intramolecular amidolysis of C-3 functionalized 2-azetidinones

Tetrahedron 69 (2013) 3857e3866

Contents lists available at SciVerse ScienceDirect

Tetrahedron journal homepage: www.elsevier.com/locate/tet

Facile, diastereoselective synthesis of functionally enriched hexahydroisoquinolines, hexahydroisoquinolones and hexahydroisochromones via inter-/intramolecular amidolysis of C-3 functionalized 2-azetidinones Vishu Mehra, Vipan Kumar * Department of Chemistry, Guru Nanak Dev University, Amritsar 143005, India

a r t i c l e i n f o

a b s t r a c t

Article history: Received 1 January 2013 Received in revised form 11 March 2013 Accepted 12 March 2013 Available online 19 March 2013

We describe herein the synthetic utility of b-lactam synthon protocol for the convenient and diastereoselective synthesis of functionally decorated hexahydroisoquinolines, hexahydroisoquinolones and hexahydroisochromones. Since the described protocol does not include the use of highly functionalized intermediates, stringent conditions or toxic reagents, the developed methodology does not suffer from the typical intricacies associated with the conventional protocols. Ó 2013 Elsevier Ltd. All rights reserved.

Keywords: b-Lactam synthon approach Hexahydroisoquinolines Hexahydroisoquinolones/ hexahydroisochromones Tandem intermolecular amidolysisecyclization Inter-/intramolecular amidolysis

1. Introduction The isoquinoline nucleus is considered as one of the most frequently encountered structural motifs in alkaloids and attracting increasing attention in the contemporary biomedical research and drug discovery programmes.1 Several members of this group exhibit various pharmacological and biological properties, i.e., as orally effective 5-HT3 antagonists demonstrating their high utility in cancer chemotherapy, anxiety, schizophrenia2 and as anti-chagas agents.3 Furthermore, some isoquinolines are useful ligands4 for catalytic asymmetric syntheses4a and electrophosphorescent complexes.5 In particular, the hydrogenated analogues of this category of alkaloids occupy a conspicuous place because of their diverse pharmacological activities viz. fibrinolytic, antiviral, hypotensive and positive inotropic effects.6,7 Tetrahydroisoquinolines have reported to induce a Parkinson-like syndrome in experimental animal models8 while other activities ranges from neurotoxicity to neuroprotection, as epitomized by neurotoxic 1ebenzyl-1,2,3,4tetrahydroisoquinoline and the neuroprotective 1-methyl-1,2,3,4tetrahydroisoquinoline.9 * Corresponding author. Tel.: þ91 183 2258802x3320; fax: þ91 183 2258819/20; e-mail address: [email protected] (V. Kumar). 0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tet.2013.03.044

Although much information concerning the synthesis of isoquinoline and congeners there of is available in the literature,10 the generation of variedly substituted isoquinolines is still a challenging problem. A number of synthetic protocols have been reported to date for the preparation of substituted isoquinolines encompassing the mercury mediated cyclization of N-alkylimines,8,11,12 the reaction of 20 -carboxy-2-hydroxydeoxybenzoin with primary amines,13 the treatment of homophthalic anhydride with imidoyl chlorides14 or the cycloaddition of benzyne to 5-phenylpyrroline-2,3-dione.15 The oxidation of corresponding 3,4-dihydroisoquinolones,16 1,2-dihydroisoquinolines and the quaternary salts of quinoline derivatives have also been considered relevant for the synthesis17 of such scaffolds. For many years, isoquinolones have attracted the attention of synthetic and medicinal chemists not only because of their pharmacological profiles but also because of their intermediacy in the synthesis of different types of chemical compounds.18 Variedly functionalized isoquinolones exhibit different therapeutic activities acting as topoisomerase I inhibitors,19 as antiemetic20 and antitumour agents.21 Tilisolol hydrochloride, a substituted isoquinolone analogue acts as a non-selective b-adrenoreceptor block useful for the treatment of hypertension and angina pectoris22 while other isoquinolone analogues act as poly(ADPribose) polymerase (PARP),

3858

V. Mehra, V. Kumar / Tetrahedron 69 (2013) 3857e3866

Rho-kinase, c-Jun N-terminal kinases (JNK) and thymidylate synthase (TS) inhibitors.23,24 In addition, isoquinolone moiety has also been employed as the chief precursor for the synthesis of natural alkaloids including protoberberines,25e27 benzo[c]phenanthridines,28,29indeno[1,2c]isoquinoline, isoindolo[2,1b]isoquinolines, 12-oxobenzo[c]phenanthridines, dibenzo[c,h][1,6] naphthyridines, and benz[b]oxepines.30,31 Another structurally related framework, isochromene can be seen in various biologically active compounds and natural products.32 Isochromene has been the central unit in flaccidin, isolated from the orchids Dendrobium amoenum and Coelogyne flaccid,33a as well as in a number of compounds isolated from Cannabis sativa.33b Recent report by Che and co-workers have revealed the isolation of Fimetarone A, a metabolite with the new spiro[chroman-3,70 -isochromene]-4,60 (80 H)-dione skeleton from cultures of the Cordyceps-colonizing fungus Fimetariella sp.34 The development of methods for effective construction of isochromene from simple, readily available building blocks has attracted considerable attention. One of the most reliable and versatile methods for the synthesis of isochromenes is the palladium-catalyzed annulation of aryl halides bearing an oxygen nucleophile with alkynes35 while recent disclosures by Morimoto and co-workers have shown their synthesis via rhodium-catalyzed oxidative coupling of a,a-disubstituted benzyl and allyl alcohols with alkynes.36 As evident, a large number of synthetic protocols have been reported for the preparation of these heterocycles, the need for highly functionalized intermediates, stringent reaction conditions and/or longer reaction times indicate that alternative syntheses of such entities is a permanent challenging task for organic chemists and interest in this field continues unabated. b-Lactams are crucial structural elements of widely utilized antibiotics viz. penicillin, cephalosporin, carbapenem and carbacephem.37 Besides their importance as key structural component of b-lactam antibiotics, this four-membered ring system has been attracting considerable interest in organic synthesis as a versatile synthetic intermediate.38 This usefulness is based on the impressive variety of transformations that can be derived from this ring system in a stereocontrolled manner.39 A large collection of such blactam based synthetic method is collectively termed as b-lactam synthon approach and provide a convenient and efficient access to a variety of non protein aminoacids, functionalized piperazines, 1,4diazepanes, enantiopure succinimides, oligopeptides, peptidomimetics along with different sized heterocycles of medicinal interest, such as indolizidine alkaloids, paclitaxel, docetaxel, taxoids, cryptophycins, lankacidins, etc.40 Further, Allene tethered b-lactam scaffolds have been investigated in metal catalyzed carbo- and heterocylization reactions, proceeding with better regio- and stereoselectivity compared to thermal or radical conditions.41 Recent revelation from our lab has shown the utilization of b-lactam synthon protocol for the synthesis of octahydroisoquinolone derivatives.42 The methodology was further utilized towards the synthesis of tetra/octahydro-isoquinolines43 along with the extension towards their single pot synthesis. In continuation of our pursuit towards the synthesis of biologically interesting frameworks especially using b-lactam-synthon protocol,44 the present manuscript entails the diastereoselective synthesis of substituted hexahydroisoquinolines using either methoxide or acid assisted tandem intermolecular amidolysiseintramolecular cyclization. Further, a range of substituted hexahydroisoquinolones and hexahydro-isochromen-3-ones were prepared using sodium borohydride mediated intramolecular amidolysis of C-3 functionalized b-lactam ring. 2. Results and discussion Thus, the treatment of 3, prepared via Sn(IV)chloride catalyzed DielseAlder cycloaddition reactions of a-dienyl-b-lactams 1 and

acrolein 2 as shown in Scheme 1,45 with sodium methoxide at 60  C for 1 h resulted in the isolation of viscous oil, which upon purification via column chromatography (Hexane:Ethyl acetatew95:5) interestingly yielded hexahydro-isoquinoline-4-carboxylic acid methyl esters 4. R

R O

O H1

N H2

R1

1

SnCl4

H

+ 2

dry CH2Cl2, -78 oC

R= H, Cl, CH3 R1=H, Cl, CH3, OCH3

O H H3

N

R1

1

H

H2

O H4

3

Scheme 1. Synthesis of desired precursor 3.

The reaction was optimized in different solvents viz. chloroform, acetonitrile and methanol at room temperature or under reflux conditions. The best result in terms of rate of reaction and yields obtained by using methanol at 60  C. A comparison of yields and the reaction time at room temperature and at 60  C using methanol as solvent is tabulated in Scheme 2. Mechanistically, the reaction is thought to involve in tandem, an initial methoxide mediated b-lactam ring amidolysis generating the corresponding b-aminoesters in situ, which underwent intramolecular nucleophilic addition with the aldehydic carbonyl followed by dehydration to yield the corresponding hexahydroisoquinoline-4-carboxylic acid methyl esters 4. The formation of diastereomerically pure 2,3,4-trisubstituted-hexahydroisoquinolines 4 is a consequence of the condensation of aforesaid proximate latent functionalities subsequent to the CeC bond rotation as shown in Scheme 2. The above transformation was also accomplished via acid mediated amidolysis of b-lactam 3 resulting in the diastereoselective formation of corresponding hexahydroisoquinoline-carboxylic acid ethyl esters 5. Thus the refluxing of 3 in 6 N HCl in ethanol for 2 h resulted in its facile conversion to 5 in good to excellent yields. Mechanistically, the reaction is thought to proceed via a sequence of steps as depicted in Scheme 3 involving an initial protonation of carbonyl of b-lactam with subsequent in tandem b-lactam ring amidolysis and nucleophilic addition to aldehydic carbon via C-2/C3 bond rotation. The low yields of 4 and 5 (52e58%) can be principally attributed to the work up under aqueous conditions since the crude spectral data confirmed the complete conversion without the formation of any side-product. The stereochemistry assigned to the products 4 and 5 is in accordance with our recently disclosed diastereoselective synthesis of octahydroisoquinolones using b-lactam synthon approach.42 Further, C-3 functionalized racemic N-aryl-2-azetidinones having free nucleophilic functionality that may assist in intramolecular amidolysis as observed in our recent contribution43 were employed as synthetic precursors. The synthetic protocol involved an initial condensation reaction of 3 with primary amines viz. p-toluidine/ cyclohexylamine to generate the corresponding imine, which was reduced in situ by the addition of sodium borohydride (NaBH4). The reaction interestingly resulted in the diastereoselective synthesis of functionalized hexahydro-2H-isoquinoline-3-ones 6 in excellent yields without the isolation of corresponding amines (Scheme 4). The plausible mechanism for the formation of 6 may involve the intramolecular amidolysis of b-lactam ring involving the amine nitrogen as nucleophile generated in situ during the sodium borohydride assisted reduction of imine. In order to ascertain the proposed mechanism, it was considered worthwhile to execute similar intramolecular amidolysis viz. the generation of an alkoxide ion via sodium borohydride assisted reduction of aldehydic group

V. Mehra, V. Kumar / Tetrahedron 69 (2013) 3857e3866

R

3859

R1 O H H3

N H1

O

(a) or (b)

H4

H2 3

R1

H2 H3CO2C H8

H1 N

R

H4 H5

H3 H5 H7 6 H 4 H6

R

R1

HN H1

CO2CH3 H3 H4 H2

Products

H1 HN H2

O

CO2CH3 H3H4

4a 4b 4c 4d 4e 4f 4g 4h 4i

O

H H

R1

R1

R

yield% 60 oC/ room temp

H H H CH3 H OCH3 Cl Cl Cl CH3 Cl OCH3 CH3 Cl CH3 CH3 CH3 OCH3

R

55/53 58/54 53/49 57/52 52/48 55/51 53/47 56/52 52/48

reaction time 60 oC/ room temp (h) 1.1/8.0 1.2/8.2 1.0/8.5 1.1/8.1 1.0/8.4 1.2/8.3 1.1/8.4 1.2/8.1 1.0/8.3

Scheme 2. Methoxide mediated synthesis of hexahydro-isoquinoline-4-carboxylic acid methyl esters 4. Reagents and conditions: (a) CH3ONa, 60  C, dry methanol. (b) CH3ONa, dry methanol, room temperature.

