HETEROCYCLES AND CARBOCYCLES FROM (0-14-DIPHENYL-2- BUTENE-1,4-DIONE (trans-DBE)

2.1 Introduction

(E)-l,4-diphenyl-Z-butene-1.4-dione (tratu-DBE) 3 is an useful multifunctional

molecule. It can be prepared by Friedel-Crafts acylation of fumaryl chloride 2 with

benzene 1 (Scheme 2.1).' Similarly several derivatives of trans-DBE 3 can be prepared

easily. trans-DBE 3 possess two a$-unsaturated carbonyl groups with two phenyl rings

in 1A-position. The nucleophilic addition to a$-unsaturated carbonyl in 3 can be

achieved either in 1.2- or 1,4- fashion. Conjugate addition, i.e., the 1,4-addition of a

nucleophile is known as Michael addition. The resultant Michael adducts can be further

utilized for the generation of carbocycles and heterocycles. We became interested in the

utility of trans-DBE 3 for the synthesis of hitherto unknown tetrahydroquinoline

derivatives via conjugate addition of the anion generated from cyclohexanone followed

by oxidative amination-cyclization. While executing this task we isolated several

carbocycles formed by following domino-pathways. We have also conducted the

Robinson annulation reaction on trans-DBE 3 with methyl acetoacetate and utilized the

product for further interesting transformations. Results from these studies are described in

the present chapter. To place the results in right perspective, we now give a brief review

of the literature on the utility of trans-DBE 3 in Synthetic Organic Chemistry. We have

gathered the literature references from 1990 onwards as there is already a review on this

topic for the previous period.2 The references are arranged in the chronological order.

While presenting the literature, only examples, of the parent molecule is given. In all the

publications selected for the review, details of the generality of the procedure are

1 2 3

Reagents and conditions: i. AICI,, rt, 2h.

Scheme 2.1

2.1.1 Synthesis of carbocycles from trans-DBE 3

Saba reported the synthesis of interesting carbocycle I-trans-2,3-cis-

tribenzoylcyclopropanes 4 by the reaction of the phenacyi bromide 5 with trans-DBE 3

(Scheme 2.2).' Thus, stereospecific cycloaddition of tt-ans-DBE 3 with the carbene

intermediate generated from phenacyl bromide 5 furnished l,2,3-tribenzoylcyclopropane

4 in good yield.

5 3

Reagents and conditions: i. KICO,, DMF, rt.

Scheme 2.2

The dienophiles such as trans-DBE 3 react with the dienes to form interesting

carbocycles. Parakka and coworkers reported the tandem [4t2] double cycloaddition

reaction of the diene, 5,6-di[(E)-l-bromomethylidene]-l.3-cyclohexadiene 7, generated

from l,2-di(dibromomethyl)benzene 6 with two moles of trans-DBE 3 to form adduct 8

(Scheme 2.3)', which sewed as an intermediate for the preparation of novel heterocycles

like pymoles and thiophenes.

6 7 3

Reagents and conditions: i. Nal, acetone, reflux.

Scheme 2.3

Br Br

Hatanaka and coworkers reponed the synthesis of cyclopentenone derivatives 13 with

defined stereochemistly from [runs-DBE 3 (Scheme 2.4).' The phosphorane 9 was

allowed to react with truns-DBE 3 in T H F at room temperature via [3+2] annulation to

give dienes 11 and 12 through intermediate 10. The treatment of the mixture of dienes 11

and 12 with aqueous acetic acid gave a single stereoisomer of cyclopentenone 13.

0 + p h ~ ~ ~ h ~ coph

0 9% COPh COPh

OEt 0

+ phl$m~t2- kc; Ph Ph

PhOC

11 12 13

Reagents and conditions: i. THF, -30 OC to rt, 48 h; ii. aq. AcOH, THF, rt

Scheme 2.4

Hatanaka and coworkers also reported the [3+2] annulation of winig salt, (3-

alkoxycarbony12-ox~pro~hyllidene)~hosphoranes 14 with trans-DBE 3 to give

cyclopenteno?e 15 in a single step in good yield (Scheme 2 . ~ 1 . ~

I Ph

3 14 15

Reagenfs and conditions: i. THF, rt, 12 h.

Scheme 2.5

Al-Arab and coworkers synthesized highly substiwted cyclohexanol derivative 17 in

a single pot reaction of acetopheneon? 16 and rrans-DBE 3 using sodium ethoxide as

base (Scheme 2.6).' Formation of this product is expected to go through Michael addition

followed by aldol condensation.

3 16 17

Reagents and conditions: i . NaOEt, anhyd. EtZO, rt, 30 mjn.

Scheme 2.6

Reagents and condilions: i. Sm12. THF, HMPA, rt, 5 min

Scheme 2.7

Cabera and coworkers synthesized highly functionalized cyclopentanol derivative 18

by the one-electron transfer reducing agent samarium (11) iodide on trans-DBE 3. The

byproduct from the reaction was 1.4-diphenyl-1,4-butanedione 19 (Scheme 2.7).'

2.1.2 Synthesis of heterocycles from trans-DBE

Atfah and coworkers reponed the synthesis of oxabicyclo[2.2.2]octanones 21 from a

facile one-pot reaction by the condensation of trans-DBE 3 and arylacetonitrile 20 in the

presence of sodium ethoxide (Scheme 2.8): Apparently, the reaction was going through

double Michael addition, ~ntramolecular aldol condensation followed by deamination-

cyclization.

0 1

ph" t Phi-m - 0

PhOC

3 20 2 1

Reagents und conditions: i. NaOEt, EtzO, rt.

Scheme 2.8

Kaupp and coworkers synthesized several polycyclic cage compounds 24 via the

intermediate 23 by the reaction of enamines 22 with truns-DBE 3. The reaction pathway

involved ene addition followed by [2+2+2] cycloaddition involving two carbonyl groups

and enamine double bond (Scheme 2.9).1°

22 3 23

Reagents and conditions: i. MeOH, n, 2-3 days.

Scheme 2.9

Rajakumar and Kannan synthesized 7-[(4-methylphenyl)sulfonyl]-5,6-di[(Z)-I-

phenylmethylidenel-7-azabicyclo[2.2.1]hept-2-ene 27 by the cycloaddition reaction o f 1-

[(4-methylphenyI)su~fonyl]-IN-pyrrole 25 with dienophile such as (runs-DBE 3 in the

presence of catalytic amount of BF,.Et20 (Scheme 2.10)." Reduction of the cycloadduct,

3-benzoyl-7-[(4-methylphenyl)sulfonyl]-7-abiclo[2.2 llhept-5-en-2-

yl(pheny1)methanone 26 with NaBH,I NiC12 resulted in 27. Remarkably, the

cycloaddition did not go without BF3.Et20 in either benzene or decalin at reflux.

Reugents undcondrtions: i. BF,.Et>O, CaHa, 50 "C, 50 h; ii. a. NaBH4, EtOH b. NiCl,.

Scheme 2.10

Rao and Subbaraju reported the straight foward synthesis o f 3,4-diaroyl-2-

pyrazolines 28 through cycloaddition of diazomethane to truns-DBE 3 (Scheme 2.1 I)."

Reagents and conditions: i. CH~NI . 0 OC, 24 h.

Scheme 2.1 1

The C2 symmetric chiral amine 31 of high enantomerlc purity have been prepared

from trans-DBE 3 in four steps (Scheme 2.12)." Important reaction in the sequence

reaction sequence is the asymmetric reduction with Ipc2BCI of dione, I,4-diphenyl-l,4-

butancdione derived from trans-DBE 3. Addition of allylamine to crude dimaylate,

obtained from 29, gave a reasonable yield of (2S,SS)-l-allyl-2,S-diphenyltetrahydro-lH-

pyrrole 30. Chiral amines of the type 31 are useful in asymmetric synthesis.

Reagents and conditions: i. SnCl21 HCI; ii. Ipc2BC1, THF, -78 OC -i rt; iii. MsCI, Et;N, CH2C12, -20 'C; iv. CHI=CHCH~NH~, EtlN, 0 "C-i n; v. (Ph,P);RhCI. H20, CH;CN, reflux.

Scheme 2.12

Mataka and coworkers synthesized [(2S,3R,4R)-4-benzoyl-I-methyl-2-

phenyltetrahydro-1H-3-pyrrolyl](phenyl)methanone 34 by the three-component

condensation reaction of N-methyl glycine 33, benzaldehyde 32 with trarrs-DBE 3

(Scheme 2.13).14 The transformation was proceeding through dipolar cycloaddition

involving acyliminium ions intermediates.

3 32 33

Reagents and conditions: i. toluene, reflux, 27 h.

Scheme 2.13

The above strategy was extended to the cyclic amino acids 35 and benzaldehyde 32 to

furnish the col~esponding bicyclic derivatives 36 (Scheme 2.141.'~

phOYph PhOC N

LX 3 35 32 36

X = S, CH2, CH2CH2

Reagents and conditions: i. toluene, reflux. 27 h.

Scheme 2.14

Kumar and Boykin synthesized 3-alkoxy-. 3-aryloxy-. and several other 3-substituted

amino-2,5-diarylfurans 37 by reductive furanization of tr.arl.r-DBE 3 with phosphorous

trichloride (Scheme 2.15).Ii The procedure was useful for the synthesis of 2,3,5-

trisubstituted hrans.

0 ph,L.&y~h L dR

o phAy,J-ph

3 37

R = OMe, OPh, 4-Me-C,H,O, 4-Et00CC6H40, morphollno

Reagents and condrtrons: i PCII. 4h, rt.

Scheme 2.15

Singal had reported the 1.3-cycloaddition of nitrone 38 to trans-DBE 3 as a method

for the synthesis of densely substituted isoxazolidine derivatives of the type 39. Thus,

trans-DBE 3 reacted with C-(2-nitrostyry1)-N-phenyl nitrone 38 to give isoxazolidine 39

as a single isomer (Scheme 2.16).16

i Q ph&ph 0 + cia- % 0 0

PhPh 3 38 39

Reagents and conditions: i. dry ChHh. reflux, 48 h.

Scheme 2.16

Several bioactive heterocycles incorporating two or more heteroatoms have been

prepared from trans-DBE 3 using 1.3-dipolar additlon strategies. Duan and coworkers

reported the reaction of trans-DBE 3 with trithiacyl trichloride 40 to give 3,4-dibenzoyl-

1,2,5-thiadiazoles 41 (Scheme 2. 17).17

0 C1 0 0

N'/S%N i - P h w p h F ' ~ T ~ ~ ~ , , , 0 CI/s+NNIs~CI N,S/N

3 40 41

Reagents and conditions: i. CC4, Nz atm, reflux, 10 h.

Scheme 2.17

ph&Ph + M ~ O N H ,

0 NH2 0

3 42 43

Reagents andconditiuns: i. NaOEt, EtOH, rt, 4 h.

Scheme 2.18

~ e i h o x ~ a m i n e 42 was found to be an efficient aminating agent for a$-unsaturated-

14-dicarbonyl compounds. Seko and Miyake synthesized 2-amino-l,4-diphenyl-2-

butene-14-dione 43 by using methoxyamine 42 as the aminating agent for trans-DBE 3

(Scheme 2.18).18

Kaupp and coworkers reported the one-pot synthesis of the pyrroles 45 from the

primary or secondary enaminoketone 44 and trans-DBE 3. The reaction of the enamino

ketone 44 and trans-DBE 3 resulted in conjugate addition product, which underwent

dehydrative cyclization to furnish pyl~ole 45 (Scheme 2. 19).19

Reagents and conditions: i. MeOH, reflux, 3 h .

Scheme 2.19

Rao and Jothilingam synthesized 2,s-diphenyl-IH-pyrole 46 from trans-DBE 3 and

ammonium formate in a microwave assisted one-pot operation. The transformation goes

through domino pathways via palladium assisted transfer hydrogenation followed by a

Paal-Knorr reaction (Scheme 2.20).'~ Ammonium formate was used as a source of

hydrogen and nitrogen.

3 46

Reagents and conditions: I HCOONHI, PdlC (lo%), PEG-200, Pv, 200 W, 2 min.

Scheme 2.20

Abu-Orabi had reported the 1,3-dipolar cycloaddition reaction of trans-DBE 3

with azide.47; enamine 48 was formed which was stabilized in the form of enolimine 49.

Formation of the enamine 48 was expected to go through thermally unstable triazoline 50

(Scheme 2.21).*'

49 50

Reagents und conditions: i. EtOH, reflux.

Scheme 2.21

Earlier in our ~ahoratory,' rrari\-DBE 3 was used as a starting material for further

elaboration to the cyclopenla[h]pyridine derivative 53. Conjugate addition of

cyclopentanone 51 to trans-DBE 3 hmished triketone 52. Amination-cyclization of the

triketone 52 with ammonium acetate resulted in the unstable heterocycle 53. In the

transformation of 52 to 53, 1,s-diketone was involved in amination-cyclization sequence

and not 1,4-diketone which is also present in 52 (Scheme 2.22).22

Reagents and conditions: i. activated Ba(OH)l, EtOH, rt, 12 h; ii. CHICOONH,, MeOH, 18 h.

Scheme 2.22

Thus, it is clear from the literature survey that trans-DBE 3 served as a versatile

precursor towards the synthesis of both the carbocycles as well as the heterocycles. In the

following units, results from the reactions of trans-DBE 3 with different nucleophiles and

their subsauent transformation to heterocycles I carbocycles are described.

