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Efficient One-Pot Synthesis of Precursorsof Some Novel AminochromeneAnnulated Heterocycles via DominoKnoevenagel–hetero-Diels–Alder ReactionNarsidas J. Parmar a , Shashikant B. Teraiya a , Hitesh A. Barad a ,Deepak Sharma b & Vivek K. Gupta ba Department of Chemistry, Sardar Patel University, VallabhVidyanagar, Gujarat, Indiab Postgraduate Department of Physics, University of Jammu, JammuTawi, IndiaAccepted author version posted online: 17 May 2012.Version ofrecord first published: 06 Mar 2013.

To cite this article: Narsidas J. Parmar , Shashikant B. Teraiya , Hitesh A. Barad , Deepak Sharma& Vivek K. Gupta (2013): Efficient One-Pot Synthesis of Precursors of Some Novel AminochromeneAnnulated Heterocycles via Domino Knoevenagel–hetero-Diels–Alder Reaction, SyntheticCommunications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,43:11, 1577-1586

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EFFICIENT ONE-POT SYNTHESIS OF PRECURSORSOF SOME NOVEL AMINOCHROMENEANNULATED HETEROCYCLES VIA DOMINOKNOEVENAGEL–HETERO-DIELS–ALDER REACTION

Narsidas J. Parmar,1 Shashikant B. Teraiya,1 HiteshA. Barad,1 Deepak Sharma,2 and Vivek K. Gupta21Department of Chemistry, Sardar Patel University, Vallabh Vidyanagar,Gujarat, India2Postgraduate Department of Physics, University of Jammu, Jammu Tawi,India

GRAPHICAL ABSTRACT

Abstract An efficient, one-pot synthetic approach to precursors of some new amino-

chromene/xanthene annulated heterocycles via a tetrabutylammonium hydrogen sulfate–

mediated intramolecular domino Knoevenagel–hetero-Diels–Alder reaction is described.

The method is general and efficient. The stereochemistry of the product was confirmed

by various NMR experiments and single-crystal x-ray diffraction data.

Supplemental materials are available for this article. Go to the publisher’s online edition

of Synthetic Communications1 to view the free supplemental file.

Keywords Aminochromene; 1,3-diketone; polyheterocycles; TBA-HS; xanthene

INTRODUCTION

Domino Knoevenagel–hetero-Diels–Alder (DKHDA) approaches continue tohave a vital significance in synthetic organic chemistry.[1,2] Aldehyde substrateshaving a suitably tethered dienophile in a side chain afforded a variety of chromeno

Received October 2, 2011.

Address correspondence to Narsidas J. Parmar, Department of Chemistry, Sardar Patel University,

Vallabh Vidyanagar 388120, Dist. Anand, Gujarat, India. E-mail: njpchemdeptspu@yahoo.co.in

Synthetic Communications1, 43: 1577–1586, 2013

Copyright # Taylor & Francis Group, LLC

ISSN: 0039-7911 print=1532-2432 online

DOI: 10.1080/00397911.2011.652755

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annulated heterocycles with 1,3-dicarbonyls and their analog systems like pyrazo-lones and iso-oxazolones.[3] Use of photochromic chromenes[4] in synthetic resinmaterials attracts the attention of many researchers engaged in building photo-chromic articles.[5] Moreover, benzopyran derivatives possess potential medicinalproperties. 6-Substituted benzopyran, for instance, has remarkable biologicalproperties and can be used as potassium channel activator,[6] anti-picornaviruscapsid binders,[7] selective estrogen receptor-b agonist,[8] and potential antagonistof mycobacterium bovis BCG.[9] They also help optimize aromatic charge-transferinteractions either by direct interaction with the receptor site or indirectly by with-drawing electrons from the phenyl moiety of the benzopyran nucleus. On the otherhand, xanthene, an intermediate in organic synthesis, has applications in lasertechnology.[10] Dibenzoxanthenes, in particular, act as sensitizers in photodynamictherapy (PDT).[11] They have been well recognized as having antibacterial,[12] anti-viral,[13] and anti-inflammatory activities.[14] In view of this, a synthetic approachaminochromeno annulated heterocycles is desirable. In continuation of our work,[15]

we report here some novel aryldiazenylchromeno=pyrano=pyranochromeno=dioxinopyrano annulated pyrano fused chromenones=pyrazoles=pyrimidinediones,all precursors to analogous amino frameworks.