R1

R

N H1

O H H3

H2 R1

O

H2 H3CH2CO2C H8

6N HCl, C2H5OH reflux, 2h

H4

3

H7

H1 N H3

H6 H6 5

R

H4 H5 H5

H R1

R R

HOC2H5

R

OH H H3

N H1 H2

C2H5 O O H N H O H3 H1 H4 2 H

O H4

H1 HN H1

CO2C2H5 H3 H4 O H2

HN H2

CO2C2H5 H3H4 O H

H R1

R1

R1 Products

R

5a 5b 5c 5d 5e

H H Cl Cl CH3

R

1

R

yield % reaction time (hrs)

H CH3 Cl CH3 CH3

55 58 57 52 56

2.1 2.3 2.0 2.1 2.2

Scheme 3. Acid mediated synthesis of hexahydro-isoquinoline-4-carboxylic acid ethyl esters 5.

in 3. Thus, the room temperature stirring of a solution of 3 in dry methanol with sodium borohydride for 1e2 h, after usual work up and purification via column chromatography (Hexane:Ethyl acetatew75:25), as expected resulted in the isolation of hexahydroisochromen-3-ones 7 in good yields (Scheme 5). The formation of 7 validated the sodium borohydride mediated intramolecular amidolysis as the underlying mechanism for the formation of 6. The stereochemistry assigned to the products 6 and 7 is in accordance with our recent disclosure on the base mediated intramolecular amidolysis of C-3 carbamoyl-functionalized racemic N-aryl-b-lactams resulting in the diastereoselective synthesis of

tetrahydro-4H-isoquinoline-1,3-diones.43 The synthesized hexahydro-2H-isoquinoline-3-ones 6 and hexahydro-isochromen-3ones 7 were subjected to iodocyclization with I2/K2CO3 in dry dichloromethane at room temperature resulting in the isolation of corresponding 8-iodo-decahydro-pyrrolo[4,3,2-de]isoquinolin3-ones 9aef and 8-iodo-1,2-diaryl-decahydro-4-oxa-1-aza-acenaphthylen-3-ones 9gei, respectively. Mechanistically, the formation of 8-iodo-decahydro-pyrrolo [4,3,2-de]isoquinolin-3-ones 9aef and 8-iodo-1,2-diaryl-decahydro4-oxa-1-aza-acenaphthylen-3-ones 9gei probably involved the usual formation of the iodonium ion 8 as elucidated in Scheme 6.

3860

V. Mehra, V. Kumar / Tetrahedron 69 (2013) 3857e3866

R O H H3

N H1

H N H1

O 1. R2NH2, dry methanol, rt H4 2. NaBH4 R

H2

6a 6b 6c 6d 6e 6f 6g 6h 6i 6j 6k 6l

In conclusion, the present manuscript describes sodium methoxide or acid mediated tandem intermolecular amidolysise intramolecular cyclization for the diastereoselective synthesis of hexahydroisoquinolines. Further, sodium borohydride assisted intramolecular amidolysis en route towards the diastereoselective synthesis of hexahydroisoquinolones and hexahydroisochromones has been developed followed by subsequent iodocyclization. Since the devised protocol does not employ Lewis acid mediation or highly functionalized intermediates, the approach does not suffer from the typical drawbacks associated with conventional protocols.

H5 H5 H6

H6

H7

R1 6

3 Products

H4

H2 H8

R1

3. Conclusions

R2 N H3

O

R1

R

H H Cl CH3 Cl OCH3 CH3 Cl CH3 CH3 CH3 OCH3 H H Cl CH3 Cl OCH3 CH3 Cl CH3 CH3 CH3 OCH3

R2

%age yield

C6H11 C6H11 C6H11 C6H11 C6H11 C6H11 CH3-C6H4 CH3-C6H4 CH3-C6H4 CH3-C6H4 CH3-C6H4 CH3-C6H4

reaction time (min)

85 88 86 88 90 83 82 85 89 85 92 81

48 52 54 55 49 54 57 54 58 59 49 58

4. Experimental section 4.1. General Melting points were determined by open capillary using Veego Precision Digital Melting Point apparatus (MP-D) and are uncorrected. IR spectra were recorded on a Shimadzu D-8001 spectrophotometer. 1H NMR spectra were recorded in deuterochloroform with Jeol 300 (300 MHz) spectrometers using TMS as internal standard. Chemical shift values are expressed as parts per million downfield from TMS and J values are in hertz. Splitting patterns are indicated as s: singlet, d: doublet, t: triplet, m: multiplet, dd: double doublet, ddd: doublet of a doublet of a doublet, and br: broad peak. 13 C NMR spectra were recorded on Jeol 300 (75 MHz) spectrometers in deuterochloroform using TMS as internal standard. Mass spectra were recorded on Shimadzu GCeMS-QP-2000 mass spectrometer. Elemental analyses were performed on Heraus CHN-O-Rapid Elemental Analyzer. Column chromatography was performed on a silica gel (60e120 mesh). All the starting materials as well as the products were racemates.

Scheme 4. Synthesis of hexahydro-2H-isoquinoline-3-ones 6.

R O O H H3

N H1

O H4

H2

H N H1

NaBH4 methanol, rt

O H3 H

R

H8

R1 R1

Products

R

7a 7b 7c 7d 7e 7f

H Cl Cl CH3 CH3 CH3

H5 H5 H6

H6

H7

7

R1

3

H4

2

%age yield reaction time (hrs)

H CH3 OCH3 Cl CH3 OCH3

55 46 53 52 55 51

4.2. General procedure for the synthesis of hexahydro-isoquinoline-4-carboxylic acid methyl esters 4

1.3 1.4 1.3 1.5 1.5 1.2

To a solution of sodium methoxide (1 mmol) in dry methanol (20 mL) was added a stirred solution of 3 (1 mmol) in dry methanol (20 mL) and the mixture was heated to 60  C. The progress of the reaction was monitored through TLC and on completion; the reaction mixture was quenched with brine solution (50 mL) and extracted with dichloromethane (50 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under

Scheme 5. Synthesis of hexahydro-isochromen-3-ones 4 via NaBH4-assisted intramolecular amidolysis.

O H N H1

X H3

R1 H4

H2

R

O

X H3

5

H H5 H6

H1

2

H NH

H4

R1 H5 H5 H6

I2/K2CO3 dry CH2Cl2

O H1

H6

H6

R Products

R

R1

9a 9b 9c 9d 9e 9f 9g 9h 9i

H Cl Cl H Cl Cl H Cl Cl

H CH3 OCH3 H CH3 OCH3 H CH3 OCH3

X

%age yield

N-C6H11 N-C6H11 N-C6H11 N-C6H4-CH3 N-C6H4-CH3 N-C6H4-CH3 O O O

53 55 59 53 57 54 58 55 58

reaction time (min) 90 92 88 91 98 96 94 96 92

8

Scheme 6. Iodocyclization using I2/K2CO3.

O H2

R1 1

H

N

H5 H5 H6

H6

I

X H3

H4 H7

H8 I 9 R

H4

H2 NH

R

R1

X H3

H5 H5 H6

H6

V. Mehra, V. Kumar / Tetrahedron 69 (2013) 3857e3866

vacuo. The crude product thus obtained was purified by column chromatography on silica gel using a mixture (95:5) of hexane and ethyl acetate as an eluent. 4.2.1. 2,3-Diphenyl-2,3(RS),4(SR),4a(SR),7,8-hexahydro-isoquinoline4-carboxylic acid methyl ester (4a). Yellow solid, [found: C, 79.89; H, 6.64; N, 4.12. C23H23NO2 requires C, 79.97; H, 6.71; N, 4.05%] mp 107e108  C dH (CDCl3, 300 MHz) 1.56e1.59 (m, 2H, eCH2), 2.35e2.38 (m, 2H, eCH2), 2.84 (dd, 1H, J¼4.0, 11.7 Hz, H2), 2.97 (d, 1H, J¼11.7 Hz, H3), 3.79 (s, 3H, eOCH3), 5.23 (d, 1H, J¼4.0 Hz, H1), 5.57 (d, 1H, J¼9.88 Hz, H8), 5.77e5.79 (m, 1H, H7), 6.68 (s, 1H, H4), 6.78e6.86 (m, 3H, ArH), 7.17e7.19 (m, 4H, ArH), 7.25e7.27 (m, 3H, ArH), dC (CDCl3, 75 MHz) 27.2, 28.1, 35.4, 47.3, 50.2, 60.3, 112.6, 116.2, 122.2, 122.7, 125.6, 128.1, 128.4, 128.9, 129.3, 129.7, 138.4, 143.2, 174.1 (C]O); nmax (KBr)/cm1 1730; m/z 345 (Mþ). 4.2.2. 2-Phenyl-3-p-tolyl-2,3(RS),4(SR),4a(SR),7,8-hexahydro-isoquinoline-4-carboxylic acid methyl ester (4b). Yellow solid, [found: C, 80.26; H, 7.09; N, 3.82. C24H25NO2 requires C, 80.19; H, 7.01; N, 3.90%] mp 109e110  C dH (CDCl3, 300 MHz) 1.55e1.59 (m, 2H, eCH2), 2.32e2.35 (m, 2H, eCH2), 2.39 (s, 3H, eCH3), 2.82 (dd, 1H, J¼4.0, 11.7 Hz, H2), 2.95 (d, 1H, J¼11.7 Hz, H3), 3.78 (s, 3H, eOCH3), 5.25 (d, 1H, J¼4.0 Hz, H1), 5.54 (d, 1H, J¼9.6 Hz, H8), 5.73e5.78 (m, 1H, H7), 6.65 (s, 1H, H4), 6.82e6.96 (m, 5H, ArH), 7.02 (d, 2H, J¼8.8 Hz, ArH), 7.12 (d, 2H, J¼8.8 Hz, ArH), 7.25e7.27 (m, 3H, ArH), dC (CDCl3, 75 MHz) 20.6, 27.4, 28.0, 35.4, 47.1, 50.4, 60.1, 112.4, 116.5, 122.4, 122.8, 128.2, 128.4, 128.6, 129.2, 129.3, 135.2, 135.8, 143.7, 174.2 (C]O); nmax (KBr)/cm1 1731; m/z 359 (Mþ). 4.2.3. 3-(4-Methoxy-phenyl)-2-phenyl-2,3(RS),4(SR),4a(SR),7,8hexahydro-isoquinoline-4-carboxylic acid methyl ester (4c). Yellow solid, [found: C, 76.68; H, 6.82; N, 3.65. C24H25NO3 requires C, 76.77; H, 6.71; N, 3.73%] mp 111e112  C dH (CDCl3, 300 MHz) 1.53e1.57 (m, 2H, CH2), 2.30e2.34 (m, 2H, eCH2), 2.84 (dd, 1H, J¼4.0, 11.7 Hz, H2), 2.96 (d, 1H, J¼11.7 Hz, H3), 3.69 (s, 3H, eOCH3), 3.78 (s, 3H, eOCH3), 5.29 (d, 1H, J¼4.0 Hz, H1), 5.58 (d, 1H, J¼9.7 Hz, H8), 5.75e5.79 (m, 1H, H7), 6.63 (s, 1H, H4), 6.78 (d, 2H, J¼8.6 Hz, ArH), 6.85e6.98 (m, 5H, ArH), 7.04 (d, 2H, J¼8.6 Hz, ArH), dC (CDCl3, 75 MHz) 27.3, 28.2, 35.3, 47.4, 50.8, 56.2, 60.1, 112.5, 114.4, 116.5, 122.4, 122.8, 128.5, 129.4, 129.7, 129.9, 131.5, 143.7, 159.6, 174.5 (C]O); nmax (KBr)/cm1 1730; m/z 375 (Mþ). 4.2.4. 2,3-Bis-(4-chloro-phenyl)-2,3(RS),4(SR),4a(SR),7,8-hexahydroisoquinoline-4-carboxylic acid methyl ester (4d). Yellow solid, [found: C, 66.77; H, 5.22; N, 3.69. C23H21Cl2NO2 requires C, 66.67; H, 5.11; N, 3.38%] mp 105e107  C dH (CDCl3, 300 MHz) 1.54e1.59 (m, 2H, eCH2), 2.32e2.36 (m, 2H, eCH2), 2.86 (dd, 1H, J¼4.2, 11.5 Hz, H2), 2.98 (d, 1H, J¼11.5 Hz, H3), 3.76 (s, 3H, eOCH3), 5.30 (d, 1H, J¼4.2 Hz, H1), 5.56 (d, 1H, J¼9.8 Hz, H8), 5.74e5.78 (m, 1H, H7), 6.65 (s, 1H, H4), 6.82e6.98 (m, 4H, ArH), 7.04 (d, 2H, J¼8.8 Hz, ArH), 7.20 (d, 2H, J¼8.8 Hz, ArH), dC (CDCl3, 75 MHz) 27.4, 28.5, 35.2, 47.1, 50.6, 56.7, 60.2, 113.4, 122.2, 122.4, 122.8, 128.7, 129.1, 129.5, 129.8, 129.9, 131.2, 136.1, 141.7, 174.2 (C]O); nmax (KBr)/cm1 1732; m/z 413 (Mþ). 4.2.5. 2-(4-Chloro-phenyl)-3-p-tolyl-2,3(RS),4(SR),4a(SR),7,8hexahydro-isoquinoline-4-carboxylic acid methyl ester (4e). Yellow solid, [found: C, 73.26; H, 6.22; N, 3.43. C24H24ClNO2 requires C, 73.18; H, 6.14; N, 3.56%] mp 112e113  C dH (CDCl3, 300 MHz) 1.52e1.58 (m, 2H, eCH2), 2.30e2.36 (m, 2H, eCH2), 2.39 (s, 3H, eCH3), 2.88 (dd, 1H, J¼4.4, 11.6 Hz, H2), 2.97 (d, 1H, J¼11.6 Hz, H3), 3.74 (s, 3H, eOCH3), 5.32 (d, 1H, J¼4.4 Hz, H1), 5.57 (d, 1H, J¼9.9 Hz, H8), 5.72e5.76 (m, 1H, H7), 6.63 (s, 1H, H4), 6.87 (d, 2H, J¼8.6 Hz, ArH), 7.06e7.20 (m, 6H, ArH), dC (CDCl3, 75 MHz) 20.7, 27.2, 28.7, 35.1, 47.4, 50.8, 60.1, 113.8, 122.0, 122.6, 122.8, 128.4, 128.8, 129.4,

