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Novel Synthesis of 3,3-Bis-(4-chromone-3-ylmethyl)-chroman-4-onesKrishnan Devarajan a , Kalpattu K. Balasubramanian a & Shanmugasundaram Bhagavathy aa Department of Chemistry, B. S. Abdur Rahman University, Chennai, IndiaAccepted author version posted online: 26 Jan 2013.

To cite this article: Krishnan Devarajan , Kalpattu K. Balasubramanian & Shanmugasundaram Bhagavathy (2013): NovelSynthesis of 3,3-Bis-(4-chromone-3-ylmethyl)-chroman-4-ones, Synthetic Communications: An International Journal for RapidCommunication of Synthetic Organic Chemistry, DOI:10.1080/00397911.2012.691594

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Novel Synthesis of 3,3-Bis-(4-chromone-3-ylmethyl)-chroman-4-ones

Krishnan Devarajan1, Kalpattu K Balasubramanian1, Shanmugasundaram Bhagavathy1,

1Department of Chemistry, B. S. Abdur Rahman University, Chennai, India

Dr. S. Bhagavathy Associate Professor Department of Chemistry, B. S. Abdur Rahman University, Seethakathi Estate, GST Road, Vandalur, Chennai 600 048, Tamilnadu,

India. Ph: +91-9444936005, Fax: +91-44-22750520 Email: bhagavathy@bsauniv.ac.in

Abstract

3-Hydroxymethylchromones have been found to undergo a novel transformation in the

presence of Cs2CO3 in toluene or xylene as solvent to afford “trimeric” chromones, viz.,

3,3-bis-(4-chromone-3-ylmethyl)-chroman-4-ones. The structure of the trimer has also

been confirmed by single crystal X-ray diffraction study.

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

of Synthetic Communications® to view the free supplemental file.

KEYWORDS: Chromones, Benzochromones, 3-Hydroxymethylchromone,

Trimerisation, X-ray diffraction, Cs2CO3

INTRODUCTION

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Coumarins, Chromones and Flavones are pharmacologically important class of

compounds that has been shown to exhibit significant activity as inhibitors of tumor

induction by carcinogenic polycyclic aromatic hydrocarbons.[1] While there are a few

reports in literature on 3,3′-methylene bis chromones[2] and their dihydro derivatives 2,[3]

there is hardly any report on related trimeric chromone derivatives. Some of the

chromone dimers have been reported to possess a strong antiallergic activity.[4] In this

communication,[5] we describe a novel synthesis of 3,3-bis-(4-chromone-3-ylmethyl)-

chroman-4-ones 8-12, a class of chromone trimers hitherto unknown in literature. In

connection with one of our projects on the new routes to rotenoid and isorotenoid class of

compounds,[6] we were in need of 3-aryloxymethylchromones 1 (Figure 1), a class of

compounds so far not reported in literature. Palladium mediated Buchwald-Hartwig

coupling[7] via O-arylation of 3-(hydroxymethyl)-4-oxo-4H-1-benzopyrans (trivial name:

3-hydroxymethylchromones) 3-6 with bromobenzenes appeared to be a simple and

attractive route for the synthesis of these aryl ethers.[8] Allyl alcohols have been converted

to allyl aryl[9] and allyl vinyl[10] ethers by Pd mediated coupling with aryl halides and

vinyl halides, respectively. When we attempted the Pd mediated coupling of 3-

hydroxymethylchromone 3 with bromobenzene, it did not furnish the expected phenyl

ether 1, but yielded the trimeric chromone 8 in good yield, thereby providing a novel and

easy route to access such trimeric chromones.

RESULTS AND DISCUSSION

3-Hydroxymethylchromones 3-7 were prepared according to the published procedure.[11]

When the carbinol 3 was subjected to typical Buchwald conditions i.e. heating in toluene

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in the presence of Pd(OAc)2, Ph3P, Cs2CO3 and bromobenzene for 16-24 h, a solid

product 8 was obtained, instead of the expected aryl ether 1, in 46% yield. NMR and

mass spectral data of this solid established that the benzene ring of bromobenzene was

not incorporated in the product and suggested it to be a ‘trimer’ of the carbinol 3 (Scheme

1). Control experiments carried out without Pd catalyst firmly ruled out any role of

palladium in this ‘trimer’ formation, but revealed the requirement of a base for this self

condensation. From its [1]H, [13]C, Dept, Homocosy and Heterocosy NMR spectral data,

the product has been identified as the hitherto unknown unique trimer 8. Thus, refluxing a

mixture of the alcohol 3 with Cs2CO3 in toluene afforded the trimer 8. The yield

considerably improved by refluxing the carbinol 3 in xylene for 15-20 h in the presence

of Cs2CO3 (Table 1).

This trimerisation reaction was found to be a general one with a few other hydroxymethyl

chromones 4-7 (Scheme 1). The yields and reaction times are summarized in Table 1.

