A simple synthesis of benzodiazonines from C-2 arylated 1, 3-indanediones

Article abstract of DOI:10.3987/COM-15-13385

A simple, facile, one-pot procedure for the synthesis of substituted benzodiazonines from phenolic adducts of ninhydrin is described. The process involves a base-catalyzed rearrangement followed by condensation of 1,3-propanediamine to furnish nine-member

Full text of DOI:10.3987/COM-15-13385

HETEROCYCLES, Vol. 92, No. 4, 2016
701
HETEROCYCLES, Vol. 92, No. 4, 2016, pp. 701 - 707. © 2016 The Japan Institute of Heterocyclic Chemistry
Received, 2nd December, 2015, Accepted, 9th February, 2016, Published online, 12th February, 2016
DOI: 10.3987/COM-15-13385
A
SIMPLE SYNTHESIS OF BENZODIAZONINES FROM C-2
ARYLATED 1, 3-INDANEDIONES
Suven Dasa,* and Arpita Duttab
a Department of Chemistry, Rishi Bankim Chandra College for Women, Naihati,
North 24-Parganas, Pin-743165, India; E-mail: suvenchem@yahoo.co.in
b
Department of Chemistry, Rishi Bankim Chandra Evening College, Naihati,
North 24-Parganas, Pin-743165, India
Abstract – A simple, facile, one-pot procedure for the synthesis of substituted
benzodiazonines from phenolic adducts of ninhydrin is described. The process
involves a base-catalyzed rearrangement followed by condensation of 1,3-
propanediamine to furnish nine-membered heterocyclic ring system.
Benzodiazonines are an important class of naturally occuring heterocycles with interesting biological
activities. The diazonine ring occurs in the alkaloids such as teleocidine and lingbiatoxin1 which can
stimulate the nervous system, possess antifungal and antihypertensive properties. Besides alkaloids, there
are synthetically prepared compounds containing diazonine skeleton as well. For example, 2,7-dioxo-
2,3,4,5,6,7-hexahydro-1H-benzo[h][1,4]diazonine acts as a CCK2-receptor antagonist,2 and 5-phenyl-7H-
dibenzo[b,g][1,5]diazonine can be used as antidepressant.3 Therefore, benzodiazonine derivatives have
become the synthetic targets of many organic and medicinal chemists. In fact, heterocyclic system
containing a diazonine fragment is very difficult to prepare due to entropic factors and transannular
interaction.4 In the literature, methods for synthesizing this type of medium ring heterocycles are
extremely limited. Among the strategies, a copper-complex catalyzed closing of a nine-membered ring in
the reaction of o-halophosphoramidates with carbamates leads to the formation of benzodiazonine
skeleton.5 Another method involves the transformation of o-(azetidinon-1-yl)aminoethylarenes.6 Other
notable synthetic methods include ring expansion resulting from oxidation,7 benzodiazepines,8 or
Sommlet-Hauser rearrangement.9 However, most of the above reported procedures employ multi-step,
harsh reaction condition, metal-catalysis to achieve the target molecule. Herein we report a simple, mild

