Dienaminodiones, new push-pull alkenes, from 3,4-dihydroxysalicylaldehyde-derived Schiff base

Article abstract of DOI:10.1016/j.tetlet.2020.152531

An atom-economical one-pot synthesis of a new push-pull dienaminodiones from a 3,4-dihydroxysalicylaldehyde-derived Schiff base and indoles in the presence of phenyliodine(III) diacetate is described. Variation of indoles and anilines constitute a broad substrate scope of the methodology with good to moderate yields. Formation of Schiff base followed by an indole addition to afford dienaminodione takes place in one-pot; thus, the present method serves as a sequential multicomponent reaction. The present work also serves as a methodology to afford indole variants of natural product talaroenamine B.

Full text of DOI:10.1016/j.tetlet.2020.152531

Journal Pre-proofs
Dienaminodiones, new push-pull alkenes, from 3,4-dihydroxysalicylaldehyde-
derived Schiff base
Jaice Ravindran, Nagaraja Ingaladal, Ravi S. Lankalapalli
PII:
S0040-4039(20)31024-8
DOI:
Reference:
https://doi.org/10.1016/j.tetlet.2020.152531
TETL 152531
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Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
3 July 2020
28 September 2020
1 October 2020
Please cite this article as: Ravindran, J., Ingaladal, N., Lankalapalli, R.S., Dienaminodiones, new push-pull
alkenes, from 3,4-dihydroxysalicylaldehyde-derived Schiff base, Tetrahedron Letters (2020), doi: https://doi.org/
10.1016/j.tetlet.2020.152531
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Dienaminodiones, new push-pull alkenes, from 3,4-dihydroxysalicylaldehyde-derived
Schiff base
Jaice Ravindran, Nagaraja Ingaladal and Ravi S. Lankalapalli*
Chemical Sciences and Technology Division, CSIR-National Institute for Interdisciplinary
Science and Technology (CSIR-NIIST), Thiruvananthapuram-695019, India; and Academy of
Scientific and Innovative Research (AcSIR) Ghaziabad-201002, India.
E-mail: ravishankar@niist.res.in
One-pot sequential synthesis
Ph
Ph
N
Application:
HO
NH
PhNH2
+
O
O
HO
HO
O
Indole
HO
HO
N
R
HN
PhI(OAc)2
Dienaminodione
(Indole variant of
R = OH, H
natural product Talaroenamine B )
One-pot sequential synthesis
Ph
Ph
N
Application:
HO
NH
O
O
HO
HO
O
PhI(OAc)2
HO
N
R
HN
HN
HO
Dienaminodione
(Indole variant of
natural product Talaroenamine B)
+
R = OH, H
PhNH2
Abstract:
An atom-economical one-pot synthesis of a new push-pull dienaminodiones from a 3,4-
dihydroxysalicylaldehyde-derived Schiff base and indoles in the presence of phenyliodine(III)
diacetate is described. Variation of indoles and anilines constitute a broad substrate scope of
the methodology with good to moderate yields. Formation of Schiff base followed by an indole
addition to afford dienaminodione takes place in one-pot; thus, the present method serves as a
sequential multicomponent reaction. The present work also serves as a methodology to afford
indole variants of natural product talaroenamine B.
Keywords: Dienaminone • Push-pull effect • One-pot synthesis • Talaroenamine analogs •
Oxidative transformation • N-salicylideneaniline Schiff base