3861

129.6, 129.9, 135.2, 135.7, 141.7, 174.5 (C]O); nmax (KBr)/cm1 1730; m/z 393 (Mþ). 4.2.6. 2-(4-Chloro-phenyl)-3-(4-methoxy-phenyl)2,3(RS),4(SR),4a(SR),7,8-hexahydro-isoquinoline-4-carboxylic acid methyl ester (4f). Yellow solid, [found: C, 70.21; H, 5.81; N, 3.49. C24H24ClNO3 requires C, 70.32; H, 5.90; N, 3.42%] mp 115e116  C dH (CDCl3, 300 MHz) 1.54e1.58 (m, 2H, eCH2), 2.32e2.37 (m, 2H, eCH2), 2.86 (dd, 1H, J¼4.0, 11.4 Hz, H2), 2.95 (d, 1H, J¼11.4 Hz, H3) 3.66 (s, 3H, eOCH3), 3.79 (s, 3H, eOCH3), 5.30 (d, 1H, J¼4.0 Hz, H1), 5.56 (d, 1H, J¼9.8 Hz, H8), 5.70e5.74 (m, 1H, H7), 6.64 (s, 1H, H4), 6.72e6.85 (m, 4H, ArH), 7.02e7.10 (m, 4H, ArH), dC (CDCl3, 75 MHz) 27.3, 28.4, 35.3, 47.2, 50.6, 56.8, 60.4, 113.8, 114.2, 122.1, 122.4, 122.6, 128.4, 129.0, 129.5, 129.9, 131.2, 141.7, 159.4, 174.4 (C]O); nmax (KBr)/cm1 1730; m/z 409 (Mþ). 4.2.7. 3-(4-Chloro-phenyl)-2-p-tolyl-2,3(RS),4(SR),4a(SR),7,8hexahydro-isoquinoline-4-carboxylic acid methyl ester (4g). Yellow solid, [found: C, 73.02; H, 6.02; N, 3.67. C24H24ClNO2 requires C, 73.18; H, 6.14; N, 3.56%] mp 113e114  C dH (CDCl3, 300 MHz) 1.53e1.57 (m, 2H, eCH2), 2.33e2.38 (m, 2H, eCH2) 2.39 (s, 3H, eCH3), 2.85 (dd, 1H, J¼4.4, 11.5 Hz, H2), 2.92 (d, 1H, J¼11.5 Hz, H3), 3.76 (s, 3H, eOCH3), 5.35 (d, 1H, J¼4.4 Hz, H1), 5.56 (d, 1H, J¼9.8 Hz, H8), 5.70e5.74 (m, 1H, H7), 6.68 (s, 1H, H4), 6.72 (d, 2H, J¼8.8 Hz, ArH), 6.86e7.08 (m, 4H, ArH), 7.20 (d, 2H, J¼8.8 Hz, ArH), dC (CDCl3, 75 MHz) 20.7, 27.3, 28.4, 35.1, 47.3, 50.4, 60.1, 112.6, 122.1, 122.7, 126.2, 128.4, 129.3, 129.5, 129.7, 130.3, 131.2, 135.7, 140.8, 174.3 (C]O); nmax (KBr)/cm1 1730; m/z 393 (Mþ). 4.2.8. 2,3-Di-p-tolyl-2,3(RS),4(SR),4a(SR),7,8-hexahydro-isoquinoline-4-carboxylic acid methyl ester (4h). Yellow solid, [found: C, 80.32; H, 7.39; N, 3.65. C25H27NO2 requires C, 80.40; H, 7.29; N, 3.75%] mp 105e106  C dH (CDCl3, 300 MHz) 1.52e1.56 (m, 2H, eCH2), 2.34e2.38 (m, 2H, eCH2) 2.39 (s, 3H, eCH3), 2.42 (s, 3H, eCH3), 2.87 (dd, 1H, J¼4.2, 11.6 Hz, H2), 2.94 (d, 1H, J¼11.6 Hz, H3), 3.79 (s, 3H, eOCH3), 5.32 (d, 1H, J¼4.2 Hz, H1), 5.54 (d, 1H, J¼9.6 Hz, H8), 5.72e5.76 (m, 1H, H7), 6.66 (s, 1H, H4), 6.75 (d, 2H, J¼8.6 Hz, ArH), 6.86 (d, 2H, J¼8.6 Hz, ArH), 7.02e7.09 (m, 4H, ArH), dC (CDCl3, 75 MHz) 20.4, 20.8, 27.4, 28.6, 35.2, 47.4, 50.6, 60.4, 112.8, 122.1, 122.5, 126.4, 128.3, 128.6, 129.2, 129.7, 130.4, 135.2, 135.7, 140.7, 174.6 (C]O); nmax (KBr)/cm1 1730; m/z 373 (Mþ). 4.2.9. 3-(4-Methoxy-phenyl)-2-p-tolyl-2,3(RS),4(SR),4a(SR),7,8hexahydro-isoquinoline-4-carboxylic acid methyl ester (4i). Yellow solid, [found: C, 77.19; H, 6.86; N, 3.48. C25H27NO3 requires C, 77.09; H, 6.99; N, 3.60%] mp 112e113  C dH (CDCl3, 300 MHz) 1.50e1.54 (m, 2H, eCH2), 2.33e2.39 (m, 2H, eCH2) 2.40 (s, 3H, eCH3), 2.86 (dd, 1H, J¼4.0, 11.5 Hz, H2), 2.96 (d, 1H, J¼11.5 Hz, H3), 3.69 (s, 3H, eOCH3), 3.78 (s, 3H, eOCH3), 5.34 (d, 1H, J¼4.0 Hz, H1), 5.52 (d, 1H, J¼9.8 Hz, H8), 5.70e5.74 (m, 1H, H7), 6.68 (s, 1H, H4), 6.65 (d, 2H, J¼8.8 Hz, ArH), 6.74e6.92 (m, 4H, ArH), 7.06 (d, 2H, J¼8.8 Hz, ArH), dC (CDCl3, 75 MHz) 20.7, 27.2, 28.5, 35.4, 47.4, 50.5, 56.2 60.3, 112.6, 114.4, 122.2, 122.6, 126.6, 128.1, 129.2, 129.8, 130.4, 131.2, 140.4, 159.4, 174.3 (C]O); nmax (KBr)/cm1 1731; m/z 389 (Mþ). 4.3. General procedure for the synthesis of hexahydro-isoquinoline-4-carboxylic acid ethyl esters 5 A stirred solution of 3 in 6 N HCl in ethanol (10 mL) was refluxed for 2 h and the progress of the reaction was monitored through TLC. On completion; the reaction mixture was quenched with sodium bicarbonate solution (50 mL) and extracted with dichloromethane (225 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under vacuo. The crude product thus obtained was purified by column chromatography on silica gel using a mixture (95:5) of hexane and ethyl acetate as an eluent.

