Abnormal Nucleophilic Substitution on Methoxytropone Derivatives: Steric Strategy to Synthesize 5-Substituted Azulenes

Article abstract of DOI:10.1002/chem.201902702

Azulene is a non-alternant non-benzenoid aromatic system, and in turn, it possesses unusual photophysical properties. Azulene-based conjugated systems have received increasing interest in recent years as optoelectronic materials. Despite the routes availa

Full text of DOI:10.1002/chem.201902702

A Journal of
Accepted Article
Title: Abnormal nucleophilic substitution on methoxytropone
derivatives: steric-guided strategy to synthesize 5-substituted
azulenes
Authors: Neha Rani Kumar, Abhijeet R Agrawal, and Sanjio
Shankarrao Zade
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Abnormal Nucleophilic Substitution on Methoxytropone
Derivatives: Steric Strategy to Synthesize 5-Substituted Azulenes
Neha Rani Kumar, Abhijeet R. Agrawal, and Sanjio S. Zade*
Abstract: Azulene is
a
non-alternant non-benzenoid aromatic
compounds that allows easy functional group modification
(Scheme 1c).6
system, and in turn, it possesses unusual photophysical properties.
Azulene-based conjugated systems are receiving increasing interest
in recent years as optoelectronic materials. Despite the routes
available for the preparation of substituted azulene derivatives, there
remain few methods that allow regioselective substitution on seven-
membered ring of azulenes due to the subtle reactivity difference
among the various positions. This report explores the reactivity of
substituted tropolones as the azulene precursors and also provides
the new method to create 5-substituted azulenes. The reaction of
cyanoacetate enolate with unsubstituted 2-methoxytropone affords
azulene via the attack of the nucleophile on C-2 center (normal
pathway). We have observed that 3-substituted 2-methoxytropones
undergo steric-guided nucleophilic addition at C-7 center (abnormal
pathway) to afford 5-substituted azulene derivatives. Based on this
observation and DFT calculation, a new synthetic strategy is devised
for the regioselective synthesis of 5-substituted multifunctional
azulenes, which cannot be accessed by any other method.
Introduction
Scheme 1. Various approaches to azulene synthesis.
Azulene is a non-alternant non-benzenoid aromatic system,
and in turn, it possesses unusual photophysical properties such
as a large dipole moment and a narrow HOMO-LUMO gap.
Although azulene-based conjugated systems remained largely
unexplored as optoelectronic materials, however, in the recent
few years, they have received increasing interest. Thus,
azulenes are explored as active materials in the field of
conducting polymers, electronic materials, fluorescence
switching materials, and anion receptors.1 2,6-Connected
azulene oligomers form donor-acceptor conjugated systems by
delocalizing the π-electrons along the direction of C2v dipolar
axis. Thus, they possess small HOMO-LUMO gaps. This idea
has been exploited in recent studies, and 2,6-connected azulene
scaffolds have been synthesized and utilized in OFET devices.2,3
In 1937, Plattner and Pfau reported azulene synthesis
involving troublesome dehydrogenation step (Scheme 1a) thus
limiting its practical application.4 Ziegler-Hafner’s azulene
synthesis (Scheme 1b) was highly effective for azulene
synthesis having substituents on the seven-membered ring.5
Nozoe et al. reported the remarkable single pot synthesis of
multifunctional azulenes from troponoids and active methylene
Tropone and tropolone derivatives are the important
precursors for the synthesis of azulenes by easy synthetic route
with the scope of functional group modifications. Several natural
products featuring tropone and tropolone have been isolated in
the past seven decades and shown to possess various
bioactivities7 which have been attributed to the pharmacophore
center based on the seven-membered carbocyclic system.