Introduction:
The push-pull effect in alkenes flanked by electron-donating and electron-accepting
substituents at either end of alkene constitute a conjugated system that enhances the polarity of
C=C double bond, thus, has a decisive influence on the chemical reactivity of this class of
compounds.1 For instance, the push-pull effect in the β-enaminone conjugated system, which
possesses a combined reactivity of enamine and enone, qualifies enaminones as suitable
precursors in the synthesis of heterocycles.2–4 Conjugated dienaminones are valuable
intermediates for the synthesis of derivatives of pyridines,5,6 azepinones,7 by heteroannulation.
Nair et al. synthesized a range of dienaminones from the reaction of vinamidinium salts with
enolates,8,9 and applied for the synthesis of spiro compounds.10
In one of the tautomeric form, N-salicylideneaniline Schiff base from salicylaldehyde
exist as enaminone that equilibrates with enolimine tautomeric forms by proton transfer.11 The
enaminone form of Schiff base I′ (Scheme 2), derived from 3,4-dihydroxysalicylaldehyde (3,4-
DSA) and aniline, offers a unique 1,2-enediol segment that can participate in phenyliodine(III)
diacetate (PIDA) mediated oxidative transformation. Herein, we report a one-pot sequential
three-component condensation by PIDA mediated activation of highly stable Schiff base 1, and
subsequent treatment with 1H-indole to afforded 2, christened as dienaminodione (Scheme 1).
A sequential one-pot multicomponent synthesis emerged as an excellent synthetic strategy with
several reports in this area.12–21 Dienaminodione 2 in E,Z-cyclic form, is an unprecedented
variant of dienaminone. Besides synthetic potential, the enaminone motif serves as a
therapeutic pharmacophore and provides a range of biological activities such as antitumor,
antibacterial, and anticonvulsant agents.22–25 Dienaminodione 2 bears a striking resemblance
to the natural product talaroenamine B (Scheme 1).26 Hence, the present work also serves as a
methodology to generate talaroenamine analogs.
Results and Discussion:
In a first attempt, N-salicylideneaniline Schiff base 1 was generated in acetonitrile in a
catalytic amount of acetic acid (Scheme 1). After concentration, the resulting imine in
dichloromethane was sequentially added 1.5 equivalent each of N-methylindole and PIDA. In
less than five minutes, a new polar product was observed over TLC, which was purified and
characterized by 2D NMR analysis (see the Supporting Information) as dienaminodione 2
(Scheme 1). To generalize the use of this methodology for expedient access to
dienaminodiones, optimization was attempted with 1H-indole in one-pot (Table 1). Schiff base

1 can be generated in quantitative yield as a precipitate by condensation in water. Accordingly,
in an initial attempt, Schiff base 1 precipitate obtained in water was decanted and dissolved in
hexafluoroisopropanol (HFIP), followed by an addition of one equivalent each of 1H-indole
and PIDA afforded dienaminodione 3a in 52% yield (entry 1). The structure of dienaminodione
3a was confirmed by single-crystal X-ray analysis (see the Supporting Information), which
aided confirmation of the assigned structure of dienaminodione 2. In a second attempt by
variation of solvent to methanol, dienaminodione 3a was produced with improved yield of 69%
(entry 2). Variation of solvent combinations did not improve the yield of 3a (entries 3-4). There
was no improvement in yields by change of other iodine-based oxidants viz. PIFA
PhI(OCOCF3)2, I2, and NIS N-iodosuccinimide (entries 5-7). Attempts with a variation of other
oxidants such as 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ), ceric ammonium nitrate
(CAN), meta-chloroperoxybenzoic acid (mCPBA)/PhI, and K2S2O8/PhI did not afford
dienaminodione 3a. In all the successful attempts, vide supra, there is some unreacted 1H-
indole; however, for the sake of atom-economy substrate scope was demonstrated with one
equivalent each of 2,3,4-trihydroxybenzaldehyde, substituted anilines, and 1H-indoles in one-
pot (Table 2).
Scheme 1. Synthesis of dienaminodione 2
H
N
Me
OH
O
p-toluidine
(1 equiv)
HO
HO
HO
HO
CHO
CH3CN
H+
1
N-salicylideneaniline ( )
(1 equiv)
H
N
R3
O
HO
R1
Talaroenamine B
natural product
when R1 = Me,
N-Methylindole
(1.5 equiv)
R2
O
PIDA
(1.5 equiv)
R2 = Me, R3 = H
Dienaminodione
CH2Cl2
2
(90%), where R1 = N-Methylindole-3-yl,
R2 = H, R3 = Me
Table 1. Optimization of reaction conditionsa
Ph(4-Me)
NH
OH
p-Toluidine
(1 equiv)
O
HO
HO
CHO
a) H2O
HO
O
+
1H-Indole
(1 equiv)
b) Solvent,
Oxidant
(1 equiv)
HN
3a