RESULTS AND DISCUSSION

All new 5-aryldiazenylsalicylaldehyde substrates 1a–c were obtained by amethod reported elsewhere, except for 1c.[15] A similar but NaI-catalyzed procedurewas used for substrate 1c. DKHDA approach of eight different active methylenecompounds 2a–g toward substrates 1a and b was studied in the presence of 25mol%tetrabutylammonium hydrogen sulfate (TBA-HS) in refluxing acetonitrile. Substrate1a gave an orange-yellow Knoevenagel heterodiene with cyclohexane-1,3-dione 2a

almost within 15min, which on subsequent reflux stirring for 8 h effected the desiredcyclo product 3a in 83% yields with 99% distereoselectivity. Coupling constantJ (4.8Hz) of ring junction protons sufficed to propose a cis-fused geometry of 3a.A molecular ion peak in the mass spectrum of 3a appeared at 388.8 (Mþ). Similarobservations were found for other products 3b and 4a and b derived from diketone2a and b (Table 1, entries 2–4). The stereochemistry of representative product 4a wasalso confirmed by double quantum filtered (DQF)–correlation spectroscopy (COSY)and nuclear Overhouser effect spectroscopy (NOESY) (Fig. 1, Scheme 1).

A plausible mechanism is outlined in Fig. 2. The reaction proceeds viageneration of a Knoevenagel alkene intermediate (v) from aldehyde (iii) and corres-ponding active methylene compound (i). A quaternary ammonium salt (ii), obtainedby a proton abstraction from (i), undergoes Michael addition (iv), followed byKnoevenagel adduct formation (v). Finally, a TBA-HS-induced complex (vi), readilyafforded from (v), might help reduce electron density on oxygen atoms, providinga favorable condition for formation of cis-product (vii) exclusively.

In the case of other diketones such as Meldrum’s acid 2c, 4-hydroxy coumarin2d, thiobarbituric acid 2e, and barbituric acid 2f, the reaction proceeds via the samepathway, except the ones involving Meldrum’s acid 2c and 2d. Meldrum’s acid gavea mixture of two cycloadducts, 5 and 6, obtained in a ratio of 20:80. Spectroscopic

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examination showed that 5a is converted 80% into 6a via a retro-Diels–Alder path-way (Scheme 2). It can be explained by formation of ketene 13 from 5a, which trapswater molecules and gives b-ketoacid 14. Finally, it is decarboxylated into 6a. It isimportant to note that �20% of 5a could not be converted into 6a (Table 1, entries5–8) (Scheme 1), making this catalytic method complementary to the DKHDAapproach.[3,16]

4-Hydroxy coumarin[17] 2d also gave two cyclo products pyrano [2,3-b]chromones 7 and pyrano [3,4-c] coumarin 8, in a ratio of �30 : 70 with 78–82%yields. Both the keto and lactone carbonyl groups take part in the DKHDA reaction.Chromone and coumarin derivatives were easily distinguished by the 13C NMRpeak that appeared in d 176–177 in chromone 7 and in d 163–164 in coumarin 8.

Table 1. TBA-HS-catalyzed DKHDA reaction of 1a and b with 2a–ga

Entry Product Time Yieldb MP (�C)c

1 3a 8 83 177–179

2 3b 8 86 168–171

3 4a 9 85 122–124

4 4b 8 88 136–138

5 5a 9 18 132–134

6 5b 8 15 148–150

7 6a 9 68 226–229

8 6b 8 72 202–205

9 7a 9 28 188–190

10 7b 7 25 170–173

11 8a 9 65 196–198

12 8b 7 70 230–232

13 9a 11 87 266–268

14 9b 10 85 245–248

15 10a 9 90 295–298d

16 10b 10 92 278–280d

17 11a 8 74 187–189

18 11b 8 80 197–200

aAll reactions were carried out at reflux in CH3CN with 25mol% TBA-HS.bIsolated yield.cUncorrected.dProduct decomposed.

Figure 1. Characteristic NOEs of 4a and 10b.

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Barbituric acid[18] 2f afforded exclusively a cis-cycloadduct 10a with great yield(Scheme 1). Similarly other products 9a, 9b, and 10b were synthesized and character-ized (Table 1, entries 13–16) (Scheme 1). Though it required a little longer, the yieldof the products remained greater than that obtained from other active methylene

Scheme 1. Synthesis of precursors to aminochromeno annulated heterocycles.

Figure 2. Plausible mechanism of TBA-HS-catalyzed DKHDA reaction.

