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Synthetic Communications: An International Journal
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Six-Membered Heterocycles with Three and Four NHeteroatoms: Microwave-Assisted Synthesis
a
Navjeet Kaur
a
Department of Chemistry, Banasthali University, Banasthali, Rajasthan, India
Accepted author version posted online: 25 Sep 2014.
To cite this article: Navjeet Kaur (2014): Six-Membered Heterocycles with Three and Four N-Heteroatoms: MicrowaveAssisted Synthesis, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, DOI: 10.1080/00397911.2013.813550
To link to this article: http://dx.doi.org/10.1080/00397911.2013.813550
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Six-Membered Heterocycles with Three and Four N-heteroatoms: MicrowaveAssisted Synthesis
Navjeet Kaur1
1
Department of Chemistry, Banasthali University, Banasthali Rajasthan, India
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Email: nvjithaans@gmail.com
Abstract
The development of new strategies for synthesis of small-sized heterocycles has
remained a highly attractive but challenging proposition. An overview of the application
of microwave irradiation in three and four nitrogen containing six membered heterocyclic
compounds synthesis is presented, focusing on the developments in the last 5-10 years.
This contribution covers the literature concerning the total synthesis of N-heterocycles.
The literature data are summarized based on the size of cycles.
KEYWORDS: Microwave-assisted synthesis, Heterocycles, Nitrogen.
INTRODUCTION
1
For more than a century, heterocycles have constituted one of the largest areas of
research in organic chemistry. Heterocyclic compounds have always been on the
forefront of attention due to their numerous uses in pharmaceutical applications. 1-2
Among them, nitrogen-containing heterocyclic compounds have maintained the interest
of researchers and their unique structures led to several applications in different areas.
Due to the widespread interest in heterocycles, the synthesis of these compounds has
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always been among the most important research areas in synthetic chemistry. 3-4 In many
cases, the classic syntheses provide reliable access to heterocyclic compounds, however,
they are simply no longer acceptable by current environmental and safety standards. For
all these reasons, the various possibilities offered by the microwave technology are
particularly attractive where fast, high-yielding protocols and the avoidance or facilitation
of purification are highly desirable.5-6 Wherever domestic microwave oven, which do not
provide a scientifically adequate level of reproducibility, was used by the authors is
mentioned in the present paper.
N-containing heteroaromatics are important substructures found in numerous natural or
synthetic alkaloids. The diversity of the structures encountered, as well as their biological
and pharmaceutical relevance, have motivated research aimed at the development of new
economical, efficient and selective synthetic strategies to access these compounds. A
diverse array of N-containing six membered heterocycles have been constructed in higher
yields and shorter reaction times as compared to conventional conditions.7-8
2
The importance of nitrogen-containing heterocyclic compounds for biomedical 9-10 and
material science applications6 has led to an increase in the number of synthetic methods
available for the preparation of this type of heterocyclic compounds. 11-13
Six membered14 heterocycles constitute an important structural component of a diverse
range of biologically active natural compounds and pharmaceuticals. In principle, such
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ring systems can be constructed by three distinct approaches viz. intramolecular
cyclization, annulations and ring expansion.15-18 Consequently, the synthesis of six
membered rings has posed a significantly greater challenge in comparison to the
construction of their high membered or large ring counterparts.19-20
In recent decades, a large number of reports related to synthesis of N-containing
heterocycles have appeared owing to a wide variety of their biological activity. In recent
years, numerous reports concerning the synthesis of heterocycles under solvent-free,
reactants immobilized on solid support, microwave irradiation condition have
appeared.21-25 In this review, we report the important role of solvent-free condition
coupled with microwave activation and their advantages in the synthesis of nitrogen
containing six membered heterocyclic compounds.
MICROWAVE-ASSISTED SYNTHESIS OF THREE NITROGEN CONTAINING
SIX MEMBERED HETEROCYCLIC COMPOUNDS:
Triazines are important class of nitrogen heterocycles that form an integral part of
therapeutically interesting compounds which display diverse biological activities. Shie et
3
al.26 reported a method for the direct conversion of aldehydes to triazines with high
optical purity via cycloadditions of intermediate nitriles with dicyandiamide and sodium
azide under MW irradiation. Formation of triazines requires refluxing (e.g., 100 °C) for a
prolonged period (12-48 h) in traditional methods. The Fang group described the direct
conversion of an aldehyde with iodine in ammonia water to a nitrile intermediate, which
without isolation was heated with dicyandiamide, using microwave heating at 80 oC, to
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furnish the [2+3] cycloaddition product 2,6-diamino-1,3,5-triazine in a one-pot operation.