Ph(4-Me)
NH
OH
O
a) H2O
HO
O
HO
HO
CHO
+
p-Toluidine
(1 equiv)
+
b) Solvent,
Oxidant
HN
(1 equiv)
HN
(1 equiv)
3a
3ab
Oxidant
(1 equiv)
PIDA
entry
Solvent
(%, two steps)
1
2
3
4
5
6
7
HFIP
MeOH
52
69
43
27
11
18
11
PIDA
PIDA
HFIP/DCM(1:1)
MeOH/H2O(9:1)
MeOH
PIDA
PIFA
I2
MeOH
NIS
DCM
aReaction conditions: All reactions were conducted at room temperature using undistilled
solvents. 2,3,4-Trihydroxybenzaldehyde (0.39 mmol) and p-toluidine (0.39 mmol) are
condensed in water (2 mL) to obtain a precipitate of N-salicylideneaniline 1. Water was
decanted, the precipitate was dissolved in a suitable solvent (2 mL) followed by sequential
b
addition of 1H-indole (0.39 mmol) followed by PIDA (0.39 mmol). Isolated yields (%) by
column chromatography.
Under the optimized conditions (entry 2, Table 1), Schiff bases derived from 2,3,4-
trihydroxybenzaldehyde and aniline, para-substituted anilines with activating groups (alkyl,
methoxy) afforded dienaminodiones 3b-e in 51-62% yields. Schiff bases with para-halo-
substituted anilines containing deactivating groups such as halides afforded dienaminodiones
3f-h in 46-60% yields. The presence of an activating or deactivating group in the para-position
of anilines does not have a significant bias in the yields of dienaminodione outcome. Attempts
with ortho-substituted anilines also afforded dienaminodiones 3i-k in moderate yields. Di-
substituted anilines with activating or deactivating groups also produced dienaminodiones 3l-
p in similar yields. An attempt of variation in 1H-indole with 2-methyl-1H-indole, led to a
decreased yield of dienaminodione 3q to 37%. Attempts with 1H-indoles of varied
substitutions also afforded dienaminodiones 3r-v in moderate yields. Reaction with substituted
N-methylindoles produced dienaminodiones 3w and 3x in 69% and 62% yields, respectively.
Finally, reaction with N-methylpyrrole provided dienaminodione 3y in 58% yield. Hence, the

present work offers a broad substrate scope with a variation of anilines and indoles to produce
dienaminodiones.
The plausible mechanistic pathway for the formation of dienaminodione 3 is provided
in scheme-2. N-salicylideneaniline derived from 2,3,4-trihydroxybenzaldehyde and aniline
exist in enolimine I (OH form) and enaminone I′ (NH form) tautomeric forms.11 Activation of
enaminone I′ with PIDA afford enol II or keto II′ intermediates. Stronger acidity of 4-hydroxy
group is credited with enhanced nucleophilic power, directing iodination with PhI(OAc)2 to
afford II or II′.27 Elimination of phenyl iodide from II affords vicinal tricarbonyl III, with high
electrophilic reactivity at the central carbonyl group,28 which ensue 1H-indole addition to
generate dienaminodione 3. Alternatively, 1H-indole addition to keto II′ intermediate and
subsequent elimination of phenyl iodide affords 3. Treatment of N-salicylideneaniline 1 with
NaBH4 in methanol provided the respective 2,3,4-trihydroxybenzaldehyde and aniline.
Treatment of N-salicylideneaniline 1 with PIDA clearly showed the formation of a polar
intermediate in TLC, but it was difficult to discern its structure by NMR; however, subsequent
1H-indole addition to the polar intermediate generated dienaminodione 3. Treatment of polar
intermediate with NaBH4 in methanol afforded the respective 2,3,4-trihydroxybenzaldehyde
and aniline, perhaps via N-salicylideneaniline. These control experiments suggest intermediacy
of vicinal tricarbonyl III as the polar intermediate, further supported by reports on the addition
of reactive aromatics such as indoles to ninhydrin, a vicinal tricarbonyl.29 Unfortunately,
attempts made with methylmagnesium bromide in place of 1H-indole to access natural product
talaroenamine itself was futile.
Table 2. Substrate scope of dienaminodiones 3a

nBu
iPr
MeO
NH
O
NH
O
NH
NH
NH
NH
O
NH
O
OH
OH
OH
OH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
O
O
O
O
3b (57%)
3c (58%)
3d (51%)
3e (62%)
Cl
Br
I
Br
NH
O
NH
O
O
NH
O
OH
OH
OH
OH
O
O
O
O
3f (60%)
3g (58%)
3h (46%)
3i (50%)
Me
OMe
COOMe
OMe
NH
Me
MeO
Me
F
NH
NH
NH
NH
O
O
O
NH
NH
NH
NH
O
OH
OH
OH
OH
O
O
O
O
3j (53%)
3k (56%)
3l (53%)
3m (49%)
Cl
Cl
Cl
Cl
MeO
F
I
F
O
NH
NH
NH
O
O
O
OH
OH
OH
OH
Me
O
O
O
O
3n (47%)
3o (42%)
3p (51%)
3q (37%)
COOMe
NH
Br
O2N
Br
F
MeO
O
O
NH
O
O
OH
OH
OH
OH
NH
NH
NH
O
O
O
O
3r (59%)
3s (53%)
3t (63%)
3u (62%)
I
MeO
I
Me
Me
Me
O
O
NH
O
O
OH
OH
OH
OH
NH
N
N
N
Me
Me
Me
O
O
O
O
3v (60%)
3w (69%)
3x (62%)
3y (58%)
aIsolated yields (%) by column chromatography.