3862

V. Mehra, V. Kumar / Tetrahedron 69 (2013) 3857e3866

4.3.1. 2,3-Diphenyl-2,3(RS),4(SR),4a(SR),7,8-hexahydro-isoquinoline4-carboxylic acid ethyl ester (5a). Yellow solid, [found: C, 80.08; H, 7.14; N, 3.79. C24H25NO2 requires C, 80.19; H, 7.01; N, 3.90%] mp 142e143  C dH (CDCl3, 300 MHz) 1.41 (t, 3H, J¼5.2 Hz, eCH3), 1.55e1.60 (m, 2H, eCH2), 2.34e2.39 (m, 2H, eCH2), 2.86 (dd, 1H, J¼4.2, 11.6 Hz, H2), 2.94 (d, 1H, J¼11.6 Hz, H3), 4.14 (q, 2H, J¼5.2 Hz, CH2), 5.20 (d, 1H, J¼4.2 Hz, H1), 5.54 (d, 1H, J¼9.86 Hz, H8), 5.77e5.80 (m, 1H, H7), 6.67 (s, 1H, H4), 6.79e6.86 (m, 3H, ArH), 7.20e7.22 (m, 4H, ArH), 7.26e7.28 (m, 3H, ArH), dC (CDCl3, 75 MHz) 14.1, 27.5, 28.2, 31.0, 50.2, 60.6, 61.2, 113.2, 115.0, 119.2, 122.1, 126.8, 127.5, 127.6, 128.4, 128.8, 129.1, 139.6, 146.0, 171.6 (C]O); nmax (KBr)/cm1 1730; m/z 359 (Mþ). 4.3.2. 2-Phenyl-3-p-tolyl-2,3(RS),4(SR),4a(SR),7,8-hexahydro-isoquinoline-4-carboxylic acid ethyl ester (5b). Yellow solid, [found: C, 80.32; H, 7.38; N, 3.64. C25H27NO2 requires C, 80.40; H, 7.29; N, 3.75%] mp 146e147  C dH (CDCl3, 300 MHz) 1.41 (t, 3H, J¼5.4 Hz, eCH3), 1.56e1.60 (m, 2H, eCH2), 2.33e2.37 (m, 2H, eCH2), 2.39 (s, 3H, eCH3), 2.88 (dd, 1H, J¼4.1, 11.6 Hz, H2), 2.93 (d, 1H, J¼11.6 Hz, H3), 4.12 (q, 2H, J¼5.4 Hz, CH2), 5.22 (d, 1H, J¼4.1 Hz, H1), 5.56 (d, 1H, J¼9.88 Hz, H8), 5.77e5.80 (m, 1H, H7), 6.68 (s, 1H, H4), 6.85e6.97 (m, 5H, ArH), 7.08 (d, 2H, J¼8.8 Hz, ArH), 7.14 (d, 2H, J¼8.8 Hz, ArH), 7.26e7.30 (m, 3H, ArH), dC (CDCl3, 75 MHz) 14.3, 20.5, 27.4, 28.1, 31.2, 50.1, 60.4, 61.1, 113.1, 115.1, 119.4, 122.0, 126.6, 127.4, 127.8, 128.2, 128.7, 129.2, 139.4, 146.2, 171.7 (C]O); nmax (KBr)/cm1 1732; m/z 373 (Mþ). 4.3.3. 2,3-Bis-(4-chloro-phenyl)-2,3(RS),4(SR),4a(SR),7,8-hexahydroisoquinoline-4-carboxylic acid ethyl ester (5c). Yellow solid, [found: C, 67.18; H, 5.32; N, 3.38. C24H23Cl2NO2 requires C, 67.29; H, 5.41; N, 3.27%] mp 140e141  C dH (CDCl3, 300 MHz) 1.43 (t, 3H, J¼5.3 Hz, eCH3), 1.57e1.62 (m, 2H, eCH2), 2.34e2.38 (m, 2H, eCH2), 2.88 (dd, 1H, J¼4.2, 11.8 Hz, H2), 2.94 (d, 1H, J¼11.8 Hz, H3), 4.10 (q, 2H, J¼5.3 Hz, CH2), 5.20 (d, 1H, J¼4.2 Hz, H1), 5.58 (d, 1H, J¼9.86 Hz, H8), 5.75e5.82 (m, 1H, H7), 6.65 (s, 1H, H4), 6.84e6.99 (m, 4H, ArH), 7.06 (d, 2H, J¼8.8 Hz, ArH), 7.24 (d, 2H, J¼8.8 Hz, ArH), dC (CDCl3, 75 MHz) 14.2, 27.2, 28.4, 31.1, 50.4, 60.1, 61.6, 113.2, 115.3, 119.2, 122.0, 126.3, 127.5, 127.7, 128.4, 128.8, 129.4, 139.2, 146.4, 171.5 (C]O); nmax (KBr)/cm1 1734; m/z 427 (Mþ). 4.3.4. 2-(4-Chloro-phenyl)-3-p-tolyl-2,3(RS),4(SR),4a(SR),7,8hexahydro-isoquinoline-4-carboxylic acid ethyl ester (5d). Yellow solid, [found: C, 73.52; H, 6.34; N, 3.51. C25H26ClNO2 requires C, 73.61; H, 6.42; N, 3.43%] mp 145e146  C dH (CDCl3, 300 MHz) 1.45 (t, 3H, J¼5.2 Hz, eCH3), 1.54e1.60 (m, 2H, eCH2), 2.33e2.36 (m, 2H, eCH2), 2.40 (s, 3H, eCH3), 2.89 (dd, 1H, J¼4.0, 11.6 Hz, H2), 2.92 (d, 1H, J¼11.6 Hz, H3), 4.12 (q, 2H, J¼5.2 Hz, CH2), 5.24 (d, 1H, J¼4.0 Hz, H1), 5.57 (d, 1H, J¼9.88 Hz, H8), 5.74e5.80 (m, 1H, H7), 6.67 (s, 1H, H4), 6.87 (d, 2H, J¼8.6 Hz, ArH), 7.06e7.20 (m, 6H, ArH), dC (CDCl3, 75 MHz) 14.4, 20.6, 27.4, 28.3, 31.2, 50.1, 60.4, 61.4, 113.3, 115.4, 119.4, 122.0, 126.2, 127.4, 127.7, 128.3, 128.8, 129.2, 139.1, 146.5, 171.7 (C]O); nmax (KBr)/cm1 1732; m/z 407 (Mþ). 4.3.5. 2,3-Di-p-tolyl-2,3(RS),4(SR),4a(SR),7,8-hexahydro-isoquinoline-4-carboxylic acid ethyl ester (5e). Yellow solid, [found: C, 80.48; H, 7.66; N, 3.68. C26H29NO2 requires C, 80.59; H, 7.54; N, 3.61%] mp 142e143  C dH (CDCl3, 300 MHz) 1.43 (t, 3H, J¼5.0 Hz, eCH3), 1.52e1.59 (m, 2H, eCH2), 2.32e2.35 (m, 2H, eCH2), 2.38 (s, 3H, eCH3), 2.40 (s, 3H, eCH3), 2.90 (dd, 1H, J¼4.2, 11.8 Hz, H2), 2.91 (d, 1H, J¼11.8 Hz, H3), 4.14 (q, 2H, J¼5.0 Hz, CH2), 5.23 (d, 1H, J¼4.2 Hz, H1), 5.56 (d, 1H, J¼9.84 Hz, H8), 5.76e5.82 (m, 1H, H7), 6.65 (s, 1H, H4), 6.75 (d, 2H, J¼8.6 Hz, ArH), 6.86 (d, 2H, J¼8.6 Hz, ArH), 7.02e7.09 (m, 4H, ArH), dC (CDCl3, 75 MHz) 14.1, 20.6, 20.8, 27.2, 28.4, 31.1, 50.2, 60.3, 61.5, 113.2, 115.4, 119.2, 122.0, 126.1, 127.6,

127.9, 128.2, 128.7, 129.1, 139.3, 146.4, 171.5 (C]O); nmax (KBr)/cm1 1730; m/z 387 (Mþ). 4.4. Procedure for the synthesis of hexahydro-2H-isoquinoline-3-ones 6 To a stirred solution of 3 in dry methanol (20 mL) was added a solution of p-toluidine/cyclohexylamine (1.2 mmol) in 10 mL of dry methanol. The progress of the reaction was monitored through TLC and on completion, sodium borohydride (2.0 mmol) was added. After completion as evidenced by TLC, brine solution (50 mL) was added and extracted with dichloromethane (50 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The crude product thus obtained was purified by column chromatography using a mixture (8:92) of ethyl acetate and hexane as eluent. 4.4.1. 2-Cyclohexyl-(4RS)-[4-(SR)-(phenyl-phenylamino-methyl)]1,4,4a(SR),7,8,8a(RS)-hexahydro-2H-isoquinolin-3-one (6a). White solid, [found: C, 81.09; H, 8.37; N, 6.62. C28H34N2O requires C, 81.12; H, 8.27; N, 6.76%] mp 182e183  C dH (CDCl3, 300 MHz) 1.19e1.52 (m, 10H, cyclohexyl), 1.59e1.72 (m, 2H, eCH2), 1.90e1.96 (m, 1H, eCH), 2.10e2.16 (m, 2H, eCH2), 2.40e2.54 (m, 1H, eCH), 3.20e3.25 (m, 2H, eCH2), 3.28 (dd, 1H, J¼2.2, 8.6 Hz, H2), 4.26 (s, 1H, NH, exchangeable with D2O), 4.46e4.54 (m, 1H, cyclohexyl), 4.62 (d, 1H, J¼8.6 Hz, H1), 5.64 (d, 1H, J¼10.1 Hz, H9), 5.94 (dddd, J¼2.1, 5.4, 8.6, 10.1 Hz, 1H, H8), 6.46 (d, 2H, J¼8.6 Hz, ArH), 7.00e7.32 (m, 8H, ArH), dC (CDCl3, 75 MHz) 21.5, 21.9, 22.6, 27.9, 30.6, 34.4, 37.8, 43.4, 47.1, 60.1, 64.2, 112.3, 116.4, 125.9, 128.3, 128.9, 129.8, 131.2, 131.4, 139.9, 143.6, 175.6 (C]O); nmax (KBr)/cm1 1732; m/z 414 (Mþ). 4.4.2. 4(RS)-[(4(SR)-Chloro-phenylamino)-p-tolyl-methyl]-2cyclohexyl-1,4,4a(SR),7,8,8a(RS)-hexahydro-2H-isoquinolin-3-one (6b). White solid, [found: C, 75.29; H, 7.72; N, 6.15. C29H35ClN2O requires C, 75.22; H, 7.62; N, 6.05%] mp 182e183  C dH (CDCl3, 300 MHz) 1.22e1.55 (m, 10H, cyclohexyl), 1.61e1.71 (m, 2H, eCH2), 1.94e1.98 (m, 1H, eCH), 2.12e2.16 (m, 2H, eCH2), 2.29 (s, 3H, eCH3), 2.42e2.52 (m, 1H, eCH), 3.22e3.26 (m, 2H, eCH2), 3.30 (dd, 1H, J¼2.1, 8.8 Hz, H2), 4.27 (s, 1H, NH, exchangeable with D2O), 4.40e4.52 (m, 1H, cyclohexyl), 4.68 (d, 1H, J¼9.2 Hz, H1), 5.68 (d, 1H, J¼10.1 Hz, H9), 5.94 (dddd, J¼2.1, 5.4, 8.6, 10.1 Hz, 1H, H8), 6.46 (d, 2H, J¼8.8 Hz, ArH), 6.95 (d, 2H, J¼8.6 Hz, ArH), 7.10e7.30 (m, 4H, ArH), dC (CDCl3, 75 MHz) 20.9, 21.7, 21.8, 22.7, 27.8, 30.5, 34.3, 37.6, 43.2, 47.5, 60.3, 64.1, 112.3, 125.9, 128.9, 129.8, 130.5, 131.1, 131.6, 131.8, 139.9, 140.6, 174.6 (C]O); nmax (KBr)/cm1 1735; m/z 462 (Mþ). 4.4.3. 4(RS)-[4(SR)(-Chloro-phenylamino)-(4-methoxy-phenyl)methyl]-2-cyclohexyl-1,4,4a(SR),7,8,8a(RS)-hexahydro-2H-isoquinolin-3-one (6c). White solid, [found: C, 72.65; H, 7.36; N, 5.75. C29H35ClN2O2 requires C, 72.71; H, 7.41; N, 5.85%] mp 182e183  C dH (CDCl3, 300 MHz) 1.26e1.57 (m, 10H, cyclohexyl), 1.60e1.72 (m, 2H, eCH2), 1.92e1.97 (m, 1H, eCH), 2.10e2.14 (m, 2H, eCH2), 2.43e2.51 (m, 1H, eCH), 3.22e3.25 (m, 2H, eCH2), 3.32 (dd, 1H, J¼2.2, 9.0 Hz, H2), 3.79 (s, 3H, eOCH3), 4.27 (s, 1H, NH, exchangeable with D2O), 4.34e4.46 (m, 1H, Cyclohexyl), 4.70 (d, 1H, J¼9.0 Hz, H1), 5.72 (d, 1H, J¼10.2 Hz, H9), 5.96 (dddd, J¼2.0, 5.2, 8.4, 10.2 Hz, 1H, H8), 6.40 (d, 2H, J¼8.8 Hz, ArH), 6.78 (d, 2H, J¼8.8 Hz, ArH), 7.00e7.10 (m, 4H, ArH), dC (CDCl3, 75 MHz) 21.4, 21.9, 22.7, 27.8, 30.3, 34.7, 37.5, 43.2, 47.5, 56.4, 60.6, 64.7, 113.7, 115.4, 128.7, 129.8, 130.8, 131.2, 131.4, 135.8, 137.9, 156.6, 175.7 (C]O); nmax (KBr)/cm1 1730; m/z 478 (Mþ). 4.4.4. 4(RS)-[(4(SR)-Chloro-phenyl)-p-tolylamino-methyl]-2cyclohexyl-1,4,4a(SR),7,8,8a(RS)-hexahydro-2H-isoquinolin-3-one (6d). White solid, [found: C, 75.12; H, 7.52; N, 6.16. C29H35ClN2O