Tropolone derivatives are part of synthetically challenging drugs
like colchicine8 and have attracted extensive studies since they
possess powerful antibacterial and antifungal activity particularly
against antibiotic-resistant bacteria. Their pharmacological
properties, in turn, are determined by the nature and position of
functional groups in the tropolone ring.9 Hashmi and group
reported the synthesis of several natural products bearing the
active unsaturated seven-membered ring.10
A wide variety of cycloaddition reactions, photochemical
transformations and nucleophilic substitutions on tropolone, 2-
methoxytropone and other substituted tropolones have been
carried out for the synthesis of biologically active compounds.11-
14 Yamamoto and co-workers have studied the regioselectivity of
nucleophilic substitution on 5-bromo-2-methoxytropone with the
various nucleophiles, where soft S-nucleophiles preferred the 5-
position and the harder O- and N-nucleophiles preferred 2-
position for the substitution.15
[a]
Neha Rani Kumar, Abhijeet R. Agrawal, Dr. Sanjio S. Zade
Department of Chemical Sciences
Indian Institute of Science Education and Research Kolkata
Mohanpur, 741246, Nadia, West Bengal, India.
E-mail: sanjiozade@iiserkol.ac.in
Pietra and Biggi have provided a detailed insight into the
normal and abnormal nucleophilic substitution and ring
contraction reactions on tropones with a labile α-substituent
where the alteration of reactivity was attributed to the nature of
Supporting information for this article is given via a link at the end of
the document.
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the leaving group, the nucleophile, and the solvent.16,17 On the
other hand, Machiguchi and co-workers18 have reported a
detailed theoretical and experimental study on the mechanism of
Nozoe’s synthesis of azulene from 2-methoxytropone.
There are limited ways to incorporate substituents on the
azulene scaffold, which include (i) Sonogashira coupling of 6-
bromoazulene with the terminal alkynes followed by catalytic
reduction,19 (ii) the reaction between fulvene ketene acetal and
α-pyrone derivatives to yield the [6+4] cycloaddition adduct
leading to azulenols,20 and (iii) Rh-catalyzed ring expansion-
annulation of -bromo--diazo ketones to afford 1-azulenols.21
(iv) gold catalysed dimerisation of diaryldialkynes for the
synthesis of substituted and modifiable azulenes.22 (v) the
(TBAOH) in dichloromethane (DCM) and allyl bromide at 45 °C
to give 2-allyloxytropone (2a) in 71% yield. Claisen
rearrangement of 2a in toluene at 120 °C gave the rearranged
product 3-allyltropolone (3a) in 90% yield. Compound 3a was
then converted to its methyl ether derivative using Mitsunobu
reaction conditions to give isomers A1 and A2 in 35% and 51%
yields, respectively. 5-Bromotropolone (1b), obtained from 1,4-
cyclohexadiene in 4 steps using De Shong’s method8 (Scheme
S2), was subjected to similar O-allylation, Claisen
rearrangement and Mitsunobu reaction to give sequentially
compounds 2b and 3b in 69% and 92% yields and isomers B1
and B2 in 37% and 55% yields, respectively. Structures of A1,
1
A2, and B1 were confirmed H NMR.27 Compounds B1 and B2
synthesis
of
1,1-dicyanoazulenes
and
subsequent
were characterized by 1H NMR, 13C NMR, and HRMS. Structure
of B2 was unambiguously confirmed by single crystal X-ray
diffraction (SCXRD) analysis (Figure 1).
