Tetrahedron Letters 53 (2012) 4974–4978

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Tetrahedron Letters

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One pot synthesis of new benzopyranopyridines via Friedlander condensation

Zeba N. Siddiqui ⇑Department of Chemistry, Aligarh Muslim University, Aligarh 202 002, India

a r t i c l e i n f o a b s t r a c t

Article history:Received 18 May 2012Revised 2 July 2012Accepted 4 July 2012Available online 11 July 2012

Keywords:Friedlander condensation2-Amino-3-formylchromoneBenzopyrano [2,3-b] pyridinesZn(L-proline)2

0040-4039/$ - see front matter � 2012 Elsevier Ltd. Ahttp://dx.doi.org/10.1016/j.tetlet.2012.07.013

⇑ Tel.: +91 9412653054.E-mail address: siddiqui_zeba@yahoo.co.in

A facile, green synthetic route to new benzopyrano [2,3-b] pyridines in excellent yield via Friedlandercondensation has been developed by the reaction of 2-amino-3-formylchromone 1a–b and cyclic activemethylene compounds 2a–e in the presence of Zn(L-proline)2 as an efficient, stable, and inexpensiveLewis acid catalyst in water. The present methodology offers several advantages such as shorter reactiontime, mild reaction conditions, simple operational procedure, recyclable catalyst, and safe to theenvironment.

� 2012 Elsevier Ltd. All rights reserved.

Friedlander condensation is an acid or base catalyzed condensa-tion–cyclodehydration reaction which takes place between an aro-matic 2-aminoaldehyde or ketone and reactive active methylenecompounds and affords heteroannulated pyridines.1 The synthesisof this condensed heterocyclic system is interesting because of po-tential biological activities associated with its structure such asantipsychotic dopamine D4 receptor antagonist,2 cancer-chemopre-ventive,3 antimicrobial,4 antirheumatic,5 antiplatelet,6 anti-inflam-matory,7 antiallergic8 and against Alzheimer, Parkinson diseases.9

Developing an easy and efficient method for the production of thisimportant class of compounds, therefore, is on priority list of chem-ists. In pursuit to achieve higher efficiency, several catalysts andreaction conditions were tried which included the use of micro-waves,10 NaOEt,11 ZnCl2,12 p-TsOH,13 I2,

14 silica sulfuric acid,15

DBU (1,8-diaza bicyclo [5.4.0] undec-7-ene),16 NaF,17 AlCl3,18 andalso multicomponent reactions.19 Unfortunately, some of thesemethods have drawbacks such as low yields, extended time, and te-dious procedures. Therefore, development of an alternative route isrequired to construct benzopyranopyridine system which is simple,easy with reduced time period, and gives products in high yield.

Zn(L-proline)2 is an efficient, stable, inexpensive, recyclable,water compatible, Lewis acid catalyst which is not dissociated un-der the reaction conditions.20 This complex is soluble in water butinsoluble in organic solvents, which allows simple and quantitativerecovery of the catalyst.21 Zn(L-proline)2 appears to be a particularlyefficient catalyst for both enamine and enolate type catalysis.22

Among the various zinc-amino acid complexes, the Zn(L-proline)2

catalyst shows higher activity.23 As part of our ongoing research

ll rights reserved.

program aimed at design and development of new catalysts, weand others have been exploring Zn(L-proline)2 as mild Lewis acidcatalyst in various organic transformations such as Aldol,24 directnitroaldol condensation,23 Hantzsch reaction,25 Knoevenagel con-densation,26 Mannich reaction27 etc. It has also been used for thesynthesis of 1,5-benzodiazepines,28 1,2-disubstituted benzimidaz-oles,20 quinoxalines,21 pyrano[2,3-d]pyrimidines,29 pyrazoles30 dic-oumarols,31 and chromonyl chalcones.32

These days water has emerged as an ecofriendly solvent for thereaction medium due to its easy availability, non-inflammablity,non-toxicity, and negligible cost.33,34 In this communication we re-port the synthesis of novel benzopyrano [2,3-b] pyridine deriva-tives 3a–j in aqueous media via Friedlander condensationemploying 2-amino-3-formyl chromone 1a–b and cyclic activemethylene compounds (2a-e).35 To the best of our knowledge,there are no earlier reports on the preparation of benzopyranopyri-dine derivatives using Zn(L-proline)2 as Lewis acid catalyst.