V. Mehra, V. Kumar / Tetrahedron 69 (2013) 3857e3866

requires C, 75.22; H, 7.62; N, 6.05%] mp 182e183  C dH (CDCl3, 300 MHz) 1.27e1.56 (m, 10H, cyclohexyl), 1.62e1.75 (m, 2H, eCH2), 1.90e1.97 (m, 1H, eCH), 2.12e2.18 (m, 2H, eCH2), 2.29 (s, 3H, eCH3), 2.40e2.51 (m, 1H, eCH), 3.20e3.26 (m, 2H, eCH2), 3.32 (dd, 1H, J¼2.1, 8.8 Hz, H2), 4.29 (s, 1H, NH, exchangeable with D2O), 4.34e4.46 (m, 1H, cyclohexyl), 4.75 (d, 1H, J¼8.8 Hz, H1), 5.70 (d, 1H, J¼10.6 Hz, H9), 5.95 (dddd, J¼2.1, 5.4, 8.7, 10.6 Hz, 1H, H8), 6.40 (d, 2H, J¼8.8 Hz, ArH), 6.95 (d, 2H, J¼8.8 Hz, ArH), 7.10e7.20 (m, 4H, ArH), dC (CDCl3, 75 MHz) 20.9, 21.2, 21.8, 22.5, 27.9, 30.1, 34.6, 37.8, 43.1, 47.5, 60.5, 64.8, 113.7, 125.6, 128.9, 129.6, 130.5, 131.6, 131.8, 132.4, 137.9, 142.6, 174.7 (C]O); nmax (KBr)/cm1 1734; m/z 462 (Mþ). 4.4.5. 2-Cyclohexyl-4(RS)-[4(SR)-(p-tolyl-p-tolylamino-methyl)]1,4,4a(SR),7,8,8a(RS)-hexahydro-2H-isoquinolin-3-one (6e). White solid, [found: C, 81.32; H, 8.57; N, 6.24. C30H38N2O requires C, 81.40; H, 8.65; N, 6.33%] mp 182e183  C dH (CDCl3, 300 MHz) 1.24e1.58 (m, 10H, cyclohexyl), 1.61e1.72 (m, 2H, eCH2), 1.90e1.98 (m, 1H, eCH), 2.08e2.14 (m, 2H, eCH2), 2.29 (s, 3H, eCH3), 2.34 (s, 3H, eCH3), 2.46e2.54 (m, 1H, eCH), 3.19e3.27 (m, 2H, eCH2), 3.35 (dd, 1H, J¼2.1, 8.8 Hz, H2), 4.29 (s, 1H, NH, exchangeable with D2O), 4.38e4.42 (m, 1H, cyclohexyl), 4.70 (d, 1H, J¼8.8 Hz, H1), 5.78 (d, 1H, J¼10.4 Hz, H9), 5.90 (dddd, J¼2.4, 5.2, 8.6, 10.4 Hz, 1H, H8), 6.45 (d, 2H, J¼8.8 Hz, ArH), 6.92 (d, 2H, J¼8.8 Hz, ArH), 7.05e7.29 (m, 4H, ArH), dC (CDCl3, 75 MHz) 20.5, 20.9, 21.6, 21.8, 22.9, 27.6, 30.5, 34.8, 37.4, 43.7, 47.2, 60.6, 64.9, 112.8, 126.8, 128.4, 129.5, 130.5, 131.4, 131.5, 135.4, 136.8, 142.6, 175.8 (C]O); nmax (KBr)/cm1 1736; m/z 442 (Mþ). 4.4.6. 2-Cyclohexyl-4(RS)-[(4(SR)-methoxy-phenyl)-p-tolylaminomethyl]-1,4,4a(SR),7,8,8a(RS)-hexahydro-2H-isoquinolin-3-one (4f). White solid, [found: C, 78.43; H, 8.22; N, 6.19. C30H38N2O2 requires C, 78.56; H, 8.35; N, 6.11%] mp 182e183  C dH (CDCl3, 300 MHz) 1.26e1.55 (m, 10H, cyclohexyl), 1.59e1.71 (m, 2H, eCH2), 1.92e1.98 (m, 1H, eCH), 2.08e2.16 (m, 2H, eCH2), 2.30 (s, 3H, eCH3), 2.44e2.53 (m, 1H, eCH), 3.15e3.27 (m, 2H, eCH2), 3.31 (dd, 1H, J¼2.1, 9.0 Hz, H2), 3.72 (s, 3H, eOCH3), 4.25 (s, 1H, NH, exchangeable with D2O), 4.38e4.46 (m, 1H, cyclohexyl), 4.78 (d, 1H, J¼9.0 Hz, H1), 5.74 (d, 1H, J¼10.6 Hz, H9), 5.90 (dddd, J¼2.4, 5.4, 8.6, 10.6 Hz, 1H, H8), 6.40 (d, 2H, J¼8.6 Hz, ArH), 6.85 (d, 2H, J¼8.6 Hz, ArH), 6.97e7.10 (m, 4H, ArH), dC (CDCl3, 75 MHz) 20.9, 21.6, 21.8, 22.5, 27.7, 30.4, 34.6, 37.4, 43.8, 47.6, 56.4, 60.5, 64.5, 112.8, 114.8, 126.6, 129.5, 130.2, 130.7, 131.7, 131.9, 140.6, 155.6, 177.8 (C]O); nmax (KBr)/cm1 1734; m/z 458 (Mþ). 4.4.7. 4(RS)-[4-(SR)-(Phenyl-phenylamino-methyl)-2-p-tolyl1,4,4a(SR),7,8,8a(SR)-hexahydro-2H-isoquinolin-3-one (6g). White solid, [found: C, 82.51; H, 7.04; N, 6.54. C29H30N2O requires C, 82.43; H, 7.16; N, 6.63%] mp 132e133  C dH (CDCl3, 300 MHz) 1.54e1.69 (m, 2H, eCH2), 1.87e1.89 (m, 1H, eCH), 2.02e2.08 (m, 2H, eCH2), 2.28 (s, 3H, eCH3), 2.41e2.56 (m, 1H, eCH), 3.18e3.24 (m, 2H, eCH2), 3.28 (dd, 1H, J¼2.4, 8.1 Hz, H3), 4.20 (s, 1H, NH, exchangeable with D2O), 4.58 (d, 1H, J¼8.8 Hz, H1), 5.80 (d, 1H, J¼10.2 Hz, H9), 5.98 (dddd, J¼2.1, 5.1, 8.1, 10.2 Hz, 1H, H8), 6.50 (d, 2H, J¼8.7 Hz, ArH), 7.00 (d, 2H, J¼8.7 Hz, ArH), 7.10e7.43 (m, 10H, ArH), dC (CDCl3, 75 MHz) 20.4, 21.7, 21.8, 34.5, 37.9, 43.8, 60.0, 64.5, 112.3, 116.9, 120.5, 125.7, 126.0, 128.3, 128.9, 129.0, 131.5, 131.8, 132.7, 137.8, 139.4, 143.5, 172.9 (C]O); nmax (KBr)/cm1 1735; m/z 422 (Mþ). 4.4.8. 4(RS)-[(4(SR)-Chloro-phenylamino)-p-tolyl-methyl]-2-p-tolyl1,4,4a(SR),7,8,8a(RS)-hexahydro-2H-isoquinolin-3-one (6h). White solid, [found: C, 76.67; H, 6.54; N, 5.88. C30H31ClN2O requires C, 76.50; H, 6.54; N, 5.95%] mp 133e134  C dH (CDCl3, 300 MHz) 1.58e1.66 (m, 2H, eCH2), 1.86e1.88 (m, 1H, eCH), 2.03e2.07 (m, 2H, eCH2), 2.28 (s, 3H, eCH3), 2.31 (s, 3H, eCH3), 2.4e2.54 (m, 1H, eCH), 3.15e3.27 (m, 2H, eCH2), 3.31 (dd, 1H, J¼2.1, 8.7 Hz, H2),