functionalization of the seven-membered ring followed by
elimination of HCN to give bromo-cyano substituted azulene.23
Traditional methods for the construction of an azulene scaffold
include long, low-yielding synthetic procedures that in many
cases do not afford the desired substitution patterns. Achieving
regioselectivity for the substitution on the seven-membered ring
of azulene is a challenging task due to very close reactivity of all
positions. Although sophisticated synthetic methodologies for
the introduction of functional groups on the seven-membered
ring have been reported recently,24 we note that, there is no
synthetic strategy to create regioselectively multifunctional 5-
substituted azulenes. Hence, the regioselective synthesis of
substituted azulenes is highly crucial considering their varied
applications. It is imperative to develop facile synthetic methods
for novel substitution motifs to extend the applications of
azulenes.25
In an attempt to introduce allyl chain as a solubilising
group on the azulene scaffold at the 4-position, we have
synthesized 3-allyltropolone and 3-allyl-5-bromotropolone and
subsequently, their methyl ethers. We here elucidate the
reactivity difference of allyl substituted isomeric 2-
methoxytropone (A1 and A2) and 5-bromo-2-methoxytropone
(B1 and B2). We observed an interesting alteration of the
reaction pathway of the construction of azulene scaffold to that
described by Machiguchi and co-workers merely by the
introduction of allyl chain, which led to the formation of diethyl 5-
allyl-2-aminoazulene-1,3-dicarboxylate (14) rather than 4-allyl-2-
aminoazulene-1,3-dicarboxylate (12) from the precursor 3-allyl-
2-methoxytropone (A1). We have further successfully extended
this observation to create a new synthetic strategy to synthesize
5-substituted azulenes.
Scheme 2. Synthesis of allyl substituted methyl ethers of tropolone and 5-
bromotropolone
Results and Discussion
In our initial attempts to create 2,6-halo substituted
azulene having solubilizing group on the seven-membered ring,
we have synthesized allyl substituted tropolone regioisomers, 3-
allyl-2-methoxytropone (A1) and 2-allyl-7-methoxytropone (A2)
and their corresponding bromo analogues i.e. 3-allyl-5-bromo-2-
methoxytropone (B1) and 2-allyl-4-bromo-7-methoxytropone
(B2) (Scheme 2). Commercially available tropolone (1a) was O-
allylated26 using tetra-butyl ammonium hydroxide solution
Figure 1. Crystal structure of B2.
Further, we have attempted the synthesis of azulenes from
compounds A1, A2, B1, and B2 by the reaction with t-BuNH2 as
a base, ethylcyanoacetate as the active methylene compound
and ethanol as solvent at 0 °C. Machiguchi and co-workers in
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their report18 provided detailed theoretical and experimental
insight of the mechanism of azulene synthesis from a troponoid
precursor (2-methoxytropone) and active methylene compound
(Scheme 3). As described,18 the process consists of the
following elementary steps. (a) The initial step includes the
coupling constant corresponding to the H at C-4. Compound A2,
on the contrary, was inert when subjected to similar reaction
conditions. Unlike the reaction of A2, the reaction of isomeric B2
afforded
ethyl
(E)-3-(3-allyl-4-hydroxy-5-methoxyphenyl)-2-
cyanoacrylate (16) under similar reaction conditions. Compound
-
1
nucleophilic attack of malononitrile anion (HC(CN)2 on the
16 was confirmed by H, 13C NMR and HRMS data. Compound
troponoid substrate, 2-methoxy tropone (4), to form
Meisenheimer-type complex 5, which rapidly converts to the
intermediate anion 7 via the compound 6. (b) The first ring closu-
16 was topochemically converted to all-trans-cyclobutane
derivative 17.
Machiguchi et al. have reported the formation of inter-
mediate 6 (Scheme 3) by the attack of the nucleophile at C-2 of
the active troponoid precursor. This pathway was termed as the
normal path and was supported by experimental observations
and theoretical calculations. The attack of the nucleophile at C-7
of troponoid system was discussed as the abnormal path
(Scheme 6), and their experimental observations confirmed that
the reaction proceeded via the normal nucleophilic substitution.
From Scheme 4, we note the following important
observations. (a) The allyl chain has occupied C-5 position in
azulene derivative 14 and 15 rather than usual C-4 position (as
in 12 and 13). (b) In contrast to the reaction of A1, the isomer A2
was found inert in this reaction under similar reaction conditions.
(c) Compound B1 smoothly underwent the azulene ring
formation, whereas B2 afforded ring-contracted product 16 and
subsequently it was converted into 17.
