Domino products from the reaction of 1,3-diaryl-2-propen-1-ones (chalcones) with cyclopentanone

The simple reaction of chalcones with cyclopcntanone in the pt·esencc of barium hydroxide furnished complex domino pt·otlucts of the types 4 and 5 along with 1,5-dil<etones 3. Mechanistic considerations reveal that the bicyclic alcohol 4 wlls formed by sequential 1\'lichaei-1\Jichael-aldol •·eactions involving two moles of chalcone and one mole of cyclopentanonc. \Vhucas, fo•· mation of spiro-bicyclic diol 5 involved sequential Michael-! ,2-atldition-aldol condensation involving one mole of chalcone anti two moles of cyclopentanone. Fot·mation of the domino pt·oducts was found to be critic;tlly dependent on electronic fine tuning in the both the at·omatic rings.


Introduction
Generation of complex products from simple starting materials under conditions in which several reactions take place one after another in domino fashion is of continuing interest to organic chemists. Generally such reactions involve multi-component condensation of starting materials. Discovery of domino-reactions on new substrates usually depends on serendipity. 1 ,3-Diaryl-2-propen-1-ones (chalcones) have been popular substrates for the generation of a variety of heterocyclic products 1 . They were also used as precursors for the synthesis ofpolyphenolic natural pi·oducts such as flavones, flavanones and flavanols 2 . In addition, there are a few reports in the literature on their utility for the synthesis of carbocyclic products, Recently, AI-Arab and coworkers 3 rep01ted the formation of cyclohexanol derivatives from the reaction of chalcones and ethyl cyanoacetate. In this domino reaction, the cyclohexanol derivatives were formed by three-component condensation involving two moles of chalcone and one mole of ethyl cynoacetate. Noguchi 4 reported that the condensation of acetophenone and benzaldehyde in biphasic medium in the 0 0

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presence of PTC results in a cyclohexanol derivative. Formation of cyclohexanol product involves two components of chalcone and one component of acetophenone, We have been interested in the utilization of I ,5-diketones generated by the base-mediated reaction of chalcones and cyclopentanone for the synthesis of 8-azagonanes. We have serendipitously discovered that this reaction affords complex bicycl ic and spirocycl ic compounds as minor products in addition to expected I ,5-diketones.