3863

4.25 (s, 1H, NH, exchangeable with D2O), 4.55 (d, 1H, J¼8.7 Hz, H1), 5.82 (d, 1H, J¼10.5 Hz, H9), 5.94 (dddd, J¼2.4, 5.1, 8.6, 10.5 Hz, 1H, H8), 6.48 (d, 2H, J¼8.8 Hz, ArH), 6.92 (d, 2H, J¼8.8 Hz, ArH), 7.06e7.32 (m, 8H, ArH), dC (CDCl3, 75 MHz) 20.4, 20.9, 21.7, 21.9, 34.8, 37.4, 43.9, 60.3, 64.2, 112.3, 120.1, 120.4, 128.5, 129.0, 129.9, 130.4, 131.5, 131.8, 132.6, 133.8, 136.7, 137.9, 143.5, 174.6 (C]O); nmax (KBr)/cm1 1730; m/z 470 (Mþ). 4.4.9. 4(RS)-[(4(SR)-Chloro-phenylamino)-(4-methoxy-phenyl)methyl]-2-p-tolyl-1,4,4a(RS),7,8,8a(SR)-hexahydro-2H-isoquinolin-3one (6i). White solid, [found: C, 73.90; H, 6.49; N, 5.62. C30H31ClN2O2 requires C, 73.98; H, 6.42; N, 5.75%] mp 125e126  C dH (CDCl3, 300 MHz) 1.59e1.71 (m, 2H, eCH2), 1.85e1.90 (m, 1H, eCH), 2.05e2.09 (m, 2H, eCH2), 2.29 (s, 3H, eCH3), 2.47e2.56 (m, 1H, eCH), 3.12e3.24 (m, 2H, eCH2), 3.36 (dd, 1H, J¼2.1, 8.9 Hz, H2), 3.80 (s, 3H, eOCH3), 4.27 (s, 1H, NH, exchangeable with D2O), 4.61 (d, 1H, J¼8.9 Hz, H1), 5.85 (d, 1H, J¼10.4 Hz, H9), 5.96 (dddd, J¼2.1, 5.6, 8.4, 10.4 Hz, 1H, H8), 6.34 (d, 2H, J¼8.6 Hz, ArH), 6.68 (d, 2H, J¼8.8 Hz, ArH), 6.95 (d, 2H, J¼8.6 Hz, ArH), 7.00e7.30 (m, 6H, ArH), dC (CDCl3, 75 MHz) 20.4, 21.5, 21.8, 34.6, 37.5, 43.7, 58.1, 60.5, 64.5, 112.3, 113.6, 120.4, 120.7, 128.5, 128.9, 129.9, 130.4, 131.6, 131.9, 132.6, 137.9, 143.5, 156.5, 174.4 (C]O); nmax (KBr)/cm1 1734; m/z 486 (Mþ). 4.4.10. 4(RS)-[(4(SR)-Chloro-phenyl)-p-tolylamino-methyl]-2-ptolyl-1,4,4a(RS),7,8,8a(SR)-hexahydro-2H-isoquinolin-3-one (6j). White solid, [found: C, 76.42; H, 6.56; N, 5.87. C30H31ClN2O requires C, 76.50; H, 6.63; N, 5.95%] mp 127e128  C dH (CDCl3, 300 MHz) 1.58e1.70 (m, 2H, eCH2), 1.82e1.88 (m, 1H, eCH), 2.04e2.10 (m, 2H, eCH2), 2.29 (s, 3H, eCH3), 2.31 (s, 3H, eCH3), 2.43e2.52 (m, 1H, eCH), 3.10e3.20 (m, 2H, eCH2), 3.38 (dd, 1H, J¼2.6, 8.8 Hz, H3), 4.22 (s, 1H, NH, exchangeable with D2O), 4.66 (d, 1H, J¼8.8 Hz, H1), 5.80 (d, 1H, J¼10.2 Hz, H9), 5.94 (dddd, J¼2.0, 5.4, 8.8, 10.2 Hz, 1H, H8), 6.35 (d, 2H, J¼8.6 Hz, ArH), 6.80 (d, 2H, J¼8.6 Hz, ArH), 6.97e7.25 (m, 8H, ArH), dC (CDCl3, 75 MHz) 20.6, 20.9, 21.4, 21.8, 34.9, 37.6, 43.8, 60.5, 64.5, 112.9, 120.4, 125.7, 128.8, 129.0, 129.4, 130.5, 131.0, 131.5, 131.7, 132.6, 137.8, 139.3, 141.4, 175.6 (C]O); nmax (KBr)/cm1 1736; m/z 470 (Mþ). 4.4.11. 2-p-Tolyl-4(RS)-[4-(SR)-(p-tolyl-p-tolylamino-methyl)1,4,4a(SR),7,8,8a(RS)-hexahydro-2H-isoquinolin-3-one (6k). White solid, [found: C, 82.53; H, 7.69; N, 6.28. C31H34N2O requires C, 82.63; H, 7.61; N, 6.22%] mp 133e134  C dH (CDCl3, 300 MHz) 1.59e1.72 (m, 2H, eCH2), 1.82e1.89 (m, 1H, eCH), 2.03e2.12 (m, 2H, eCH2), 2.26 (s, 3H, eCH3), 2.29 (s, 3H, eCH3), 2.31 (s, 3H, eCH3), 2.40e2.51 (m, 1H, eCH), 3.15e3.22 (m, 2H, eCH2), 3.40 (dd, 1H, J¼2.6, 8.6 Hz, H2), 4.28 (s, 1H, NH, exchangeable with D2O), 4.64 (d, 1H, J¼8.6 Hz, H1), 5.87 (d, 1H, J¼10.6 Hz, H9), 5.92 (dddd, J¼2.2, 5.2, 8.4, 10.6 Hz, 1H, H8), 6.38 (d, 2H, J¼8.8 Hz, ArH), 6.80 (d, 2H, J¼8.8 Hz, ArH), 6.98e7.13 (m, 8H, ArH), dC (CDCl3, 75 MHz) 20.6, 20.7, 20.9, 21.6, 21.9, 34.5, 37.7, 43.8, 60.4, 64.6, 112.6, 120.5, 125.6, 128.3, 129.4, 129.8, 130.6, 131.4, 131.8, 132.6, 134.3, 137.9, 139.2, 143.1, 176.8 (C]O); nmax (KBr)/cm1 1738; m/z 450 (Mþ). 4.4.12. 4(RS)-[(4(SR)-Methoxy-phenyl)-p-tolylamino-methyl]-2-ptolyl-1,4,4a(SR),7,8,8a(RS)-hexahydro-2H-isoquinolin-3-one (6l). White solid, [found: C, 79.71; H, 7.28; N, 6.04. C31H34N2O2 requires C, 79.79; H, 7.34; N, 6.00%] mp 120e121  C dH (CDCl3, 300 MHz) 1.55e1.70 (m, 2H, eCH2), 1.80e1.87 (m, 1H, eCH), 2.05e2.16 (m, 2H, eCH2), 2.29 (s, 3H, eCH3), 2.31 (s, 3H, eCH3), 2.44e2.52 (m, 1H, eCH), 3.13e3.20 (m, 2H, eCH2), 3.42 (dd, 1H, J¼2.6, 8.8 Hz, H2), 3.78 (s, 3H, eOCH3), 4.25 (s, 1H, NH, exchangeable with D2O), 4.68 (d, 1H, J¼8.8 Hz, H1), 5.84 (d, 1H, J¼10.2 Hz, H9), 5.96 (dddd, J¼2.4, 5.6, 8.2, 10.2 Hz, 1H, H8), 6.37 (d, 2H, J¼8.8 Hz, ArH), 6.82 (d, 2H, J¼8.6 Hz, ArH), 6.94 (d, 2H, J¼8.8 Hz, ArH), 7.00e7.20 (m, 6H, ArH), dC (CDCl3, 75 MHz) 20.4, 20.8, 21.6, 21.9,

3864

V. Mehra, V. Kumar / Tetrahedron 69 (2013) 3857e3866

34.8, 37.6, 43.9, 56.5, 60.8, 64.4, 112.7, 113.8, 120.9, 126.3, 128.7, 128.9, 129.4, 131.6, 131.8, 132.6, 135.6, 137.9, 140.2, 155.1, 176.8 (C]O); nmax (KBr)/cm1 1737; m/z 466 (Mþ). 4.5. Procedure for the synthesis of hexahydro-isochromen-3ones 7 To a stirred solution of 3 in dry methanol (20 mL) was added sodium borohydride (2.0 mmol) and the progress of the reaction was monitored through TLC. The reaction mixture on completion was quenched with brine solution (50 mL) and extracted with dichloromethane (50 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The crude product thus obtained was purified via column chromatography on silica gel using a mixture (5:95) of ethyl acetate and hexane as an eluent. 4 . 5 . 1. 4 ( R S ) - [ 4 - ( S R ) - ( P h e n y l - p h e n y l a m i n o - m e t h y l ) 1,4,4a(SR),7,8,8a(RS)-hexahydro-isochromen-3-one (7a). White solid, [found: C, 79.14; H, 6.82; N, 4.41. C22H23NO2 requires C, 79.25; H, 6.95; N, 4.20%] mp 108e109  C dH (CDCl3, 300 MHz) 1.52e1.65 (m, 2H, eCH2), 1.82e1.87 (m, 1H, eCH), 2.02e2.08 (m, 2H, eCH2), 2.61e2.72 (m, 1H, eCH), 3.26 (dd, 1H, J¼2.2, 8.8 Hz, H2), 3.81e3.90 (m, 2H, eCH2), 4.22 (s, 1H, NH, exchangeable with D2O), 4.52 (d, 1H, J¼8.8 Hz, H1), 5.82 (d, 1H, J¼10.4 Hz, H9), 5.90 (dddd, J¼2.2, 5.4, 8.2, 10.4 Hz, 1H, H8), 6.48 (d, 2H, J¼8.8 Hz, ArH), 7.00e7.22 (m, 8H, ArH), dC (CDCl3, 75 MHz) 26.4, 30.9, 31.8, 39.4, 50.4, 55.8, 71.0, 112.3, 116.5, 125.3, 128.7, 128.9, 129.4, 131.5, 131.8, 139.4, 143.2, 175.9 (C]O); nmax (KBr)/cm1 1738; m/z 333 (Mþ). 4.5.2. 4(RS)-[(4(SR)-Chloro-phenylamino)-p-tolyl-methyl]1,4,4a(SR),7,8,8a(RS)-hexahydro-isochromen-3-one (7b). White solid, [found: C, 72.26; H, 6.21; N, 3.75. C23H24ClNO2 requires C, 72.34; H, 6.33; N, 3.67%] mp 110e111  C dH (CDCl3, 300 MHz) 1.54e1.66 (m, 2H, eCH2), 1.80e1.87 (m, 1H, eCH), 2.08e2.16 (m, 2H, eCH2), 2.31 (s, 3H, eCH3), 2.63e2.71 (m, 1H, eCH), 3.29 (dd, 1H, J¼2.4, 8.6 Hz, H2), 3.85e3.92 (m, 2H, eCH2), 4.24 (s, 1H, NH, exchangeable with D2O), 4.57 (d, 1H, J¼8.6 Hz, H1), 5.80 (d, 1H, J¼10.2 Hz, H9), 5.92 (dddd, J¼2.1, 5.4, 8.1, 10.2 Hz, 1H, H8), 6.40 (d, 2H, J¼8.8 Hz, ArH), 7.00e7.32 (m, 6H, ArH), dC (CDCl3, 75 MHz) 20.7, 26.7, 30.5, 31.5, 39.9, 50.6, 55.4, 71.6, 112.6, 122.3, 128.4, 129.5, 130.8, 131.5, 131.6, 134.1, 137.4, 141.2, 175.6 (C]O); m/z 381 (Mþ) nmax (KBr)/cm1 1732. 4.5.3. 4(RS)-[(4(SR)-Chloro-phenylamino)-(4-methoxy-phenyl)methyl]-1,4,4a(SR),7,8,8a(RS)-hexahydro-isochromen-3-one (7c). White solid, [found: C, 69.54; H, 6.18; N, 3.46. C23H24ClNO3 requires C, 69.43; H, 6.08; N, 3.52%] mp 112e113  C dH (CDCl3, 300 MHz) 1.52e1.64 (m, 2H, eCH2), 1.81e1.88 (m, 1H, eCH), 2.04e2.12 (m, 2H, eCH2), 2.62e2.70 (m, 1H, eCH), 3.32 (dd, 1H, J¼2.4, 8.8 Hz, H2), 3.72 (s, 3H, eOCH3), 4.20 (s, 1H, NH, exchangeable with D2O), 3.87e3.94 (m, 2H, eCH2), 4.54 (d, 1H, J¼8.8 Hz, H1), 5.82 (d, 1H, J¼10.1 Hz, H9), 5.92 (dddd, J¼2.6, 5.2, 8.3, 10.1 Hz, 1H, H8), 6.45 (d, 2H, J¼8.6 Hz, ArH), 6.75 (d, 2H, J¼8.6 Hz, ArH), 7.05e7.34 (m, 4H, ArH), dC (CDCl3, 75 MHz) 26.4, 30.2, 31.6, 39.8, 50.5, 55.4, 56.7, 71.4, 113.6, 114.5, 122.4, 129.6, 130.5, 131.6, 131.7, 135.1, 141.4, 158.2, 176.6 (C]O); nmax (KBr)/cm1 1736; m/z 397 (Mþ). 4.5.4. 4(RS)-[(4(SR)-Chloro-phenyl)-p-tolylamino-methyl]1,4,4a(SR),7,8,8a(RS)-hexahydro-isochromen-3-one (7d). White solid, [found: C, 72.18; H, 6.25; N, 3.56. C23H24ClNO2 requires C, 72.34; H, 6.33; N, 3.67%] mp 113e114  C dH (CDCl3, 300 MHz) 1.55e1.67 (m, 2H, eCH2), 1.78e1.85 (m, 1H, eCH), 2.07e2.12 (m, 2H, eCH2), 2.34 (s, 3H, eCH3), 2.64e2.72 (m, 1H, eCH), 3.30 (dd, 1H, J¼2.4, 8.7 Hz, H2), 3.83e3.93 (m, 2H, eCH2), 4.25 (s, 1H, NH, exchangeable with D2O), 4.57 (d, 1H, J¼8.7 Hz, H1), 5.85 (d, 1H,