Scheme 2. Plausible mechanistic pathway for the formation of dienaminodione
OAc
I
Ph
H
H
Ph
OH
N
N
O
O
Aniline
(1 equiv)
HO
HO
Ph
OAc
HO
HO
HO
HO
O
(1 equiv)
H2O
-AcOH
I
I'
enaminone
enolimine
NHPh
H
H
O
Ph
Ph
O
N
N
H
O
HO
1H-indole
(1 equiv)
O
O
AcO
Ph
I
HN
-AcOH
-PhI
O
O
O
3
III
II
-AcOH
-PhI
NHPh
H
O
Ph
N
O
HO
1H-indole
O
O
(1 equiv)
AcO
Ph
HN
AcO
I
O
I
H
II'
Ph
IV
In an attempt to demonstrate the synthetic utility of dienaminodione 2, treatment with
NaBH4 led to 1,2-reduction product 4 in quantitative yield (Scheme 3), confirmed by 2D NMR
analysis (see the Supporting Information). Further treatment of dienaminone 4 with a Lewis
acid such as BF3.Et2O, led to aromatization to afford imine 5 in 81% over two steps. Structural
confirmation of imine 5 was carried out by 2D NMR analysis (see the Supporting Information).
As observed over TLC, dienaminodione 2 is polar than dienaminone 4, which in turn is polar
than imine 5. The polarity of dienaminodione 2 is attributed to the push-pull effect. Though the
imine 5 was obtained in pure form without purification, as evident from TLC and NMR, an
attempt to pass it through silica gel column chromatography led to the partial formation of a
non-polar product along with imine 5. Structural characterization of this non-polar product by
2D NMR analysis (see the Supporting Information), surprisingly, confirmed an unusual loss of
C3-OH of imine 5 to obtain imine 6. The plausible mechanistic pathway of formal reduction
to imine 6 during contact of imine 5 with silica gel is depicted in scheme-S1 (see the Supporting
Information), which warrants a detailed mechanistic investigation in an independent study.
Dienaminodione 3a was also subjected to the same series of reaction conditions (Scheme 3);
however, the obtained imines exhibited a complex NMR.

Scheme 3. Synthetic utility of dienaminodione 2
R
R
N
(a) NaBH4
(excess)
MeOH
NH
O
HO
HO
O
(b) BF3.Et2O
(excess)
N
N
Me
HO
Me
2
5
CH2Cl2
R = Ph(4-Me)
(81%, two steps)
-H+
Me
R
Me
R
N
N
N
H
NH
OH
H
OH
O
F
HO
B
O
O
F
V
4
(quant.)
Dienaminone
R
R
N
After silica gel
chromatography
N
HO
HO
N
N
Me
Me
HO
5
6
(6%, two steps)
(45%, two steps)
+ 5
Conclusions
In conclusion, an unprecedented synthesis of polyfunctional dienaminodione 2 paves
the way for further diversification and warrants its utility in synthesis and biological activity.
The present methodology was superior in the generation of dienaminodiones with indoles and
related nucleophilic heteroaromatics, demonstrated with N-methylpyrrole. Though attempts
with alkyl/phenyl Grignard reagents failed in this method, triumph with indoles makes the
methodology essential owing to the significance of indoles in medicinal chemistry. Hence,
exploring the biological potential of the library of the dienaminodiones will be pursued. The
synthetic transformation of dienaminodione 2 to imine 5 opens a new avenue in nucleophilic
aromatic substitution of a polyhydroxy system by PIDA mediated oxidative transformations of
Schiff bases.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal
relationships that could have appeared to influence the work reported in this paper.

Acknowledgements
Financial support from DST, ASEAN-India Collaborative Research Project (Grant number:
CRD/2018/000064) is gratefully acknowledged. The authors are also thankful to Sophisticated
Analytical Instrument Facility, IIT Madras for single-crystal XRD analysis.
Appendix A. Supplementary data
Supplementary data to this article can be found online.
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Highlights:

 Atom-economical one-pot synthesis of new push-pull dienaminodiones by a sequential
multicomponent reaction
 Broad substrate scope of the methodology by variation of indoles and anilines
 The present work also serves as a methodology to afford indole variants of natural
product talaroenamine B.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal
relationships that could have appeared to influence the work reported in this paper.