Synthesis of new heterocycles through the reaction of β-lapachone with 1,2-diamines using Triton X-100 surfactant as catalyst in aqueous medium

Article abstract of DOI:10.1080/00397911.2017.1281420

An efficient and an environmentally benign protocol has been developed for the synthesis of new naphtha-azaquinoxaline and naphtha-benzoquinoxaline derivatives from the reaction of β-lapachone, a naturally occurring 1,2-naphthoquinone with various 1,2-diamines using surfactant as catalyst in aqueous medium. This method has advantage of easy handling and good yield of products in shorter time. The structures were assigned with the help of analytical and ¹H, ¹³C NMR, IR, and mass spectral studies.

Full text of DOI:10.1080/00397911.2017.1281420

Synthesis of New Heterocycles via the Reaction of β-Lapachone with 1,2-Diamines
Using Triton X-100 Surfactant as Catalyst in Aqueous Medium
Poonam Khandelwal1, Pooja Vyas1, Dinesh Kumar Yadav1, Neetu Koolwal2, Pahup
Singh3
1Department of Chemistry, Mohanlal Sukhadia University, Udaipur-313001, India
2Department of Chemistry, IIS University, Jaipur- 302020, India
3Department of Chemistry, University of Rajasthan, Jaipur-302004, India.
Corresponding to author: Poonam Khandelwal. E-mail: poonamkhandelwal@mlsu.ac.in
Abstract
An efficient and an environmentally benign protocol has been developed for the synthesis
of new naphtha-azaquinoxaline and naphtha-benzoquinoxaline derivatives from the
reaction of β-lapachone, a naturally occurring 1,2-naphthoquinone with various 1,2-
diamines using surfactant as catalyst in aqueous medium. This method has advantage of
easy handling and good yield of products in shorter time. The structures were assigned
with the help of analytical and 1H, 13C NMR, IR and mass spectral studies.
Graphical Abstract
KEYWORDS: β-Lapachone, Lapachol, 1,2-Diamines, Surfactants, Triton X -100.
1

INTRODUCTION
Quinones form an important class of natural products exhibiting a wide range of
[2]
biological properties (cytotoxic[1], antimalarial , anti-inflammatory[3] antifungal and
antiviral[4,5]) together with a great structural diversity and complexity, which makes them
interesting challenges to organic synthesis.
Lapachol and its congener β-Lapachone occur naturally in heartwood of various trees of
Bignoniaceous family. β-Lapachone, an 1,2-naphthoquinone exhibited a wide variety of
pharmacological effects including anticancer, antibacterial, antifungal, and trypanocidal
activities[6-9]. Literature[10-13] has revealed that the introduction of heterocyclic moieties
modified the pharmacological properties of the parent skeleton. Thus the transformation
in the quinonoid skeleton has recently been a subject of great interest from the
pharmacological point of view. Further the synthesis of novel and specific heterocyclic
compounds by the using recent synthetic methodologies is an intense area of research. In
this regard, efforts have been constantly made to introduce new methodologies that are
efficient and more compatible with an environment.
The high catalytic activity and benign character of surfactants have fascinated
considerable interest in organic synthesis.[14,15] The formation of vesicular cavities or
micelles with hydrophobic core and hydrophilic corona at ambient conditions of
2

surfactants in aqueous medium has been proved to increase the reactivity of aqueous
mediated reactions.
RESULTS AND DISCUSSION
Earlier the reactions of lapachol and β-lapachone with ethylene diamine, 1,2-
diaminopropane, o-phenylene diamine and 2,3-diaminopyridine by conventional heating
and with solid support under microwaves irradiation have been studied by our group.[16,17]
Considering the significance of surfactants, herein we report new efficient protocol for the
reaction of β-lapachone with 2,3-diaminopyridine employing green tools. Using this
protocol, we have synthesized naphthazaquinoxaline and naphthabenzoquinoxaline
derivatives as new polycyclic heterocycles by the reaction of β-lapachone with other 1,2-
diamines i.e. 5-bromo-2,3-diaminopyridine, 3,4-diaminotoluene, 3,4-diaminopyridine and
2,3-diaminonaphthalene. This report represents a new entry into the synthesis of
heterocyclic compounds from β-lapachone in aqueous media using surfactant as catalyst.
The similar reactions on lapachol did not succeed.
Initially, the reaction of β-lapachone 2 with 2,3-diaminopyridine 3, as a model reaction
was investigated to optimize the reaction conditions and established the feasibility of the
strategy. When the reaction was performed in water only at room temperature as well as
on heating, no product was formed. When the β-lapachone with 2,3-diaminopyridine
were stirred at room temperature in water using surfactant, products were obtained in 21
hrs. On heating along with stirring gave product in shorter time. In order to study the
effect of surfactant, various ionic (cationic and anionic) and non ionic surfactants were
3