J¼10.2 Hz, H9), 5.94 (dddd, J¼2.4, 5.4, 8.4, 10.2 Hz, 1H, H8), 6.35 (d, 2H, J¼8.8 Hz, ArH), 6.90e7.24 (m, 6H, ArH), dC (CDCl3, 75 MHz) 20.7, 26.7, 30.5, 31.5, 39.9, 50.6, 55.4, 71.6, 113.4, 126.5, 128.7, 129.4, 130.1, 130.7, 131.4, 131.7, 136.4, 141.2, 176.9 (C]O); nmax (KBr)/cm1 1732. m/z 381 (Mþ). 4 . 5 . 5 . 4 ( R S ) - [ 4 - ( S R ) - ( p -T o l y l - p - t o l y l a m i n o - m e t h y l ) 1,4,4a(SR),7,8,8a(RS)-hexahydro-isochromen-3-one (7e). White solid, [found: C, 79.65; H, 7.42; N, 3.73. C23H27NO2 requires C, 79.74; H, 7.53; N, 3.87%] mp 114e115  C dH (CDCl3, 300 MHz) 1.53e1.66 (m, 2H, eCH2), 1.75e1.82 (m, 1H, eCH), 2.07e2.14 (m, 2H, eCH2), 2.30 (s, 3H, eCH3), 2.34 (s, 3H, eCH3), 2.63e2.73 (m, 1H, eCH), 3.32 (dd, 1H, J¼2.6, 8.8 Hz, H2), 3.84e3.90 (m, 2H, eCH2), 4.29 (s, 1H, NH, exchangeable with D2O), 4.59 (d, 1H, J¼8.8 Hz, H1), 5.82 (d, 1H, J¼10.0 Hz, H9), 5.94 (dddd, J¼2.2, 5.6, 8.6, 10.0 Hz, 1H, H8), 6.35 (d, 2H, J¼8.6 Hz, ArH), 6.90 (d, 2H, J¼8.6 Hz, ArH), 7.00e7.24 (m, 4H, ArH), dC (CDCl3, 75 MHz) 20.5, 20.7, 26.7, 30.5, 31.5, 39.9, 50.6, 55.4, 71.6, 113.2, 126.4, 128.8, 129.9, 130.2, 131.8, 131.9, 134.4, 136.3, 140.2, 176.4 (C]O); nmax (KBr)/cm1 1734; m/z 361 (Mþ). 4.5.6. 4(RS)-[(4(SR)-Methoxy-phenyl)-p-tolylamino-methyl]1,4,4a(SR),7,8,8a(RS)-hexahydro-isochromen-3-one (7f). White solid, [found: C, 76.45; H, 7.15; N, 3.76. C24H27NO3 requires C, 76.36; H, 7.21; N, 3.71%] mp 106e107  C dH (CDCl3, 300 MHz) 1.55e1.65 (m, 2H, eCH2), 1.73e1.80 (m, 1H, eCH), 2.05e2.13 (m, 2H, eCH2), 2.35 (s, 3H, eCH3), 2.62e2.71 (m,1H, eCH), 3.30 (dd,1H, J¼2.4, 8.6 Hz, H2), 3.75 (s, 3H, eOCH3), 3.82e3.91 (m, 2H, eCH2), 4.25 (s, 1H, NH, exchangeable with D2O), 4.62 (d, 1H, J¼8.6, 10.2 Hz, 1H, H8), 6.33 (d, 2H, J¼8.8 Hz, ArH), 6.72 (d, 2H, J¼8.8 Hz, ArH), 6.96e7.22 (m, 4H, ArH), dC (CDCl3, 75 MHz) 20.9, 26.4, 30.2, 31.6, 39.8, 50.5, 55.4, 56.7, 71.4, 112.4, 113.4, 126.7, 128.8, 129.6, 130.8, 131.2, 131.8, 131.9, 134.2, 140.1, 156.2, 176.8 (C]O); nmax (KBr)/cm1 1736; m/z 377 (Mþ). 4.6. Procedure for the synthesis of decahydro-pyrrolo[4,3,2de]isoquinolin-3-one/decahydro-4-oxa-1-aza-acenaphthylen3-one 9 To a well stirred suspension of K2CO3 (5 mmol) in dry dichloromethane (50 mL) was added molecular iodine (1 mmol) till the solution acquired violet colouration. To this was added a solution of 6/7 (1 mmol) in dry dichloromethane (20 mL) and the progress of the reaction was monitored through TLC. The reaction mixture was then filtered, washed with water (50 mL), and extracted with dichloromethane (50 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuo. The crude product so obtained was purified by flash chromatography on silica gel using a mixture of (20:80) ethyl acetate and hexane as the eluent. 4 . 6 .1. 4 - C y c l o h e x y l - 8 ( R S ) - i o d o - 1, 2 ( S R ) - d i p h e n y l(2aRS,5a,RS,8aRS,9aSR)decahydro-pyrrolo[4,3,2-de]isoquinolin-3one (9a). White solid, [found: C, 62.12; H, 6.04; N, 5.06. C28H33IN2O requires C, 62.22; H, 6.15; N, 5.18%] mp 163e164  C dH (CDCl3, 300 MHz) 1.24e1.58 (m, 10H, cyclohexyl), 1.64e1.72 (m, 2H, eCH2), 1.91e1.96 (m, 1H, eCH), 2.11e2.16 (m, 2H, eCH2), 3.22e3.27 (m, 2H, eCH2), 3.31 (ddd, 1H, J¼6.6, 7.3, 7.7 Hz, H3), 3.42e3.58 (m, 1H, eCH), 3.94 (dd, 1H, J¼7.3, 7.7 Hz, H2), 4.40e4.54 (m, 1H, cyclohexyl), 4.93 (dd, 1H, J¼6.6, 13.7 Hz, H9), 5.42 (d, 1H, J¼7.7 Hz, H1), 6.62 (d, 2H, J¼8.8 Hz, ArH), 6.90e7.23 (m, 8H, ArH), dC (CDCl3, 75 MHz) 21.3, 21.8, 22.4, 27.6, 28.4, 30.5, 34.7, 37.8, 43.7, 47.6, 57.6, 60.5, 64.7, 112.4, 116.5, 125.7, 128.2, 128.9, 129.7, 139.6, 143.4, 175.4 (C]O); nmax (KBr)/cm1 1734; m/z 540 (Mþ). 4.6.2. 1-(4-Chloro-phenyl)-4-cyclohexyl-8(RS)-iodo-2(SR)-p-tolyl(2aRS,5a,RS,8aRS,9aSR)-decahydro-pyrrolo[4,3,2-de]isoquinolin-3one (9b). White solid, [found: C, 59.03; H, 5.94; N, 4.66.

V. Mehra, V. Kumar / Tetrahedron 69 (2013) 3857e3866

C29H34ClIN2O requires C, 59.14; H, 5.82; N, 4.76%] mp 165e166  C dH (CDCl3, 300 MHz) 1.23e1.59 (m, 10H, cyclohexyl), 1.62e1.71 (m, 2H, eCH2), 1.90e1.98 (m, 1H, eCH), 2.10e2.18 (m, 2H, eCH2), 2.28 (s, 3H, eCH3), 3.20e3.28 (m, 2H, eCH2), 3.34 (ddd, 1H, J¼6.8, 7.2, 7.5 Hz, H3), 3.44e3.56 (m, 1H, eCH), 3.92 (dd, 1H, J¼7.2, 7.5 Hz, H2), 4.42e4.56 (m, 1H, cyclohexyl), 4.97 (dd, 1H, J¼6.8, 13.7 Hz, H9), 5.45 (d, 1H, J¼7.7 Hz, H1), 6.50 (d, 2H, J¼8.8 Hz, ArH), 6.98 (d, 2H, J¼8.6 Hz, ArH), 7.12e7.35 (m, 4H, ArH), dC (CDCl3, 75 MHz) 20.6, 21.5, 21.9, 22.5, 27.6, 28.9, 30.5, 34.1, 37.8, 43.1, 47.8, 57.8, 60.1, 64.5, 112.6, 125.6, 128.8, 129.4, 130.6, 131.1, 136.4, 141.8, 174.7 (C]O); nmax (KBr)/cm1 1732. m/z 588 (Mþ). 4.6.3. 1-(4-Chloro-phenyl)-4-cyclohexyl-8(RS)-iodo-2-(4-methoxyphenyl)-(2aRS,5a,RS,8aRS,9aSR)-decahydro-pyrrolo[4,3,2-de]isoquinolin-3-one (9c). White solid, [found: C, 57.44; H, 5.52; N, 4.71. C29H34ClIN2O2 requires C, 57.58; H, 5.66; N, 4.63%] mp 166e167  C dH (CDCl3, 300 MHz) 1.20e1.57 (m, 10H, cyclohexyl), 1.61e1.70 (m, 2H, eCH2), 1.92e1.99 (m, 1H, eCH), 2.11e2.19 (m, 2H, eCH2), 3.22e3.29 (m, 2H, eCH2), 3.36 (ddd, 1H, J¼6.6, 7.0, 7.8 Hz, H3), 3.42e3.55 (m, 1H, eCH), 3.94 (dd, 1H, J¼7.0, 7.8 Hz, H2), 4.42e4.56 (m, 1H, Cyclohexyl), 4.97 (dd, 1H, J¼6.4, 13.4 Hz, H9), 5.42 (d, 1H, J¼7.8 Hz, H1), 6.48 (d, 2H, J¼8.6 Hz, ArH), 6.78 (d, 2H, J¼8.6 Hz, ArH), 7.07e7.34 (m, 4H, ArH), dC (CDCl3, 75 MHz) 21.3, 21.7, 22.8, 27.6, 28.7, 30.5, 34.6, 37.4, 43.8, 47.9, 57.4, 56.6, 60.5, 64.8, 113.8, 115.4, 123.8, 129.6, 131.4, 135.6, 140.4, 157.4, 175.4 (C]O); nmax (KBr)/cm1 1730; m/z 604 (Mþ). 4.6.4. 8-(RS)-Iodo-1,2(SR)-diphenyl-4-p-tolyl-(2aRS,5a,RS,8aRS,9aSR)-decahydro-pyrrolo[4,3,2-de]isoquinolin-3-one (9d). White solid, [found: C, 63.45; H, 5.25; N, 5.02. C29H29IN2O requires C, 63.51; H, 5.33; N, 5.11%] mp 169e170  C dH (CDCl3, 300 MHz) 1.65e1.70 (m, 2H, eCH2), 1.90e1.98 (m, 1H, eCH), 2.10e2.16 (m, 2H, eCH2), 2.28 (s, 3H, eCH3), 3.22e3.27 (m, 2H, eCH2), 3.35 (ddd, 1H, J¼6.5, 7.1, 7.5 Hz, H3), 3.40e3.56 (m, 1H, eCH), 3.96 (dd, 1H, J¼7.1, 7.5 Hz, H28.6 Hz, H1), 5.81 (d, 1H, J¼10.2 Hz, H9), 5.92 (dddd, J¼2.1, 5.4), 4.95 (dd, 1H, J¼6.5, 13.6 Hz, H9), 5.40 (d, 1H, J¼7.5 Hz, H1), 6.50 (d, 2H, J¼8.7 Hz, ArH), 7.00 (d, 2H, J¼8.7 Hz, ArH), 7.10e7.43 (m, 10H, ArH), dC (CDCl3, 75 MHz) 20.4, 21.7, 21.8, 30.2, 34.5, 37.9, 43.8, 56.4, 60.0, 64.5, 112.3, 113.8, 120.6, 125.7, 126.0, 128.3, 128.9, 129.0, 129.8, 137.8, 139.4, 143.5, 172.9 (C]O); nmax (KBr)/cm1 1735; m/z 548 (Mþ). 4.6.5. 1-(4-Chloro-phenyl)-8(RS)-iodo-2(SR),4-di-p-tolyl-(2aRS,5a,RS,8aRS,9aSR)-decahydro-pyrrolo[4,3,2-de]isoquinolin-3-one (9e). White solid, [found: C, 60.27; H, 5.17; N, 4.57. C29H30ClIN2O requires C, 60.36; H, 5.07; N, 4.69%] mp 160e161  C dH (CDCl3, 300 MHz) 1.67e1.72 (m, 2H, eCH2), 1.94e1.99 (m, 1H, eCH), 2.12e2.18 (m, 2H, eCH2), 2.29 (s, 3H, eCH3), 2.33 (s, 3H, eCH3), 3.20e3.27 (m, 2H, eCH2), 3.39 (ddd, 1H, J¼6.7, 7.0, 7.4 Hz, H3), 3.45e3.57 (m, 1H, eCH), 3.98 (dd, 1H, J¼7.0, 7.4 Hz, H2), 4.95 (dd, 1H, J¼6.7, 13.7 Hz, H9), 5.42 (d, 1H, J¼7.5 Hz, H1), 6.56 (d, 2H, J¼8.8 Hz, ArH), 6.98 (d, 2H, J¼8.8 Hz, ArH), 7.06e7.37 (m, 8H, ArH), dC (CDCl3, 75 MHz) 20.6, 20.9, 21.6, 21.9, 28.4, 34.9, 37.7, 43.6, 56.5, 60.2, 64.5, 112.3, 120.5, 125.3, 128.6, 128.7, 129.2, 129.7, 130.2, 132.5, 137.8, 139.7, 143.6, 173.5(C]O); m/z 596 (Mþ) nmax (KBr)/cm1 1732; m/z 596 (Mþ). 4.6.6. 1-(4-Chloro-phenyl)-8(RS)-iodo-2(SR)-(4-methoxy-phenyl)-4p-tolyl-(2aRS,5a,RS,8aRS,9aSR)-decahydro-pyrrolo[4,3,2-de]isoquinolin-3-one (9f). White solid, [found: C, 58.71; H, 4.82; N, 4.46. C30H30ClIN2O2 requires C, 58.79; H, 4.93; N, 4.57%] mp 165e166  C dH (CDCl3, 300 MHz) 1.64e1.71 (m, 2H, eCH2), 1.92e1.98 (m, 1H, eCH), 2.10e2.16 (m, 2H, eCH2), 2.30 (s, 3H, eCH3), 3.19e3.28 (m, 2H, eCH2), 3.38 (ddd, 1H, J¼6.4, 7.2, 7.6 Hz, H3), 3.41e3.54 (m, 1H, eCH), 3.72 (s, 3H, eOCH3), 3.94 (dd, 1H, J¼7.2, 7.6 Hz, H2), 4.93 (dd, 1H, J¼6.4, 13.4 Hz, H9), 5.42 (d, 1H, J¼7.6 Hz, H1), 6.53 (d, 2H,