The reaction time was shortened to 15-30 min. In comparison with the conventional
heating method using prolonged reflux (17-48 h) at a high temperature (>100 oC), the
microwave-accelerated reaction in aqueous media is safer and more efficient (Scheme
1).27
Conventional thermal conditions (Scheme 2) were quickly adapted and optimized on the
Smithsynthesizer™ to deliver the previously unknown 3-imidazoly-1,2,4-triazine in 85%
isolated yield. The optimized conditions involved reacting benzil and an imidazoyl acyl
hydrazide, in a 1:1 ratio, with 10 equiv. of ammonium acetate in 1 mL of acetic acid for 5
min at 180 °C, 60 °C above the boiling point of HOAc (Scheme 3). During the course of
the reaction, the pressure never exceeded 5 psi. Upon rapid cooling of the reaction vessel
to 40 °C, a yellow precipitate formed which proved to be 3-imidazoly-1,2,4-triazine.
With this result in hand, a 48-membered library was then synthesized employing a
diverse set of acyl hydrazides using benzil as the 1,2-diketone component. The desired
product was obtained in every instance, with crude LCMS purity in excess of 75% and
isolated yields in excess of 79%. For 60% of this library, the desired product precipitated
4
out of solution upon rapid cooling, and clean material could be obtained by filtration and
washing. The remaining 40% of the library was purified by mass-triggered preparative
LCMS on a custom Agilent 1100 instrument. This new protocol also allowed for the
synthesis of saturated heterocyclic congeners as well as other aminoalkyl derivatives
demonstrating the generality of this methodology for analog library synthesis. The
majority of the triazine analogs from this library have not been previously described in
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the primary or patent literature and represent novel heterobicyclic structures.
Conventional heating with heterocyclic diketones or heterocyclic acylhydrazides
produced the target material in <30% yield with multiple side products. Optimization of
microwave heating conditions led to the synthesis of previously triazine.
By the application of microwave technology, a general protocol has been developed for
the rapid synthesis of diverse 3,5,6-trisubstituted 1,2,4-triazines (Scheme 4) in excellent
yield and purity, including many previously unknown 3-heterocyclic-1,2,4-triazines
(Scheme 5). While developing structure activity relationships (SAR) for a small
heterocyclic lead compound, the need arose for a general protocol to synthesize 3 heterocyclic-1,2,4-triazines, preferably in a manner amenable to analog library synthesis.
Examination of the literature provided numerous methods for the synthetic preparation of
triazines. However, the examples highlighted by these protocols typically focus on only
simple aliphatic, phenyl and ester substituent at R1-R3. This was especially true for the
synthesis of 1,2,4-triazines via the condensation of 1,2-diketones with acyl hydrazides
and ammonium acetate under traditional thermal and ‘dry media’ microwave-assisted
5
reaction conditions. Due to our in-house reagent library of diverse acyl hydrazides, our
efforts centered on exploring this synthetic route.28
The 1,2,4-triazine core is a synthetically important scaffold because it could be readily
transformed into a range of different heterocyclic systems such as pyridines via
intramolecular Diels-Alder reactions with acetylenes. 1,2,4-Triazines have been
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synthesized by the condensation of 1,2-diketones with acid hydrazides in the presence of
NH4OH in acetic acid for up to 24 h at reflux temperature. Microwave dielectric heating
in closed vessels allowed the reaction to be performed at 180 oC. As a result, the reaction
time was reduced to merely 5 min 28(Scheme 6).
Broadening the scope of 1,2,4-triazine synthesis by the application of microwave
technology Zhijian Zhao et al.28 developed the rapid synthesis of diverse 3,5,6trisubstituted 1,2,4-triazines in excellent yield and purity, including many previously
unknown 3-heterocyclic-1,2,4-triazines. 1,2,4-triazines were prepared from the
condensation of thiosemicarbazide with diketons under microwave irradiation in a
solvent-less system by Heravi et al. 29 (Scheme: 7-11).30
In a one pot microwave reaction, an acyl hydrazide-tethered indole underwent a 3component condensation to form a triazine, followed by an inverse-electron demand
Diels-Alder reaction and subsequent chelotropic expulsion of N 2 to deliver novel,
unnatural β-carboline alkaloids in good isolated yields31 (Scheme 12).