The following consideration can explain these observa-
tions. In the synthesis of azulene scaffold from A1, we envision
that the first step would be the nucleophilic attack either at C-2
(Path A, normal) or C-7 (Path B, abnormal) of the allyl-
substituted active troponoid precursor A1 as shown in Scheme 5.
The reaction will afford 14 if it proceeds via ‘Path B’, which was
earlier considered as the abnormal path. The attack of a
nucleophile (ethyl cyanoacetate anion) at the C-2 i.e. methoxy
centre via Path A (normal) cannot lead to the formation of 14.
The primary nucleophilic addition of ethyl cyanoacetate anion
and elimination are through Path B, i.e. at C-7 on the tropone
ring which by the loss of methoxide subsequently forms 21 via
the intermediate anion 20. The attack of the nucleophile at C-2 is
sterically unfavoured due to the presence of allyl substituent on
the adjacent carbon that hinders the formation of 19 via the
sterically unfavored Meisenheimer adduct 18. Formation of 15
can also be explained by a similar mechanism. The rest of the
steps proceed similar to that-described by Machiguchi et al.
(Scheme S8).
Unlike A1 and B1, in isomers A2 and B2, the attack of
nucleophile cannot occur at C-7 as the allyl group blocks the
nucleophilic attack. But, attack of the nucleophile at C-2 is
sterically favorable, despite that there is no nucleophilic
substitution at C-2. This anomalous behavior of A2 and B2
compared to A1 and B1 can be explained only by the
reversibility of nucleophilic attack either at C-2 position or at the
other free conjugate positions of A2 and B2. Inactivity of A2 and
B2 in the formation of azulene derivatives may also be possible
due to the tautomerism as the alternate channel, which is absent
Scheme 3. Key steps of Machiguchi’s mechanism for azulene formation.
re reaction of anion 7 gives an isolable intermediate, 2-imino-2H-
cyclohepta[b]furan-3-carbonitrile (8).(c) Nucleophilic addition of
-
the second HC(CN)2 to the imine 8 at C-8a position produces
the second Meisenheimer-type adduct 9. (d) The second ring
closure
leads
to
1-carbamoyl-1.3-dicyano-2-imino-2,3-
dihydroazulene (10). A base attacks the imine 10, which results
in the generation of a conjugate base of the final product
azulene (11) Based on Machiguchi’s mechanism, the expected
products from the reaction of A1 and A2, with ethylcyanoacetate
and t-BuNH2 is diethyl 4-allyl-2-amino azulene-1,3-dicarboxylate
(12), whereas B1 and B2 would afford diethyl 4-allyl-2-amino-6-
bromoazulene-1,3-dicarboxylate (13) (Scheme 4).
However, all the four reactions resulted in the unexpected
outcomes indicating the subtle reactivity of these tropolone
derivatives (Scheme 4). Compound A1 led to formation of
diethyl 5-allyl-2-aminoazulene-1,3-dicarboxylate (14) instead of
diethyl 4-allyl-2-aminoazulene-1,3-dicarboxylate (12). Similar to
the reaction of A1, the reaction of the corresponding bromo-
derivative B1 afforded diethyl 5-allyl-2-amino-7-bromoazulene-
1,3-dicarboxylate (15) rather than the expected product diethyl
4-allyl-2-amino-6-bromoazulene-1,3-dicarboxylate
(13).
Structures of compound 14 and 15, as well as the position of
allyl chain in both of these compounds, were confirmed by
SCXRD analysis (Scheme 4). 1H NMR spectra of 14 and 15 also
revealed a highly deshielded singlet or a doublet with a very low
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Scheme 4. Expected products from cyclisation of allyl substituted active troponoid precursors and the products obtained (Crystal structure of 14 and 15, Grey: C,
Red: O, Blue: N, Yellow: Br, pale grey: H)
Scheme 5. Possibility of the attack of nucleophile in the first stage
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in A1 and B1 thus favoring the nucleophilic attack on the later driven solid-state [2+2] cycloaddition (solid state dimerization) to
isomers.