Results and Discussion
The reaction of chalcone I a with cyclopentanone 2 in the presence of barium hydroxide in ethanol at room temperature resulted in the diastereomeric mixture ofknown 5 I ,5-diketones 3a (70%, Scheme I). Further elution of column chromatogram during the purification of the diketones 3a furnished a bicyclic alcohol ( .ta, 21 %), which crystal-! ized out of the fractions (Scheme 1 ). Elemental analysis and mass spectral data of 4a indicated that the molecular formula was C 35 H 32 0 3 (mol. wt 500). The IR spectrum revealed the presence of hydrogen bonded hydroxy group (3459 cm-1 ) and two aromatic ketones in which one was involved in hydrogen bond with hydroxyl (1676, 1647 em -I). The 1 H NMR spectrum revealed the presence of aromatic and aliphatic protons in the ratio of 5 : 3 indicating that the product was formed by the condensation of two molecules of chalcone and one molecule of cyclopentanone. The 13 C NMR spectrum revealed 15 I ines out which 9 were of aliphatic type, 16 of aromatic type and 2 of carbonyl carbons. The DEPT spectrum indicated the presence of 4 quarternary carbons. On the basis of the above spectral data and mechanistic considerations the structure of 4a was assigned as ( 6-benzoyl-3a-hydroxy-5, 7-diphenylperhydro-4indenyl)(phenyl)methanone.
Stereochemistry to various substituents located on the bicyclic alcohol 4a was assigned on the bases of analysis of 1 H NMR, COSY, HETCOR and NOESY spectra. The C 4 -H appeared as a doublet at c5 4.2 ppm with a coupling constant of 12.1 Hz indicating its axial orientation; consequently, the C 4 -benzoyl group was equatorially oriented. The C 5 -H appeared as double doublet at c5 4.5 ppm with coupling constants 12.1 and 5.2 Hz accounting for axial-axial and axial-equatorial couplings with adjacent hydrogens. This data indicates that the C 5 -H was axially oriented; consequently, the phenyl group was equatorially oriented. The C 6 -H appeared as a triplet at 54.3 ppm with coupling constant of 5.2 Hz indicating equal equatorial-axial coupling to adjacent vicinal hydrogens. Thus C 6 -H was equatorially oriented; consequently, benzoyl group was axially oriented. The C 7 -H appeared as a double doublet at 53.38 ppm with axial-axial and axial-equatorial coupling constants of 12.6 and 5.2 Hz, indicating its axial orientation; consequently, the CTphenyl was equatorially oriented. These data also indicate that the bridgehead C 73 -H was axially oriented, which appeared as broad double doublet at 52.9 ppm. The trans stereochemistry to the ring junction was assigned on the basis of strong hydrogen bonding interactions between C 3 a-hydroxyl group and adjacent C 4 -benzoyl group indicating their syn orientation. The energy-minimized structure was generated in MM2 mode (minimum energy== 19.99 kcal; Fig. I), which clearly shows hydrogen-bonding inter- Energy m1mmtzed structure of (6-benzoyl-:h-hydroxy-5,7diphenylpcrhydro-4-Jndenyl)(phenyl)methanone 4a action between the C 3 a-hydroxy group and carbonyl oxygen of the adjacent C 4 -benzoyl group (hydrogen bond distance = 184.8 pm). Theoretical coupling constants generated ft·om minimum energy conformation of 4a also agreed well with the experimentally observed values 6 . The mechanism for the formation of 4a is given in Scheme 2. The conjugate addition (Michael reaction) of the anion generated from cyclopentanone to chalcone leads to The axial orientation ofC 6 -benzoyl group instead of equatorial orientation in 4a during its formation appears to be a deviation from normal expectations. The axial-orientation of C 6 -benzoyl group is likely to relieve severe steric congestion with adjacent equatorially oriented bulky phenyl rings in C 5 -and Crpositions.
We have made attempts to improve the yield of the bicyclic alcohol 4a by changing the solvent and as well as the base used in the reaction. We have conducted this multicomponent condensation reaction in a selection of solvents like methanol, t-butanol, THF or dichloromethane. However, best yield of 4a was obtained in ethanol medium. A variety of bases such as potassium hydroxide in ethanol, sodium hydroxide in ethanol, sodium methoxide in methanol or in dry diethyl ether, and sodium hydride in THF were tried for promoting the multi-component condensation reaction. Surprisingly, in all the cases the desired bicyclic alcohol was either obtained in minute quantities (less that 3% yield) or did not form at all. Interestingly, when the reaction was conducted in biphasic medium under the conditions described by Nogouch 4 only conjugation addition product 3a was obtained in 96% yield. Thus, barium hydroxide and ethanol appeared to be unique in propelling the reaction towards domino pathways.
Next, we studied the effect of electron-donating and withdrawing substituents on the phenyl rings towards the formation of bicyclic alcohol of the type 4. When the chalcones having electron-donating 4-methoxy ( 1 b) and 4 · methyl (I c) groups in the aryl ring Ar 1 ring were employed as substrates, the reaction was sluggish and it furnished only conjugate addition products 3b-c. However, when the chalcone I d having electron-withdrawing 4-chloro substituent was used as substrate, the reaction furnished diastereomeric mixture of conjugate addition products 3d, bicyclic alcohol 4b and a novel spiro-bicyclic diol Sa (Scheme I). The structure of the bicycl ic alcohol 4b was confirmed on the basis of 1 Hand IJc NMR spectra, which were remarkably similar to the parent bicyclic alcohol 4a.
Furthermore, 2D-NMR spectral data (COSY, HETCOR, NOESY) were also in conformity with the proposed structure for 4b.