6
The traditional thermal conditions involve heating a 1,2-diketone and an acyl hydrazide,
in a 1:1 ratio, with excess ammonium acetate in refluxing acetic acid for 6-24 h. These
conditions with either a heterocyclic acyl hydrazide or heterocylic-containing 1,2diketone afforded low yields (<30%), required extended heating to consume starting
materials (10-24 h) and resulted in numerous side products. Applying these same reaction
conditions with non-heterocyclic starting materials delivered the desired triazines in
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under 8 h and in >65% isolated yields, in accord with literature precedent. Recently, ‘dry
media’ microwave-assisted protocols have emerged wherein an inorganic support, such
as silica gel, is employed as the energy transfer medium in lieu of solvent. This approach
has been applied to the preparation of 1,2,4-triazines to successfully deliver products in
good yields using a conventional microwave oven. Unfortunately, attempts to reproduce
this work utilizing Personal Chemistry’s Smithsynthesizer afforded poor yields with nonheterocyclic reactants and no desired product when heterocyclic reactants were
employed. The 3,5,6-trisubstituted-1,2,4-triazines have synthesized from fatty acid
hydrazides under microwave assisted solvent-free conditions32, 30 (Scheme 13).
Rapid and efficient solvent-free synthesis of 4-amino-3-mercapto-6-[2-(2-thienyl)vinyl]1,2,4-triazin-5(4H)-one under microwave irradiation is described. 4-Amino-3-mercapto6-[2-(2-thienyl)vinyl]-1,2,4-triazin-5(4H)-one were prepared by several routes33 in order
to establish the best method for the preparation of this compound. First, the conventional
method by refluxing thiocarbohydrazide34 with 2-oxo-4-(2-thienyl)but-3-enoic acid35 in
glacial acetic acid.36 Second, carrying out the solvent free reaction between the two above
compounds, under microwave irradiation as described in the literature (Scheme 14).37
7
Third, via the second method, but using some drops of glacial acetic acid, under
microwave irradiation, to compare the results of the two methods (Scheme 15). In the
conventional method the reaction was complete after two h of reflux and the yield was
62%, while in case of microwave irradiation the yield was improved to 98% and the
reaction was finished in only 2 min. Microwave irradiation of the starting materials in the
presence of a few drops of glacial acetic acid yielded 4-(N-acetylamino)-3-mercapto-5-
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oxo-6-[2-(2-thienyl)vinyl]-1,2,4-triazine.38
Peng et al.39 published a “green” and efficient methodology for microwave-promoted
synthesis of 6-aryl-2,4-diamino-1,3,5-triazines from the corresponding arylnitriles and
cyanoguanidines in [BMIM]PF 6. The “specific microwave effects” were presumably
responsible for the observed 40-fold acceleration in microwave-assisted synthesis of
1,3,5-triazines compared to conventional thermal conditions. Thus, microwave heating of
benzonitrile and dicyandiamide in an ionic liquid ([bmim]PF 6) in the presence of
powdered KOH at 130 oC for just 12 min afforded 2,4-diaminotriazine in 87% yield.
Under otherwise identical conditions the reaction in a pre-heated oil-bath (130 oC) took 8
h to afford the target heterocycle 1,3,5-triazines in 79% yield (Scheme 16).40
A 20-membered library of 1,3,5-triazines was prepared in a parallel format employing a
one-pot, three-component condensation of anilines, dicyandiamide and acetone. The
reaction time was reduced from 22 h to 35 min by using microwave dielectric heating at
90 oC in a sealed tube.41 It is noteworthy that the workup consisted simply of cooling the
8
reaction mixture to 4 oC and a subsequent filtration of the precipitated product (Scheme
17).
The rapid, cost-effective manner in which MAOS operates allows scientists access to a
wide range and quantity of molecules that can be screened as potential biosensors. This
section describes the application of MAOS to the synthesis of some fluorescent
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components in sensors. Perumal et al42 reported the microwave synthesis of an array of
pyridinyl-1,2,4-triazine derivatives used as fluorescent sensors for ferric salts with
reduced reaction times and comparable yields (66-85%). Bisaryl-3-pyrazine-1,2,4triazine derivatives displayed good sensor property with Fe(III) ions in micro level
concentrations (Scheme 18).
A simple and highly efficient procedure has been described for the synthetic derivatives
of 3-(4-ethylbenzyl)-1-(4-methoxybenzyl)-6-(methylthio)-1,3,5-triazine-2,4(1H,3H)dione under solvent free condition at microwave power 400 W using domestic
microwave. 4-Bromobenzene sulfonyl chloride was found as one of the better leaving
groups in substitution reactions. First 4-bromo benzenesulfonyl chloride was coupled
with 4-ethyl benzyl alcohol then a substitution reaction with triazine compound was
done. Yield of 76% with high purity with microwave irradiation at 700C (400 W) with in
0.5 h was obtained. But in a conventional route it took 18 h to complete starting material.