The structure of the trimer was further confirmed by single crystal X-ray diffraction study

of 9 (Figure 2).[12]

Among the few bases examined viz. K2CO3, Cs2CO3 and NaOMe, Cs2CO3 was found to

be the best, while there was no reaction observed in the cases of Na2CO3, tBuOk,

Na2HPO4 and KF when used as a base. The use of other solvents like CH3OH, DMF,

DMSO, etc did not yield a clean product.

While the exact mechanism of this novel transformation is under investigation, our

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preliminary work has revealed that this trimerisation proceeds through the intermediacy

of the dimer 2 (Scheme 2). Arresting the reaction of carbinol 3 at shorter duration, we

were able to isolate the dimer 2. The structure of the dimer 2 was confirmed by spectral

and analytical methods (HPLC), and also by comparing with an authentic sample

prepared by literature method.[13] The authentic dimer 2 was smoothly transformed to the

trimer when refluxed in xylene with the carbinol 3. Mechanism of transformation of

carbinol 3 to dimer 2 is being investigated. In summary, this is the first report on the

synthesis of unusual trimeric chromones 8-12 from the reaction 3-

hydroxymethylchromones in xylene using Cs2CO3.

CONCLUSION

In summary, this is the first report on the base catalyzed trimerisation of 3-

hydroxymethylchromones leading to novel trimeric chromanones.

EXPERIMENTAL

All [1]H and [13]C NMR spectra were taken on Bruker DPX-300 spectrometer. Chemical

shifts are reported in ppm relative to tetramethylsilane as the internal standard and

referenced to the proton signal of the solvent (CDCl3 7.26 ppm for proton, and 77.0 ppm

for carbon magnetic resonance spectroscopy). Melting points are uncorrected and were

recorded on Veego Model VMP-PM melting point apparatus. IR spectra were recorded

on Perkin Elmer FT-IR. High-resolution mass spectra (HRMS) were recorded on a

Micromass Q-Tof mass spectrometer.

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Typical Experimental Procedures For The Synthesis Of 3,3-Bis-(4-Oxo-Chromen-3-

Ylmethyl)-Chroman-4-One (8) :

A mixture of the hydroxymethyl chromone 3 (1.135 mmol) and Cs2CO3 (1.362 mmol) in

7 mL of xylene is heated to reflux and maintained for the required time (See Table 1).

The reaction was monitored by TLC. Evaporation of solvent followed by column

chromatography using ethyl acetate/hexane as eluant afford 8 in 81% yield, as off-white

solid, Mp. 165-167 °C, [1]H NMR (300MHz, CDCl3): δ 2.95 (s, 4H, 2 × CH2), 4.39 (s,

2H, CH2), 6.91(d, 1H, J1 =8.4 Hz, Ar-H), 6.99 (t, 1H, J =7.8 Hz, Ar-H), 7.345-7.46 (m,

5H, Ar-H), 7.60-7.66 (m, 2H, Ar-H), 7.91 (dd, 1H, J1 =1.2, J2 =7.8 Hz, Ar-H), 7.97 (s,

2H, 2 X =CH), 8.10 (dd, 2H, J1 =1.5, J2 =8.1 Hz, Ar-H). [13]C NMR (75 MHz, CDCl3): δ

27.01 (CH2), 51.35 (C), 72.30 (CH2), 117.83 (Ar-C), 118.11 (Ar-C), 119.45 (C), 120.57

(C), 121.62 (Ar-C), 123.67 (C), 125.11 (Ar-C), 125.97 (Ar-C), 127.72 (Ar-C), 133.52

(Ar-C), 135.94 (Ar-C), 155.79 (CH), 156.31 (C), 161.14 (C), 177.93 (C), 194.99 (C). IR

(KBr, cm-1): 2926, 1689, 1649, 1637, 1608, 1465, 1348, 1299, 1216, 1163, 1016, 760.

HRMS for C29H21O6: Calc. 465.1338, found. 465.1340.

Please see the Supplementary Information, available online, for complete experimental

details.

ACKNOWLEDGMENT

The authors thank DST, New Delhi for funding and Shasun Research Centre - QC for

NMR data.

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(5) Part of this work was presented in the 3rd international conference on

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Table 1 Base mediated trimerisation of 3-7

in Toluene in Xylene

S.

No

Substrate Product Base Reaction

time (h)

Yielda)

(%)

Reaction

time (h)

Yielda)

(%)

1 3 8 Cs2CO3 21 46 15 81

2 4 9 Cs2CO3 19 52 15 83

3 5 10 Cs2CO3 22 38 18 71

4 6 11 Cs2CO3 24 26 21 58

5 7 12 Cs2CO3 24 31 20 63

6 3 8 K2CO3 30 11b) - -

7 3 8 NaOMe 33 7b) - -

a)based on isolated yield after column chromatography. b)Reaction did not go to

completion.

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Scheme 1. Trimerisation of 3-hydroxymethyl chromones 3-7

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Scheme 2. Proposed mechanistic pathway.

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Figure 1. Chromone derivatives.

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Figure 2. ORTEP diagram of the ‘trimer’ 9.

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