Synthesis of 7-methyl-6-indolopterin and 7-methyl-6-indoloquinoxaline

Article abstract of DOI:10.1080/00397911.2016.1215467

The first syntheses of indolopterin and indoloquinoxaline, two important and dissimilar diheterocycles linking C-2 of indole with C-6 of pterin (significant positions for showing biological activity), and quinoxaline, respectively, have been achieved base

Full text of DOI:10.1080/00397911.2016.1215467

Synthetic Communications
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Synthesis of 7- Methyl-6-indolopterin and 7-
Methyl-6-indoloquinoxaline
Shyamaprosad Goswami, Manas Kumar Das, Annada C. Maity, Ching Kheng
Quah & Hoong-Kun Fun
To cite this article: Shyamaprosad Goswami, Manas Kumar Das, Annada C. Maity, Ching
Kheng Quah & Hoong-Kun Fun (2016): Synthesis of 7- Methyl-6-indolopterin and 7- Methyl-6-
indoloquinoxaline, Synthetic Communications, DOI: 10.1080/00397911.2016.1215467
To link to this article: http://dx.doi.org/10.1080/00397911.2016.1215467
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Date: 29 July 2016, At: 19:24

Synthesis of 7- Methyl-6-indolopterin and 7- Methyl-6-indoloquinoxaline
Shyamaprosad Goswami1, Manas Kumar Das, Annada C. Maity, Ching Kheng Quah2,
Hoong-Kun Fun2,3
1Department of Chemistry, Indian Institute of Engineering Science and Technology,
Shibpur, Howrah , West Bengal, India
2X-ray Crystallography Unit, School of Physics, Universiti Sains Malaysia, USM, Penang
3Department of Pharmaceutical Chemistry College of Pharmacy, King Saud University,
Riyadh , Kingdom of Saudi Arabia.
Corresponding to author: Shyamaprosad Goswami Department of Chemistry, Indian
Institute of Engineering Science and Technology, Shibpur, Howrah - 711 103, West
Bengal, India E-mail: spgoswamical@yahoo.com.
Abstract
First synthesis of indolopterin and indoloquinoxaline, two new important dissimilar
diheterocycles linking C-2 of indole with C-6 of pterin (significant position for showing
biological activity) and quinoxaline respectively has been achieved based on two famous
classic reactions. The introduction of keto methyl group onto the 6-position of pterin and
quinoxaline by several steps followed by Fischer indole synthesis led to these target
dissimilar diheterocycles. These indole substituted diheterocycles will significantly
increase the electron density on the pterin-5-N and quinoxazoline-2-N which may change
the redox properties of pterin and quinoxaline and also the electron withdrawing pterin or
quinoxazoline should make the indole NH more acidic.
Graphical abstract
1

KEYWORDS: Pterin, indole, quinoxaline, indolopterin, indoloquinoxaline
INTRODUCTION
Pterin is one of the most important heterocyclic compounds containing bicyclic ring
system. The most well-known compounds, pterins and folates are derived from pterin.
Pterins are those compounds which posses the additional functional groups bonded to
pyrazine subring. On the other hand, the conjugated pterins containing p-aminobenzoic
acid and L-glutamates are called folates. These are the most significant compounds in
large number of natural and biological group transfer reactions.1–8 The fused
heteroaromatic coenzymes originating from guanosine are called pterins which are also
ubiquitous and highly redox-active molecules.9 From the physiological point of view, the
investigation of pterins is their correlations to several diseases, including hematological
neoplasias,10 sudden infant death syndrome11 etc. Now, methotrexate, an important anti-
leukemia drug and the folic acid, a significant nutrient and vitamin (vitamin B9) are also
derived from pterins.
The existence of pterin moiety12,13 in molybdenum cofactor also gives us a visible
evidence of its importance in medicinal chemistry. Indole is also a hetero-bicyclic
compound containing the six-membered benzene ring fused with five-membered pyrrole
ring. Indole is the essential constituent of fragrances and it can take part as the precursor
of many pharmaceuticals.14 Indole-derived compounds are also of significance in natural
product chemistry and pharmacology.15 In alkaloid chemistry, on the other hand, indole
has the significant role and many indole alkaloids16 have the important possession in
2