tested and the results are summarized in Table-1. In the presence of SDS (Sodium
dodecyl sulphate- an anionic surfactant) and CTAB (Cetyl trimethylammonium bromide-
cationic surfactant), the desired products were obtained in 4-5 hours. In the presence of
TBAB (Tetrabutyl ammonium bromide - cationic surfactant) the desired products were
obtained in 12 hours. The best result (good yields in shorter reaction time) was obtained
in aqueous medium with non ionic surfactant Triton X-100 (TX-100).
Further, above reaction was carried out at different temperatures with varying
concentration of the surfactant and the data are presented in Table 2. It is clear from the
data that the rate of reaction increased continuously with increasing catalyst
concentration upto 15 mol% without any considerable difference on increasing catalyst
concentration further. Thus it was concluded that the concentration of catalyst plays a
significant role in controlling the rate of the reaction and in aqueous medium 15 mol % of
Triton X-100 gave best results at 800C.
It was noticed that on introduction of surfactants followed by stirring, the initially
floating reactants in the mixture converted to an orange-brown turbid emulsion, which
implies that there is formation of micelle like colloidal aggregates. It can assume that
most of the organic substrates are concentrated in the spherical particles, which act as a
hydrophobic reaction site and results in the rapid reaction in water. In the micellar
solution, the organic substrates which are hydrophobic, escape away from water molecule
towards the hydrophobic core of micelle droplets where the reaction occurs more easily.
The hydrophobic interior of the micelles rapidly excludes the water molecules generated
during the reaction, thus shifting the equilibrium towards the product side.[18]
4

Mechanism of condensation of β-lapachone 2 with 2,3-diaminopyridine 3 has been
explained in our previous report[17] and it was concluded that 4a should be major product,
if reaction was conducted by thermal method. But when the reaction is carried out in
aqueous medium using surfactant as catalyst, the percentage yield of 4b increases. The
structure of 4b was unambiguously established by single crystal X-ray studies[17] and it
was characterized as 6,7-dihydro-8,8-dimethyl-8H-pyrano [3´,2´:4]naphtha[2,1-e]
pyrido[2,3-b] pyrazine; 4b.
Encouraged by these results, the reaction of β-lapachone 2 was extended to other
diamines i.e. 5-bromo-2,3-diaminopyridine, 3,4-diaminotoluene, 3,4-diaminopyridine
and 2,3-diamino- naphthalene using triton X-100 (15 mol%) in distilled water at 80◦C.
Results are shown in Table 3 and probable products are given in Fig 1.
Reaction of β-lapachone with 5-bromo- 2,3-diaminopyridine gave two regioisomeric
products 5a and 5b in the ratio of 3:5. Here 5b is major product rather than 5a. It can be
explained by attack of more nucleophilic 2-amino group on the more electrophilic 1-
carbonyl function of β-lapachone. 2-Amino group is more nucleophilic rather than 3-
amino group due to the presence of Br. There are several reports in the literature[12-13]
mentioning that the carbonyl nearest to the aromatic ring is more reactive than 2-carbonyl
group in β-lapachone. The ESI mass spectra of 5a and 5b showed two base peak with
equal intensity at 394 and 396, which indicates the presence of bromine. Further both
regioisomers were identified on the basis of 1H NMR spectrum.
5