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compounds. The compound 10b showed a broad singlet at d 10.94 and 11.35 for NHprotons. DQF-COSY and NOESY supported the proposed structure of 10b (Fig. 1).Pyrazolones 2g afforded products 11a and 11b, with 1a and b in 8 h in 74% and 80%yields respectively (Table 1, entries 17 and 18) (Scheme 1). Polycyclic pyrano[2, 3-c]pyrazole structure of 11a was also corroborated by single-crystal x-ray diffractionanalysis. An ORTEP view of the title compound 11a with atomic labelling is shownin Fig. 3.

In another identical experimental setup in refluxing xylene, we developeda DKHDA reaction of 2a, 2b, and 2h each with 1c (Scheme 3). In each case, ifafforded an isomeric mixture of two domino products (Table 2). We could isolatechromatographically only products 19 and 20 from a mixture that resulted from1c with pyrazolone 2h (Table 2, entries 5 and 6). The components of a mixture inother cases were identified based on 1H NMR data. A mixture of 17 and 18, from1c with 2b, showed two separate signals, one 13b proton in 17 at d 3.69 with

Figure 3. ORTEP view of compound 11a. (Figure is provided in color online.)

Scheme 2. Retro-Diels–Alder product 6 from 5.

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J8b–13b¼ 12.0Hz and the second one at d 4.41 in 18. Similarly 15 and 16 from 1c and2a were identified and confirmed present (Table 2, entries 1 and 2).

As part of developing methods to assess novel amino chromeno annulatedheterocycles, we reduced 3b and 4b in the presence of SnCl2=HCl to new aminobenzopyranes 3c and 4c (Scheme 4) in 20–30% yields. The spectroscopic data arein good agreement with the proposed structures for 3c and 4c. Two sharp bands,one at �3300 cm�1 and a second one at �3340 cm�1 in Fourier transform–infrared (FT-IR), as well as a broad signal at d 4.34 in 1H NMR, may be assignedto NH2 group in 4c. A doublet appeared at d 4.16 with J, 4.0Hz and retainedcis-configuration in the molecule.

Scheme 3. TBA-HS-catalyzed DKHDA reaction of substrate O-cyclohexenyl salicylaldehyde.

Table 2. TBA-HS-catalyzed DKHDA reaction of 1c with 2a and b and 2ha

Entry Product Time Ratio of the products cis=trans Overall yield (%) MP �(C)b

1 15 12 40=60 60 202–204

2 16

3 17 14 55=45 65 138–140

4 18

5 19 9 60=40 75 180–182

6 20 246–248

aAll reactions were carried out at reflux in xylene with 25mol% TBA-HS.bUncorrected.

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CONCLUSION

In conclusion, we described a new synthetic approach to a variety of pyranofused polycyclic heterocycles via a new TBA-HS-mediated DKHDA reaction. Anefficient reduction of the diazo group in all domino products afforded a novel classof amino chromenes with anticipated biological activity. Advantages of this methodinclude an easy workup procedure, high stereoselectivity, and isolation of productsin good yield. Furthermore, TBA-HS is a nontoxic, noncorrosive, commerciallyavailable, and inexpensive catalyst.

EXPERIMENTAL

Intramolecular Domino Knoevenagel–Hetero-Diels–Alder Reactionof 1a–c with 2a–h

Amixture of aldehydes 1a–c (1mmol), corresponding active ethylene compoundsincluding pyrazolone 2a–h (1mmol), and TBA-HS (25mol%), was stirred in an appro-priate refluxing solvent (acetonitrile for 1a and b, xylene for 1c), for a specified time asshown in Tables 1 and 2. After the completion of reaction as confirmed by (TLC), it wascooled and the solvent was evaporated in vacuo. The mixture was washed with acetoni-trile to remove any residual starting material and dried. The products were obtained ingood yields with high purity. While preparative TLC, using eluent ethyl acetate=hexane(3:7), was applied for products 3–11, column chromatography was used for purificationof products 15–19 using eluent ethyl acetate=hexane (5:95).

