Lactic acid-catalyzed fusion of ninhydrin and enamines for the solvent-free synthesis of hexahydroindeno[1,2-b]indole-9,10-diones

Article abstract of DOI:10.1515/hc-2016-0048

The lactic acid-catalyzed reactions of ninhydrin and secondary enaminones were conducted by solvent-free grinding at room temperature to yield polycyclic 4b,9b-dihydroxy-4b,5,6,7,8,9b-hexahydroindeno[1,2-b]indole-9,10-diones.

Full text of DOI:10.1515/hc-2016-0048

Heterocycl. Commun. 2016; aop
Xuwen Chen and Yunyun Liu*
Lactic acid-catalyzed fusion of ninhydrin and
enamines for the solvent-free synthesis of
hexahydroindeno[1,2-b]indole-9,10-diones
DOI 10.1515/hc-2016-0048
herein a solvent-free protocol for the facile synthesis of
products 3 by employing nontoxic and bio-available lactic
acid (LA) as catalyst.
Received April 7, 2016; accepted April 30, 2016
Abstract: The lactic acid-catalyzed reactions of ninhydrin
and secondary enaminones were conducted by solvent-
free grinding at room temperature to yield polycyclic
4b,9b-dihydroxy-4b,5,6,7,8,9b-hexahydroindeno[1,2-b]
indole-9,10-diones.
Results and discussion
Keywords: enaminone; grinding; ninhydrin; polycyclic To start the exploration, the reaction of nihydrin (1) and
product; solvent-free.
secondary enaminone 2a was selected. An attempted
reaction of 1 and 2a in the absence of any catalyst did
not produce the desired product 3a. On the other hand,
compound 3a was produced in a 41% yield in the pres-
ence of a catalytic amount of acetic acid and the yield was
increased to 46% in the presence of a catalytic amount of
lactic acid. Under optimized condition the amount of lactic
acid was 50 mol% and this treatment furnished compound
3a in an 87% yield. After the optimization of the reaction
conditions, this solvent-free catalytic approach was then
employed for the efficient synthesis of a variety of other
ring-fused products 3b–j (Scheme 1) (See also Supplemen-
tal Material).
Introduction
The synthesis of polycyclic organic molecules with fused
heterocycles is of significant importance because of their
structural resemblance with natural products [1, 2]. 4b,9b-
Dihydroxy-4b,5,6,7,8,9b-hexahydroindeno[1,2-b]indole-
9,10-diones (3 in Scheme 1) are a class of heterocyclic
molecules with fused indeno[1,2-b]indole polycyclic struc-
ture which are known to possess various biological activi-
ties [3–7]. Therefore, synthesis of such fused heterocyclic
scaffolds has received significant attention in recent years.
Currently, the synthesis of compounds 3 is predominantly
accessed by the reaction of ninhydrin with amine deriva- Conclusions
tives of 1,3-dicarbonyl compounds [8] alkyl propiolates [9]
dialkyl acetylenedicarboxylates [10] or 1,1-bis(methylthio)- A solvent-free method for the synthesis of hexahydro-
2-nitroethene compounds [11]. Since a common feature of indeno[1,2-b]indole derivatives 3 via the reactions of
all these methods is the in situ generation of an enami- nihydrin and secondary enaminones was developed. The
none (or enamino ester) intermediate product, the direct environmentally benign feature of the method makes
application of enaminones as the reaction partners of it useful in the sustainable synthesis of these important
ninhydrin has also been developed [12]. Upon on our long- polycyclic scaffolds.
standing interest in developing environmentally benign
synthesis and enaminone chemistry [13–15] we report
Experimental
*Corresponding author: Yunyun Liu, College of Chemistry and
Secondary enaminones 2 were synthesized following the literature
Chemical Engineering, Jiangxi Normal University, Nanchang 330022, procedure [1] and other chemicals were obtained from commercial
1
P.R. China, e-mail: chemliuyunyun@jxnu.edu.cn
Xuwen Chen: College of Chemistry and Chemical Engineering,
Jiangxi Normal University, Nanchang 330022, P.R. China
sources and used directly without purification. H NMR (400 MHz)
and 13C NMR (100 MHz) spectra were recorded in DMSO-d6. Melting
points are not corrected.
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2ꢀ ꢀX. Chen and Y. Liu: Solvent-free synthesis of hexahydroindeno[1,2-b]indole-9,10-diones
O
O
O
O
O
OH
Lactic acid
OH
OH
R2
R2
Grind,10 min, rt
R2
R2
HN
R1
HO
N
R1
1
2
3a–j
R1
R2
Product
Ph
PhCH2
H
Me
Me
Me
H
H
H
H
H
H
H
3a
3b
3c
3d
3e
3f
3g
3h
3i
Ph
4-MeC6H4
3-ClC6H4
PhCH2
i-Pr
HO(CH2)2
H
3j
Scheme 1ꢀSynthesis of indeno[1,2-b]indole derivatives 3a–j.