2.2 Results and discussion

2.2.1 Convenient synthesis of 4-aroyl-2-aryl-5,6,7,8-tenrahydroquinolines from 1,s

diketone precursors

The quinoline nucleus and its partially reduced forms can be readily recognized as

structural motifs in many physiologically active alkaloids.23 Therefore, synthesis and

characterization of various quinoline derivatives is of continuing interest. We have been

particularly interested in the synthesis and characterization of 5,6,7,8-tetrahydroquinoline

derivatives as possible precursors for aza-steroid type compounds. The 5,6,7,8-

tetrahydroquinoline moiety is found in alkalo~ds isolated from the plants belonging to

aizoaceae 5 4 - ~ 5 , ~ ~ arnaryllidaceae 5fi2$ and mtaceae 57-58'' families. In addition to the

n a ~ r a l products, a few 5,6.7.8-tetrahydroquinoline derivatives 59-61 also found

therapeutic use (Fig. 2.

H ~ N ~ S

59 60 Fig. 2.1

In an effort to develop convenient and environment friendly synthesis of 5,6,7,8-

tetrahydroquinoline derivatives, we attempted amination-cyclization reaction on the

triketones 63 derived from the conjugate addition of cyclohexanone 62 to ham-DBE 3.

The triketone 63 bas been transformed to the conesponding hitherto unknown phenyl(2-

phenyl-5,6,7,8-tetrahydro-4-quinolinyl)metham)ne 70 following one-pot amination-

cyclization-aromatization route. This multi-step one-pot transformation can be conducted

in a very short duration under environmentally benign microwave mediated reactivity

enhancement conditions.

Conjugate addition (Michael Reaction) of the anion generated from cyclohexanone 62

to tram-DBE 3 in the presence o f activated Ba(OH)> in ethanol medium furnished

inseparable mixture of diasterorneric triketones 63 in 60 % yield in 3:l ratio (Scheme

2.23).

0 0 p h y O o ph*ph + 6 -pha

0

3 62 63

Reagents and conditions: i. activated Ba(OH)2, EtOH, rt, 12 h.

Scheme 2.23

The structure of the triketone 63 was secured on the basis of IR, 'H NMR, l3C NMR

and mass spectra. The IR spectrum of the triketone 63 showed the cyclohexanone

carbonyl absorption at 1700 cm.' and the aromatic ketone absorption at 1670 ern.'. The

'H NMR spectrum (Fig. 2.2) revealed a multiplet for C-2-H at 6 4.66-4.72 ppm. The "C

NMR spectrum (Fig. 2.3) revealed seven signals in the aliphatic region, three for

carbonyl groups and eight for aromatic carbons for the major isomer.

Previously, we had isolated several carbocyclic products along with anticipated 1,5-

diketones from activated Ba(OH)2 mediated condensation reaction of some .a$-

unsaturated ketones, viz. chalcone or ~henyl vinyl ketone and cy~lopentanone.~~ In the

present case, the rnaction of rrans-DBE 3 with cyclohexanone 62, we did not detect the

formation of any such c&ocylic products. Similarly, we found only the formation of the

(3IXl MHz, CDCI1'CClr. I 1 1

Fig. 2.2 300 MHz (CDCI,/CCII, 1:l) 'H NMR spectnrm of 2-(2-oxocyclohexyl)-l.4-diphenyl-l,4-butaned1one (63)

:: inisaaeammss 11ssn¶111111au \fy [ !2$ ;!yfi/;

II IIV

3 63

(75 M H z CDC131CC14. 1 1 I

- - r . p --- -

Fig. 2.3 75 MHz (CDCIJICCI,, I : I ) "C NMR spectrum of 2-(2-oxocyclohcxyl)-13-diphenyl-l,4-butanedione (63)

triketone 63 when the reaction was conducted in the presence of different bases such as

sodium ethoxide, potassium hydroxide and sodium hydroxide in ethanol medium.

The reaction of (4- l,4-di(4-chloropheny1)-2-butene-I ,4-dione 64 and (Q- 1,4-di(4-

methylpheny1)-2-butene-1,4-dione 65 with cyclohexanone 62 in the presence of activated

Ba(OH)2 also resulted in the corresponding didereomeric mixture of triketones 66 and

67, respectively in good yields (Scheme 2.24). The spectral data (Fig. 2.4-2.7) of these

compounds matched well with the parent triketone 63.

Reagents and conditions: i. activated Ba(OH)*, EtOH, rt, 12 h

Scheme 2.24

The triketone of the type 63 has two aromatic and one aliphatic ketone groups.

Molecular stitching involving two carbonyl groups on C-1 and C-4 in the dehydrative

amination-cyclization sequence would generate 2,3,5-trisubstituted pyrrole derivative 68

with a cyclohexanone moiety as a substitutent. On the other hand, similar transformation

involving two carbonyl groups on C-1 and C-2' would lead to 2,3-disubstituted 1,4,5,6-

tetrahydrocyclohexa[b]pyrrole derivative 69. Finally, cyclization connecting C-4 and C-

2' carbonyl groups in 63 would furnish 2,4-disubstituted 5,6,7,8-tetrahydroquinoline

derivative 70 (Scheme 2.25). To test above possibilities, the amination-cyclization

reaction on the triketones 63 with ammonium acetate was conducted. Literature search

revealed that the 4-aroyl 5,6,7,8-tetrahydroquinoline derivatives of the type 70 are not

known.

Fig. 2.4 300 MHz (CDCI,/CCI,, 1 . 1 ) 'H NMR spectrum of 1,4-di(4-chlorophenyl)-2 (2-oxocyclohexyl)-l,4-butanedione (66)

Fig. 2.5 75 MHz (CDCI,/CC14. I : I ) "C NMR spectrum of 1,4-di(4-chlorophenyI>Z- (2-oxocyclohexyl)-l,4-butanedione (66)

Fig. 2.6 300 MHz (CDCIJCCI,, I : I ) 'H NMR spectrum of 1,4-di(4-methylpheny1)-2. (2-oxocyclohexyl)-l,4-butaned1one (67)

I@ Inn PaS(REaellPII EI @IS& ssIaeCs~PsaBI [ yf ry[; !I Ill H,c

Ill? 3 , 67

(75 MIIz.CDC131C~ I, I I)

.-.-----l--- .. M -- 1 ----- Fig. 2.7 75 MHz (CDCI,/CCI,. 1 1) "C NMR spectrum of 1.4-d1(4-methylphcnyl)-2-

(2.oxocyclohexy 1)- 1.4-butanedlone (67)

H

68

Scheme 2.25

The triketone 63 was treated with ammonium acetate in dry methanol reflux for 18 h

to result in phenyl(2-phenyl-5,6,7,8-tetrahydro-4-quinolinyl)methanone 70 as a single

product in about 13% yield (Scheme 2.26). The reaction time could be reduced to 5 min

when it was conducted in polyethylene glycol-200 (PEG-200) under microwave

irradiation using domestic microwave oven (BPL-Sanyo, India; mono-made, rnulti

power; power source: 230 V, 50 Hz, Microwave Frequency: 2450 MHz). However, in

spite of best efforts to optimize the reaction conditions the yield of the desired product

did not go above 15 %. The product 70 was found to be unstable and was decomposing

even when stored at -5 OC. Pyridine is similar to halogen (Cl) in its -I effect.29 Therefore,

it is possible that 70 is similar to acid halide in its reactivity.

The microwave-mediated oxidative-amination-cyclization was also attempted by

under solvent free conditions, on silica gel, alumina and acid clay solid support. In all the

conditions except in PEG-200 the yield of the desired product 70 was lower than 10%.

PEG-200 has several desirable characteristics for an environmentally benign solvent.

It is highly miscible in water; it shows high-boiling point, low viscosity, low vapor

pressure and reasonably high dielectric constant (-20).1° For these reasons, PEG-200 was

selected to conduct microwave-mediated reactions.

Reagents and conditions: i. CH,COONH4. MeOH, rt, 18 h or CH,COONH4, PEG-200, kv, 300 W, 5 min.

Scheme 2.26

Fig. 2.8 300MHz (CDCI,ICCI., I : ] ) 'H NMR spectmm ofphenyl(2-phenyl-5,6,7,8-tetrahydro-4- qu~nol~nyl)methanone (70)

Formation of 5,6,7,8-tetrahydroquinoline 70 was identified on the basis of spectral

and analytical data. The IR spectrum of 70 showed carbonyl group absorption at 1650

cm-'. The 'H NMR spectrum (Fig. 2.8) showed two triplets at 62.33 (J= 6.2 Hz) ppm, 6

2.58 (J = 6.3 Hz) ppm and two multiplets at 6 1.16-1.38 ppm, 6 1.66-1.88 ppm for eight

hydrogens in the aliphatic region accounting for the cyclohexane ring hydrogens. The C-

3-H aromatic hydrogen appeared as a singlet at 6 7.33 ppm. Decent 'H NMR spectrum

could not be recorded as the compound was decomposing fast. For the same reason, we

could not obtain satisfactory mass and analytical data for 70. Presence of aromatic keto

group (IR) coupled with observation of methylenes ('H NMR) in 70 ruled out the

formation of pyrrole derivatives of the trpe 68 or 69 in the amination-cyclization step.

Having obtained an indication for the formation of 70, next, the scope of the

amination-cyclization reaction was studied by conducting the oxidative amination-

cyclization on triketones having electron withdrawing (Cl, 66) and electron donating

(Me, 67) groups located on the para position of the atyl rings. The triketones 66 and 67

were transformed to relatively stable 5,6,7,8-tetrahydroquinoline derivatives 71 and 72 in

15-17% yield (Scheme 2.27). The 'H NMR spectral data (Fig. 2.9 and 2.1 1) for 71 and 72

matched well with the parent 5,6,7,8-tetrahydroquinoline 70. The "C NMR spectra (2.10

and 2.12) and DEPT spectra for 71 and 72 gave expected signals thereby confirming

assigned structure.

Reagents and condition^: i. CH3COONH4, MeOH, rt, 18 h or CHaCOONb, PEG-200, pv, 300 W, 5 min.

Scheme 2.27

Thus, in this study the triketones of the type 63 on one-pot molecular stitching

through oxidative amination-cyclization sequence furnish 5,6,7,8-tetrahydroquinoline

derivatives of the type 70 exclusively. The yield of the tetrahydroquinoline product 70

was found to be moderate, possibly because the system 70 is behaving like a highly

reactive acid halide. We have found that the rate of the formation of the product 70 from

triketones 63 is promoted by microwave heating methods when PEG-200 is used as a

solvent.

M N - + - - - N - * N .. 11 1

CI

71 (400 MHz. CDCII)

J

, ? 7 6 5 4 3 e I 9 . rn

Fig. 2.9 400 MHz (CDCI,) 'H NMR specturn of (4-chlorophenyl)[2-(4-chlorophenyl). 5,6,7,8-tetrahydro-4-q~1nol1nyl]mc~anone (71)

- Ci

Fig. 2.10 100 MHz (CDCI,) "C NMR spectmrn of (4-chlorophcnyl)[2-(4-chlorophenyl). 5,6,7.8-tetrahydro-4-quinolinyl]metbnon (71)

9 8 $ q k : 8 - N N ? ~ 7

I 1 I I I i I

(400 MHz. CDCI,)

- A.

9 8 7 6 5 4 3 P i

Fig. 2.11 400 MHz (CDCI)) 'H NMR spectrum of (4-methylphenyl)[2-(4-methylphenyl)-5,6,7,8-tetrahydro4-quinolinyl]methanone (72)

I I

Fig. 2.12 100 MHz (CDCI,) "C NMR spectrum of (4-methylphenyl)[2-(4-me1hylphenyl)-5,6,7,8- tetrahydro-4-qutnolinyl]methanone (72)

2.23 Nuclcophile triggered self-condensation of E-1,4-diphenyl-2-butene-1,4-dione

(rrans-DBE) and its derivatives

The domino reactions are the processes, where the starting material is undergoing a

transformation via two or more reactions one after another in an inseparable fashion. In

the domino reactions several bonds are formed in a 'single-pot' operation. Functionality

generated as a result of the initial bond-forming transformation serves to form the next

bond in the subsequent step. Domino reactions can significantly decrease the number of

steps required for the synthesis of complex target structures." We have discovered the

formation of densely substituted cyclopentanol denvatives 73 from ~~QIIs -DBE 3 by

domino reaction pathways. In this unit, isolat~on and stereo-chemical structure

elucidation of the cyclopentanol product 73 is presented.

When conjugate addition of the anion generated from cyclohexanone 62 to trans-

DBE 3 was attempted in bulk scale (sl g) the reaction furnished an interesting ethoxide

triggered self condensation producl, cyclopentanol 73 as a minor product in about 6%

yield along with the anticipated expected triketone 63 in about 63% yield. When the same

reaction was conducted without cyclohexanone 62, cyclopentanol 73 was isolated as the

only product in about 67% yield as a mixture of diastereomers (Scheme 2.28). The 'H

NMR and the "C NMR spectrum of crude product indicated the presence of at least three

diasteromeric cyclopentanols in the ratio of 61:28:1 I . The dominant product 73 (white

solid, mp 184-186 'C, CwH300s) could be isolated in a pure form through fractional

crystallization.

3 73 Reagents and conditions: i. activated Ba(OH)z, EtOH, rt, 12 h.