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HETEROCYCLES, Vol. 92, No. 4, 2016
and straightforward procedure for the synthesis of substituted benzodiazonines from easily accessible 2-
hydroxy-2-(2′-hydroxyaryl)-1,3-indanediones under metal free condition.
Recently we have reported 2-hydroxy-2-(2′-hydroxyaryl)-1,3-indanediones as starting material for the
synthesis of fused heterocyclic compounds, namely, benzimidazo[2,1-a]isoindoles.10 Previously it was
shown that phenolic adducts of ninhydrin is a good precursor to afford benzodiazocine skeleton.11 In the
present work, we extend the scope of the reaction using same substrate to achieve the benzodiazonine
framework. To the best of our knowledge, nine-membered heterocyclic ring system has not been obtained
yet exploiting ninhydrin adducts.
We have prepared 2-hydroxy-2-aryl-1,3-indanediones 1 by refluxing phenols and ninhydrin in acid
medium.12 The adducts so formed preferentially remain in the cyclic hemiketal form 2.12a-c On the basis
of our previous experience in the synthesis of heterocyclic skeletons from ninhydrin, we thought that
phenolic adducts 1 could also be a flexible precursor for the preparation of nine-membered ring. To
achieve this, 1,3-propanediamine was chosen as nucleophile for the reaction. Initially, the reaction of 2-
hydroxy-2-(2′-hydroxyphenyl)-1,3-indanedione 1a with 1,3-propanediamine was examined at room
temperature. During stirring, formation of orange colour solution indicates completion of the reaction
(TLC) and the product 7-[α-hydroxy-α-(2-hydroxyphenyl)methyl-3,4,5-trihydro-2,6-benzodiazonin-
1(2H)-one 3a is formed within 3 h. In order to establish the scope of the procedure, various substituted
phenolic adducts of ninhydrin, viz. 2-hydroxy-2-(2′-hydroxyaryl)-1,3-indanediones 1b-h are employed.
To our satisfaction, 1b-h affords substituted benzodiazonines 3b-h in moderate yields (Scheme 1, Table
1). The reaction holds good for ninhydrin adducts of phenols containing halogen substituent (entry 6-8).
R2
O
R3
O
R4
OH R4
R1
OH
R3
R2
R3
R2
R4
HO
NH2
rt, stirr, ~3h
H2N
OH
O
O
HO
*
HO
H
N
2a-h
R1
R1
1a-h
1, 2 and 3
--------------------------------------------------------------------------------------------
e: R1 = R2 = R4 = H, R3 = OMe
f: R1 = Cl, R2 = R3 = R4 = H
g: R1 = R2 = R4 = H, R3 = Cl
h: R1 = R2 = R4 = H, R3 = Br
a: R1 = R2 = R3 = R4 = H
N
H
b: R1 = Me, R2 = R3 = R4 = H
c: R1 = R2 = R4 = H, R3 = Me
d: R1 = OMe, R2 = R3 = R4 = H
O
3a-h
Scheme 1

HETEROCYCLES, Vol. 92, No. 4, 2016
703
Table 1. Synthesis of 2, 6- benzodiazonin-1(2H)-one derivatives 3
------------------------------------------------------------------------------------------------------
Entry
Substrates
Product
Time (h)
Yield/%a
Mp/°Cb
------------------------------------------------------------------------------------------------------
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
3a
3b
3c
3d
3e
3f
3.0
2.5
2.5
2.5
2.5
3.0
3.0
3.0
58
50
50
48
52
45
48
42
154-155
165-166
110-111
102-103
115-116
163-164
180-181
158-159
1g
1h
3g
3h
-------------------------------------------------------------------------------------------------------
aYields are for isolated products. bMps are uncorrected.
The present protocol provides a simple work-up procedure, requiring acidification with 6N HCl followed
by filtration of the precipitated products. The structures of products were established on the basis of
spectral data. As an example, the spectral data of compound 3e are as follows: the most important
absorption band in the IR spectrum due to the carbonyl group stretching frequencies of amide of nine-
membered ring appeared as 1685 cm-1. The 1H NMR spectrum of 3e exhibited a singlet at δ 12.07 due to
N-H proton. A sharp singlet at δ 3.80 was identified as methoxy protons of the aromatic ring. The 13C
NMR spectrum of 3e showed nineteen distinct signals, in agreement of the proposed structure. The
signals at δ 36.8, 35.6 and 27.9 were due to three CH2 groups of the benzodiazonine ring system and the
carbon of the –CHOH group was observed at δ 82.4.
The formation of 3 can be explained from the proposed mechanism depicted in Scheme 2 and in
accordance with our previous results.10 Under the basic conditions nucleophilic attack of phenolic OH on
either carbonyl group of 1 produces a bicyclo[3.3.0]octane system 2 which initiates the cleavage of the
central C-C bond to afford an eight-membered lactone intermediate 4. The intermediate 4 tautomerizes to
keto form 5. Subsequently amino group of 1,3-propanediamine attacks the ketone carbonyl to produce
intermediate 6. Then intramolecular nucleophilic attack of nitrogen on the lactone carbonyl affords
isoindolone skeleton 7. Finally, attack of amino group and breaking of C-N bond result in the formation
of benzodiazonine skeleton 3. It is noteworthy that none of the intermediates 4-7 was possible to isolate
under the reaction conditions.

