Copper-catalyzed one-pot synthesis ofglycosylated iminocoumarins and 3-triazolyl-2-iminocoumarins†
Pintu Kumar Mandal*
A general strategy was developed for the synthesis of glycosyl iminocoumarins (5a–x) in a one-pot, copper-
catalyzed multicomponent reaction involving a domino reaction of sulfonyl azides, sugar alkynes, and
salicylaldehydes via ketenimine intermediate formation. Similarly, glycosyl 3-triazolyl-2-iminocoumarin
derivatives (6a–o) have also been synthesized in a one-pot, three component condensation via tandem
“CuAAC-aldol-cyclization-dehydration” sequence. In this event, a copper-catalyzed cycloaddition
reaction between 2-azidoacetonitrile and sugar alkynes furnished a triazole derivative in situ and
activated the neighboring methylene group, inducing an aldol–cyclization–dehydration sequence in the
presence of a salicylaldehyde. The yields were very good in all reactions.
Introduction
The transformation of simple substrates into a library ofcomplex molecules with structural diversity constitutes a greatchallenge in organic synthesis. The use of one-pot multicom-ponent reactions (MCRs) is attractive in terms of atom- andstep-economy, operational simplicity, and environmentalfriendliness for generating highly functionalized moleculeswith complexity and diversity.1,2 Coumarins and iminocou-marins are privileged structural frameworks exhibiting wide-spread biological, medicinal, and material applicationsincluding anticancer,3a antitumor,3b antifungal,3c antimicrobialproperties,3d and anti-HIV activities.3e Whereas iminocoumar-ins have been shown to be inhibitors of protein tyrosine kinasep56lck,4a dynamins I and II GTPase,4b in cancer research.4c Manycoumarin triazoles (Fig. 1) have been widely used as drugs andin biochemistry due to their high emission yield, excellentphotostability.5 Furthermore, iminocoumarins are widely used
stituted triazoles (a–c).
, CSIR-Central Drug Research Institute,
Sitapur Road, Lucknow, 226 031, India.
(ESI) available: Copies of 1H and 13C39/c3ra46844e
hemistry 2014
as dyes6a and uorescent sensors for the estimation of metalions in micromolar concentrations.6b
During the regular practice of screening novel heterocyclesas drug candidates against various diseases, it was observedthat several active molecules become toxic or incapable ofdelivering the exact function due to lack of specicity or insol-ubility. In general, oligosaccharides and glycoconjugates exertimportant effects on many complex biological events7 includingthe cellular recognition, inammation, immune response,tumor metastasis, and bacterial and viral infections, etc.8
There is a number of naturally occurring coumarins glyco-sides9 [e.g. dauroside A, diosfeboside A, gumoside A, eleu-theroside B etc.10 Fig. 2], the only coumarin C-glycoside that hasbeen found in nature is dauroside D,11 also known as
Fig. 2 Example of some biologically active natural products con-taining “coumarin glycoside” scaffolds.
a The reaction was carried out with propargyl glucoside (1a, 1.0 msalicylaldehyde (2, 1.0 mmol) in the presence of CuI (0.1 mmol) andyields refer to propargyl glucoside (1a).
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mulberroside B,11c which exhibits spasmolytic and hypotensiveactivities.12 In accord with the intriguing biological prole ofcoumarins, coumarin glycoside class of scaffold compoundsexhibit a broad spectrum of biological activities13 such as anti-coagulant, anticancer, antibacterial, antifungal activity and theyare also useful as uorescent probes for studies on ultrafastDNA dynamics14a as well as inhibitors of the Hsp90.14b
In view of the biological and other applications of coumarinand iminocoumarin derivatives, a number reaction conditionshave been developed for the synthesis15,16 of coumarin glyco-sides. However, most of these methods have several shortcom-ings, such as a lack of generality or a lack of tolerance tosensitive functional groups. As a consequence, the developmentof simple methods for the synthesis of iminocoumarin deriva-tives is thus attractive and challenging. Therefore it was envis-aged that linking of an iminocoumarin scaffold to acarbohydrate unit might lead to a new class of glycoconjugatesthat might have interesting biological proles. Hence, a facile,one-pot synthesis of iminocoumarin glycosides and 3-triazolyl-2-iminocoumarin – glycosides using sugar alkynes, salicylalde-hyde – and sulfonyl azides or 2-azidoacetonitrile is reportedherein.