Scheme 2.28

The structure and the stereochemistry of the cyclopentanol derivative 73 was

confirmed on the basis analytical and spectral data and finally by X-ray crystal stmcture

analysis. The IR SPec tm of 73 revealed the presence of the hydmxyl (v 3466 cm.') and

the c h n y l functional groups (v 1683 cm"). The 'H NMR spectrum (Fig. 2.13) revealed

presence of the aromatic and the aliphatic pmtons in the ratio of 2:1, which indicated that

the product 73 was formed from the condensation of two units of trans-DBE. The

hydroxyl group (washable with D20) was observed as a singlet at 6 4.2 ppm. The 'H

NMR revealed two doublets at 64.55 (J = 10.5 Hz) and 64.49 ( J = 7.8 Hz) indicating the

presence of C-I-H and C-3-H, respectively, next to C-2. There was also a peak at 6 5.76

( J = 10.2 Hz) as a triplet due to C-5-H and a double doublet at 6 4.78 ( J = 10.5, 7.8 Hz)

attributable to C-4-H.

The 'H-'H COSY NMR spectrum (Fig. 2.14) was useful in establishing the

connectivity of the vicinal hydrogens. The spectrum revealed cross peaks for the methyl

with prochiral methylene hydrogens of the ethoxy substituent. The spectrum revealed the

connectivity between C-5-H with both C-I-H and C-4-H. Similarly, cross peaks were

observed for the coupling of C-5-H and C-3-H with C-4-H. Thus the COSY spectrum

helped to assign resonance to various hydrogens and establish the connectivity.

2.2.2.1 Stereochemistry of cyclopentanol derivative (73)

The stereochemistry of different substituents in the cyclopentanol product 73 was

fixed on the basis of the analysis of coupling constants and the NOESY spectral data. The

cyclopentanol is expected to adopt envelope conformation. The substituents adopt

pseudo-axial and pseudo-equatorial conformations. The cyclopentane ring is flexible and

undergoes conformational changes faster than cyclohexane ring.'*

Analysis of I-D 1H NMR spectrum revealed that the C-5-H appeared as a triplet at 6

5.76 ppm with coupling constants 10.2 Hz indicating that C-5-H is having coupling with

C-1-H and C-4-H. There was a peak at S 4.78 ppm as a double doublet for C-4-H with

coupling constants 10.5 and 7.8 Hz. The magnitude of the coupling constants indicated

that C-4-H is having axial-axial coupling with C-5-H and axial-equatorial coupling with

C-3-H. There were also two doublets 6 4.49 ( J = 7.8 Hz) and 8 4.55 ( J = 10.5 Hz)

assignable to C-3-H and C-I-H respectively. The upfield resonance (6 0.68 ppm) found

for CH, group indicates that it mostly resides in the shielding environment of neighboring

phenyl groups.

Fig. 2.17 75 MHz (CDCI,) "C Nh4R spectrum of [(IR,ZR,3R,4S,5S)-4,5-dibenzoyl-3-ethoxy.?- hydroxy-2-phenylcyclopentyl](phenyl)methnone (73)

Fig. 2.14 300 MHz (CDCi,) 'H-'H HOMOCOSY spectrum of [(IR,2R,3R,4S,SS)-4,5-dibenzoyl-3- ethoxy-2-hydroxy-2-phenylcyclopentyl](phmyl)methanone (73)

Fig. 2.15 300 MHz (CDCI,) NOESY spectrum of [(IR,2R.3R,4S,5S)4,5-dibenzoyl-3-cthoxy-2- hydroxy-2-phenylcyclopentyl](phenyl)mcthanonc (73)

The NOESY spectrum (Fig. 2.15) revealed s!eric proximity of different hydrogens

present in 73. The prochiral methylene hydrogens on ethoxy substituent revealed cross

peaks with methyl and also with C-3-H. The methylene hydrogens showed a cross peak

with C-2-OH. The C-5-H revealed cross peaks for C-4-H and C-I-H indicating their

steric proximity. The C-1-H of henzoyl groups located on C-5 and C-4 appearing down

field compared to other hydrogens revealed cross peaks with C-5-H and C-4-H

respectively. Thus the NOESY data was helpful in the assignment of different resonance

to various hydrogen atoms in the molecule. The spectral assignment of characteristic

protons is given in Fig. 2.16.

,. ................................. * 6 5.76 (t, J = 10.2 Hz) ppm

.............. ,-- + 62.82-2.88 (m) & 3.07-3.12 (m) ppm

-------.. * S 0.68 (t, J = 7.2Hz) ppm

PI1

! ...................... * 6 4.49 (d, J = 7.8 Hz) ppm

! H ..................... - 64.55 (d, J = 10.5 Hz) ppm

,. .................................... - 64.78 (dd, J = 10.5, 7.8 Hz)ppm

Fig. 2.16 'H NMR assignments for characteristic protons of 73

The '.'c NMR spectrum of 73 (Fig. 2.17) showed the presence of seven aliphatic type

carbons, sixteen aromatic type carbons and three carhonyl carbons. The carbon attached

to hydroxyl group was observed at 6 89.73 ppm. The spectral assignment for

characteristic carbons is given in Fig. 2.18.

, ........................................... - 6 46.09 ppm

.............................. I... * S 82.73 ppm

............................ I , * I a 6 62.27 ppm , 0

........ * 6 14.64 ppm

................. + 6 89 73 ppm

............................. * 6 68.76 ppm H

...................................... * 6 54.79 ppm

Fig. 2.18 "C NMR assignments for characteristic carbons of 73

The EI mass spectrum of 73 did not reveal molecular ion peak as it was disintegrating

to smaller daughter ions readily. However, the FAB MS could be recorded and it

indicated the molecular formula to he C14H3001.

When the reaction of trans-DBE 3 with activated Ba(0H)z was conducted under

microwave irradiation at 215 W for 4 min., it hmished 73 in 79% yield as a mixhlre of

isomers. Hence the rate as well as yield of the reaction increased under microwave

irradiation.

The confirmation of the proposed structure of 73 was obtained by X-ray analysis

(done by Professor H. -K. Fun, Universiti Sains Malaysia, Malaysia) on the crystalline

sample obtained directly from column chromatography. The ORTEP diagram is shown in

Fig. 2.19.

Having established the structure of cyclopentanol derivative 73, the reaction was also

studied by performing the conjugate addition of different tratts-DBE derivatives having

electron withdrawing (CI, 64, Br, 74) and electron donating (Me, 65) groups located on

the para position of the aryl rings (Scheme 2.29).

Fig. 2.19 ORTEP diagram of [(IR,2R,3R,4S,5S)-4,5-d1benzoyl-3-ethoxy-2-hydroxy-2-

phenylcyclopcntyl](phcnyl)methanone (73)

Ar Ar

64 ,65 , 74 75-77

64, 75: Ar = C,H,-4-CI; 74 ,76: Ar = C6H4-4-Br; 65, 77: Ar = C6H4-4-CHs.

Reagents and conditions: i. activated Ba(OH)*, EtOH, rt, 12 h.

Scheme 2.29

(Ej-1,4-di(4-chlorophenyl)-2-butene-1,4-dione 64 undenvent ethoxide triggered self-

condensation to furnish diastereomeric mixture of cyclopentanol derivatives in 69%

yield. From the mixture, major diastereomer 75 could be isolated in 7% yield by

fractional crystallization. The IR, 'H NMR (Fig. 2.20) and "C NMR (Fig. 2.21) of the

product was similar to the parent molecule, confirming the structure and stereochemistry

of 75. Similarly, (0-l,4-di(4-bromophenyl)-2-butene-1,Cdione 74 underwent self-

condensation to furnish a mixture of cyclopentanol derivative in 72% yield. From the

mixture, the major diastereomer 76 could be isolated in 6% yield by fractional

crystallization. The IR, the 'H NMR (Fig. 2.22) and the I3c NMR (Fig. 2.23) of the

product were similar to the parent molecule, confirming the structure and stereochemistry

of 76. The reaction of (E)-1,4-di(4-methylphenyl)-2-butene-1,4-dione 65 in presence of

activated Ba(0H)z to give the cyclopentanol product 77 in 58% yield. The diastereomeric

product distribution was such that a single isomer could not be obtained both by

chromatographic or recrystallization techniques. The spectral data (Fig. 2.24-2.25)

revealed the isomeric ratio 52:30:18 for 77.

The three component condensation reaction to generate cyclopentanol derivative of

the type 73 was conducted with other bases such as KOH-EtOH and NaOEt-EtOH apart

from activated Ba(OH)2-EtOH. The motif behind the experiments was to evaluate the

eficacy of the bases in promoting the multi-component condensations. While the

condensation reaction did not take place with KOH-EtOH, with EtONa-EtOH the

cyclopentanol derivative 73 formed in a low yield. Moreover, in EtONa-EtOH there was

extensive decomposition of the reaction mixture. Thus it can be concluded that activated

Ba(OH)2-EtOH is unique to trigger frans-DBE 3 towards domino product of the type 73.

2.2.2.2 Mechanism for the formation of cyclopentanol derivative 73

The proposed mechanism for the formation of cyclopentanol 73 is given in Scheme

2.30. A series of domino steps are expected to take place to result in the formation of the

cyclopentanol 73. The initial step is the Michael addition of ethanol 78 to trans-DBE 3 in

a Michael fashion to result the intermediate enolate anion 79. This intermediate 79 further

reacts with another molecule of trans-DBE 3 in a Michael fashion to result enolate anion

80. Intramolecular aldol condensation of 80 furnished cyclopentanol derivative 73 via 81.

Fig. 2.20 300 MHz (CDCI,ICCI,, 1: I ) 'H spectrum of (4-chlomphenyl)[(IR.ZR.3R,4S,5S)-4.5- di(4-chlorobenzoyl)-2-(4-chlomphenyl)-3-ethoxy-2-hydroxycyclontyl]metnne (75)

7s (15 MHz. CDC131CC4. l .I)

Fig. 2.21 75 MHz (CDCIIICCI,, I:!) "C spectrum of (4-chlorophenyl)[(lR.ZR.3R,4S.5S)-4,5-di(4- chlorobenzoyl)-2-(4-chlomphenyl)-3-ethoxy-2hydmxycyclontyl]methanone (75)

Fig. 2.22 300 MHz (CDC13!CC14, 1 : I ) '1-1 spectrum of (4-bromophenyl)[(lR.2R.3R,4S,5S)-4.5- di(4-hromohenzoyl)-2-(4-bromorophenyl)-3-ethoxy-2-hydoycycontyl]methanonc (76)

I 76 - (75 M H z , CDCII!CC~. I I) i; -

I

I I

- , y r - . , , . , . , i

m Ilp . Fig. 2.23 75 MHz (CDCl,ICC14, I : I ) "C spectrum of (4-bromophenyl)[(lR,2R.3R,4S,5~-4,5-di(4- btomobenzoy\)-2-(4-bromorophenyl)-3-ethoxy-2-hydoxycycotyl]mt (76)

Fig. 2.24 301 hlHz (CDCII CCI.. I : I I H NMR speclmm old~as~crcornenc rnlxture o f 13-ethox)- 2-h!drox! -4.5.d1(4-mcrh! lbenzo) l)-2-(4-mth) p h n I c c l o p e n ] 4 m e h Iphm) I)n~rthanonc

(77)

(75 MHz.CDClj (C',, 1.1)

Fig. 2.25 75 MHz (CDCI,/CCI,, 1:l) "C NMR spectrum of diastereomeric mixture of [3-ethoxy- 2-hydroxy-4,5-di(4-methylbenzoyl)-2-(4-methylphenyl)cyclopentyl](4-rnethylphenyl)methanone

(77)

73

Scheme 2.30

Next, the three-component dommo reaction was attempted w~th different nucleophiles

to assess the formation of the cylopentanol derivatives. The reactions of trans-DBE 3

with az~de, cyanide, n~tromethane and thiolate anions were conducted. There was no

reaction of rrans-DBE 3 w ~ t h the phenyl thiolate and the heptanethiolate anlon. While

n~tromethane and methoxy anlons added to rrans-DEE 3 in conjugate mode to furnish

known and 84;' the product from conjugate addition of azide anion underwent

reduction to yield the reported'8~3~-amino-l,4-diphenylbut-2-ene-~,4-dione 43 (Scheme

2.31). The reaction of rrans-DBE 3 with cyanide anion resulted in a complex mixture of

products. The NMR spectra of crude material indicated the presence of conjugated

addition product 82 along with several other polymeric species. However, there was no

lndicat~on for the formation of cyclopentanol derivatives of the t y e 73. In conclusion,

the present smdy revealed that cylopentanol formation I S resh~cted to ethoxy anion.

Ph+'h OMeO

/ iii

' h h

I

Ph . 0 0

L ph+~h ph+~h

O2N 0 NH, 0 83 3 43

Reagents and conditions: i. NaCN, activated Ba(OH)2, EtOH, rt, 12h; ii. CH,N02, activated Ba(OH)2, EtOH, rt, 12 h; iii. activated Ba(OH)z, MeOH, rt, 12 h; iv. NaN,, activated Ba(OH)z, EtOH, IT, 12 h.

Scheme 2.31

2.2.3 Condensation reactions of trans-DBE with methyl acetoacetate

Robinson annulation of a$-unsaturated carbonyl compounds with active methylene

ketones is a well-known method for generating six-member rings.36 In thls method, three

reactions namely Michael addition, aldol condensation and dehydration take place

consecutively in domino process. The 2-ene- 1,4-diones e.g. trans-DBE 3 are interesting

substrates to study Robinson annulation reaction, I~~II .? -DBE 3 is a bifunctional molecule

with two carbonyl groups conjugated to a common double bond. To the best of our

knowledge Robinson annulation on ene-diones are not known. Therefore, we conducted

Robinson annulation on trans-DBE 3 and its derivatives with methyl acetoacetate (MAA)

85. Initial reaction would be base mediated M~chael addition of the anion generated from

methyl acetoacetate 85 to trans-DEE 3 to furnish triketone 86. Subsequently, the reaction

may follow Robinson annulation course leading to the formation o f cyclohexenone

derivative 87. On the other hand, reaction may also result in cyclopentenone derivative

88 (Scheme 2.32).