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HETEROCYCLES, Vol. 92, No. 4, 2016
O
O
O
OH
HO
O
OH
OH
O
O
R
O
R
R
H
HO
2
4
1
NH2
R
HO
HO
NH
OH
HO
OH
O
NH2
H2N
OH
3
N
O
R
O
R
O
O
O
5
H2N
6
7
Scheme 2
In conclusion, we have developed a simple and efficient procedure for the synthesis of novel
benzodiazonine scaffold from 2-hydroxy-2-(2′-hydroxyaryl)-1,3-indanediones through a base-catalyzed
rearrangement followed by condensation with 1, 3-propanediamine. The present method provides a mild
and one-pot reaction from easily prepared starting materials towards the synthesis of medium ring
heterocycles which is otherwise difficult to achieve. Further studies for exploring the scope of the
reaction are now in progress.
EXPERIMENTAL
Melting points were determined in open capillary and were uncorrected. IR spectra were examined in
KBr disc on a Perkin Elmer-782 spectrophotometer. Proton magnetic resonance (1H NMR) and carbon
magnetic resonance (13C NMR) spectra were recorded on a Bruker Avance 300 spectrometer in the
solvents indicated. TLC analyses were run on a Merck Kieselgel 60 PF254. Elemental analyses were
performed on a Perkin-Elmer 240C analyser.
General procedure for the preparation of 3a-h: The appropriate substrate 1a-h (1.4 mmol) was added
to 1,3-propanediamine (5 mL) and the mixture was stirred at room temperature for about 3 h. The reaction
mixture was then acidified with 6N HCl. The solid products separated was filtered and washed
thoroughly with cold water. Crystallization from acetone gives pure products 3a-h.
7-[α-Hydroxy-α-(2-hydroxyphenyl)]methyl-3,4,5-trihydro-2,6-benzodiazonin-1(2H)-one (3a): white
solid, mp 154-155 °C. IR (KBr): 3306, 1690, 1597 cm-1. 1H NMR (300 MHz, CDCl3/2-drops DMSO-d6)
δ: 8.34 (s, 1H), 7.83-7.57 (m, 2H), 7.54-7.41 (m, 3H), 7.32-7.27 (m, 1H), 6.87-6.79 (m, 2H), 5.74 (s, 1H),
3.73-3.45 (m, 4H), 3.32-3.22 (m, 1H), 1.97-1.81 (m, 1H). 13C NMR (75 MHz, CDCl3/2-drops DMSO-d6)
δ: 169.7, 168.3, 161.2, 144.4, 133.5, 131.9, 131.3, 129.3, 126.2, 123.2, 122.7, 118.5, 117.8, 114.5, 82.2,