Exclusive formation of product 6 in the reaction of β-lapachone with 3, 4-
diaminotoluene can be understood by the presence of methyl group in the ring, which
makes 4-amino group more reactive than the 3-amino group. The formation of product 7
in the case of reaction of β-lapachone with 3,4-diaminopyridine is thought to arised from
the attack by more nucleophilic 3-amino group[19] on the more electrophilic 1-carbonyl
function of β-lapachone (Scheme-II). The isolated products were characterized on the
basis of their IR, 1H and 13 CNMR spectroscopy and mass spectrometry. All the products
showed absence of carbonyl group in IR Spectra.
The similar methodology was applied for the reaction of lapachol 1 with above diamines,
but the reactions were not successful in the all optimized conditions. The reaction of
lapachol 1 with diamines in the presence of some drops of H2SO4 using above
methodology were successful and gave the same products which are obtained by the
reaction of β-lapachone with diamines. These results indicate that lapachol first
converted in β-lapachone in the presence of H2SO4 and then reaction proceeds.
CONCLUSION
In conclusion, we have developed an exceedingly simple, mild and clean synthetic
protocol for the synthesis of new naphthazaquinoxaline and naphtha-benzoquinoxaline
derivatives in water. Non ionic surfactant (Triton X-100) was found to be an efficient
catalyst to accelerate the reaction in water.
6

EXPERIMENTAL
Melting points were determined in soft glass capillaries in an electrothermal melting
point apparatus and are uncorrected. Qualitative and quantitative thin layer
chromatography was conducted on TLC aluminium sheets Kieselgel 60F
(E. Merck).
254
1
13
H NMR and C NMR spectra were recorded on a Bruker 300 and JEOL 400 FT NMR
spectrophotometer using CDCl as solvent. FAB Mass spectra were generated on a JEOL
3
SX-102 mass spectrometer. All compounds were homogenous on TLC in various solvent
systems.
Typical Procedure For Synthesis Of 4a And 4b
A mixture of β-lapachone 2 (1.0 mmol), 2,3-diaminopyridine (1.0 mmol), Triton X-100
(15 mol%) and distilled water (5.0 ml) were taken in a round bottom flask. The reaction
mixture was allowed to stir magnetically at 80◦C for 2 hours. Progress of the reaction was
monitored by TLC. After completion of the reaction, the crude mass was obtained. The
residue was purified over a column of silica gel (100-200 mesh) eluting with a mixture of
hexane and ethyl acetate in different ratio, to yield regioisomers (4a and 4b).
Characterization Data For Compounds
6,7-Dihydro-8,8-Dimethyl-8H-Pyrano[3’,2’:4]Naphtha[1,2-E]Pyrido[2,3-B]Pyrazine
(4a)
-1
Bright yellow needles; mp 210-120C[17]; IR (KBr cm ): 3150-2960, 1625, 1600, 1540
(C=N); 1H NMR (300 MHz; CDCl3; Me4Si): δ 1.54 (6H, S, 2 Me), 2.06 (2H, t, J=6.57
Hz,-CH2-), 3.31 (2H, t, J=6.57 Hz, -CH2-), 7.73 (1H, dd, J=8.43, 4.02 Hz, 1×Ar-H), 7.80
7