Substituted benzyl amines are taken for this process because these are liquid in nature, so
it helps in solvent free synthesis. After 5 min microwave irradiation at 120 o C compound
9
was consumed. Crude as it is was purified by silica gel column chromatography without
any workup (Scheme 19).43
Fatty hydrazides were made from acid oil and oil recovered from spent bleaching earth
by treating their methyl esters with hydrazine hydrate. Rapid and efficient solvent free
synthesis of 3,5,6-trisubstituted-1,2,4-triazines from chemically synthesized fatty
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hydrazides made from AO or ORSBE under microwave irradiation was studied, using
silica gel as an inorganic solid support. The traditional thermal conditions involve heating
a 1,2-diketone and an acyl hydrazide, a 1:1 ratio, with excess ammonium acetate in
refluxing acetic acid for 6-24 h. Recently, ‘dry media’ microwave assisted protocols have
emerged where in an inorganic support, Such as silica gel, is employed as the energy
transfer medium in lieu of solvent. This approach has been applied to the preparation of
1,2,4-triazine to successfully deliver products in good yield using a conventional
microwave oven. A mixture of fatty acid hydrazide, diketone and silica gel was ground in
a pestle, NH4OAc and Et3N were added in catalytic amounts and the prepared mixture in
an open beaker was subjected to microwave irradiation for the appropriate time (8 min.
for 3-alkyl-5,6-dimethyl-[1,2,4]triazine and 10 min. for 3-alkyl-5,6-diphenyl-[1,2,4]
triazine at 100% power). After complete conversion the mixture was extracted with
petroleum ether and washed with water (Scheme: 20-21).44
1,3,5-Triazines are used as templates in supramolecular chemistry and dendrimer
synthesis, due to their C3 symmetric core structure.45-46 Synthesis of symmetrically
substituted 1,3,5-triazines was performed by cyclotrimerization of nitriles under solvent-
10
free conditions using silica-supported Lewis acids as catalysts (Scheme 22).47 The
catalysts used in these reactions were Lewis acids, such as ZnCl 2 , AlCl3 and TiCl4,
supported on silica gel. Piperidine or morpholine were used as promoters for the
cyclotrimerization reactions. Although the microwave-assisted reactions gave good
results in short times (1 h), the reactions under conventional conditions over a period of
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24 h gave higher isolated yields (up to 84%).48
It is also worth noting that compounds 2-(α-phenylacetyl)-N-(3,6-diphenyl-5-aryl-5,6dihydro-1,2,4-triazine-4yl)benzamide were prepared through direct Diels-Alder reaction
between dibenzylidene hydrazine (III) as diene (was prepared by condensation of
hydrazine hydrate (80%) with benzaldehyde in the presence of aqueous acetic acid (50%)
to give yellowish green crystalline products in a good yield, 1 and dienophile. The reaction
was found to proceed smoothly under microwave irradiation within (6 min.) at (360 W),
(Scheme 23).49-51
MICROWAVE-ASSISTED SYNTHESIS OF THREE NITROGEN CONTAINING
SIX MEMBERED POLYCYCLIC HETEROCYCLIC COMPOUNDS:
The target molecule 1,2-dihydro-2,3-dimethyl-1-phenyl-4H-pyrazolo[4,3-e][1,2,4]triazin5(6H)-one were synthesized by eco-friendly microwave irradiation. An efficient protocol
for the synthesis of 1,2-dihydro-2,3-dimethyl-1-phenyl-4H-pyrazolo[4,3-e][1,2,4]triazin5(6H)-one was developed. The process adopted in this process follows operational
simplicity, cleaner reaction, easer work-up and are environmentally co-friendly reactions
compared to other methods (Scheme 24).52
11
Heravi et al.53 reported the synthesis of [1,3,4]-thiadiazolo[2,3-c][1,2,4]-triazin-4-ones
were one-pot condensation and cyclization of 4-amino-[1,2,4]triazine-3-thione-5-ones
with various aromatic carboxylic acids in the presence of silica-gel/sulfuric acid in
solvent-less condition (Scheme 25).
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Rostamizadeh and Sadeghi54 have prepared 1,2,4-triazines from the one-pot
condensation reaction of acid hydrazide, ammonium acetate and dicarbonyl compounds
on the surface of silica gel in the presence of triethylamine under microwave irradiation.
Novel highly functionalized benzimidazoles were synthesized in two steps by microwave
irradiation: construction of the benzimidazole ring followed by ring closure to the new
tricyclic system. The 1,3-dipole like nitrile imines were generated in situ from the
reaction of triethylamine with the hydrazonyl chlorides. Treatment of with the nitrile
imines using microwave irradiation was explored under solvent-free conditions using
silica gel as a solid support. The reactants were impregnated on the support and then
irradiated at 900 W for 4 min using a domestic microwave apparatus to give the new
tricyclic benzimidazole derivatives in 81-88% yields55(Scheme 26).