O / Y C i 3 P ~ $ ~ ~

,TOCH, OCH, 0 H,COC

85 86. "+,

0

88

Scheme 2.32

When trans-DBE 3 was treated with methyl acetoacetate 85 in the presence o f

activated Ba(OH)* in methanol, the reaction furnished the cyclohexanone derivative 89 as

a single diastereomer in about 60% yield (Scheme 2.33). The product was formed by

Michael addition followed by aldol condensation.

OCH,

3 85 89

Reagents andconditions: i. activated Ba(OH)2, MeOH, rt, 12 h.

Scheme 2.33

2.2.3.1 Structure and stereochemistry of cyclohexanone derivative 89

Structure and stereochemistry of the product (white solid, mp 152-154 OC, C21H2005)

methyl (IS,2R,4R)-2-benzoyl-4-hydroxy-6-oxo-4-phenylcyclohexane-~-carboxylate 89

was confirmed on the basis of spectral and analytical data. The IR spectrum of 89 showed

the frequencies at v 3409, 1732 and 1663 cm" for hydroxyl group, ester and benzoyl

carbon~ls, respectively. The 'H NMR spectrum (Fig. 2.26) showed a triple doublet at 6

4.83 ppm (J= 13.0,4.0 Hz) for C-2-H having two diaxial coupling with C-I-H and C-3-

Ha, and one axial-equatorial coupling with C-3-H,,. There was a peak at 6 2.38 ppm as

douhle triplet (J= 16.5 Hz, 2.5 Hz) due to C-3-H,, for coupling with C-2-H, C-3-Ha, and

also a weak W-coupling with C-5-He,. The peak at 62.15 ppm ( J = 13.5 Hz) as triplet is

due to C-3-H,, coupled with both C-%He, and also C-2-H. The C-5-He, appeared as

double doublet at 6 2.73 ppm ( J = 14.0, 2.5 Hz) coupled with C-5-H., and also a weak

W-coupling with C-3-H,,. The broad doublet at 6 3.10 ppm ( J = 14.0 Hz) was due to C-

5-H,,. There was a singlet at 6 3.72 ppm for methoxy of the ester functionality. There

was a doublet for C- I-H at 64.19 ppm ( J = 12.0 Hz) for axial oriented C-2-H.

The 'H-'H COSY spectrum (Fig. 2.27) of 89 showed the connectivity between C-2-H

i C-3-H,, and C-3-He,. The COSY spectrum also revealed the connectivity of C-2-H with

C-1-H. C-5-Ha, and C-3-H,, displayed connectivity with C-5-Hq and C-3-H,,

respectively. Thus the COSY spectrum helped to assign each resonance to various

hydrogens and establish their connectivity.

The NOESY spectrum (Fig. 2.28) of 89 revealed the steric proximity of various

hydrogens. The C-2-H displayed cross peaks with C-4-OH and C-3-He,. The C-I-H

showed cross peaks with C-5-H,, and C-3-Ha,. Likewise, C-5-H,, and C-3-H., revealed

cross peaks individually with C-5-I-I,, and C-3-He, respectively. The C-2-H revealed

coupling with one of the doublets at 6 8.03 ppm ( J = 8.0 Hz) in the aromatic region

assignable to C-2-H of C-2-Bz group. The spectral assignment of the characteristic

hydrogens1 carbons is given in Fig. 2.29.

Fig. 2.26 500 MHz (CDCI,) 'H C R spectrum of methyl (lS,2R,4R)- 2-benzoyl-4-hydroxy-6- oxo-4-phenylcyclohrxane- I-carboxylate (89)

Fig. 2.30 75 MHz (CDCI,/CCI,. I : I) 'k C R spectrum of methyl (IS,ZR,4R)- 2-benzoyl-4- hydmxy-6-0x0-4-phenylcyclohexane- I-carboxylate (89)

' i~ -- ,---7*-. ._, _ _ _ _ . 1 l i ' l . , t

PI ( 0 0 . )

Fig. 2.27 500 MHz (CDCII) 'H - 'H COSY spectrum of methyl (IS,2R,4R)- 2-bcnroyl-4-hydmxy- 6-0x0-4-phcnylcyclohexane-I-carborylate (89)

(303 MHz. CDCI,)

3

~ - ~ ' ~ ' ' " ~ ' ' ' ' i ' " i , , . ' Fig. 2.28 300 MHz (CDCI,) NOESY spcclmm of methyl (IS32R,4R)- 2-bcnzoyl-4-hydroxy-6-

0x0-4-phenylcyclahexanr-I -carboxylare (89)

,........... ................ + 64.83 (td, J = 13.0,4.0 Hz) ppm

3 r . . . .................. * 8 I 82.73 (dd, J = 14.0.2.5 Hz) ppm I I

5111

COOCH, ...................... 6 3 . 1 0 ( h r d . J = 14.0Hz)ppm

..................... i y H * 84.19(d, J = 12.0 Hz)ppm 0 4

I ,

I ...................................... * 62.38 (dt, J = 16.5 Hz, 2.5 Hz) ppm

Fig. 2.29 'H NMW "C NMR assignments for characteristic protons1 carbons of 89

The ''C NMR spectrum (Fig. 2.30) of 89 showed totally seventeen signals out of

which six are due to aliphatic carbons, eight are due to aromatic carbons and three for

carbonyl groups. The DEPT spectrum clearly explained the type of carbon atoms present

in the molecule. The spectral assignment of the characteristic carbons is given in Fig.

2.29. Based on the above spectral data and analytical data the compound was assigned as

methyl (IS,2R,4R)-2-benzoyl-4-hydroxy-6-oxo-4-phenylcyclohexane-I-carboxylate 89.

It is worth noting that out o f the possible four diastereomers, a single stereoisomer 89

formed in the reaction. I t appears that the first step in the sequence of reactions, Michael

addition, leads to triketoester 86 in which COOCH; and COPh are anti and CHzCOPh

and COCH, are gauche (Fig. 2.31). Subsequent intramolecular aldol condensation leads

to cyclohexanone derivative 89.

CH]COPh

H 3 c o o c ~ H 3 H 3 c 0 0 ~ @ 1 ~ ~ 3

HICOOC

P ~ O C ' C H ~ C O P ~ PhOC H H

86

Fig. 2.31

TO test the generality of the above reaction, (E)-l,4-di(4-chloro-3-methylphenyl)-2-

butene-l,4dione 90, (E)-l,4-di(4-bromophenyl)-2-butene-1,4-dione 74, (E)- 1,4-di(4-

methylpheny1)-2-butene-1,4-dione 65, (E). I ,4-di(4-methoxyphenyl)-2-butene-1,4-dione

91 were reacted with methyl acetoacetate 85 in the presence of activated Ba(OH)2. The

reactions furnished the corresponding cyclohexanone 92, 93, 94 and 95 in 54-65% yield

(Scheme 2.34). The products 92-95 were assigned structure and stereochemistry on the

basis of spectral data (Fig. 2.32-2.39), which is matched well with the parent compound

89, except the product 92, which was isolated as a mixture of isomers.

Reagents and conditions: i. activated Ba(OH)2, MeOH, rt, 12 h.

Scheme 2.34

2.2.3.2 Dehydration-decarbomethoxylation product 96 from the reaction of 89 with

pTSA

Even though mechanism of Robinson annulation is well understood and the final

products are enones, it is surprising that in the present case expected dehydration did not

take place in the last step leading to 96 even after acidic work-up. Thus the

cyclohexanone 89 was subjected dehydration with p-TSA under refluxing benzene by

using Dean-Stark apparatus to furnish known3' 5-benzoyl-3-phenyl-2-cyclohexen-I-one

96 in 96% yield (Scheme 2.35).

lI3('0OC

H,(' $r.H, 91

(400 Mlli.('ll( 1 % )

i% -., -.-.--..71.-.Ir.----r-. ~ .-.. khu! .

1 0 9 8 7 6 5 4 3 2 p p a

C ' 1:r 1----,$,y5T----J Fig. 232 400 MHz (CDCI,) 'H NMR spectrum of d~astereomeric mixture of methyl 2-(4-chloro- 3-methylbenzoyl)-4-(4-chloro-3-methylpheny)4-hydroxy6-oxocyclohexane I-carboxylate (92)

(IW MHL.CKI~)

Fig. 233 100 MHz (CDC13) "C NMK spectiurn of diastereomeric mixture of methyl 2-(4-cbloro- 3-mcthylbenzoyl)-l-(4-chloro.3-methylphenyl)-4-hydroxy-6-oxocyclohexaneeI-carboxylate (92)

Fig. 234 400 MHz (CDCI,) 'H N M R spectlum of methyl (lS,2R,4R)-2-(4-bromobenzoy1)-4-(4- bromopheny1)-4-hydroxy-6-oxocyclohexane- I-carboxylate (93)

Fig. 2.35 100 MHz (CDCI,) "C NM R spectrum of methyl (lS,2R,4R)-2-(4-bromobenzoyl)-4-(4- bmmophenyl)-4-hydro~y~6~oxocyclohexane-l-caoxylae (93)

Fig. 2.36 400 MHz (CDCI,) 'H NMR spectmrn of methyl (lS.ZH.4R)-4-hydroxy-2-(4- methylbenzoyl)-4-(4-methylphcnyl)-6-oxocyclohexane- I-carhoxylate (94)

- , T _ . ---_- . . ----- 1 1 0 ,/" , I " " I . , , 1>0 In" "(1 "* .C ." 0 -

Fig. 237 100 MHz (CDCI,) "C h\tR spectrum of methyl (IS,2R,4R)-4-hydroxy-2-(4- methylbenroyl)-4-(4-methylphenyl)-6-oxocyclohexane-I-carhoxylate (94)

. . r- . . ,---------.-

I =" ,Au ,"" . I 1 0 I D " .r * a .u 2.1 0 ,.

HJc@x$ 0 ..

b q OCHl OC'"

9s

(ao MHZ. rncl,)

-

Fig. 2.39 100 MHz (CDCI,) "C NMR spectrum of methyl (l$2R.4R)-4-hydmxy-2-(4- methoxybcnzoyl)-4-(4-methoxyphenyl)-6-oxocyclohexane-I-carboxylate (95)

4

a A 4 - t d U l 7 ,

1 0 9 8 7 6 5 4 3 2 1 0 PPm

\ ( i 141 lilsB bisiiz15 Fig. 2.38 400 MHz (CDCI,) 'H NMK spectrum of methyl (lS,ZK,4R)-4-hydroxy-2-(4-

methoxybenzoyl)-4-(4-methoxyphenyl)-6-oxocyclohexane-I -carboxylate (95) - r- rn - 4 - - 4 - - - - , w u

. . " 2 o z g z v . . . . - - - - - - - v - - m m - e - . . , - - - - - 7 - r a ? - - 1 0 9 r

89 96 Reagents and conditions: i.p-TSA, benzene, Dean-Stark, reflux, 5 h.

Scheme 2.35

The product 96 was formed by both dehydration and decarbomethoxylation taking

place in the same step. The structure of the product was assigned on the basis of spectral

and analytical data. The compound 96 did not show hydroxy and ester functionalities in

its IR spectrum. Instead it showed enone carbonyl and aromatic ketone absorption at

1676 c m ' . Thc 'H NMR spectrum of 96 showed a doublet at 66.42 ppm (J= 2.4 Hz) for

C-2-H. The "C NMR spectrum of 96 showed totally fifteen signals out of which three for

aliphatic carbon atoms, eight due to aromatic carbons, two for olefinic carbon atoms and

two due to carbonyl groups present in the molecule. Based on DEPT spectrum, the types

of carbon atoms present in the molecule could be clearly observed. The 'H and I3c NMR

chemical shift values matched well with the published data."

2.2.3.3 Decarhomethoxylation-dehydration reaction with DMSONaCI

The decarbornethoxylation-dehydration reaction was conducted using DMSOi N~CI''

under our newly developed microwave mediated reaction conditions. The reagent

NaCVDMSO is well known for deesterification of !3-ketoesters and diesters.

OH - 0 Ph Ph Ph Ph

89 96 97 Reagents and conditions: i. DMSOI NaCI, pv, 650 W, 5 min.

Scheme 2.36

We intended to generate decarbomethoxylated, hut not dehydrated product for further

synthetic1 mechanistic studies. However, present reaction furnished an interesting

hitherto unknown 7-hydroxy-3,S-diphenyl-1,3-dihydro-l-isobenzofuranone 97 (53%)

was formed along with the cyclohexenone 96 (23%) (Scheme 2.36).

The product 97 (white solid, mp 156-158 'C, C20H1403) was analyzed on the basis of

spectral data and analytical data. The presence of the peaks at v 3273 and 1733 cm.' in IR

spectrum revealed the presence of phenolic hydroxyl and lactone carbonyl groups. The

'H NMR spectrum (Fig. 2.40) of 97 showed a broad singlet at 6 7.81 ppm for C-7-OH.