During the present study a series of benzopyranopyridine deriv-atives 3a–j were prepared by condensing 2-amino-3-formylchro-mone and substituted 2-amino-3-formylchromone 1a–b withdifferent cyclic active methylene compounds 2a–e under conven-tional heating method by using piperidine as a basic catalyst inmethanol (Scheme 1). The reaction took longer time (7–10 h) forcompletion of reaction with moderate yield (67–76 %) of products.Then, we studied the efficacy of Zn (L-proline)2 by carrying out thereaction of 2-amino-3-formyl chromone (1a–b) with a variety ofactive methylene compounds (2a–j) in molar ratios in water at re-flux temperature. The reaction proceeded smoothly and resulted inthe formation of corresponding products 3a–j in excellent yields(88–92 %) within few minutes (5–10 min) (Table 1).

In order to optimize the reaction conditions and show the supe-riority of Zn(L-proline)2-water catalytic system, a model reaction

O NH2

C H

OO

+ 2a-eZn(L-proline)2, 5mol%

Reflux,Water

NH

HN SO

O

NH

HN OO

O

R

1a-b

a; R = CH3b; R = H

3a-j

O

O

O

OCH3CH3

2e

2c

2d

2b

2a

3j

O N

OHa

R

o

X = C

S

HN NH

C

O

HN NH

X =3b

3f

3d X =

CO O

3h

X = R = H

R = H

R = H

R = H

R = H

X = C

S

HN NH

C

O

HN NH

X =

X =

CO O

X =R = CH3

R = CH3

R = CH3

R = CH3

R = CH3

3i

3a

3e

3c

3g

NH3C C

O

N CH3

NH3C C

O

N CH3

X

X =

X =

O

O

N

N OO

O

CH3

CH3

Scheme 1. Synthesis of benzopyrano [2,3-b] pyridine derivatives using the Zn(L-proline)2 catalyst in water.

Z. N. Siddiqui / Tetrahedron Letters 53 (2012) 4974–4978 4975

was conducted under various reaction conditions (including load-ing of catalyst, effect of solvent, and catalysts in terms of yieldsand time) using 6-methyl-2-amino-3-formyl chromone (1a) and2,2-dimethyl-1,3-dioxane- 4,6-dione (2a).

In order to establish the best reaction conditions, we performedan optimization study using model substrate in the presence ofvarying amounts of catalyst Zn(L-proline)2. It is thus, clear from Ta-ble 2, that 5 mol % of the catalyst is sufficient to get optimum yieldin shorter reaction time. Using less than 5 mol % catalyst(2.5 mol %) lower yield of the product is obtained (76 %), whilewith excess in mol % of catalyst (10–15 mol%) there is no increasein the yield of the product.

To assess the capability and efficiency of the catalyst a compar-ative study of variety of catalysts was conducted (Table 3). Whenthe model reaction was examined with AlCl3, 6 M HCl, FeCl3 thereaction was not successful and the mixture of compounds was ob-tained in trace amount (entries 7–9), whereas using Zn(NO3)2 andZnCl2 the reaction again took longer time period for completionwith lower yield of products (entries 5 and 6). The use ofZn(CH3COO)2 and L-proline, accelerated the reaction, but gave dis-appointing results in terms of yields (entries 3 and 4), whereas noproduct formation was observed when the reaction was carried outin PTS (p-toluene sulfonic acid) and CuCl2 (entries 10 and 11). Themodel reaction was also performed in some Zn(L-amino acid) com-plex such as with Zn (L-histidine)2 and it was observed that thereaction completed relatively in shorter time but again a mixtureof products was obtained in poor yield (entry 2) . These observa-tions argue in favor of the conclusion that the present reaction isparticularly facilitated by acid catalyst as there was a low yield(25 %) of product formation in the absence of Zn(L-proline)2 com-

plex (entry 12). From Table 3 it is, thus, clear that Zn(L-proline)2

exhibits the highest catalytic activity as compared to other Lewisacid catalysts (entry 1).