An efficient protocol associated with readily available starting materials, mild conditions,
excellent yields, and a broad range of products in synthetic chemistry has been
established for the synthesis of thiazolo-triazine N-nucleosides derivative.
Cyclocondensation of N-benzylidene-5-phenylthiazol-2-amine and chloromethanamine
on montmorillonite K-10 under microwave irradiation give thiazole-triazine, which
12
undergo nucleophilic substitution with 4-chlorobutanl. This substituted thiazole-triazine
compound on control aldol condensation with formaldehyde yield hydroxylated
compound, which on subsequent chemoselective reduction with NaBH 4 give title
compound. Result obtained show considerable enhancement of yields and reduction in
time. Coexistence of acidic and basic sites on surface of montmorillonite K-10
accelerates the organic reactions synergistically. Further it could be easily filtered from
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the reaction mixture and may be used 2-3 times with same efficiency. However, the use
of other mineral supports viz. silica gel, neutral or basic alumina was far less effective,
resulting in either no reaction (basic alumina) or relatively very low yields (acidic
alumina). Moreover, the reactions did not take place if they were performed using
microwave without the montmorillonite K-10, either neat or in an organic solvent. The
key element in the present approach is to minimize the mechanical loss of the
intermediate during the process of isolation, enhances the yield and reduces the reaction
time. The reactions were also carried out using a thermostated oil-bath at the same
temperature (90 oC) as for the MW-activated method for a longer period of time to
ascertain whether the MW method improved the yield or increased conversion rates. It
was found that significantly lower yields were obtained using oil-bath heating rather than
the MW-activated method (Scheme 27).56
This procedure describes the microwave-assisted synthesis of canthine. Canthine is a
triazine containing molecule. Canthine inhibit Akt. This method led to the synthesis of
unnatural canthine. Microwave-assisted synthesis resulted in 10 to 700-fold reduction in
reaction times (Scheme 28).57
13
MICROWAVE-ASSISTED SYNTHESIS OF FOUR NITROGEN CONTAINING
SIX MEMBERED HETEROCYCLIC COMPOUNDS:
In a three component reaction benzaldehyde aminoacetal is formed. A sequence of
metathesis reactions connect the amino functions of both benzaldehyde aminoacetal and
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urea together forming 6-aryl-1,2,4,5-tetrazinane-3-one in good yields of 68-80%. Two
equivalents of hydrogen are released. The proposed mechanism is favored by the lack of
any solvent, so that N-H moieties are in direct contact with each other and are strongly
activated by microwave irradiation. A strong evidence for the proposed mechanism is
given by comparing the data of the MW-supported reaction with the conventionally
heated reaction. The MW-supported reaction rate is 15 fold and the product yield twice
that of the conventionally heated process (Scheme 29).58
The Diels-Alder reaction between aza-olefins and aza-dicarboxylic ester to give
tetrazines is speeded-up by a factor of 1000 by microwave enhancement as shown in
Scheme 30.59
Symmetrical 3,5-substituted-4-amino-1,2,4-triazoles are quickly prepared from aromatic
aldehydes via nitriles by two-step reactions without any separation under microwave
irradiation for each several minutes60 (Scheme 31).
14
A novel approach to the synthesis of triazolo[4,3-b][1,2,4,5]tetrazines has been developed
via reactions of 4-amino-5-methyl-1,2,4-triazole-3(2H)-thione with hydrazonoyl halides
using chitosan as a basic catalyst under microwave irradiation. The conventional routes
for reactions of hydrazonoyl halides with heterocyclic thiones were used triethylamine or
sodium ethoxide as basic catalysts to generate, in situ, nitrilimine from the corresponding
hydrazonoyl halides. In this context, chitosan was used as novel eco-friendly basic
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catalyst in these reactions under microwave irradiation to afford a new environmentally
benign route for synthesis of fused heterocyclic compounds. The reactions of 4-amino-5methyl-1,2,4-triazole-3(2H)-thione with ethyl arylhydrazonochloroacetate and N-aryl 2oxo-2-phenylaminoethanehydrazonoyl chloride in absolute ethanol in the presence of
chitosan under microwave irradiation for 10 minutes are shown in Scheme 32. In all
cases, the respective triazolo[4,3-b][1,2,4,5]tetrazines were formed via S-alkylation
followed by Smiles rearrangement and finally cyclization of the intermediates via
elimination of hydrogen sulfide. 61
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