There were also three sharp singlets at 6 7.23, 6.95 and 6.40 ppm for C-4-H, C-6-H and

C-3-H respectively. The I3c NMR spectrum (Fig. 2.41) of 97 also showed sixteen signals

out of which one signal was due to one aliphatic carbon, ten due to aromatic carbon

s~gnals and one signal due to carbonyl group. Based on DEPT spectrum, the types of

carbon atoms present in the molecule could be clearly assigned. The structure for 97 was

assigned as 7-hydroxy-3,5-diphenyl-l,3-dihydro-l-isobenzo~ranone. The EI mass

spectrum of 97 showed the miz peak at 302 was an additional support for 97.

98 99

Fig. 2.42

The phenolic lactone 97 forms a structural motif on natural products

bassidifferquinone A 98 and bassidifferquinone B 99 (Fig. 2.42). These natural products

are produced by S~reptom!~ces sp. 8-412 and found to induce fruiting body formation of

Favolus ur~ulur ius?~

2.2.3.3.1 Mechanism for the formation of isobenzofuranone derivative (97)

The mechanism of the formation of the 1,3-dihydroisobenzofwanone 97 could be

explained as follows (Scheme 2.37). Initially the reaction is likely to lead to dehydration

product 100, will be equilibrated viu keto-en01 tautomerism to give 101. The intermediate

101 would generate phenol 102 on aromatization. The phenol 102 on lactonization

provides 97.

Fig. 2.40 300 MHz (CDCIIICCI,) 'H NMR spectrum o f 7 hydroxy 3.S-d1phenyl-1.3-d1hydro-l- ~ r o q u ~ n o l ~ n e (97)

I

, rnpce ;r

h-- ;= 2 . r; 4

Fig. 2.41 75 MHz(CDCIIICClr) "cNMR spectrum of 7-hydroxy-3,5-d1phenyl-1.3-d1hydro-I- ~ < o q u ~ n o l ~ n e (97)

Scheme 2.37

2.4 Experimental section

General

For general details about experimental conditions see Chapter-]. [runs-DBE and its

derivatives were prepared according to literature procedure.' Activated Ba(OH)2 was

prepared by heating commercial Ba(OH)2,8H20 at 200 "C for 3 h in moffile furnace and

then stored in a de~iccator.'~

General procedure for Michael addition of trans-DBE (3) with cyclohexanone (62)

under basic conditions

To a stirred suspension of freshly activated Ba(OH)2 (heated to 100 "C for 2h and

cooled in a desiccator. 136 mg, 0.8 mmol) in 10 mL of absolute alcohol, cyclohexanone

62 (432 mg, 4.4 mmol) was added drop-wise at room temperature and stirred for 10 min.

trans-DBE 3 (944 mg, 4 mmol) was added to the reaction mixture in three equal portions

during 15 minutes and stirred for 12 h at room temperature. The reaction was monitored

by TLC and indicated formation of the product. The reaction mixture was diluted with

dichloromethane (25 mL), washed with ice water (2 x 20 mL), brine (2 x 10 mL), dried

(anhydrous Na2S04) and concentrated. The crude product was purified through column

chromatography on silica gel (100-200 mesh) using 5-15% EtOAc-hexanes as the eluent

to give an inseparable diastereomeric mixture of triketones 63 (815 mg, 61%). The

spectral data of the major isomer culled from the mixture is given below.

2-(2-O~oc~clohexyl)-1,4-diphen~l-1,4-butanedi0 (63): a

viscous oil; Rr = 0.45 (15% EtOAc-hexanes); IR (neat) v 680, 740,

995, 17-10> 1440, 1450, 1590, 1670, 1700 cm.'; 'H NMR (300 MHz,

CDC13!CCL3 1: 1) 6 1.54-1.62 (m, 3H); 1.89-2.03 (m, 3H). 2.28-2.46

(m, 2H), 2.72-2.78 (m, IH), 3.18 (dd, J = 18.0, 4.5 HZ, IH), 3.48

% @ (dd, J = 12.6, 3.9 Hz, IH), 4.66-4.72 (m, IH), 7.30-7.51 (m, 6H), 7.92 (dd, J = 8.7, 8.4

Hz, 2H), 8.06 (dd, J = 8.4, 6.9 Hz, 2H) ppm; "C NMR (75 MHz, CDC131CCL, 1:1) 6

25.3, 27.2, 29.3, 36.9, 39.6, 42.0, 51.3, 128.1, 128.4, 128.6, 128.8, 133.0, 136.1, 136.6,

138.3, 197.3, 201.5, 209.3 ppm; LRMS 334 (Mi, 8), 316 (6), 229 (a), 212 (lo), I33 (4),

lo5 (loo), 77 (56), 51 (8); HRMS calcd. for C12H220; 334.1569, found 334. 1562.

Reaction of (Q-1,4-di(4-chlorophenyl)-2-buten-1,4-dione (64) with cyclohexanone

(62)

Following the general procedure described above, the reaction of (@-1,4-di(4-

chl0rophenyl)-2-buten-1,4-dione 64 (1.0 g, 3.3 mmol) and cyclohexanone 62 (356 mg,

3.63 m o l ) in the presence of activated Ba(0H)z (1 13 mg, 0.66 m o l ) in absolute

ethanol (10 mL) resulted in 701 mg (53%) of inseparable mixture of 1,4-di(4-

chlorophenyl)-2-(2-oxocyclohexyl)-1,4-butanedione 66.

1,4-Di(4-chlorophenyl)-t-(2-oxocyclohexyl)-1,4- C1

butanedione (66). The spectral data of the major isomer

culled from the mixture is given in the following: a viscous

oil; Rr = 0.47 (15% EtOAc-hexanes); IR (neat) v 750, 840,

1085, 1210, 1480, 1560, 1670, 1700 cm"; 'H NMR (300

MHz, CDC13!CClr, 1:I) 6 1.52-1.64 (m, 3H), 1.91-2.07 (m,

% ,KJ 3H), 2.29-2.48 (m,2H), 2.71-2.78 (m, IH), 3.13 ( d d , J = 18.0, 4.2 Hz, IH), 3.42 ( d d , J =

18.0, 8.7 Hz, IH), 4.57-4.60 (m, IH), 7.36-7.47 (m, 4H), 7.83 (dd, J = 8.7, 8.4 Hz, 2H),

7.99 (dd, J = 8.7, 8.4 Hz, 2H) ppm; "C NMR (75 MHz, CDCI;!CC4, I :]) 625.3, 27.3,

29.4, 37.0, 39.7, 42.0, 51.4, 1.28.9, 129.0, 129.5, 130.1, 134.5, 134.8, 139.6, 139.7, 196.2,

200.5, 209.3 ppm; LRMS 402 (Mi, 6), 384 (5), 263 (5), 248 (lo), 139 (loo), 141 (35).

1 11 (40), 113 (15). 75 (10); HRMS calcd. forC22H~(1C110~402.0789, found 402. 0785.

Reaction of (.@l,4-di(4-methylphenyl)-2-buten-l,4-dione (65) with cyclohexanone

(62)

Following the general procedure described above, the reaction of (0-1.4-di(4-

methylpheny1)-2-buten-l,4-dione 65 (1056 mg, 4 m o l e ) and cyclohexanone (432 mg,

4.4 m o l ) in the presence of activated Ba(0H)l (137 mg, 0.8 m o l ) in absolute ethanol

(10 mL) resulted in 868 mg (60%) of inseparable mixture of 1,4-di(4-methylpheny1)-2-

(2-oxocyclohexyl)-l.4-butaned1one 67.

1,CDi(4-methylphenyl)-2-(2-oxocyclohexyl)-l,4-

butanedione (67). The spectral data of the major isomer

culled from the mixture is given in the following: R,= 0.42

(15% EtOAc-hexanes): viscous oil; IR (neat) v 750, 1170,

1595, 1665, 1710 cm"; ' H N M R (300 MHz, CDCIlICClr, 1:l)

6 1.55-1.62 (m, 3H), 1.87-2.03 (m, 3H), 2.22-2.36 (m, 2H),

2.38 (s, 3H), 2.40 (s, 3H), 2.26-2.80 (m, IH), 3.14 (dd, J = 17.7,4.5 Hz, IH), 3.36 (dd, J

= 18.0, 8.1 Hz, IH), 4.62-4.68 (m, IH), 7.2 (dd, J = 8.4, 8.1 Hz,2H), 7.3 (dd, J = 8.4, 8.1

Hz, 2H), 7.79 (dd, J = 8.4, 8.1 Hz, 2H), 7.94 (dd, J = 8.4, 8.1 Hz, 2H) ppm; "C NMR (75

MHz, CDC13ICCI,, 1:l) 621.6 (2C), 25.3, 27.3, 29.4, 36.9, 39.5,42.0, 51.5, 128.2, 128.7,

129.1, 129.3, 133.6, 134.2, 143.3, 143.5, 196.8, 201.2, 209.4 ppm; LRMS 362 (M*, 7),

344 (6), 243 (8), 226 (lo), 119 (loo), 91 (35), 65 (6); HRMS calcd. for C21H26O3

362.1882, found 362. 1884.

General procedure for the preparation of 5,6,7,8-tetrahydro-4-

quinolinyl)methanone derivatives, Reaction of 2-(2-oxocyclohexyl)-1,4-diphenyl-1,4-

butanedione (63) with ammonium acetate

The hiketone 63 (221 mg, 0.66 mmol). dissolved in dry methanol (4 mL), ammonium

acetate (508 mg, 6.6 mmol) was added and allowed to stir at room temperature for 18 h.

The reaction mixture was concentrated in ~ ~ c u o , diluted with dichloromethane (10 mL),

washed with water (2 x 15 mL), brine (2 x I0 mL), dried (anhydrous Na2S0,) and

concentrated in vucuo. The crude product was purified by column chromatography with

silica gel (100-200 mesh) using mixture of 5% EtOAc-hexanes as an eluent furnished 27

Phen~l(2-~hen~l-5,6,7,%tetrahydro-4-quinoin~)methanone 70: a

viscous oil; RJ= 0. 5 1 (10% EtOAc-hexanes); IR (neat) v 1650 cm-';

'H NMR (300 MHz, CDC13ICC14, I :[) 6 1.16-1.38 (m, 2H), 1.66-

1.88 (m, 2H), 2.33 (1, J = 6.2 Hz, 2H), 2.58 (t, J = 6.3 Hz, LH), 7.05-

7.56 (m, 6H), 7.33 (s, IH), 7.70 (d, J = 7.5 HZ, 2H), 7.93 (d, J = 7.5

Hz, 2H) ppm.

Reaction of 1,4-di(4-chlorophenyI)-2-(2-oxocyclohexyl)-1,4-butanedlone (66) with

ammonium acetate

Following the general procedure described above, the reactlon of 1,4-di(4-

chlorophenyl)-2-(2-oxocyclohexyl)-1,4-butanedione 66 (265 mg, 0.66 mmole) and

ammonium acetate (508 mg, 6.6 mmol) in dry methanol (5 mL) resulted in 36 mg (17%)

of (4-~hlorophenyl)~2-(4-chlorophen~l)-5,,7,8-tetrahydro-4-~uinolin~l]methanone 71.

(4-Chlorophenyl)(2-(4-chlorophenyl)-5,6,7,8-tetrahydr&4-

quinolinyl~methanone (71): a viscous oil: Ri= O,49 (10% EtOAc-

hexanes); IR (neat) v 1655 cm.'; 'H NMR (400 MHz, CDCI,) 6

1.77-1.81 (m, 2H), 1.91-1.94 (m, 2H), 2.65 (t, J = 6.4 Hz, 2H),

3.07(t, J = 6.4Hz,2H), 7.35 (s, IH), 7.40(d, J = 8.4Hz,2H), 7.47 CI,

(d, J = 8.4 Hz, 2H), 7.71 (d, J = 8.4 Hz, 2H), 7.90 (d, J = 8.4 Hz, 2H) ppm; "C NMR

(100 MHz, CDCI,) 6 22.3, 22.7, 26.1, 33.2, 115.2, 127.8, 128.2, 128.9, 129.3, 131.4,

Reaction of 1,4-di(4-methylphenyI)-2-(2-oxocyclohexyl)-l,4-hutanedione (67) with

ammonium acetate

Following the general procedure described above, the reaction of 1,4-di(4-

methylphenyl)-2-(2-oxocyclohexyl)-1.4-butanedione 67 (347 mg, 0 96 mrnol) and

ammonium acetate (739 mg, 9.6 mmol) in dry methanol (5 mL) resulted in 49 mg (15%)

of (4-methylphenyl)[2-(4-methylphenyl)-5,6,7,8-tetrahydro-4- HIC

quinolinyl]methanone 72.

(4-Methylphenyl)[2-(4-nlethylphenyl)-5,6,7,R-tetrahydro-4- O v o

quinolinyllmethanone (72): a viscous oil; Rr = 0.53 (10%

EtOAc-hexanes); IR (neat) v 1650 c m ; 'H NMR (300 MHz, H,C

CDC1dCCL, 1:1) 6 1.76-1.80 (m, 2H), 1.93 (m, 2H), 2.39 (s, 3H), 2.44 (s, 3H), 2.65 (t, J

=6.3Hz,2H),3.06(t,J=6.3Hz,2H),7.20(d,J=8.1 Hz,2H),7.25(d,J=8.1 Hz,2H),

7.33 (s, IH), 7.72 (d, J = 8.1 Hz, 2H), 7.83 (d, J = 8.1 Hz, 2H) ppm; "C NMR (75 MHz,

CDCIdCCI4, 1:l) 621.2, 21.7, 22.4, 22.7, 25.9, 33.2, 115.3, 127.0, 129.4, 129.8, 130.5,

131.4, 133.6, 136.2, 138.7, 145.1, 147.3, 154.2, 158.2, 196.8 ppm.