In order to establish the superiority of water as reaction med-ium on Zn(L-proline)2 catalyzed reaction, the model reaction wascarried out in various polar and non polar solvents (Table 4). Whenthe reaction was carried out in solvents such as CH2Cl2, CH3CN,even after long reaction time none of the expected products weredetected (entries 5 and 6). Using MeOH, CH3COOH, and EtOH rela-tively high yields of the product were obtained but the reactioncompleted in longer time period (entries 2–4), whereas under sol-vent-free condition, lower yield of the product was obtained afterprolonged heating (entry 7). When the reaction was carried outusing water as a sole solvent the product was obtained in excellentyield within 5 min. Further in a comparative study using green sol-vent the model reaction was also performed using PEG-600 as areaction medium and it was observed that the reaction was notsuccessful (entry 8). Thus, our study reveals that water is the bestsolvent in terms of reduced reaction time and maximum yield ofthe products (entry 1).

After completion of reaction in specified time, the crude productobtained was extracted with dichloromethane, and the catalystwas recovered by separation of the aqueous and organic phases.The catalyst present in the aqueous medium was used for the sub-sequent cycle. The same procedure was applied to all recyclingstudies. The results (Table 5) show that the catalyst exhibits excel-lent catalytic activity up to three cycles. After fourth and fifth runthere is a slight decrease in the product yield and an increase in thereaction time period perhaps due to loss of catalytic activity as aresult of decomposition of catalyst.

Table 1Zn(L-proline)2 catalyzed synthesis of benzopyranopyridine compounds 3a–j

Entry Product Reflux in MeOH Reflux in Water Mp (�C)

Time (h) Yieldb (%) Time (min) Yield (%)

3aa

O N O

O

H3C

O

O

CH3CH3

1

37

910 11 12

Ha

8 70 5 91 265–268

3ba

O N O

O

H

O

O

CH3CH3

8 74 5 90 247–250

3ca

O N N

O

H3C

O

N

O

CH3

CH3

8 71 8 89 >300

3da

O N N

O

H

O

N

O

CH3

CH3

10 68 10 90 >300

3ea

O NHN

O

H3C

O

NH

S

7 69 8 92 >300

3f

O NHN

O

H

O

NH

S

7 76 8 90 >300

3ga

O NHN

O

H3C

O

NH

O

10 72 10 89 >300

3h

O NHN

O

H

O

NH

O

9 67 7 90 >300

3i

O N

O

H3C

O

8 68 7 88 256–258

3ja

O N

O

H

O

8 71 8 89 231–233

a New compounds.b All yields refer to isolated products.

4976 Z. N. Siddiqui / Tetrahedron Letters 53 (2012) 4974–4978

To further evaluate the scope of Zn(L-proline)2-water catalyticsystem we performed the reaction with a variety of cyclic activemethylene compounds and 2-amino-3-formylchromone at reflux

temperature in the presence of catalyst in water, and in all caseshigh yields of the products were obtained emphasizing the gener-ality of our methodology (Scheme 1).

Table 3Comparison of the efficiency of Zn(L-proline)2 for synthesis of 3a

Entrya Catalyst Timeb Yieldc (%)

1 Zn(L-proline)2 5 min 912 Zn(L-histidine)2 10 52 (Impure)3 Zn(CH3COO)2 15 484 L-Proline 15 44

5 Zn(NO3)2 8 h 396 ZnCl2 8 h 357 AlCl3 24 h Trace8 HCl 24 h Trace9 FeCl3 24 h Trace

10 PTS No reaction —11 CuCl2 No reaction —12 No catalyst 24 h 25

a Reaction of 6-methyl-2-amino-3-formylchromone (1 mmol) with 2,2-dime-thyl-1,3-dioxane-4,6-dione (1 mmol) in the presence of 5 mol % of catalyst.

b Reaction progress monitored by TLC.c Isolated yield.