HETEROCYCLES, Vol. 92, No. 4, 2016
705
36.6, 35.4, 27.8. Anal. Calcd for C18H18N2O3: C, 69.66; H, 5.85; N, 9.03. Found: C, 69.55; H, 5.89; N,
9.12.
7-[α-Hydroxy-α-(2-hydroxy-3-methylphenyl)]methyl-3,4,5-trihydro-2,6-benzodiazonin-1(2H)-one
(3b): white solid, mp 165-166 °C. IR (KBr): 3342, 3312, 1690, 1591 cm-1. 1H NMR (300 MHz, CDCl3/2-
drops DMSO-d6) δ: 8.25 (s, 1H), 7.71(d, J = 7.3 Hz, 1H), 7.56-7.41 (m, 4H), 7.17 (d, J = 7.0 Hz, 1H),
6.72 (t, J = 7.8 Hz, 1H), 5.74 (s, 1H), 3.72-3.45 (m, 4H), 3.30-3.19 (m, 1H), 2.17 (s, 3H), 1.93-1.80 (m,
13
1H). C NMR (75 MHz, CDCl3/2-drops DMSO-d6) δ: 170.3, 168.4, 159.8, 144.4, 134.3, 132.0, 131.4,
129.4, 126.8, 123.5, 123.2, 122.8, 117.8, 113.6, 82.2, 36.6, 35.5, 27.9, 15.5. Anal. Calcd for C19H20N2O3:
C, 70.35; H, 6.21; N, 8.64. Found: C, 70.26; H, 6.15; N, 8.78.
7-[α-Hydroxy-α-(2-hydroxy-5-methylphenyl)]methyl-3,4,5-trihydro-2,6-benzodiazonin-1(2H)-one
1
(3c): white solid, mp 110-111 °C. IR (KBr): 3339, 1687, 1591 cm-1. H NMR (300 MHz, DMSO-d6) δ:
12.25 (s, 1H), 8.75 (s, 1H), 7.58-7.50 (m, 4H), 7.47-7.41(m, 1H), 7.12 (d, J = 8.4 Hz, 1H), 6.71 (d, J = 8.4
Hz, 1H), 6.57(d, J = 8.1 Hz, 1H), 5.78 (d, J = 7.5 Hz, 1H), 3.59-3.49 (m, 1H), 3.35-3.27 (m, 3H), 2.15 (s,
3H), 1.86-1.74 (m, 2H). 13C NMR (75 MHz, DMSO-d6) δ: 169.2, 167.1, 157.8, 145.2, 134.8, 132.6, 131.8,
129.8, 128.0, 127.9, 124.0, 122.8, 117.6, 115.4, 81.3, 38.4, 37.2, 28.2, 20.5. Anal. Calcd for C19H20N2O3:
C, 70.35; H, 6.21; N, 8.64. Found: C, 70.25; H, 6.17; N, 8.76.
7-[α-Hydroxy-α-(2-hydroxy-3-methoxyphenyl)]methyl-3,4,5-trihydro-2,6-benzodiazonin-1(2H)-one
1
(3d): white solid, mp 102-103 °C. IR (KBr): 3298, 1688, 1597 cm-1. H NMR (300 MHz, DMSO-d6) δ:
12.75 (s, 1H), 8.80 (s, 1H), 7.62-7.49 (m, 4H), 7.36 (d, J = 7.8 Hz, 1H), 7.05 (d, J = 7.5 Hz, 1H), 6.77 (d,
J = 7.5 Hz, 1H), 6.60 (d, J = 8.7 Hz, 1H), 5.82 (d, J = 8.7 Hz, 1H), 3.74 (s, 3H), 3.60-3.56 (m, 1H), 3.40-
13
3.20 (m, 4H), 1.86-1.84 (m, 1H). C NMR (75 MHz, DMSO-d6) δ: 169.5, 166.3, 150.9, 148.6, 145.0,
131.9, 131.7, 129.3, 123.6, 122.3, 118.6, 117.8, 115.5, 115.0, 80.9, 55.9, 37.0, 36.9, 27.9. Anal. Calcd for
C19H20N2O4: C, 67.05; H, 5.92; N, 8.23. Found: C, 67.12; H, 5.98; N, 8.14.
7-[α-Hydroxy-α-(2-hydroxy-5-methoxyphenyl)]methyl-3,4,5-trihydro-2,6-benzodiazonin-1(2H)-one
(3e): white solid, mp 115-116 °C. IR (KBr): 3314, 1685, 1597 cm-1. 1H NMR (300 MHz, CDCl3/2-drops
DMSO-d6) δ: 12.07 (s, 1H), 8.39 (s, 1H), 7.72 (d, J = 7.2 Hz, 1H), 7.79-7.52 (m, 2H), 7.48-7.44 (m, 1H),
7.30 (d, J = 2.7 Hz, 1H), 6.94 (dd, J = 9.0, 3.0 Hz, 1H), 6.83 (d, J = 9.0 Hz, 1H), 6.10 (br s, 1H), 5.78 (br
s, 1H), 3.80 (s, 3H), 3.72-3.64 (m, 2H), 3.58-3.50 (m, 1H), 3.38-3.27(m, 1H), 1.98-1.90 (m, 2H). 13C
NMR (75 MHz, DMSO-d6) δ: 169.6, 168.3, 155.3, 151.7, 144.4, 132.0, 131.4, 129.4, 123.2, 122.9, 121.1,
118.6, 114.3, 109.9, 82.4, 55.8, 36.8, 35.6, 27.9. Anal. Calcd for C19H20N2O4: C, 67.05; H, 5.92; N, 8.23.
Found: C, 67.16; H, 5.99; N, 8.12.
7-[α-Hydroxy-α-(3-chloro-2-hydroxyphenyl)]methyl-3,4,5-trihydro-2,6-benzodiazonin-1(2H)-one
1
(3f): white solid, mp 163-164 °C. IR (KBr): 3344, 1672, 1587 cm-1. H NMR (300 MHz, DMSO-d6) δ:
13.71 (s, 1H), 9.08 (s, 1H), 7.79 (d, J = 7.2 Hz, 1H), 7.62-7.46 (m, 5H), 6.87 (t, J = 7.8 Hz, 1H), 6.61 (d, J

