of Organic Chemistry
formed along with indene 5 while major portion of 1a remained unchanged. The above
observations suggest that the reaction pathway depends on the nucleophile as good
nucleophiles lead to substitution reaction while weaker nucleophiles fail to compete with the
intramolecular cyclization of the substrate. Nevertheless, in both reaction pathways, TMB 4
is eliminated under the acidic reaction conditions via C-C bond cleavage. In our previous
work, we have demonstrated that the leaving ability of arenes depend on their electron-
richness.[2o-p] From this vantage, we realize that the nucleophiles employed in the study are
also electron-rich and hence the C-C bond breaking reaction may be reversible to an extent.
To evaluate our hypothesis, we tried the backward reaction where we reacted 3a with TMB 4
in the optimized reaction conditions and found that the reactants remain unreacted for 24 h
(Scheme 2C, See SI for experimental details, page S3). This result supports the high product
yield obtained in Table 2 and Table 3 as the reaction is not reversible in optimized reaction
conditions. However, when we increased the equivalents of TMB 4 along with the catalyst
loading to facilitate the backward reaction, the results indicated that a small amount of 5-
nitroindole was eliminated via C-C bond cleavage (Scheme 2D). In perpetuation, we also
found that 1-methylindole was eliminated when 3d reacted with TMB 4 in the above reaction
conditions (Scheme 2E). Such kind of activation of indole derivatives and their subsequent
elimination under acidic medium was also observed previously.[7] To summarize, these
observations suggest that electron-rich aryl groups are activated to variable extent depending
on their electron-richness under the influence of an acid. Some spectroscopic experiments
were then carried out to shed light on the mode of activation of electron-rich aryl groups
under acidic conditions.
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Scheme 2: Control experiments for insight into the mechanism.
It is conventionally known that the electron-rich arenes undergoes proton exchange in
Lewis acidic conditions and Castellani et al. recently studied proton-exchange in TMB.[5,8] To
understand our reaction, we investigated the protonation of TMB and the 2,4,6-
trimethoxyphenyl group of 1a in presence of PTSA. Literature suggests that protonation of
TMB 4 results in the formation of species 4ꞌ as outlined in Scheme 3A.[5] We employed UV-
Vis spectroscopy to corroborate the formation of 4ꞌ from 4 upon addition of PTSA. The UV-
Vis spectrum of TMB 4 in anhydrous MeCN shows an absorption maxima at λmax(TMB) =
206 nm. When 1 equiv. of PTSA is added to the solution of 4, we noted that the absorbance at
12
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λmax(TMB) decreases. The absorbance decreases further and further on increasing the amount
of PTSA as depicted in Figure 2A. We understand that as the acid concentration is increasing,
more amount of TMB is getting protonated to 4ꞌ which decreases the concentration of free
TMB and hence decreases the absorbance at λmax(TMB). A similar trend is observed when 1a
which shows absorption maxima at λmax(1a) = 207 nm is treated with PTSA (Figure 2B). We
interpret that the decrease in absorbance at 207 nm may be because of the formation of a
species 1aꞌ analogous to the formation of 4ꞌ from 4 as outlined in Scheme 3B. A proton-
deuterium exchange experiment in acidic medium have established that the 2,4,6-
trimethoxyphenyl group of 1a also reciprocates the aptitude for proton-exchange as TMB
1
(Figure 3).[5] In the H NMR spectra recorded in CD3OD, the peak for aromatic C-H
belonging to 2,4,6-trimethoxyphenyl group of 1a [ (ppm) = 6.200 (s, 2H)] loses its relative
intensity after PTSA is added to the solution (Figure 3A and 3B). This clearly indicates that
the aromatic C-H protons of the 2,4,6-trimethoxyphenyl group of 1a are in a dynamic
equilibrium with solvent deuteriums (or protons) under acidic condition. It is understood that
the proton-deuterium exchange is a result of deprotonation of the transiently formed species
1
analogous to 1aꞌ. In a bid to further support our claim; we used H NMR spectroscopy in
CD3CN to investigate possible change in the peak positions of the protons of TMB in absence
and presence of PTSA (Figure 4A). No discernable shift was observed for the protons of –
OCH3 group of TMB [ (ppm) = 3.763 (s, 9H)] upon addition of PTSA (Figure 4A).
However, we observed a gradual downfield shift of the peak for aromatic C-H of TMB [
(ppm) = 6.119 (s, 3H)] upon subsequent addition of PTSA. Kříž et al. demonstrated that in
presence of acid, such a downfield shift of aromatic C-H of arene indicates protonation of the
arene.[9] Similarly, when we studied 1a in presence of increasing amount of PTSA, we noted
a similar but more prominent downfield shift of the aromatic C-H of the 2,4,6-
trimethoxyphenyl moiety [ (ppm) = 6.263 (s, 2H)] (Figure 4B). Moreover, the doublet of
methylene C-H [ (ppm) = 5.407 (d, J = 8.4 Hz, 1H)] adjacent to the 2,4,6-trimethoxyphenyl
moiety of 1a also showed a prominent downfield shift upon subsequent addition of PTSA.
The downfield shift of the methylene proton of 1a further validates the idea that the adjacent
2,4,6-trimethoxyphenyl group is getting protonated. There was no shift in the –OCH3 peaks
belonging to 1a. Conceivably, protonation of the 2,4,6-trimethoxyphenyl moiety of 1a may
lead to several possible structures and the spectra obtained is only a weighted average
reflection of all the structures. We evaluated that the C-C bond breaking reaction may
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originate from species 1aꞌ (Scheme 3B) which is one of the possible protonated structures
participating in a fast dynamic equilibrium between 1a and H+.
Scheme 3: Protonation of electron-rich arenes in acidic conditions.