The copper-catalyzed Huisgen17 cycloaddition reaction or socalled “click chemistry” has already earned a great deal ofmedicinal interest18 for the preparation of functionalizedmolecules. Exploiting this phenomenon, several methods havebeen developed to create functionally diverse classes ofcompounds using the MCR approach.19 Similarly, reaction ofpropargyl glycoside with salicylaldehyde and sulfonyl azide inthe presence of CuI and triethylamine, resulted in the formationof the glycosyl iminocoumarin via ketenimine intermediate
(Scheme 1, SET-A). Moreover, one-pot synthesis of glycosyl 3-triazolyl-2-iminocoumarin has also been achieved directly fromthe condensation of 2-azidoacetonitrile, propargyl glycoside,and salicylaldehyde in a tandem “CuAAC-aldol-cyclization-dehydration” sequence (Scheme 1, SET-B).
Results and discussion
To test this hypothesis, several sugar-derived alkynes (1a–k)(Fig. 3) was prepared by the literature procedures.20 Having
Table 2 Copper-catalyzed synthesis of glycosylated iminocoumarin
prepared these glycosyl alkynes, initially the copper-catalyzedmulticomponent reaction has been examined using propargylglucoside (1a, 1.0 mmol) with tosyl azide (3, 1.0 mmol) andsalicylaldehyde (2, 1.0 mmol) in the presence of copper(I) iodide(0.1 mmol) and triethylamine (2.0 mmol) in dichloromethane atroom temperature (Table 1, entry 1). The reaction was sluggishand was incomplete even aer 10 hours, giving the requiredproduct 5a in only 40% yield.
In order to optimize the reaction condition, several condi-tions have been screened with various solvent systems, bases
and copper salts (Table 1). When the reaction was performed intetrahydrofuran (entry 2) for 3 hours, it went nearly to comple-tion, giving the desired glycosyl iminocoumarin 5a in 88% yield.As shown in Table 1, the desired product could be obtained in42–44% yield using CH3CN or EtOH as a solvent (Table 1, entry3 and 8). Whereas 1,4-dioxane (entry 10) or toluene (entry 11)gave the desired product 5a in 33% and 31% yield respectively.Aer the reaction solvent was changed from EtOH to MeOH asignicant reduction in isolated product yield 42% and 25%respectively were observed (Table 1, entries 8 and 9).
Although the reason for getting better yields using THF assolvent is not clear, one possibility could be the solvation ofcopper salts by the THF through the ring oxygen atoms of THF,which improved the accessibility of the copper salts in thereactions. When triethylamine was replaced with pyridine(entry 5) in tetrahydrofuran, the yield of compound 5a was poor(20%). Furthermore, no reaction was observed in the presenceof potassium carbonate (entry 4) or 4-(N,N-dimethylamino)pyridine (entry 12). However, the required glycosyl iminocou-marin (5a) was obtained in a moderate yield (33%) when thereaction was performed in the presence of N,N-diisopropyle-thylamine (entry 7). Extensive screening of reaction parameterssuch as varying base, and solvent led to an optimal reactioncondition triethylamine as the base and tetrahydrofuran as thesolvent to produce 88% yield of compound 5a. Next, differentcopper salts were tested using THF as solvent. When CuCl wasused as the catalyst, the yield of the desired product wasmoderate (40%). However, CuBr failed to catalyze the reaction.Application of CuI as the catalyst resulted in the formation ofthe desired product in satisfactory yield. Considering theeconomic aspect and availability, CuI was the best choice for thereactions using other substrates. The reaction optimizationexperiments are illustrated in Table 1. The reaction conditionhas been generalized by using a variety of propargyl glycosides,azide and salicylaldehydes to generate a diverse range of prod-ucts. Once the reaction condition was optimized for thesynthesis of 5a, it was decided to prove the generality of thereaction condition to construct glucosyl iminocoumarin deriv-atives with different sugar alkynes, salicylaldehyde, and sulfonylazides. Further 4-methylbenzenesulfonyl azide, naphthalenesulfonyl azide and 4-methoxybenzenesulfonyl azide were alsoused in the reactions with different sugar alkynes. A series offour different substituted 2-hydroxy benzaldehyde were alsoinvestigated. In all the cases, the multicomponent reactionoccurred smoothly to give the corresponding glucosyl imino-coumarin derivatives in 64–88% yields. Reactions with prop-argyl glycosides of deoxy sugars afforded the target compoundin 2 h, whereas normal pyranosides are converted completelywithin 3 h. For S-propynyl, and sulfonyl glycosides derivatives,the reactions were completed in approximately 4 h. The timedifference for complete reaction can be attributed to therespective reactivity difference among various sugars. Results ofthese reactions are summarized in Table 2.