(2H, m, 2×Ar-H), 8.31-8.34 (1H, m, 1×Ar-H), 8.57 (1H, dd, J=8.43, 1.83 Hz, 1×Ar-H),
9.21 (1H, dd, J=1.83, 4.02 Hz, 1xAr-H) and 9.48-9.51 (1H, m, 1xAr-H). 13C NMR (75.45
MHz; CDCl3; DEPT, Me4Si): 26.7 (C-CH3), 26.7 (C-CH3), 18.2 (CH2), 32.30 (CH2), 76.6
(C8), 109.23 (C5b), 124.59-128.09 (aromatic C), 129.71 (C9b), 130.47 (aromatic C),
137.72 (aromatic C), 147.5 (C9a), 142.25 (C14a), 145.59 (C5a), 152.65 (aromatic C); FAB
MS (m/z): 316 (100) [M+H]+, 300 [M-Me]+, 260, 120, 107; Anal C20H17N3O. Cald For:
C, 76.19; H, 5.39; N, 13.33. Found: C, 76.09; H, 5.31; N, 13.25.
6,7-Dihydro-8,8-Dimethyl-8H-Pyrano[3’,2’:4]Naphtha[2,1-E]Pyrido[2,3-B]Pyrazine
(4b)
-1
Bright orange needles; mp 202-050C [17]; IR (KBr cm ): 3140-2975, 1600, 1625, 1550
(C=N), 1400; 1H NMR (300 MHz; CDCl3 ; Me4Si ): δ 1.54 (6H, s, 2 Me), 2.09 (2H, t,
J=6.60 Hz,-CH2-), 3.41 (2H, t, J=6.60 Hz, -CH2-), 7.69 (1H, dd, J=8.40, 4.20 Hz, 1×Ar-
H), 7.79 (2H, m, 2×Ar-H), 8.32-8.35 (1H, m, 1×Ar-H), 8.64 (1H, dd, J=8.43, 1.83 Hz,
1×Ar-H), 9.22 (1H, dd, J=4.20, 2.01 Hz, 1×Ar-H) and 9.27-9.30 (1H, m, 1×Ar-H). 13C
NMR (75.45 MHz; CDCl3; DEPT, Me4Si): 26.8 (C-CH3), 26.7 (C-CH3), 18.2 (CH2),
32.32 (CH2), 76.6 (C8), 109.23 (C5b), 122.47- 148 (aromatic C), 153 (C2), 153.98 (C14a);
FAB MS (m/z): [M+H]+ 316 (100) , 300 [M-Me]+, 260, 120, 107; Anal C20H17N3O. Cald
For: C, 76.19; H, 5.39; N, 13.33. Found: C, 76.01; H, 5.35; N, 13.03.
ACKNOWLEDGMENT
The authors are grateful to UGC, New Delhi, India for financial assistance.
8

SUPPORTING INFORMATION
Experimental detail, 1H and 13C NMR spectra of novel compounds are given in
supporting information.
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11

Table 1. Study of 4a and 4b under different reaction conditionsa
Entry
Solvent/ Surfactant
Temp.(◦C) Reaction time
Yieldb(%)
4a
4b
10
1.
2.
3.
4.
5.
6.
Ethanol
Reflux
Reflux
Reflux
RT
72 hr
24 hr
24 hr
24 hr
24 hr
21 hr
30
36
29
Ethanol + GAA
Ethanol + Piperidine
Water
13
8
N Rc
N Rc
Water
Reflux
RT
Water/TX-100e
35
25
7.
Water/TX-100e
Water/SDSe
80
80
80
80
80
2 hr
5 hr
4 hr
12 hr
6 hr
45
30
40
39
27
39
20
32
30
21
8.
9.
Water/CTABe
Water/TBABe
Water/PEG-1000
10.
11.
a Reaction conditions:1.0 mmol of both β-lapachone 2 and 2,3-diaminopyridine 3; GAA
(glacial acetic acid); Triton X-100 (TX-100);
b Isolated yield;
e Surfactant (15 mol%);
c No reaction
12

Table 2. Effect of the different surfactant concentration and temperature on the yield of
4a and 4b.
Entry
Solvent/Surfactant
Temp.(◦C) Reaction
Yieldb(%)
Time
4a
35
4b
28
39
35
1.
2.
3.
Water/TX-100e
Water/TX-100e
Water/TX-100e
60
4.5 hr
2.0 hr
2.5 hr
80
45
100
40
4.
5.
6.
Water/TX100c
Water/TX-100d
Water/TX-100f
80
80
80
4.0 hr
3.5 hr
2.0 hr
30
36
39
25
29
32
a Reaction conditions:2.0 mmol of both β-lapachone 2 and 2,3-diaminopyridine 3;
b Isolated yield;
cTriton X-100 (5 mol%);
d Triton X-100 (10 mol%);
eTriton X-100 (15 mol%);
fTriton X -100 (20 mol%)
13

Table 3: Study of reaction of β-lapachone with various diamines
Entry Diamine
Reaction
time
Product
Yieldb(%)
1.
2.
3.
4.
5-bromo-2,3-diaminopyridine 2 hrs
5a & 5b
30 & 50
90
3,4-diamino toluene
3,4-diaminopyridine
2,3-diamino naphthalene
2 hrs
4 hrs
2 hrs
6
7
8
70
85
a Reaction conditions:1.0 mmol of β-lapachone (2) and 1.0 mmol of diamine in
Water/Triton X- 100e (15 mol%) at 80◦ C;
b Isolated yield.
14

Scheme 1.
15

Scheme 2.
16

Figure 1.
17