General procedure for nucleophile triggered do mi^ reactions of (E)-14-diphenyl-

2-butene-1,4-dione (3)

To a stirred mixture of activated Ba(OHi2 (73 mg, 0.43 mmol) in 10 mL absolute

ethanol, tra~ls-DBE 3 (500 mg, 2.12 mmol) was added in four equal portion and allowed

to stir at room temperature for 12 h. The reaction mixture was turned yellow to reddish

brown. The reaction was monitored by TLC and showed the product formation. The

suspended solid particles were filtered through celite pad and concentrated the filtrate to

3 mL. The reaction mixture was dissolved In 30 mL of dichloromethane and poured over

ice-cooled water. The organic layer was separated, washed again with water (3 x 20 mL)

and collected the organic layer. The organic layer further washed with brine solution (2 x

10 mL) and finally dried over anhydrous Na2S04. The dichloromethane from the reaction

mixture was removed using rotevaporator. The resulted reddish brown mixture was

loaded into column chromatography (silica gel, 100-200 mesh) using 10% EtOAc-

hexanes as an eluent resulted 63 mg (12%) pure isomer 73 and 302 mg (55%) as mixture

of isomers.

~(lR,2R,3R,4S,5S)-4,S-Dibenzoyl-3-ethoxy-2-hydrox~ C,Hsl O H 0

2-phenylcyclopentyll(phenyl)methanone (73): a H,CH,CO

colorless solid; mp 184- 186 'C; Rr = 0.43 (10% EtOAc- C,H, hexanes); IR (KBr) 691, 709, 987, 1095, 1180, 1258,

*? O C 6 H ~

1449, 1596, 1683, 2915, 2978, 3062, 3466 cm"; 'H NMR (300 MHz, CDC13) 60.68 (t, J

= 7.2 Hz, 3H), 2.82-2.88 (m, IH), 3.07-3.12 (m, IH), 4.20 (s, IH), 4.49 (d, J = 7.8 Hz,

IH), 4.55 (d, j = 10.5 Hz, IH), 4.78 (dd ,JZ7.8 , 10.5 HZ, IH), 5.76 (t ,J= 10.5 Hz, IH),

7.05(1, j=7 ,8Hz,2H) , 7.21-7.54(m, I4H) ,7 .89(d , J=7 .5Hz ,2H) ,8 .26(d , J=7 .5Hz5

2H) ppm; "C NMR (75 MHz, CDCI,) 6 14.64, 46.09, 54.79, 62.27, 68.86, 82.73, 89.7,

124.82, 127.26, 127.76, 128.02, 128.28, 128.52 (2c), 128.62, 129.44, 132.36, 133.10,

133.60, 136.20, 137.21, 137.30, 144.65, 196.89, 197.45, 202.51 ppm; FAB-MS 519

( ~ + 1 ) ; Anal. Calcd for C U H J ~ O ~ : C, 78.74; H, 5.83. Found: C, 78.77; H, 5.87.

Crystal and structure refinement of [(lR,2R,3R,4S,SS)-4,S-dibenzoyl-3-ethoxy2-

hydroxy-2-phen~lcyclopentyl)(phenyl)rnethanone (73). Single crystals were obtained

by slow evaporation from a solution of EtOAc-hexanes (2:I). The crystal data are

summarized in Table 2.1. The refinement converged to a final R-index of 0.14. The

fractional atomic coordinates and equivalent isotropic displacement parameten for all the

non-hydrogen atoms are listed in Table 2.2.

Table 2.1 Crystal data and structure refinement f o ~ cyclopentanol 73

Empirical Formula: C34H300s

Formula weight: 518.58

Temperature: 293(2) K

Wavelength: 0.71073

Crystal system, space group: Triclinic, P-l

Unit cell dimensions: a = 11.0603(4) A a = 108.079(1) deg.

b = l1.2631(4) A 0 = 91.207(1) deg.

c = 12.4962(4)A y=106.913(l)deg.

Volume: 1405.18(8) A3 z, calculated density: 2, 1.226 ~ ~ l m '

Absorption coefficient: 0.08 1 mm-'

F(000): 548

Crystal size: 0.40 x 0.32 x 0.24 mm

Theta range for data collection: 1.73 to 29.37 deg.

Limiting indices: - 13<=hc= 15, .9<=k<=15, - 17<=1<= 16

Reflection collected/ unique: 1007 11 6641 [R(~nt) = 0.04991

Completeness to theta = 29.37 85.7%

Absorption correction: None

Refinement method: Full-Matrix least-squares on F*

Datd restraints1 parameters: 66411 01 352

Goodness -of - fit: 0.882

Final R indices [1>2 sigma(l)]: Rl = 0.0657, wR2 = 0.15 16

R indices (all data): R1 = 0.1400, wR2 =0.1803

Largest diff. Peak and hole: 0.272 and -0.287 e ~ . '

Reaction of (Ef-l,4-di(4-chlorophenyl)-2-butene-1,4-dione (64) and activated

Ba(OH)l

Following the general procedure described above, the reaction of (E)-1.4-di(4-

chloropheny1)-2-butene-13-dione 64 (600 mg, 1.97 mmol) and activated Ba(0H)l (67

mg, 0.39 mrnol) using 10 mL 3:2 EtOH:CHCI3 as solvent furnished pure cyclopentanol

derivative 75 (37 mg, 6%) and mixture of isomers (393 mg, 66%) which was purified by

column chromatography using 10% EtOAc-hexanes as an eluent.

(4-ChIorophenyl)[(lR,ZR,3R,4S,SS)-4,5-di(4- p-Cl-C6H,,,, OHO

chlorobenzoyl)-2-(4-chloropheny1)-3-ethoxy-2- ~ ~ ~ ~ ~ ~ ~ ~ ~ b - ~ c l

hydroxycyclopentyl]methanone (75): a colorless P-CI-C~H,

solid; mp 168-170 "C; Rf = 0.36 (10% EtOAc- 0 C,H4-p-CI

hexanes); IR (KBr) 756, 840, 1006, 1093, 1247, 1401, 1489, 1588, 1684, 2929, 2975,

3069, 3091, 3466 cm"; 'H NMR (300 MHz, CDCIIICCL, 1:l) 6 0.76 (t, J= 6.9 HZ, 3H),

2.81-2.91 (m, lH), 3.06-3.16 (m, IH), 4.04 (s, IH), 4.30 (d, J = 10.8 Hz, IH), 4.35 (d, J =

7.8 Hz, IH), 4.60 (t, J = 9.9 Hz, IH), 5.56 (t, J= 10.2 Hz, IH), 7.07 (d, J = 8.4 Hz, 2H),

7.24(d, J=8.1 Hz,2H),7.31 (d, J = 8 . 1 Hz,2H),7.39-7.50(m,6H),7.81 (d, J = 8 . 4 H z ,

2H), 8.16 (d, J = 8.4 Hz, 2H) ppm; "C NMR (75 MHz, CDCl,iCC&, 1:l) 6 14.98, 45.86,

54.60, 62.44, 69.04, 82.53, 89.73, 126.38, 128.29, 129.00, 129.15, 129.51, 129.77,

130.21, 131.15, 133.87, 134.29, 135.50, 135.61, 139.33, 139.87, 140.63, 143.37, 194.65,

195.09, 200.72 ppm; LRMS M' did not appear, 639 (7%), 517 (19%), 515 (30%). 497

(la%), 468 (29%), 447 (IS%), 445 (35%), 443 (27%), 428 (20%), 364 (31%), 348 (24%),

348 (18%), 307 (69%), 305 (loo%), 304 (74%), 181 (12%), 183 (7%). 113 (27%), 11 1

(78%), 89 (19%), 75 (55%), 69 (18%); Anal. Calcd for C I ~ H Z ~ C I ~ O S : C, 62.24; H, 3.99.

Found: C, 62.21; H, 4.02.

Table 2.2 Atomlc coordinates (XIO') and equ~valent ~sotroplc d~splacement parameters

(A2x I 0') for 73

X Y z Weq) o(1) -937(2) 11583(2) 1558(2) 66(1) o(2) 2262(2) 12689(2) 3054(2) 74(1) o(3) 2209(2) 973 l(2) 2974(1) so([) I :::; 141(2) 8095(2) 3314(1) 49( 1)

-1345(2) 9956(2) 4500( 1) 64( 1) '31) -35(2) 10765(2) 2800(2) 38(1)

950(2) 1 9:; 10533(2) 1982(2) 40(1) 9297(2) 2072(2) 41(1)

c(4) -77(2) 8427(2) 2344(2) 38(1) I c(5) -950(2) 9356(2) 2569(2) 38(1) 1 c(6) -7 19(?) 11664(2) 2555(2) 44(1)

C(7) - 1 158(2) 12602(2) 3466(2) 46(1) C(8) -794(3) 12923(2) 46 1 1(2) 56( 1) I c (9) -1221(3) 17825(3) 5415(2) 67(1)

c ( 10) -1992(3) 14430(3) 5078(3) 79(1) 1 C(l1) -2368(4) 14131(3) 3948(3) 97( 1) C(12) -1947(3) 13226(3) 3 144(3) 76(1) C(13) 2144(2) 1 1707(2) 2234(2) 48(1) c ( l4 ) 3 148(2) 11684(2) 1454(2) 48(1) c ( I s ) 4314(3) 12691(3) 1806(3) 72(1) C(16) 5242(3) 12767(4) 1092(3) 93(1) c ( 17) 5033(4) 11834(4) 323) 98(1) C(18) 3904(3) 10818(4) -326(3) 79(1) (719) 2962(3) 10758(3) 389(2) 59(1) '320) 2988(3) 8884(3) 2878(3) 81(1) c(21) 4170(5) 9579(5) 3551(5) 214(4) c(22) -685(2) 7153(2) 1361(2) 40(1) C(23) -991(2) 5931(2) 1507(2) 51(1) c(24) -1536(3) 4786(3) 589(3) 65(1) ~ ( 2 5 ) -1783(3) 4849(3) -466(3) 68( 1) c(26) -1492(3) 6040(3) -632(2) (327) -938(3) 7185(2) 276(2) 56(l) c(28) -1726(2) 91 73(2) 3536(2) 44(1)

I c(29) -2915(2) 8038(2) 3330(2) 46( 1) ~ ( 3 0 ) -3582(2) 73090) 2254(2) 6 l ( l ) 1 c(31) -4730(3) 6338(3) 2131(3) 82(1) (732) -5210(3) 6065(3) 3070(4) 99(1) '233) -45333) 6747(3) 4133(3) 93(1)

c(34) -3400(3) 7729(3) 4268(2) 67( 1)

Reaction of (&1,4-di(4-bromophenyl)-2-butene-1,4-dione (74) and activated

B~(OH)I

Following the general procedure described above, the reaction of (E)-1,4-di(4-

bromopheny1)-2-butene-1,4-dione 74 (560 mg, 1.42 mmol) and activated Ba(OH)2 (49

mg, 0.28 mmol) using 10 mL 3:2 EtOH:CHCI, as solvent furnished pure cyclopentanol

derivative 76 (37 mg, 6%) and mixture of isomers (393 mg, 66%) which was purified by

column chromatography using 10% EtOAc-hexanes as an eluent.

(4-Bromophenyl)[(lR,2R,3R,4S,SS)-4,5-di(4-

bromobenzoyl)-2-(4-bromopheny1)-3-ethoxy H3CH2C0 C6H,-p-Br

hydroxycyciopentyl]methanone (76): a colorle~s

solid; mp 176-178 OC; Ri = 0.38 (10% EtOAc- 0 C6H4-p-Br

hexanes); 1R (KBr) 834, 980, 1003, 1073, 1096, 1234, 1398, 1486, 1585, 1671, 2927,

2971, 3081, 3496 cm-'; 'H NMR (300 MHz, CDCI,ICCI+, 1: 1 ) 60.71 (t, J = 7.2 Hz, 3H),

2.82-2.92 (m, IH), 3.03-3.13(m, lH),4.07(s, lH),4.36(d,J= 10.8Hz, lH) ,4 ,42(d , J=

7.8 Hz, lH),4.62(t, J = 8 . 1 Hz, 1H),5.61 ( I , J = 10.2Hz, lH) ,7 .17(d , J=7 .5Hz,2H) ,

7.25 (d, J = 8.1 Hz, 2H), 7.38 (d, J = 8.1 Hz, 2H), 7.46 (d, J = 8.7 Hz, 2H), 7.60 (dd, J =

6.9, 4.8 Hz, 4H), 7.74 (d, J = 8.4 Hz, 2H), 8.1 1 (d, J = 8.4 Hz, 2H) ppm; "C NMR (75

MHz, CDC131CC4, I :]) 6 14.72, 45.81, 54.56, 62.29, 69.14, 82.40, 89.32, 121.74,

126.60, 127.94, 128.55, 129.44, 129.64, 130.97, 131.23, 131.84, 131.96, 132.11, 134.71,

135.91, 143.41, 195.42, 196.10,201.24 ppm; LRMS M' peak did not appear, 338 (20%),

228 (loo%), 216 (12%), 117 (lo%), 117 (38%), 90 (40%), 57 (42%); Anal. Calcd for

C34H14Br401: C, 48.94; H, 3.14. Found: C, 48.91; H, 3.19.

Reaction of (E)-1,4-di(4-methylphenyl)-2-butene-1,4-dione (65) and activated

Ba(OH)t

Following the general procedure described above, the reaction of (@-1,4-di(4-

methylpheny1)-2-butene-1,4-dione 65 (528 mg, 2 mmol) and activated Ba(0H)l (68 mg,

0.4 mmol) using 10 mL EtOH as solvent furnished 3-ethoxy-2-hydroxy-4,5-di(4-

methylbenzoyl)-2-(4-methylphenyl)cyclopenty](4-methyphenyl)methanone as a mixture

of isomers (307 mg, 64%) which was purified by column chromatography using 10%

EtOAc-hexanes as an eluent.