Compound 3a. Yellow solid, mp 177–179 �C [found: C, 74.33; H, 6.30; N,7.13. C24H24N2O3 requires C, 74.21; H, 6.23; N, 7.21%]; IR (KBr) nmax 3030,2930, 1685, 1620, 1365, 1255, 980 cm�1; 1H NMR (400MHz, CDCl3) dH 1.17 (s,3H, 6-CH3), 1.55 (s, 3H, 6-CH3), 2.05 (m, 2H, 3-CH2), 2.11 (m, 1H, 6a-H),2.42–2.70 (m, 4H, 2 & 4-CH2), 4.30 (d, 1H, J 4.8Hz, 12b-H), 4.45 (dd, J 11.4,3.6Hz, 1H, 7-H), 4.53 (dd, J 12.0, 3.4Hz, 1H, 7-H), 6.86 (d, J 8.0Hz, 1H, Ar-H),7.31–7.93 (m, 7H, Ar-H); 13C NMR (100MHz, CDCl3) dC 20.43, 23.80, 28.10,29.84, 36.69, 38.12, 64.98, 79.84, 112.43, 116.88, 121.12, 123.19, 123.44, 127.59,129.13, 135.43, 147.68, 152.66, 156.66, 171.80, 198.47; m=z (ESI) 388.8 (Mþ).

Compound 19. Yellow solid, mp 180–182 �C [found: C, 73.17; H, 5.70; N,11.15. C29H26N4O2 requires C, 75.30; H, 5.67; N, 12.11%]; IR (KBr) nmax 3050,2900, 1650, 1600, 1460, 1200, 1080, 750 cm�1; 1H NMR (400MHz, CDCl3) dH

Scheme 4. Formation of aminochromene annulated heterocycles.

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1.59–1.99 (m, 4H, CH2), 2.03 (s, 3H, CH3), 2.10 (m, 1H, 7b-H), 2.34–2.72 (m, 2H,CH2), 4.05 (m, 1H, 4a-H), 4.42 (d, 1H, J 9.6Hz, 12b-H), 4.52 (m, 1H, 7a-H), 7.01(d, 1H, J 8.8Hz, Ar-H), 7.18–8.00 (m, 12H, Ar-H); 13C NMR (100MHz, CDCl3)dC 14.10, 15.35, 27.93, 28.29, 32.18, 39.09, 77.52, 78.35, 99.19, 118.38, 120.13,122.65, 122.76, 123.75, 1285.21, 128.82, 129.06, 130.53, 130.76, 138.67, 146.48,147.63, 150.86, 152.78, 160.96; m=z (ESI) 462.0 (Mþ).

Reduction of Aryldiazenyl Compound to Amino BenzopyraneDerivatives

Dissolve 0.5 g of diazo compound 3b or 4b in a minimum volume of concen-trated hydrochloric, and to the hot solution add a solution of 2 g of tin(II) chloridein 5ml of concentrated hydrochloric acid until decolourization takes place; gentleboiling may be necessary. Cool the resulting solution in ice. To separate the freebase, add 10% sodium hydroxide solution until the precipitate of tin hydroxide redis-solves. Extract the cold solution with three or four 20-ml portions of ether, dry theextract with anhydrous potassium carbonate, and remove the ether by distillation.The crude product thus obtained is purified by preparative TLC using ethyl acetate=hexane (5:5) as an eluant. The pure products 3c and 4c was obtained in 25% and 20%yields respectively.

Compound 4c. Off-white solid: mp 182–186 �C; [found: C, 73.45; H, 7.63; N,4.35. C20H25NO3 requires C, 73.37; H, 7.70; N, 4.28%]; IR (KBr) nmax 3340, 3300,2950, 2810, 1740, 1670, 1500, 1310, 1240, 830, 750 cm�1; 1H NMR (400MHzDMSO-d6) dH 1.07 (s, 3H, 6-CH3), 1.11 (s, 3H, 3-CH3), 1.14 (s, 3H, 3-CH3), 1.49(s, 3H, 6-CH3), 2.07 (m, 1H, 6a-H), 2.39 (m, 4H, 2 & 4-CH2), 3.47 (t, 1H, J10.8Hz, 7-H), 3.99 (d, J 11.2Hz, 1H, 7-H), 4.16 (d, J 4.0Hz, 1H, 12b-H), 4.34 (brs, 2H, NH2), 6.59–7.05 (m, 3H, Ar-H); 13C NMR (100MHz, DMSO-d6) dC 23.88,27.16, 27.62, 28.03, 28.13, 28.54, 32.36, 37.86, 42.77, 51.12, 65.22, 80.28, 110.87,116.78, 120.68, 122.41, 125.10, 151.79, 169.13, 197.67; m=z (ESI) 327.6 (Mþ).

Complete experimental details are available online in the SupplementaryMaterial.

ACKNOWLEDGMENTS

We sincerely express our thanks to the head, Department of Chemistry,S. P. University, for providing necessary research facilities. Two of us (S. B. T.and H. A. B.) are grateful to the University Grants Commission (UGC), New Delhi,for research fellowships under the UGC scheme of RFSMS.

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