physiological activity and some of them are used in medicine. Consequently, the
synthesis of indole derivatives is an essential area of research.
Now, in our laboratory, we are interested in synthesizing pterin derived new compounds
of potential medicinal interest. Pterin, indole and quinoxaline are important heterocycles
which have been utilized in many biologically active natural products used as a wide
variety of medicines. Many designed synthetic medicines possess these heterocycles.
Interestingly, most important pterin natural compounds are substituted at 6-position.
Since pterin and indole both are naturally and synthetically important as they have strong
relevance in medicinal chemistry, we wanted to synthesise pterin substituted by indole
specifically at 6-position (6-substitution has natural and synthetic significance).
Quinoxaline and their derivatives are useful as antitumor antibiotics and potent
bactericides. Though 2-(2-furyl) quinoxaline is known,17 to the best of our knowledge,
indoloquioxaline or indolopterin are not known naturally or synthetically.
RESULTS AND DISCUSSION
Here we report the total synthesis of these combined heterocycles or conjugated
heterocycles to be present not as fused system but as a distinct identity with making an
intra-molecular H-bonding including a stable five-membered ring framework (Scheme 1,
1f and scheme 2, 2d). In the retro analysis of the synthesis of dissimilar targeted
diheterocycles 1f and 2d originates from quick development of pterin-6-keto-methyl and
quinoxaline-2-keto-methyl intermediates (1c and 2b) which should allow the construction
3

of indole moiety by Fisher indole synthesis from the corresponding phenyl hydrazones of
the corresponding keto methyl groups of pterin and quinoxaline (scheme 1) respectively.
In continuation of our work on tri and tetracarbonyl compounds18 for the synthesis of
heterocycles, the formation of 6-keto-methyl pterin ring can be conveniently achieved by
the condensation of the stable tricarbonyl compound19 1h with triamino-4-oxopyrimidine.
The selenium dioxide oxidation (one equivalent) of acetylacetone produces the desired
stable tricarbonyl compound pentane-2,3,4-trione (1h). Thus, the total synthesis of 7-
methyl-6-indolylpterin begins from 2,5,6-triamino-4-oxo-pyrimidine (1a) as shown in
scheme 2. The trione (1h) was allowed to react by Gabriel-Isay condensation20 with the
above pyrimidine (1a) to give rise to the synthesis of 7-methyl-6-keto-methyl pterin (1c)
in the crude form which gave the soluble product 1d by the action of pivalic anhydride in
the presence of catalytic DMAP. The compound 1d was then converted to the
corresponding phenylhydrazone (1e) which undergoes Fischer indolisation to afford the
yellow fluorescent target compound 1f in good yield. Thus, we have achieved the first
synthesis of indolylpterin or pterinindole (1f).
Reagent & Condition: (i) Na2SO3 and H2O, rt, 30 min. (ii) 1h, H2O, rt, 8h (iii) Pivalic
anhydride, DMAP (cat.), 100 οC, 7h (iv) phenylhydrazine, EtOH, AcOH (few drops), 70-
80 οC, 2h (v) ZnCl2, AcOH, 150 οC, 1-2 h.
We have also similarly synthesised another target indolylquinoxaline (2d) (scheme 3).
4

Reagent & Condition: (i) 1h, EtOH, rt, 1-2h (ii) Phenylhydrazine, EtOH, AcOH (few
drops), 70-80 οC, 2h (iii) ZnCl2, AcOH, 150 οC, 1-2h.
We have been able to develop suitable single crystals for the intermediates (2b and 2c)
for X-ray studies. Crystallographic data are presented in Table S1 (S21). The asymmetric
unit of the compound 2b (Fig. 1a) contains two independent molecules, molecules A and
B, disordered over two sets of sites corresponding to a rotation of approximately 180°,
with refined site occupancies of 0.557(4) and 0.443(4) for both molecules. Overall, all
molecules are close to being planar [r.m.s. deviation for all the non-H atoms = 0.0542 and
0.0638 Å (molecule A), 0.0591 and 0.0717 Å (molecule B), for the major and minor
components, respectively]. Full molecule disorder has also been observed in 2c (Fig. 1b).
The molecule is disordered over two positions with occupancies of 0.615(5) and
0.385(5), exhibiting an inversion disorder. The benzene ring forms dihedral angles of
6.51 and 5.99° for the major and minor components, respectively, with the mean plane of
the quinoxaline ring system. In the crystal structure, C1B—H1BD···N1A hydrogen bonds
[Table S2 (S21)] in 2b bridge the molecules A and molecules B into pairs (Fig. 2a, also
shown in full-page size in SI, S17) and these molecule pairs are further stacked down the
c-axis whereas the molecules in 2c are linked into a zigzag chain (Fig. 2b, also shown in
full-page size in SI, S18) along [001] via N1—H1B···N4 hydrogen bonds.
PHOTOPHYSICAL PROPERTIES
We have studied here the fluorescence experiments of 1f (indolylpterin) and 2d
(indolylquinoxaline) in several solvents. In non-polar aprotic solvents (e.g hexane, CCl4
5