The new compound Sa, a colorless crystalline solid, m.p. 225°, obtained in 3% yield, was found to have molecular fonnula C 25 H 27 CI0 3 from analytical and mass spectral data. The I R spectrum revealed the presence cf a hydrogen bonded hydroxyl group (3192) and a carbonyl group (I 716 cm-1 ). The 1 H NMR spectrum revealed the presence of aromatic and aliphatic protons in the ratio I :2, which indicated that the product was formed from two units of cyclopentanone and one unit of chalcone. The two hydroxy groups (hydrogen exchangeable with deuterium in D 2 0) were observed as broad singlets at 8 3.3 and 3.98 ppm. The absence of characteristic signals in the IR spectrum for an aromatic carbonyl group (~1660 cm-1 ) and signals in the 1   The stereochemistry of the various substituents in Sa was assigned on the basis of coupling constants as revealed in high-resolution 1 H NMR spectrum. As expected from the structure of Sa c 5 • proton appeared as double doublet at 8 3.43 with coupling constants of 13.5 and 4.0 Hz. The magnitude of the coupling constants indicated that C 5 proton is having axial-axial coupling with C 6 .-H axial and axial-equatorial coupling with C 6 ,-H equatorial. Thus the C 5 ,-phenyl group was equatorially oriented and consequently the c 5 ,-H is axially oriented. The two protons on C 6 , appeared as double doublets at c5 3 and 1.76. As discussed earlier, hydrogen-bonding interaction between the two OH groups at C 7 , and C 33 was indicated by the IR spectrum. This arrangement requires both the C 3 a-OH and CrOH to be in axial position. By deduction the C 7 chlorophenyl group can be taken as located in equatorial orientation. The ste-' reochemistry ofthe ringjunction being trans was indicated by the coupling constants of C 7 a-H (c5 2.95, dd, J I 3, 7.5 Hz). Final confirmation ofthe proposed structure of Sa was obtained by X-ray analysis on a thin needle shaped crystalline sample obtained by recrystallization from dichloromethane hexane solvent mixtures (ORTEP diagram with crystallographic numbering, Fig. 2). The crystal structure analysis revealed a short hydrogen bond of length 266 pm between 0 1 and symmetry-related 0 2 . The structure appears J.'ig. 2.
to be stabilized mainly by van der Waals interactions. The minimum energy conformation of this molecule was generated using molecular mechanics calculation using MMXE mode (MMXE = 39.78 kcal; Fig. 3), which clearly shows hydrogen bonding interactions between two hydroxyl groups and the cyclopentanone carbonyl oxygen.
A possible mechanism for the formation of the spirobicyclic diol Sa is given in Scheme 3. The I ,5-diketone 3d formed via the Michael addition of anion generated from cyclopentanone reacts with one more unitofcyclopentanone in I ,2 fashion to furnish the diketone alcohol 8. Intramolecular aidol condensation of8 results in spiro-bicyclic diol Sa. The involvement of two hydroxy groups in intramolecular hydrogen bonding may be the driving force for the formation of the final product.  changing various reaction conditions, such as concentration, solvent, base etc. Change of solvent from absolute alcohol to acetonitrile, as well as sonication also did not increase the yield ofthe desired product. A variation in the reaction conditions, such as heating to reflux or prolonged stirring (36 h) also did not improve the yield of Sa. According to the proposed mechanism, the formation of spirodiol was due to the addition of two cyclopentanone moieties to one chalcone moiety. Hence, I ,5-diketone 3d and cyclopentanone 2 were allowed to react (Scheme 4). But instead ofthe spiro-0 + 6 3d 2 chalcone I k having electron-withdrawing 4-chloro substituent in Ar 1 and Ar 2 rings also resulted in only diketone 3k. However, the reaction of chalcone II having electron-withdrawing Cl in Ar 1 and electron-donating OMe in Ar 2 rings resulted in diketoncs 31 and bicyclic alcohol 4d (I 0%). Un-fOiiunately, the bicyclic alcohol 4d was obtained only as a mixture ofstereoiosmers, which could not be separated by column chromatography or by fractional crystallization. The reaction of chalcone I e having electron-withdrawing bromo substituent in Ar 1 ring with cyclopentanone furnished the diastereomeric mixture of diketones 3e along with spirobicyclic diol Sb in 5% yield (Scheme I). The structure of Sb was assigned on the basis of spectral data (IR, 1 H, 13c NMR, MS) and on comparison with the data for Sa.
Surprisingly this reaction did not furnish any bicyclic alcohol of the type 4.
Interestingly, the reaction of chalcone If having strongly electron-withdrawing 4-nitro group resulted in only in the diastereomeric mixture of I ,5-diketones 3f. There was no trace ofbicyclic alcohols ofthe type 4 or 5 in the product mixture.
Next we studied the barium hydroxide mediated reaction of chalcones having electron donating ( lg-h) and withdrawing groups ( l i-j) in Ar 2 ring with cyclopentanone. The reaction of chalcone I g having strongly electron-donating OMe group in Ar 2 ring furnished bicyclic alcohol 4c along with the diastereomeric mixture of diketones 4g. The spectral data ofbicyclic alcohol 4c (IR, 1 H, 13 c NMR, COSY, HETCOR, NOESY) were remarkably similar to 4a and 4b. The reaction of chalcones I h-j having moderately electrondonating methyl group, electron-withdrawing Cl or nitro group resulted only in diketones 3h-j. The reaction of chalcone a push-pull system. These substituents also promote conjugate addition characteristics of the system. Our studies show that the presence of moderately electron-withdrawing substituents on Ar 1 ring and strongly electron-donating substituents on Ar 2 ring drive the initial conjugate addition intermediates towards second conjugate addition leading to the formation of domino products. Fwihermore, our studies also revealed that the formation of the domino products is critically dependent on reaction conditions such as choice of base and solvent.
In conclusion, we have shown in this study that the reactionof chalcones with cyclopentanone in the presence of barium hydroxide in ethanol medium furnishes novel and interesting bicyclic alcohols of the type 4 or spiro-bicyclic dials of the typeS depending on the electronic fine-tuning ofthe aryl rings. The structure and stereochemistry ofthe different substituents were assigned on the basis of analysis of the high resolution NMR data and 20 NMR spectral data. In the case ofspiro-bicyclic diol Sa, the structure was confirmed on the basis of X-ray structure analysis.

Experimental
Hexanes/ethyl acetate (9 : I) solvent mixture for TLC (TLC silica gel, Qualigens or TLC neutral alumina, SRL, India) was used to monitor the progress of the reactions. The column chromatography was performed on silica gel (I 00-200 mesh, Acme Synthetic Chemicals) using increasing percentage of ethyl acetate in hexane. All the solvents were distilled before use. Barium hydroxide (B.D.H.) was activated by heating at 120° for I h and cooled to room temperature (30°) in a desiccator. The chalcones were prepared according to literature procedures 7 . Melting points were noted using a Gallenkamp apparatus. IR spectra (KBr/ nujol) were recorded on a Jasco FTIR spectrophotometer, 1 H, 13 e and 20 NMR spectra (eDel 3 ) on Bruker 500 MHz, JEOL 400 MHz, Varian 300 MHz or Bruker 200 MHz spectrometers with internal TMS as reference and mass spectra on a GEOL Ge/MS low-resolution instrument.