3-Ethox~-2-h~droxy-4,Mi(4-meth~1henzo~1)-- pMe-C,H,

(4-methylphenyl)cyclopenty~l(4- "3c~2c0&2~4-p~e

methylphen~l)methanone (77): a colorless solid; p-Me-C6H4

mP 200-202 OC; Rf = 0.40 (10% EtOAc-hexanes); 0 C&-p-Me

IR (KBr) 7213 828, 1006, 1104. 1182, 1240, 1377, 1463, 1573, 1606, 1670, 2853. 2923,

3463 cm.'; 'H NMR (300 MHz. CDCI,ICCI,, I :]) 60.76 (1, J = 7.5 Hz, 3H), 2.28 (s, 3H).

2.31 (s, 3H), 2.37 (s, 3H), 2.44 (s, 3H), 2.86-2.91 (m, 1H). 3.09-3.17 (m, IH), 4.15 (s,

IH), 4.31 id, J = 7.2 112, IH). 4.40 (d, J = 7.8 Hz, IH), 4.58 (dd, J = 5.7, 13.8 Hz, IH),

5.59 (t. J = 10.2 Hz, IH), 6.81-6.86 (m, 2H), 7.07-7.29 (m, 41-1). 7.42-7.53 (m, 2H), 7.75-

7.85 (m, 4H), 7.95 (d, J = 8.40 Hz, 2H), 8.08 (d, J = 8.40 Hz, 2H) ppm; "C NMR (75

MHz, CDC13ICC14, [ :I) 6 15.38, 21.09, 21.25 (2C), 21.79, 47.05. 56.24, 62.71, 68.66.

83.00. 90.42, 125.03, 126.02, 128.34, 128.47, 128.95, 129.16. 129.29, 129.84, 132.98.

134.08, 135.07, 136.20, 138.28, 139.90, 142.85, 145.10, 196.01, 199.98, 201.71 ppm;

FAB-MS 575 (M++I); Anal. Calcd for C,xH3~Or: C, 79.44; H, 6.66. Found: C, 79.42; H,

6.69.

Microwave promoted condensation reaction of trans-DBE (3)

The mixture of trans-DBE 3 (100 mg, 0.42 mmol), activated Ba(OHj2 (14.4 mg, 0.09

mmol) and I mL absolute ethanol were taken in a Teflon sealed vessel and kept in a

microwave oven at 215 W for 4 min. The solid particles present in the reaction mixture

was filtered through celite pad, dissolved in I0 mL dichloromethane and poured over ice-

cooled water. The organic layer was separated, washed with water (3 x 5 mL). The

organic layer funher washed with brine solution (2 x 5 mL), dried over anhydrous

Na2S04 and concentrated. The resulted mixture was subjected to column chromatography

(silica gel 100-200 mesh) to give 4,5-Dibenzoyl-3-ethoxy-2-hydroxy-2-

phenylcyclopentyl](phenyl)methanonc 73 (87 mg, 7Y%), as a gummy yellow liquid as

mixture of isomers.

Reaction of (&1,4-diphenyl-2-hutene-l,4-dione (3) with sodium azide

To a stirred mixture of activated Ba(OH)2 (98 mg, 0.57 mmol) and sodium azide (465

mg, 7.2 rnmoi) in I0 mL absolute EtOH, (E)-i,4-diphenyl-2-butene-I,4-dione 3 (675 mg,

2.86 mmol) was added portion wise and allowed to stir at room temperature for 12 h. The

reaction was monitored by TLC and showed the product formation. Then activated

Ba(OH)2 was present in the reaction mixture was filtered through celite pad, concentrated

the reaction mixture to 3 mL. The reaction mixture was dissolved in 35 mL of

dichloromethane and poured over ice-cooled water. The organic layer was separated,

washed again with water (3 x 25 mL) and collected the organic layer. The organic layer

further washed with brine solution (2 x 20 mL) and finally dried over anhydrous Na2SO4.

The dichloromethane present in the reaction mixture was removed under reduced

pressure. The resulted brown mixture was subjected into column (silica gel. 100-200

mesh) using 10°/o EtOAc-hexanes as an eluent timished a yellow solid, (Z)-2-amino-1.4-

diphenyl-2-butene-l,4-d~one 43 (418 mg. 58%).

(Z)-2-Amino-1,4-diphenyl-2-butene-1,4-dlone (43): a 0 @=.

yellow solid; mp 132-134 "C (lit.133-134 OC); H, = 0.48 . , g! if (10% EtOAc-hexanes); 1R (KBr) v 725, 768. 1172, 1239, ljHl I)

1275, 1445, 1527, 1593, 1613, 1664. 3269, 3378 cm-'; ' H

NMR (300 MHz, CDCI]) G 6.23 (s. IH), 7.39-7.56 (m, 5H), 7.66 (t, J = 7.37 Hz, IH),

7.82 (t, J = 7.02 Hz, 2H), 7.88 (t, J = 7.19 Hz, 2H), 9.5 (br s, 2H) ppm; "C NMR (75

MHz, CDCI]) 697.63, 127.37, 128.51 (2C), 129.81, 131.96, 133.41, 135.42, 139.28,

152.57, 191.75, 193.63 ppm.

Reaction of (E)-1,4-diphenyl-2-butene-l,4-dione (3) with nitromethane

Following the general procedure described above, the reaction of (0-1,4-diphenyl-2-

butene-1,4-dione 3 (708 mg, 3 mmol), nitromethane (458 mg, 7.5 mmol) and activated

Ba(OH)2 (103 mg, 0.6 mmol) in I0 mL absolute EtOH as solvent furnished 2-

(nitromethyl)-l,4-diphenyl-l,4-butanedione 83 (423 mg, 54%) which was purified by

column chromatography uslng 10% EtOAc-hexanes as an eluent.

2-(Nitromethyl)-14-diphenyl-1,Cbutanedione (83): a

colorless solid; mp 128 'C; R,= 0.30 (10% EtOAc-hexanes); 4 4 IR (KBr) 691, 757,961, 984. 1216, 1253, 1386, 1416, 1447, '+

1552, 1679, 2978, 3066 cm"; 'H NMR (300 MHz, CDCI,) G i N ~ q

3.25 (dd, J = 6.91, 7.40 Hz. IH). 3.55 (dd, J = 4.76, 1.58 Hz, IH). 4.60-4.68 (m, IH),

4.88-4.96 (m, 2H), 7.44-7.63 (m, 6H), 7.91 (d, J = 8.69 Hz, 2H), 8.04 (d, J = 8.74 Hz,

2H) ppm; I3c NMR (75 MHz, CDCI,) 6 37.99, 39.5, 74.62, 128.12, 128.66, 128.84,

Reaction of (@-1,4-diphenyl-2-buten+1,4-dione (3) with sodium cyanide

Following the general procedure described above, the reaction of (@-1.4-diphenyl-2-

butene-l94-dione 3 (944 mg, 4 mmol), sodium cyanide (490 mg, I0 mmol) and activated

Ba(OH)z (136.8 mg, 0.8 mmol) using 10 mL absolute EtOH as solvent furnished mixture

of products (666 mg, 67%). The NMR spectra of the crude materials did not show any

evidence for cyclopentanol formation. But conjugate addition product 82 along with

polymeric products was present in the mixture.

Reaction of (@-1,4-diphenyl-2-butene-l,4-dione (3) in methanol

Following the general procedure described above, the reaction of (E)-1,4-diphenyl-2-

butene-l,4-dione 3 (300 mg, 1.27 mmol) and activated Ba(OH)2 (43.4 mg, 0.26 mmol)

using 5 mL absolute EtOH as solvent furnished 2-rnethoxy-l,4-diphenyl-l,4-butanedione

84 (208 mg, 65%) which was purified by column chromatography using 10% EtOAc-

bexanes as an eluent.

2-Methoxy-1,4-diphenyl-1,4-butanedione 84: a colorless

gummy liquid; Rr = 0.38 (10% EtOAC-hexanes); IR (KBr)

763, 841, 1005, 1250, 1401, 1489, 1588, 1683, 2929, 2977,

&,J3 0, 0

CH3 3070 cm"; 'H NMR (400 MHz, CDCI,) 6 1.83 (t, J = 6.35 Hz,

IH), 2.31 (t, J = 6.35 Hz, lH), 3.41 (s, 3H), 5.39 (dd, J = 4.39, 11.72 Hz, IH), 7.41-7.59

(m, 6H), 7.95 (d, J = 7.81 Hz, 2H), 8.04 (d, J = 7.81 Hz, 2H); '"2 NMR (100 MHz,

CDCL) 640.62, 57.80, 78.59, 127.58, 128.21, 128.32, 128.35, 133.42, 133.53, 135.06,

136.53, 196.72, 199.60 ppm.

Condensation Reactions of (E)-1,4-diphenyl-2-butene-1,4-dione (3) with methyl

acetoacetate (85)

To the stirred suspension of activated Ba(OH)2 (145 mg, 0 3 5 mmol) in 10 mL dry

methanol, methyl acetoacetate 85 (540.6 mg, 4.66 mmol) was added and allowed to stir at

room temperature for 15 min. Then, truns-DBE 3 (1.0 g, 4.24 mmol) was added onion wise and continued the stirring for 12 h. The reaction mixture turned to reddish brown.

The reaction was monitored by TLC, which showed a product formation. Then, activated

Ba(OH)2 was filtered through celite pad, concentrated the reaction mixture under vacuo

to 3 m ~ , ~h~ reaction mixture was then dissolved in 40 mL dichloromethane and poured

over ice-cooled water. The organic layer was separated, washed again with water (3 x 30

mL) and collected the organic layer. The organic layer was further washed with brine

solution (2 x 10 mL) and finally dried over anhydrous Na2S04. The dichloromethane

from the reaction mixture was removed under reduced pressure. The resulted reddish

brown mixture was loaded into column (silica gel, 100-200 mesh) and eluted using 15%

EtOAc-hexanes as an eluent to furnish methyl (IS,2R,4R)-2-benzoyl-4-hydroxy-6-0~0-4-

phenylcyclohexane-I-carboxylate 89 (599 mg, 60%).

Methyl (1S,2R,4R)-2-benzoyl-l-hydroxy-6-0~0-4-

phenylcyclohexane-1-carboxylate (89): a colorless sol~d; mp

152-154 "C; R, = 0.22 (20% EtOAc-hexanes); IR (KBr) 698, 0

752, 986, 1017, 1163, 1269, 1368, 1449, 1595, 1663, 1703,

~ ~ ~ ~ ~ ~ 7 5 ~ ~ 1732, 2998, 3409 cm"; 'H NMR (500 MHz, CDC13) S 2.15 (t, J

0 = 13.5 Hz, IH), 2.38 (dt, J = 16.5, 2.5 Hz, IH), 2.73 (dd, J = 14.0, 2.5 Hz, IH), 3.10 (d, J

= 14.0 Hz, IH), 3.72 (s, 3H), 4.19 (d, J = 12.0 Hz, IH), 4.83 (td, J = 13.0, 4.0 Hz, IH),

7.26-7.30 (m, 2H), 7.36 (t, J = 7.5 Hz, 2H), 7.43-7.49 (m, 3H), 7.58 (td, J = 8.0 Hz, 1.5,

IH), 8.03 (d, J = 8.0 Hz, 2H) ppm; "C NMR (75 MHz, CDCI,ICC4, 1:l) 6 41.6, 44.3,

52.3, 54.0, 57.9, 77.2, 124.3, 127.9, 128.8, 128.9 (2C), 133.6, 135.2, 145.5, 169.4, 199.9,

203.9 ppm; LRMS 352 (MI, did not appear), 334 (7%), 247 (31%), 215 (20%), 173

(11%), 120 (12%), 105 (loo%), 77 (79%), 51 (13%); Anal. Calcd. for C21H2005: C,

71.58; H, 5.72. Found: C, 71.54, H, 5.75.

Reaction of (~-1,4-di(4-chloro-3-methylphenyl)-2-butene-1,4-dione (90) and methyl

acetoacetate (85).

Following the general procedure described above, activated Ba(OH)2 (58.1 mg, 0.34

mmol), methyl acetoacetate 85 (214.6 mg, 1.85 mmol) and (0-l,4-di(4-chloro-3-

methylpheny1)-2-butene-I,4-dione 90 (500 mg, 1.68 mmol) in 10 mL MeOH to give

methyl 2-(4-chloro-3-methylbenzoyl)-4-(4-chloro-3-methylphenyl)-4-hydrox~6-

oxocyclohexane-1-carboxylate 92 (371 mg, 54%) which was purified by column

chromatography using 15% EtOAc-hexanes as an eluent.