form the trans substituted cyclobutane isomer 17 under ambient
Compound B2, however, undergoes nucleophilic ipso- light in ~35% yield in 7 days. Compound 17 was isolated from a
substitution followed by the electrocyclic reaction and mixture of 16 and 17 by column chromatography, and its
rearrangement to form 16. The presence of bromo-substituent at structure was confirmed by SCXRD analysis (Scheme 6). A
C-4 of B2 enhances the orbital interaction (soft-soft interactions) CDCl3 solution of compound 16 was found to be stable as
between the nucleophilic and C-Br center to facilitate the ipso- monitored by 1H NMR over a long period, confirming its
substitution (Scheme 6).15 The nucleophilic attack at the C-Br topochemical solid state dimerization.
center leads to the formation of 23 via the intermediate anion 22
with bromide as the leaving group. Under the basic reaction
conditions, subsequent tautomerism form 25 via intermediate
anion 24. Compound 25 then undergoes intramolecular electro-
Theoretical Calculations
To shed more light on the experimentally observed
abnormal nucleophilic substitution, we have carried out DFT
calculations at M06-2X/6-311+G(d,p) [SCRF = PCM, solvent =
ethanol]//B3LYP/6-31G(d) + ZPVE. For DFT calculation, we have
considered the first crucial step of substitution of methoxy group
by ethyl cyanoacetate anion for A1. We have considered both,
normal and abnormal, pathways (nucleophilic attack at the C-2
and C-7 position, respectively), which are important to obtain
information about the regioselectivity of the final azulene
products (Figure 2).
The ‘normal path’ and ‘abnormal path’ involve two and four
elementary steps, respectively, as shown in Figure 1. For normal
path (the attack of the nucleophile at C-2), the first step is the
formation of Meisenheimer adduct A1-C2-P1 via transition state
(TS) A1-C2-TS1. From this adduct, the MeO- group is
dissociated via A1-C2-TS2 to form the product A1-C2-P2, which
is a neutral intermediate. First step of abnormal pathway (the
attack of the nucleophile at C-7) is the attack of the nucleophile
to form anionic intermediate A1-C7-P1 via TS A1-C7-TS1. The
next step involves C-H bond formation at C-2 to give neutral
intermediate A1-C7-P2 via TS A1-C7-TS2. The H-atom on C-7 is
sufficiently acidic to be abstracted by the base to form the
anionic intermediate A1-C7-P3 via TS A1-C7-TS3. The anionic
intermediate A1-C7-P3 loses a molecule of MeOH under the
influence of base to form neutral intermediate A1-C7-P4 via the
transition state A1-C7-TS4. The neutral intermediate A1-C7-P4
would be then converted to azulene skeleton via the
intermediates proposed by Machiguchi et al.17 The activation
energy of the first step of the abnormal path is lower by 2.6
kcal/mol than that of the normal path. Overall, the formation of
A1-C7-P4 by the abnormal path was more favorable considering
the lower energy barriers of the rate-determining step by 3.6
kcal/mol compared to the formation of A1-C2-P2 by the normal
path. Overall, DFT study indicates that ‘abnormal path’ is more
favarable than ‘normal path’ in presence of 3-allyl substituent.
Thus, DFT study is consistent with the experimental observation
and provides the indication of developing a synthetic strategy to
Scheme 6. Proposed mechanism of nucleophilic substitution at bromo center
synthesize 5-substituted azulene regioselectively from the 3-
substituted 2-methoxytropone.