Figure 2: (A) UV-Vis spectra of TMB and solutions of TMB+PTSA at various ratios. (B)
UV-Vis spectra of 1a and solutions of 1a+PTSA at various ratios.
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Figure 3: (A) Partial 1H NMR spectra of 1a in CD3OD; (B) Partial 1H NMR spectra of 1a in
presence of PTSA in CD3OD; * Peaks belonging to PTSA
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1
Figure 4: (A) H NMR spectra of TMB and solutions of TMB+PTSA at various ratios
(CD3CN); (B) 1H NMR spectra of 1a and solutions of 1a+PTSA at various ratios (CD3CN); *
Peaks belonging to PTSA.
1
Besides, when we recorded a H NMR spectrum of a 1a and PTSA (1:1) after 3 h of
mixing, in CDCl3, we observed a few additional peaks (Figure 5). Among the new peaks,
presence of TMB 4 can readily be noted (Figure 5B), which may have eliminated from the
species 1aꞌ (Scheme 2B). We suppose that compound 5 was also formed in the process via
intramolecular cyclization (Scheme 2B), although its presence is not discernable from the
spectrum.
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Figure 5: Partial 1H NMR spectra of (A) 1a, (B) 1a + PTSA (1:1) (Peaks for eliminated
TMB 4 indicated by arrows), (C) TMB 4.
With the help of relevant literature and the above mentioned experiments, we propose
the reaction mechanism outlined in Scheme 4. Initially, the electron-rich 2,4,6-
trimethoxyphenyl moiety of 1a gets protonated in presence of an acid which may involve
several possible protonated structures under dynamic equilibrium. We propose that the
structure with ipso-protonation of the 2,4,6-trimethoxyphenyl group 1aꞌ as the intermediate
species which is responsible for the C-C bond breaking reaction. Such an ipso-protonated
structure like 1aꞌ of arene in acidic medium leading to C-C bond cleavage was also reported
by Mudududdla et al.[10] An equivalent ipso-substituted species may be formed in the Lewis
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acid activated electron-rich arene.[2o-p,7] Species 1aꞌ under the influence of a good nucleophile
leads to product 3 and in absence of any ideal nucleophile leads to compound 5 via
intramolecular cyclization. In both events, TMB 4 is eliminated through a Csp3-Csp2 bond
cleavage. The failure of protic solvents as the reaction medium may also be explained in the
light of above observations as rapid proton-exchange between 1aꞌ and the protic solvent does
not allow for a nucleophile to participate in the reaction.[5] It may be noted that, the Csp3-Csp2
bond between the 2,4,6-trimethoxyphenyl group and the allylic backbone in species 1aꞌ is
adequately polarized which evidently allows nucleophilic 4-methoxythiophenol 2j to react
and form a C-S bond replacing the C-C bond. It is important to notice that the effect of the
allylic moiety is largely insignificant on the activation of the electron-rich arene and such
activation may also take place when a benzylic moiety is present instead of the allylic moiety.
This deduction is supported by our previous results[2o-p] and also help us understand the
unexpected C-C bond cleavage observed by Kim et al.[3a] and Jaratjaroonphong et al.[3b]
Scheme 4: Proposed reaction path for the C-C bond breaking reaction.
Conclusion
In summary, we have explored the unusually labile Csp3-Csp2 bond between 2,4,6-
trimethoxyphenyl group and allylic moieties in acidic conditions where we observed that the
C-C bond may be rendered labile by a variety of Lewis or Brønsted acids in aprotic solvents.
The 2,4,6-trimethoxyphenyl group may be readily substituted by nucleophiles such as
indoles, 2-methylfuran, 2-methylthiophene, 4-hydroxycoumarin etc. A measure of the lability
of the C-C bond may be grasped as a new C-S bond is able to replace the existing C-C bond.
Weaker nucleophile, however, failed to compete with the intramolecular cyclization which
led to the formation of an indene derivative. Mechanistic studies using UV-Vis and 1H NMR
spectroscopy suggested that the electron-rich arene gets reversibly protonated in presence of
PTSA. Based on the studies and relevant literature, we proposed that the C-C bond breaking
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European Journal of Organic Chemistry
reaction results when the ipso position of the electron-rich aryl group is protonated. The
findings of this work employing 1,3,5-trimethoxybenzene as a case study, presents a general
insight into the acidic labilization of electron-rich aryl groups. Further investigation about the
mechanism and on adopting the reaction for other application in organic syntheses is
underway in our laboratory.
Experimental Section
General procedure for the cleavage of the Csp2-Csp3 bond
A 25 mL round-bottom flask equipped with a magnetic bar and water condenser were
charged with 1 (0.55 mmol), 2 (0.5 mmol), MeNO2 (2 mL) and PTSA (10 mol%) in an air
atmosphere. The flask was placed in a constant temperature oil-bath at 80 °C and the progress
of the reaction was monitored by TLC. After the completion of the reaction, the solvent was
removed under reduced pressure and the crude product was purified by dry column vacuum
chromatography (silica gel G, petroleum ether 60-80 °C/EtOAc) to obtain the desired product
3.
Conflict of Interest
The authors declare no conflict of interests.
Supporting Information
Experimental details for reaction condition optimization, control reactions, UV-Vis
studies and NMR studies are described in the supporting information. Analytical data along
1
13
with H and C NMR spectra of compound 1, 3, 4 and 5 are also given in the supporting
information.
Acknowledgement
Scientific and Engineering Research Board (SERB) is gratefully acknowledged for
financial support to P.N.C (sanction order no. SB/FT/CS-115/2014; dated 24/08/2015). D.P.
thanks NIT Meghalaya for financial support. SAIF, NEHU is acknowledged for analytical
facilities.
19
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10.1002/ejoc.202000631
European Journal of Organic Chemistry
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