Next, it was decided to study the one-pot synthesis of glu-cosyl 3-triazolyl-2-iminocoumarin (6a) directly from thecondensation of 2-azidoacetonitrile 4, propargyl glucoside 1a,and salicylaldehyde 2 under the optimized conditions (Table 1,
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entry 2) via a tandem “CuAAC–aldol–cyclization–dehydration”sequence (Scheme 2) as “click-and activate nucleophiles”approach toward MCRs. The reaction was complete aer 6hours, giving the required product 6a in 76% yield (Table 1,entry 2). A number of reaction conditions have been tested forthe optimisation of this reaction as shown in Table 1. Thedesired product could be obtained in 20–55% yield usingCH3CN, CH2Cl2, CH3OH, 1,4-dioxane or EtOH as a solvent(Table 1, entry 1, 3, and 8–10). Furthermore, no reaction wasobserved in the presence of other bases such as pyridine,K2CO3, DMAP and DIPEA.
Interestingly, the inuence of the third component, salicy-laldehyde in the formation of triazole on the CuAAC step hasalso been observed here (Table 3). The rate of triazole formationwas very slow when 1.0 equiv. of propargyl glucoside (1a) wasadded to 2-azidoacetonitrile (4) in the presence of CuI (0.1 mol)and (2 equiv.) of triethylamine (7% and 8% isolated yield at 4 h,entries 1 and 4, respectively) and the reaction rate was greatlyaccelerated by the addition of salicylaldehyde 2 in the presenceof triethylamine (entry 2).
A possible explanation for the improved yield of the reactionmay be due to the property of salicylaldehyde to act as bidentateligand in forming a wide variety of Cu complexes with differentcoordination numbers and geometries.21 In earlier studies, it wasshown that some ligands such as tris-(benzyltriazolylmethyl)amine, tris-(benzimidazole) and tris-(benzothiazole) ligandssignicantly accelerate the CuAAC reaction via activation orstabilization of the catalytic Cu(I) species.22 So it could be assumedthat the deprotonated salicylaldehyde 2 can play a similar
Scheme 3 Control experiments on 2-iminocoumarin formation.
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chelating role to promote the reaction, though to a lesser extent.The “click-and-activate” concept was demonstrated in thefollowing control experiments (Scheme 3). Treatment of glucosyltriazole (7) with 1.0 equiv. of 2 and 2.0 equiv. of triethylamine inTHF led to the formation of 3-triazolyl-2-iminocoumarin (6a) in
Table 4 Copper-catalyzed one-pot synthesis of glycosylated 3-triazoly
76% yield in 4 h, whereas 2-azidoacetonitrile (4) failed to affordany amount of 3-azido-2-iminocoumarin (8) under the sameconditions.
Since the reaction condition requires same base and solventin both steps, it was decided to run the entire three-componentcondensation in one pot synthesis as follows Table 4.
It is worth noting that two rings and four bonds of threedifferent types (e.g. one C–C, one C–O, and two C–N bonds) wereformed in one pot three component condensation and all fournew bonds are formed with 2-azidoacetonitrile (4). This three-component reaction provides rapid access to a diverse range ofglycosylated 3-triazolyl-2-iminocoumarins by condensing avariety of salicylaldehydes (2) and sugar derived alkynes (1a–k)with 4 as shown in Table 4. Both electron-donating and elec-tron-withdrawing groups are tolerated at various positions onthe salicylaldehyde component.
In summary, synthesis of a variety of glycosyl iminocoumarinsand glycosyl 3-triazolyl-2-iminocoumarin derivatives in whichthe carbohydrate unit is attached to the C-3 carbon of the imi-nocoumarin skeletons as well as triazole linked iminocoumar-ins have been achieved in good yield through copper catalysedmulticomponent reaction and “click-and-activate nucleophiles”protocol. The resulting glycosyl iminocoumarins can serve asintermediates for the synthesis of the corresponding coumaringlycosides. The present strategy therefore provides a path to thesynthesis of a series triazole linked glycosyl iminocoumarinsand simple glycosyl iminocoumarins that might have inter-esting biological proles.