J ꢁ=ꢁ 8.0 Hz), 7.21–7.17 (m, 3 H), 6.68 (d, 1 H, J ꢁ=ꢁ 7.2 Hz), 5.96 (s, 1 H),
2.38 (s, 4 H), 2.14–1.95 (m, 3 H), 1.78 (d, 2 H, J ꢁ=ꢁ 4.8 Hz); 13C NMR: δ
197.6, 189.7, 164.8, 147.3, 137.4, 134.79, 134.71, 133.2, 130.1, 129.4, 129.2,
124.9, 123.2, 106.4, 96.3, 83.5, 37.1, 23.6, 21.7, 20.7. ESI-HR-MS. Calcd for
General procedure for the synthesis of indeno[1,2-b]
indoles 3a–j
A mixture of ninhydrin 1 (0.3 mmol), enaminone 2 (0.3 mmol) and
lactic acid (0.15 mmol) was thoroughly grounded using a pestle
and mortar at room temperature for 10 min. Then the mixture was
washed with saturated NaHCO3 solution and water, filtered, and the
crude product was crystallized from ethanol.
+
C22H19NNaO4 [M+Na] : m/z 384.1206. Found: m/z 384.1210.
5-(3-Chlorophenyl)-4b,9b-dihydroxy-4b,5,6,7,8,9b-hexahydro-
indeno[1,2-b]indole-9,10-dione (3f)ꢀWhite solid; yield 80%; mp
223–226°C; 1H NMR: δ 7.74 (d, 1 H, J ꢁ=ꢁ 7.2 Hz), 7.62–7.49 (m, 5 H), 7.34 (s, 1
H), 7.24 (d, 1 H, J ꢁ=ꢁ 6.8 Hz), 6.67 (d, 1 H, J ꢁ=ꢁ 7.6 Hz), 6.06 (s, 1 H), 2.46 (s,
1 H), 2.16–2.00 (m, 3 H), 1.82–1.77 (m, 2 H); 13C NMR: δ 197.9, 190.5, 164.8,
147.5, 138.1, 135.5, 135.2, 133.6, 130.9, 130.8, 129.5,128.6, 128.4, 125.2, 123.8,
107.7, 97.0, 83.9, 37.6, 24.0, 22.2. ESI-HRMS. Calcd for C21H16ClNNaO4
4b,9b-Dihydroxy-7,7-dimethyl-5-phenyl-4b,5,6,7,8,9b-hexa-
hydroindeno[1,2-b]indole-9,10-dione (3a)ꢀWhite solid; yield
87%; mp 210–212°C (lit. [11] mp 211–212°C); 1H NMR: δ 7.73 (d, 1 H, J ꢁ=ꢁ
6.8 Hz), 7.58–7.45 (m, 5 H), 7.30 (d, 2 H, J ꢁ=ꢁ 6.8 Hz), 7.26 (s, 1 H), 6.63
(d, 1 H, J ꢁ=ꢁ 6.4 Hz), 6.00 (brs, 1 H), 2.40 (d, 1 H, J ꢁ=ꢁ 17.2 Hz), 2.15 (d, 1
H, J ꢁ=ꢁ 15.6 Hz), 1.92 (d, 1 H, J ꢁ=ꢁ 15.6 Hz), 1.81 (d, 1 H, J ꢁ=ꢁ 17.2 Hz), 0.96
(s, 3 H), 0.89 (s, 3 H).
+
[M+Na] : m/z 404.0660. Found: m/z 404.0667.
5-Benzyl-4b,9b-dihydroxy-4b,5,6,7,8,9b-hexahydroindeno[1,2-
b]indole-9,10-dione (3g)ꢀWhite solid; yield 86%; mp 207–208°C
1
(lit. [11] mp 209–210°C]; H NMR: δ 7.82 (d, 1 H, J ꢁ=ꢁ 7.6 Hz), 7.73–7.68
5-Benzyl-4b,9b-dihydroxy-7,7-dimethyl-4b,5,6,7,8,9b-hexa-
hydroindeno[1,2-b]indole-9,10-dione (3b)ꢀWhite solid; yield
82%; mp 186–188°C (lit. [11] mp 188–189°C); 1H NMR: δ 7.78 (d, 1 H, J ꢁ=ꢁ
7.6 Hz), 7.73–7.66 (m, 2 H), 7.56 (t, 1 H, J ꢁ=ꢁ 7.6 Hz), 7.32–7.22 (m, 5 H), 7.01
(brs, 1 H), 5.96 (brs, 1 H), 5.13 (d, 1 H, J ꢁ=ꢁ 16.8 Hz), 4.83 (d, 1 H, J ꢁ=ꢁ 16.8
Hz), 2.08–1.92 (m, 4 H), 0.84 (s, 3 H), 0.70 (s, 3 H).
(m, 2 H), 7.57 (t, 1 H, J ꢁ=ꢁ 7.2 Hz), 7.33–7.24 (m, 5 H), 6.93 (s, 1 H), 5.79 (s,
1 H), 5.13 (d, 1 H, J ꢁ=ꢁ 16.8 Hz), 4.82 (d, 1 H, J ꢁ=ꢁ 16.8 Hz), 2.22–2.14 (m, 1
H), 2.03–1.96 (m, 3 H), 1.72–1.55 (m, 2 H).