Table 4Effect of various solvents on the model reaction

Entrya Solvent Timeb Yieldc (%)

1 Water 5 min 912 Methanol 8 h 703 Acetic acid 3.5 h 684 Ethanol 24 h 645 CH2Cl2 24 No reaction6 CH3CN 24 No reaction7 No solvent 5 h 328 PEG-600 — No reaction

a Reaction of 6-methyl-2-amino-3-formylchromone (1 mmol) with 2,2-dime-thyl-1,3-dioxane-4,6-dione (1 mmol) in the presence of 5 mol % of catalyst.

b Reaction progress monitored by TLC.c Isolated yield.

Table 5Reusability of the catalyst for the model reactiona

No. of cycles Timeb (min) Yieldc (%)

1 5 912 5 913 5 914 5 895 10 89

a Reaction of 6-methyl-2-amino-3-formylchromone (1 mmol) with 2,2-dime-thyl-1,3 dioxane-4,6-dione (1 mmol) in the presence of 5 mol % of catalyst.

b Reaction progress monitored by TLC.c Isolated yield.

Table 2Effect of catalyst loading on the synthesis of 3a

Entry Catalyst (mol %) Timea (min) Yieldb (%)

1 2.5 15 762 5 5 913 10 5 914 15 5 915 20 5 89

a Reaction progress monitored by TLC.b Isolated yield.

Z. N. Siddiqui / Tetrahedron Letters 53 (2012) 4974–4978 4977

All the newly synthesized compounds were recrystallized fromsuitable solvents and characterized by elemental analysis andspectroscopic data. Thus, the IR spectrum of compound 3a showeda strong absorption band for carbonyl groups of chromone and

dioxane moiety at 1668 cm�1. Another sharply absorbed band at1617 cm�1 was assigned to C@N group. The 1H NMR spectrumshowed sharp and downfield singlet at d 9.33 for Ha proton. Theappearance of Ha signal in the downfield region is due to aniso-tropic effect displayed by two carbonyl groups (C-4, C-6).Theremaining three protons of chromone nucleus were present inthe form of multiplets at d 7.26–8.09. The 13C NMR spectrumshowed signals at d 175.7 and 163.6 for carbonyl groups of chro-mone and dioxane moieties whereas signal for C-5 carbon ap-peared at d 141.6. Further confirmation for the structure wasprovided by mass spectrum, which showed M+ at m/z 311.

In conclusion we have developed a simple, efficient, mild, andenvironmentally benign methodology for the synthesis of newbenzopyranopyridine derivatives. The green protocol offers advan-tages such as excellent yields of products, shorter reaction timeperiod, simple operational procedure, and reusability of thecatalyst.

Acknowledgments

Financial assistance in the form of major research project [F.No.37-15/2009 (SR)] from the University Grants Commission, NewDelhi, is gratefully acknowledged. The author would also like tothank SAIF Punjab University Chandigarh and SAIF, CDRI, Lucknowfor spectral data.

Supplementary data

Supplementary data associated with this article can be found,in the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.07.013.

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35. General procedure for the synthesis of benzopyranopyridine [2,3-b]derivatives(3a–j): A mixture of 2-amino-3-formylchromone/6-methyl-2-amino-3-formylchromone (1a–b) (1.00 mmol), active methylene compounds (2a–e)(1.00 mmol) and Zn(L-proline)2 (5 mol %) was refluxed in water (10 ml) for thespecified time (Table 1). After the completion of the reaction monitored by TLC,the reaction mixture was allowed to cool to room temperature. The crudeproduct was extracted with dichloromethane, dried over anhydrous Na2SO4,and concentrated to furnish (3a–j). The recrystallization of crude products (3a–j) was done with chloroform-methanol mixture (1:4 v/v). The catalyst wasrecovered by simple separation of the aqueous and organic phases. The catalystpresent in the aqueous layer was used for the subsequent cycle.