and toluene) they show deep blue fluorescence including bathochromic shift (λmax
)
respectively. Now the intensity of the blue fluorescence gradually decreases with
increasing the polarity of the solvents (moderately polar aprotic). Here we also observe
the compound 1f similar emission in CHCl3, CH2Cl2 and THF whereas the compound 2d
gives different emission spectra with decreasing λmax from CHCl3, to THF. Now among
the polar aprotic solvents, acetone, DMF and CH3CN show the almost similar emission
spectra (yellow fluorescence) but DMSO and ethyl acetate give a blue-shifted spectra of
compound 1f (Fig. 3).
On the other hand, the compound 2d shows the greater red-shifted emission
spectra in DMSO and CH3CN compared to other polar aprotic solvents (Fig. 4)
indicating the fast ESIPT phenomenon.
In polar protic solvent such as methanol both the compounds do not show any
fluorescence probably because here methanol acts as a strong H-bond donor
molecule and consequently ESIPT is prevented due to possible inter-molecular H-
bonding interaction with methanol (Scheme 4).21 The fluorescence quenching by
MeOH may also be enhanced by proton-coupled depopulation of the excited state
due to intermolecular hydrogen bonding. Furthermore, the positive
solvochromicity rather accounts for a highly polar vibrationally relaxed excited
singlet state. Therefore, ESIPT phenomena depend not only on solvent polarity but
also on H-bond donor and acceptor ability of the solvents.22
6

It is a very interesting fact that if we compare the fluorescence properties of the target
molecule 1f with the indole free 1f i.e. the only 7-methyl pterin (1i) compound, the
later one exhibits only blue fluorescence in different solvents (Fig. 5). Again, if we
compare the two molecules 1f and 1i, it is clear that 1f has no fluorescence in polar
protic solvent methanol where as 1i gives blue fluorescence in methanol indicating
the greater importance of indole moiety connected at 6-position of pterin molecule.
Therefore, the indole moiety of compound 1f is the driving heterocyclic moiety onto
pterin for solvatochromic ESIPT phenomena. On the other hand, eliminating indole
moiety from compound 2d i.e only quinoxaline methyl moiety has no naked-eye
fluorescence property itself. Thus, the combination of the two dissimilar suitable
heterocycles has a greater importance in modern ESIPT based research.
CONCLUSION
Thus, we have achieved the synthesis of two important dissimilar diheterocycles,
indolopterin (1f) and indoloquinoxaline (2d) using Gabriel-Isay synthesis for pterin ring
system followed by Fischer indole synthesis for the development of the substituted indole
ring. The new system of such array of two important heterocycles has the potential of
new conjugated donor-acceptor moieties having interesting solvatochromic properties
and for development of other possible fluorescence markers. Further studies are in
progress in our laboratory for the synthesis of new arrays of heterocycles from pterins
and quinoxalines for their possibility of new biological and sensor activities.
ACKNOWLEDGMENTS
7

We thank the CSIR and DST, Government of India for financial support. M.D. thanks the
CSIR, Government of India for research fellowships.
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Scheme 1. Retrosynthetic route of Indolopterin and Indoloquinoxaline.
11

Scheme 2. Synthesis of N-[6-(1H-Indole-2-yl)-7-methyl-4-oxo-3,4-dihydro-pteridin-2-
yl]-2,2-dimethyl- propionamide (1f).
12

Scheme 3. Synthesis of 2-(1H-Indole-2-yl)-3-methyl-quinoxalin (2d).
13

Scheme 4: Mechanism of ESIPT.
14

Figure 1. Molecular view of compounds (a) 2b and (b) 2c, with atomic numbering
schemes. Both major (solid bonds) and minor (open bonds) components of the disorder
are shown.
15

Figure 2. The crystal packing of the major component of compounds (a) 2b and (b) 2c,
viewed along the (a) b-axis and (b) a-axis.
16

Figure 3. Comparative fluorescence of compound 1f in different solvents at 1x 10-5 M
(up) and their naked-eye fluorescence change under hand held UV lamp (down).
17

Figure 4. Comparative fluorescence spectra of compound 2d in different solvents at 1x
10-5 M (up) and their naked-eye fluorescence change under hand held UV lamp (down).
18

Figure 5. Naked–eye fluorescence change of 1i (7- Methyl pterin) with different
solvents.
19