ExperimentalGeneral methods
All reactions were monitored by thin layer chromatographyover silica gel-coated TLC plates. The spots on TLC werevisualized by warming ceric sulfate [2% Ce(SO4)2 in 5% H2SO4
in EtOH]-sprayed plates on a hot plate. Silica gel 230–400mesh was used for column chromatography. 1H and 13C NMRspectra were recorded on Bruker DPX-400 MHz spectrometer.Chemical shis d are given in ppm relative to the residualsignals of tetramethylsilane in CDCl3 for 1H and 13C NMR.Coupling constants are given in Hertz. ESI-MS were recordedon a JEOL spectrometer. Elementary analysis was carriedout on Carlo ERBA analyzer. IR spectra were recorded onShimadzu Spectrophotometers. Optical rotations were deter-mined on Autopol III polarimeter. Commercially availablegrades of organic solvents of adequate purity are used in allreactions.
Typical experimental protocol for the synthesis of 2-propynyl2,3,4,6-tetra-O-acetyl-b-D-glucopyranoside (1a)
To a solution of penta-O-acetyl-b-D-glucopyranose (10 g, 25.6mmol) in anhydrous CH2Cl2 (200 mL) was added freshlydistilled propargyl alcohol (1.8 mL, 30.7 mmol) and BF3$OEt2(4.8 mL, 38.4 mmol) at 0 �C and the reaction mixture was stirredat room temperature for 6 h. Aer completion of the reaction,the reaction mixture was diluted with CH2Cl2 (100 mL) andwashed with saturated aqueous NaHCO3, and water, dried(Na2SO4) and concentrated which was crystallised (CH2Cl2–hexane) to obtain the compound 1a (9.10 g, 92%) as a whitesolid. mp 112–113 �C; [a]25D �40 (c 1.0, CHCl3); IR (KBr): 3060,2128, 1744, 1633, 1566, 1081, 758, cm�1; 1H NMR (400 MHz,CDCl3): d 5.26 (t, J ¼ 9.4 Hz, 1H), 5.12 (t, J ¼ 9.5 Hz, 1H), 5.04 (t,J¼ 9.1 Hz, 1H), 4.80 (d, J¼ 8.0 Hz, 1H), 4.39 (br s, 2H), 4.31–4.27(m, 1H), 4.18–4.15 (m, 1H), 3.77–3.73 (m, 1H), 4.29 (t, J¼ 2.8 Hz,1H), 2.10 (s, 3H), 2.08 (s, 3H), 2.04 (s, 3H), 2.02 (s, 3H); 13C NMR(100 MHz, CDCl3): d 170.6, 170.2, 169.4 (2C), 98.1, 78.1, 75.5,72.8, 71.9, 70.9, 68.3, 61.8, 55.9, 20.7, 20.6, 20.5 (2C); ESI-MS:m/z 409.1 [M + Na]+. Anal. calcd for C17H22O10 (386.12): C, 52.85;H, 5.74. Found: C, 52.74; H, 5.83%.
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General procedure for the preparation of compound (5a–x)
To a solution of carbohydrate-derived alkyne (1.0 mmol), TsN3
(1.0 mmol), CuI (0.1 mmol), and salicylaldehyde (1.0 mmol) inTHF (5 mL) was dropwise added Et3N (2.0 mmol) at roomtemperature and the mixture was stirred at room temperaturefor 2 h. The reaction mixture was concentrated and the residuewas diluted with CH2Cl2 (20 mL) and washed successively withH2O (10 mL) and brine (10 mL). The organic layer was dried(Na2SO4) and concentrated under reduced pressure. The crudeproduct was puried by column chromatography (silica gel,hexane–EtOAc; 1 : 1) to give the corresponding glycosyl imino-coumarin derivative.
General procedure for the preparation of compound (6a–o)
To a solution of 2-azidoacetonitrile (1.0 mmol), appropriatecarbohydrate-derived alkyne (1.0 mmol), CuI (0.1 mmol), andsalicylaldehyde (1.0 mmol) in THF (5 mL) was dropwise addedEt3N (2.0 mmol) at room temperature and the mixture wasstirred at room temperature for 6 h. The reaction mixture wasconcentrated and the residue was diluted with CH2Cl2 (20 mL)and washed successively with H2O (10 mL) and brine (10 mL).The organic layer was dried (Na2SO4) and concentrated. Theresulting crude product was puried by column chromatog-raphy (basic alumina, hexane–EtOAc; 1 : 1) to give the corre-sponding glycosylated 3-triazolyl-2-iminocoumarin derivatives.
Author gratefully acknowledges the Director of CSIR-CDRI fornancial support and SAIF Division of CSIR-CDRI for providingthe spectroscopic and analytical data. CDRI communication no.8587.
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