of B2 leading to solid state dimerized product 17 (Crystal structure of 17, Grey:
C; Red: O, Blue: N, pale grey: H)
cyclic reaction to form ethyl cinnamate derivative 16 via the
intermediate 26. Compound 16 then undergoes topochemically
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Figure 2. Energy profile diagram of nucleophilic substitution on A1
Scope of the Methodology
Based on the experimental results and theoretical calculation,
we have proposed a synthetic strategy to obtain regioselectively
5-substituted azulenes. Regioselective substitution on the five-
membered ring of azulenes is well documented in the
literature.28 Ito and coworkers also reported the synthesis of 2-
azulenyl boronate and direct arylation of 2- and 6-halo azulenes
that provide access to a wide variety of substituted azulene
derivatives.29 However, there remain very limited methods that
allow regioselective substitution on the seven-membered ring of
azulenes because of the small difference in the reactivity of the
positions of the seven-membered ring of azulenes. To check the
scope of the proposed synthetic methodology, we have
synthesized several 2-methoxytropone derivatives with varied
substituents at C-3 and subjected to similar reaction conditions.
The substituents were varied from alkyl to aryl to heteroaryl.
Alkyl substituted tropolone was synthesized by reduction of allyl
chain and subsequent conversion of tropolone to its methyl ether
(Scheme S4). Benzyl substituted tropolone was prepared by
thermal rearrangement of O-benzyl substituted tropolone
(Scheme S5). Heck reaction of styrene with 3-iodotropolone
gave the styryl substituted tropolone (Scheme S6). Phenyl, 4-
tert-butyl phenyl, naphthyl, 3-thienyl, and 2-thienyl substituted
tropolones were prepared by following the general procedures
reported by Ononye and co-workers (Scheme S7), and the
substituted tropolones were converted to their methyl ethers by
using dimethyl sulfate. In all the cases excellent yields of 5-
substituted azulene derivatives 14, 27-34 were obtained from
the C-3 substituted 2-methoxytropone (Scheme 7). In all the
synthesized azulene derivatives a highly deshielded singlet or a
doublet with a very low coupling constant was observed in their
1H NMR spectra confirming that the substituents were at C-5 of
azulene. Further confirmation was obtained by SCXRD studies
in some cases. The C-7 substituted 2-methoxy tropone isomers
remained inert to the reaction conditions as observed in the allyl-
substituted isomer.
Conclusions
In summary, we have explored anomalous reactivity of 3- and 7-
substituted 2-methoxytropones towards azulene synthesis. The
position of the substituents on the 2-methoxytropone dictates the
mechanism and hence the product formation. The initial study
on allyl substituted 2-methoxy tropone indicates unexpected
reactivity difference of the regioisomers. Unsubstituted 2-
methoxytropone forms azulene by the attack of the nucleophile
at C-2 as the primary step, whereas the presence of a
substituent on the carbon adjacent to methoxy group facilitates
the attack of the nucleophile at C-7 and leads to the formation of
steric guided 5-substituted azulenes. We note that the
regioselective modifications of the seven- membered ring of
azulenes and tropones are challenging due to the subtle
reactivity difference among the various positions. Based on the
study on allyl substituted 2-methoxytropone and subsequent
DFT calculation, we have devised the synthetic strategy to
obtain 5-substituted azulenes regioselectively. Thus, the
modification of the precursor tropolone as described here
provides easy access to the otherwise difficult to synthesize
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Acknowledgements
We acknowledge SERB, India, for financial support
(project no. EMR/2015/000241 and CRG/2018/002784). N.R.K.
thanks DST for INSPIRE fellowship. A.R.A. thanks IISER
Kolkata for fellowship.
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Keywords: methoxytropone • multifunctional azulene •
regioselective • nucleophilic • ipso
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Entry for the Table of Contents (Please choose one layout)
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Neha Rani Kumar, Abhijeet R. Agrawal,
Dr. Sanjio S. Zade*
Page No. – Page No.
Abnormal Nucleophilic Substitution
on Methoxytropone Derivatives:
Steric Strategy to Synthesize 5-
Substituted Azulenes
Text for Table of Contents
Abnormal nucleophilic attack on the 3-substituted 2-methoxytropones, rather than the expected normal nucleophilic attack, leads to a
new steric strategy for the synthesis of 5-substituted multifunctional azulenes.
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