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HETEROCYCLES, Vol. 92, No. 4, 2016
13
= 9.0 Hz, 1H), 5.82 (d, J = 9.0 Hz, 1H), 3.63-3.53 (m, 1H), 3.41-3.31 (m, 3H), 1.93-1.84 (m, 2H). C
NMR (75 MHz, DMSO-d6) δ: 169.2, 166.3, 156.8, 145.0, 133.8, 131.9, 131.7, 129.3, 125.8, 123.6, 122.3,
121.2, 118.8, 115.8, 80.9, 37.2, 36.9, 27.7. Anal. Calcd for C18H17N2O3Cl: C, 62.70; H, 4.97; N, 8.12.
Found: C, 62.61; H, 4,91; N, 8.03.
7-[α-Hydroxy-α-(5-chloro-2-hydroxyphenyl)]methyl-3,4,5-trihydro-2,6-benzodiazonin-1(2H)-one
1
(3g): white solid, mp 180-181 °C. IR (KBr): 3319, 1684, 1590 cm-1. H NMR (300 MHz, DMSO-d6) δ:
12.51 (s, 1H), 8.88 (s, 1H), 7.87 (d, J = 2.1 Hz, 1H), 7.61-7.48 (m, 4H), 7.39 (dd, J = 9.0, 2.4 Hz, 1H),
6.89 (d, J = 9.0 Hz, 1H), 6.58 (d, J = 9.0 Hz, 1H), 5.82 (d, J = 9.0 Hz, 1H), 3.70-3.50 (m, 2H), 3.37-3.32
13
(m, 3H), 1.90-1.80 (m, 1H). C NMR (75 MHz, DMSO-d6) δ: 167.4, 166.3, 158.5, 145.0, 133.2, 132.0,
131.7, 129.4, 127.4, 123.6, 122.4, 122.3, 119.3, 117.0, 80.9, 37.1, 36.8, 27.8. Anal. Calcd for
C18H17N2O3Cl: C, 62.70; H, 4.97; N, 8.12. Found: C, 62.59; H, 4.87; N, 8.04.
7-[α-Hydroxy-α-(5-bromo-2-hydroxyphenyl)]methyl-3,4,5-trihydro-2,6-benzodiazonin-1(2H)-one
1
(3h): white solid, mp 158-159 °C. IR (KBr): 3347, 1677, 1587 cm-1. H NMR (300 MHz, DMSO-d6) δ:
9.51 (s, 1H), 8.61 (br s, 1H), 8.24-8.11 (m, 5H), 7.47 (d, J = 8.7 Hz, 1H), 7.21(d, J = 9.0 Hz, 1H), 6.44 (d,
13
J = 9.0 Hz, 1H), 4.22-4.18 (m, 1H), 4.00-3.92 (m, 3H), 2.50-2.44 (m, 2H). C NMR (75 MHz, DMSO-
d6) δ: 167.3, 166.2, 158.9, 145.0, 136.0, 131.9, 131.7, 130.2, 129.3, 123.5, 122.3, 119.7, 117.5, 109.7,
80.9, 37.1, 36.8, 27.7. Anal. Calcd for C18H17N2O3Br: C, 55.54; H, 4.40; N, 7.20. Found: C, 55.65; H,
4.34; N, 7.12.
ACKNOWLEDGEMENTS
S.D. and A.D. acknowledge University Grants Commission, New Delhi for Minor Research Projects
[F.PSW-123/10-11 (ERO) and F.PSW-114/12-13 (ERO) respectively].
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