4b,9b-Dihydroxy-5-isopropyl-4b,5,6,7,8,9b-hexahydroindeno
[1,2-b]indole-9,10-dione (3h)ꢀWhite solid; yield 76%; mp 206–
1
208°C (lit. [11] 205°C); H NMR: δ 7.95 (d, 1 H, J ꢁ=ꢁ 7.6 Hz), 7.80 (t, 1 H,
4b,9b-Dihydroxy-7,7-dimethyl-4b,5,6,7,8,9b-hexahydro-
indeno[1,2-b]indole-9,10-dione (3c)ꢀWhite solid; yield 77%; mp
226–228°C (lit. [11] mp 229–230°C); 1H NMR: δ 9.04 (s, 1 H), 7.79 (d, 2 H,
J ꢁ=ꢁ 3.6 Hz), 7.65 (d, 1 H, J ꢁ=ꢁ 7.6 Hz), 7.55–7.52 (m, 1 H), 6.47 (s, 1 H), 5.49
(s, 1 H), 2.21 (d, 1 H, J ꢁ=ꢁ 17.2 Hz), 2.09 (d, 1 H, J ꢁ=ꢁ 17.2 Hz), 1.97–1.87 (m,
2 H), 1.01 (s, 3 H), 0.80 (s, 3 H).
J ꢁ=ꢁ 7.2 Hz), 7.70 (d, 1 H, J ꢁ=ꢁ 7.6 Hz), 7.58 (t, 1 H, J ꢁ=ꢁ 7.6 Hz), 6.75 (s, 1 H),
5.69 (s, 1 H), 4.63–4.56 (m, 1 H), 2.71–2.67 (m, 1 H), 2.51–2.45 (m, 1 H),
2.04 (s, 2 H), 1.83–1.74 (m, 2 H), 1.45 (d, 3 H, J ꢁ=ꢁ 6.4 Hz), 1.24 (d, 3 H,
J ꢁ=ꢁ 6.4 Hz).
4b,9b-Dihydroxy-5-(2-hydroxyethyl)-4b,5,6,7,8,9b-hexahydro-
indeno[1,2-b]indole-9,10-dione (3i)ꢀWhite solid; yield 77%; mp
208–209°C (lit. [11] mp 209–210°C); 1H NMR: δ 7.93 (d, 1 H, J ꢁ=ꢁ 7.2 Hz),
7.79 (t, 1 H, J ꢁ=ꢁ 7.2 Hz), 7.70 (d, 1 H, J ꢁ=ꢁ 7.6 Hz), 7.58 (t, 1 H, J ꢁ=ꢁ 7.2 Hz),
6.68 (s, 1 H), 5.64 (s, 1 H), 4.93 (s, 1 H), 3.81–3.78 (m, 1 H), 3.62 (s, 3 H),
2.61–2.35 (m, 2 H), 2.04 (s, 2 H), 1.84–1.67 (m, 2 H).
4b,9b-Dihydroxy-5-phenyl-4b,5,6,7,8,9b-hexahydroindeno[1,2-
b]indole-9,10-dione (3d)ꢀPale yellow solid; yield 85%; mp 209–
211°C (lit. [11] mp 212°C); 1H NMR: δ 7.73 (d, 1 H, J ꢁ=ꢁ 6.8 Hz), 7.56–7.48
(m, 5 H), 7.33–7.28 (m, 3 H), 6.62 (d, 1 H, J ꢁ=ꢁ 7.2 Hz), 6.02 (s, 1 H), 2.47–
2.39 (m, 1 H), 2.16–1.96 (m, 3 H), 1.81–1.77 (m, 2 H).
4b,9b-Dihydroxy-5-(p-tolyl)-4b,5,6,7,8,9b-hexahydroindeno[1,2- 4b,9b-Dihydroxy-4b,5,6,7,8,9b-hexahydroindeno[1,2-b]indole-
b]indole-9,10-dione (3e)ꢀWhite solid; yield 84%; mp; 228–231°C; 9,10-dione (3j)ꢀWhite solid; yield 84%; mp 235–236°C (lit. [11] mp
1H NMR: δ 7.72 (d, 1 H, J ꢁ=ꢁ 7.2 Hz), 7.58–7.51 (m, 2 H), 7.29 (d, 2 H, 237–238°C); 1H NMR: δ 9.16 (s, 1 H ), 7.81 (s, 1 H), 7.67 (d, 1 H, J ꢁ=ꢁ 7.6 Hz),
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ꢂ3
X. Chen and Y. Liu: Solvent-free synthesis of hexahydroindeno[1,2-b]indole-9,10-dionesꢂ
7.56 (m, 1 H), 6.53 (s, 1 H), 5.56 (s, 1 H), 2.40 (m, 1 H), 2.24–2.19 (m, 1 H),
2.02 (m, 2 H), 1.82–1.68 (m, 2 H).
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