Methyl (1S,2R,4R)-2-(4-chloro-3-methylbenzoyl)4-(4-chloro-3-methylphenyl~4-

hydroxy-6-oxocyclohexane-1-carboxylate (92): a VISCOUS oil; R f = 0.25 (20% EtOAc-

hexanes); IR (KBr) 615,698, 760, 894, 1048, 1165, 1216, 1340, 1377, 1445, 1480, 1569,

1593, 1641, 1715, 1743,2854,2954,3480 cm-' ; 'HNMR (400 MHz, CDCI,) S2.lO (t, J

= 13.b41 IH)? 2.31 (s, IH), 2.33 (s, 3H), 2.39 (s, 3H), 2.70 0 (dd, J = 13.8432.08 Hz, IH), 3.05 (d, J = 13.84 Hz, IH), 3.68 HlCOOC

(s, 3H), 4.15 (d, J = 11.72 Hz, IH), 4.74 (td, J = 12.36, 3.64

Hz, 7.19 (t, J = 6.16 Hz, IH), 7.29 (m, IH), 7.30 (s, IH), & \

7.42 (d, J = 8.32 Hz, ]HI, 7.77 (d, J = 6.48 Hz, IH), 7.85 (s, \ , CH, H3C , IH) PPm; "C NMR (100 MHz, CDCI,) 6 19.60, 20.13,41.27, CI

44.28, 52.46, 53.75, 57.80, 76.76, 123.1, 126.9, 127.5, 129.3, 129.7. 131.1, 133.4, 136.4,

137.0, 140.6, 143.9, 169.6, 199.6,204.3ppm.

Reaction of (E)-1,4-di(4-bromophenyl)-2-butene-l,4-dione (74) and methyl

acetoacetate (85).

Following the general procedurc described above, activated Ba(OH)2 (43.4 mg, 0.25

mmol), methyl acetoacetale 85 (162.4 mg, 1.4 mmol) and (E)-l,4-di(4-bromopheny1)-2-

butene-1,4-dione 74 (500 mg, 1.27 mmol) in 10 mL 3:2 MeOH:CHCI, to give methyl

( I S,2R,4R)-2-(4-bromobenzoyl)-4-(4-bromophenyl)-4-hydroxy6-oxocyclohexane- 1-

carboxylate 93 (427 mg, 61%) as colorless solid which was purified by column

chromatography by using 15% EtOAc-hexanes as an eluent.

Methyl (1S,2R,4R)-2-(4-bromobenzoyl)-4-(4-bromophenyl)-

4-hydroxy-6-oxocyclohexane-1-carboxylate (93): a colorless H3COOC

solid; mp 160-162 OC; RI = 0.26 (20% EtOAc-hexanes); IR O\+

(KBr) 740, 822, 1009, 1072, 1166, 1226, 1257, 1377, 1458,

-p._ 1584, 1681, 1715, 1733, 2854, 2925,3462, cm-I; 'H NMR (400

$q Br

Br MHz,CDCl3) 62.09 (t, J = 13.36Hz, IH), 2.30(dt, J = 18.0, 6.0

Hz, IH), 2.70 (dd, J = 13.92, 2.32 Hz, IH), 3.04 (s, IH), 3.05 (d, J = 10.6 Hz, IH), 3.71

(s, 3H), 4.15 (d, J = 11.72 Hz, IH), 4.73 ( t d , J = 12.44, 3.72 Hz, IH), 7.31 (d, J = 8.56

Hz, 2H), 7.47 (d, J = 8.52 Hz. 2H), 7.61 ( d , J = 8.44 Hz, 2H), 7.86 (d, J = 8.52 Hz, 2H)

ppm; "C NMR (100 MHz, CDCI,) 640.3, 44.2, 52.6, 53.7, 57.8 76.9, 122.1, 126.1,

129.2, 130.3, 131.9, 132.3, 133.7, 144.2, 169.4, 199.2, 203.7 ppm; FAB-MS 511 (MI+]);

Anal. Calcd. for C2,HIRBr*O~: C, 49.44; H, 3.56. Found: C, 49.42, H, 3.52.

Reaction of (E)-l,4-di(4-methyIphenyl)-Z-butene-1,4-dione (65) and methy)

acetoacetate (85)

Following the general procedure described above, activated Ba(OH)? (68.4 mg, 0.4

mmol), methyl acetoacetate 85 (255.2 mg, 2.2 mmol) and (E)-l,4-di(4-methylphenyl)-2-

butene-1,4-dione 65 (528 mg, 2 mmol) in 10 mL MeOH to give methyl (lSV2R,4R)-2-(4-

~~~h~~b~~~~~~)-4-(4-methylphenyl)-4-hydroxy-6-oxoc~clohexane-I-carboxylate 94 (513

mg, 65%) as colorless solid which was purified by column chromatography using 15%

EtOAc-hexanes as an eluent.

Methyl (lS,2R,4R)-4-hydroxy-2-(4-methylbenzoyl)-4-(4- 0

methylpheny1)-6-oxocyclohexane-1-carboxyate (94): a H,COOC&, 1 1

colorless solid; mp 158-160 'C; K, = 0.30 (20% ErOAc-hexanes); Oy 'eOH IR(KBr)736,766,817,843,978, 1016, 1041, 1076, 1127, 1169, $9 1186, 1235, 1265, 1340, 1379, 1435, 1462, 1517, 1568, 1604, ,\

1670, 1712, 1749,2922,3402 cm-I; 'H NMR (400 MHz, CDCI,) CH, CH3

62.1 1 (t, J = 12.84 H z , IH), 2.30 (s, 3H), 2.34 (dt, J = 18.0, 7.0 Hz, IH), 2.39 (s, 3H),

2.71 (dd, J = 13.88, 2.32 Hz, IH), 2.86 (s, IH), 3.05 (d, J = 13.8 Hz, IH), 3.69 (s, 3H),

4.16 (d, J = 11.72 Hz, IH), 4.79 (td, J = 12.44, 3.6 Hz, IH), 7.14 (d, J = 8.12 Hz, 2H),

7.25 (d, J = 8.04 Hz, 2H), 7.31 (d, J = 8.16 Hz, 2H), 7.92 (d, J = 8.2 Hz, 2H) ppm; "C

NMR (100 MHz, CDCI,) 620.9, 21.7, 41.6, 44.3, 52.3, 54.0, 57.9, 77.1, 124.1, 128.9,

129.4, 129.6, 132.5, 137.7, 142.5, 144.7, 169.6, 199.9,204.5 ppm; FAB-MS 381 (Mt+l);

Anal. Calcd, f 0 r C ~ ~ H ~ ~ 0 ~ : C, 72.61; H, 6.36. Found: C, 72.65, H, 6.39.

Reaction of (E)-1,4-di(4-methoxyphenyl)-2-butene-1,4-dione (91) and methyl

acetoacetate (85)

Following the general procedure described above, activated Ba(OH)2 (58.1 mg, 0.34

mmol), methyl acetoacetate 85 (214.6 mg, 1.85 mmol) and (E)-1,4-di(4-methoxypheny1)-

2-butene-1,4-dione 91 (500 mg, 1.68 mmol) in I0 mL MeOH to give methyl (IS,2R,4R)-

~~(~-methoxybe~~oy~)-4-(4-methoxyphenyl)-4-hydroxy-6ox~~ycl~he~ane- I -carboxylate

95 (371 mg, 54%) as colorless solid which was purified by column chromatography using

15% EtOAc-hexanes as an eluent.

Methyl ( ~ ~ , ~ ~ , 4 ~ ) - 4 - h ~ d r o x ~ - 2 - ( 4 - m e t h o x y h e n z o y l )

oxocyc~ohexa~~l-carboxylate (95): a colorless solid; mp 142-144 OC; Rr= 0.27 (30%

WAC-hexanes); IR (KBr) 846, 976, 1022, I 161, 1261, 1463,

151 1, 1599, 1651, 1719, 1743, 2853,2922, 3455 cm-'; 'H NMR

(400 MHz, CDCII) 6 2.12 (t, J = 13.4 Hz, IH), 2.35 (dt, J = OY

18.76, 6.25 Hz, IH), 2.39 (s, IH), 2.72 (dd, J = 13.8, 2.44 Hz,

IH), 3.05 (d, J = 13.76 Hz, IH), 3.72 (s, 3H), 3.78 (s, 3H). 3.86 I OCH,

(s, 3H), 4.15 (d. J = 11.76 Hz. IH), 4.74 (td, J = 12.6, 3.72 Hz, OCH,

IH), 6.87 (d, J = 8 . 8 8 Rz, 2H). 6.94 (d, J = 8.92 Hz, 2H), 7.34 (d. . l=8.88 Hz, 2H), 8.01

(d, J = 8.92 Hz. 2H) ppm: "C NMR (100 MHz, CDCI,) 6 41.8, 43 9, 52.4. 54.1, 55.3,

55.5, 58.0, 77.0, 114.1 (2C), 125.4, 128.0, 131.2, 137.6, 163.1 (ZC), 169.5, 198.5, 204.1

ppm; FAB-MS 413 (MT+l); Anal. Calcd, for C?3H?107: C, 66.98: H, 5.87. Found: C,

66.95. H, 5.91.

Reaction of methyl (1S,2R,4R)-2-benzovl-4-hydroxy-6-oxo-4-phenylcyclohexane-l-

carboxylate (89) withpTSA

Methyl (IS,2R,4R)-2-benzoyl-4-hydroxy-6-oxo-4-phenylcyclohexane-l-carboxylate

89 (120 mg, 0.34 mmol) was dissolved in 5 mL dry benzene, to that 2 mg p-TSA was

added and allowed to reflux in a reaction vessel having Dean-Stark setup for 5 h. The

reaction was monitored by TLC, which showed the product formation. The solvent was

concentrated under vacuo to 2 mL, dissolved in 10 mL of dichloromethane and poured

over ice-cooled water. The organic layer was separated and washed further with water (3

x 5 mL), brine solution (1 x 5 mL) and finally dried over anhydrous Na2S04. The resulted

organic layer was concentrated. The brown mixture was subjected to column

chromatography (silica gel 100-200 mesh) using 10% EtOAc-hexanes as an eluent to

yield 5-benzoyl-3-phenyl-2-cyclohexen-I-one 96 (90 mg, 96%).

5-Benzoyl-3-phenyl-2-cyclohexen-1-one 96: a colorless solid; mp

104-106 OC (1it.l' 107-108 'C); RI= 0.47 (20% EtOAc-hexanes); IR

(KBr) 698, 759, 892, 925, 999, 1031, 1161, 1257, 1353, 1446,

1494, 1577, 1600, 1676, 2950, 3060 cm - I ; 'H NMR (300 MHz,

CDC131CClr, 1:I) 62.67(t, J = l l .4Hz,2H). 2.93 (dd.J-4.5, 18.0

Hz, IH), 3.64(td, J = 2 . 4 , 10.5 Hz, IH),4.11-4.22(m, IH), 6.42(d, J = 2 . 4 H z , IH), 7.37

(1, J = 3.3 Hz, 3H). 7.46-7.57 (m, 5H), 7.98 (d, J = 7.5 Hz, 2H) ppm; 'k NMR (75 MHz,

CDCIl/CCl4, 1:1)630.56,39.71,42.46, 125.00, 126.12. 128.45, 128.80, 128.90, 130.13,

133.46, 135.18, 138.29, 157.09, 196.47, 198.96 ppm; LRMS 276 (4%, Mt), 197 (8%),

171 (loo%), 153 (8%), 141 (12%), 128 (16%), 115 (18%). 105 (loo%), 77 (44%), 51

(8%).

Microwave reaction of methyl (lS,2R,4R)-2-benzoyl-4-hydroxy-6-0~0-4-

phenylcyclobexane-1-carboxylate (89) with DMSOI NaCI.

Methyl (IS,2R,4R)-2-benzoyl-4-hydroxy-6-oxo-4-phenylcyclohexane-l-carboxylate

89 (120 mg, 0.34 mmol) was dissolved in 5 mL DMSO, to that sodium chloride (19.8

mg, 0.34 mmol) was added and allowed to subject microwave irradiation at 650 W for 5

min. The reaction was monitored by TLC and shown the formation of product. The

reaction mixture was cooled to room temperature, dissolved in 25 mL dichloromethane

and poured over ice-cooled water. The organic layer was separated and washed water (3

x 5 mL) to remove excess DMSO present in the reaction mixture. Then the organic layer

was washed with brine solution (I x 10 mL) and dried over anhydrous Na2S04. Then, the

reaction mixture was concentrated under vacua and the resulting mixture was subjected

to column chromatography (silica gel 100-200 mesh) using 10-20% EtOAc-hexanes as an

eluent furnished 5-benzoyl-3-phenyl-2-cyclohexen-I-one 96 (22 mg, 23%) and 7-

hydroxy-3,5-diphenyl-1,3-dihydro-l-isobenzohranone 97 (55 mg, 53%).

7-Hydroxy-3,Ediphenyl-1,3-dihydro-l-isobenzofuranone 97: a

colorless solid; mp 156- 158 OC; R,= 0.15 (20% EtOAc-hexanes);

IR (KBr) 699, 767, 871, 975, 1037, 1084, 1209, 1293, 1326,

1424, 1455, 1615, 1733, 3273 cm - '; 'H NMR (300 MHz,

& CDCI,ICCl4, 1:1)66.40(s, IH),6.95(s, IH),7.14(s, IHh7.30- \ ' 7.41 (m, 8H), 7.50 (br d, J = 6.0 Hz, 2H), 7.81 (br s, 1H) ppm: "C NMR (75 MHz,

CDC131CC14, 1:l) 6 109.85, 113.02, 114.83, 127.19, 127.58, 128.77, 129.00, 129.1 1,

129.51, 136.15, 139.79, 150.43, 151.04, 156.60, 171.49ppm: LRMS 302 (SO%, M'), 197

(loo%), 168 (lo%), 139 (12%), 115 (16%), 105 (38%), 77 (36%), 51 (12%); ~ n a l .

Calcd. for C20H1403: C, 79.46; H, 4.67. Found: C, 79.49, H, 4.7 1 .

2.5 References

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