3865

J¼8.6 Hz, ArH), 6.75 (d, 2H, J¼8.8 Hz, ArH), 6.97 (d, 2H, J¼8.6 Hz, ArH), 7.00e7.20 (m, 6H, ArH), dC (CDCl3, 75 MHz) 20.2, 21.7, 21.8, 28.4, 34.5, 37.8, 43.3, 57.4, 58.1, 60.6, 64.3, 112.5, 113.4, 120.4, 128.6, 128.9, 129.7, 130.7, 132.8, 137.7, 139.2, 143.9, 156.4, 175.4 (C]O); m/z 612 (Mþ) nmax (KBr)/cm1 1732; m/z 612 (Mþ). 4.6.7. 8-(RS)Iodo-1,2(SR)-diphenyl-(2aRS,5a,RS,8aRS,9aSR)-decahydro-4-oxa-1-aza-acenaphthylen-3-one (9g). White solid, [found: C, 57.56; H, 4.63; N, 3.05. C22H22INO2 requires C, 57.63; H, 4.63; N, 3.05%] mp 168e169  C dH (CDCl3, 300 MHz) 1.63e1.72 (m, 2H, eCH2), 1.91e1.96 (m, 1H, eCH), 2.11e2.17 (m, 2H, eCH2), 3.37 (ddd, 1H, J¼6.6, 7.0, 7.5 Hz, H3), 3.43e3.58 (m, 1H, eCH), 3.94 (dd, 1H, J¼7.0, 7.5 Hz, H2), 4.14e4.26 (m, 2H, eCH2), 4.90 (dd, 1H, J¼6.6, 13.4 Hz, H9), 5.45 (d, 1H, J¼7.5 Hz, H1), 6.56 (d, 2H, J¼8.8 Hz, ArH), 6.90e7.23 (m, 8H, ArH), dC (CDCl3, 75 MHz) 24.1, 24.9, 28.1, 28.7, 34.1, 41.2, 56.3, 63.0, 72.3, 112.5, 116.4, 125.2, 128.5, 128.9, 129.7, 139.3, 143.7, 175.8 (C]O); nmax (KBr)/cm1 1738; m/z 459 (Mþ). 4.6.8. 1-(4-Chloro-phenyl)-8(RS)-iodo-2(SR)-p-tolyl-(2aRS,5a,RS,8aRS,9aSR)-decahydro-4-oxa-1-aza-acenaphthylen-3-one (9h). White solid, [found: C, 54.32; H, 4.48; N, 2.64. C23H23ClINO2 requires C, 54.40; H, 4.57; N, 2.76%] mp 162e163  C dH (CDCl3, 300 MHz) 1.65e1.74 (m, 2H, eCH2), 1.90e1.98 (m, 1H, eCH), 2.09e2.13 (m, 2H, eCH2), 2.28 (s, 3H, eCH3), 3.36 (ddd, 1H, J¼6.5, 7.2, 7.7 Hz, H3), 3.40e3.56 (m, 1H, eCH), 3.97 (dd, 1H, J¼7.2, 7.5 Hz, H2), 4.10e4.24 (m, 2H, eCH2), 4.95 (dd, 1H, J¼6.5, 13.7 Hz, H9), 5.40 (d, 1H, J¼7.7 Hz, H1), 6.45 (d, 2H, J¼8.6 Hz, ArH), 6.90 (d, 2H, J¼8.8 Hz, ArH), 7.00e7.32 (m, 4H, ArH), dC (CDCl3, 75 MHz) 24.2, 24.4, 28.7, 28.9, 34.0, 41.2, 56.5, 63.5, 72.5, 112.5, 126.1, 128.7, 129.6, 130.7, 132.4, 137.3, 141.7, 175.8 (C]O); nmax (KBr)/cm1 1736; m/z 507 (Mþ). 4.6.9. 1-(4-Chloro-phenyl)-8(RS)-iodo-2(SR)-(4-methoxy-phenyl)(2aRS,5a,RS,8aRS,9aSR)-decahydro-4-oxa-1-aza-acenaphthylen-3one (9i). White solid, [found: C, 52.66; H, 4.34; N, 2.56. C23H23ClINO3requires C, 52.74; H, 4.43; N, 2.67%] mp 169e170  C dH (CDCl3, 300 MHz) 1.62e1.742 (m, 2H, eCH2), 1.92e1.98 (m, 1H, eCH), 2.12e2.17 (m, 2H, eCH2), 3.34 (ddd, 1H, J¼6.4, 7.0, 7.4 Hz, H3), 3.41e3.54 (m, 1H, eCH), 3.70 (s, 3H, eOCH3), 3.94 (dd, 1H, J¼7.0, 7.4 Hz, H2), 4.12e4.25 (m, 2H, eCH2), 4.97 (dd, 1H, J¼6.4, 13.7 Hz, H9), 5.43 (d, 1H, J¼7.4 Hz, H1), 6.45 (d, 2H, J¼8.6 Hz, ArH), 6.95 (d, 2H, J¼8.6 Hz, ArH), 7.05e7.34 (m, 4H, ArH), dC (CDCl3, 75 MHz) 24.4, 24.9, 28.3, 28.9, 34.6, 41.2, 56.7, 56.9, 63.4, 72.2, 113.8, 114.9, 128.3, 129.7, 130.6, 135.1, 137.3, 158.1, 176.7 (C]O); nmax (KBr)/cm1 1734; m/z 523 (Mþ). Acknowledgements The financial support from CSIR New Delhi under Scheme No. 01(2407)/10/EMR-II (V.K.) is gratefully acknowledged. References and notes 1. Bhadra, K.; Kumar, G. S. Med. Res. Rev. 2010, 31, 821. 2. Briet, N.; Brookes, M. H.; Davenport, R. J.; Galvin, F. C. A.; Gilbert, P. J.; Mack, S. R.; Sabin, V. Tetrahedron 2002, 58, 5761. 3. Byler, K. G.; Arias, M. B.; Navarro, A. M.; Torres, B. N.; Bustillos, L. G. T.; Mayorga, K. M. Bioorg. Med. Chem. 2012, 20, 2587. 4. (a) Chen, C.; Li, X.; Schreiber, S. L. J. Am. Chem. Soc. 2003, 125, 10174; (b) Lim, C. W.; Tissot, O.; Mattison, A.; Hooper, M. W.; Brown, J. M.; Cowley, A. R.; Hulmes, D. I.; Blacker, A. J. Org. Process Res. Dev. 2003, 7, 379; (c) Durola, F.; Sauvage, J. P.; Wenger, O. S. Chem. Commun. 2006, 171. 5. Su, E. Y. J.; Huang, H. L.; Li, C. L.; Chien, C.; Tao, Y. T.; Chou, P. T.; Datta, S.; Liu, R. S. Adv. Mater. 2003, 15, 884. 6. (a) Bentley, K. W. Nat. Prod. Rep. 2003, 20, 342; (b) Scott, J. D.; Williams, R. M. Chem. Rev. 2002, 102, 1669; (c) Bentley, K. W. Nat. Prod. Rep. 2001, 18, 148. 7. Charifson, P. S. Drugs Future 1989, 14, 1179. 8. Lorenc-Koci, E.; Smialowska, M.; Antkiewicz-Michaluk, L.; Golembiowska, K.; Bajkowska, M.; Wolfarth, S. Neuroscience 2000, 95, 1049.

3866

V. Mehra, V. Kumar / Tetrahedron 69 (2013) 3857e3866

9. (a) Abe, K.; Saitoh, T.; Horiguchi, Y.; Utsunomiya, I.; Taguchi, K. Biol. Pharm. Bull. 2005, 28, 1355; (b) Antkiewicz-Michaluk, L.; Lazarewicz, J. W.; Patsenka, A.; Kajta, M.; Zieminska, E.; Salinska, E.; Wasik, A.; Golembiowska, K.; Vetulani, J. J. Neurochem. 2006, 97, 846. 10. Wang, Y.-F.; Toh, K. K.; Lee, J.-Y.; Chiba, S. Angew. Chem., Int. Ed. 2011, 50, 5927. 11. (a) Mondon, A. Erythrina Alkaloids In Chemistry of the Alkaloids; Pelletier, S. W., Ed.; Van Nostrand, Reinhold: New York, NY, 1970; p 137; (b) Whitlock, H. W., Jr.; Smith, G. L. J. Am. Chem. Soc. 1967, 89, 3600. 12. (a) Girling, I. R.; Widdowson, D. A. Tetrahedron Lett. 1982, 23, 1957; (b) Girling, I. R.; Widdowson, D. A. J. Chem. Soc., Perkin Trans. 1 1988, 1, 1317. 13. Letcher, R. M.; Kwok, N. C.; Cheung, K. K. J. Chem. Soc., Perkin Trans. 1 1992, 1, 1769. 14. (a) Stanoeva, E.; Haimova, M. A.; Ognyanov, V. I. Liebigs Ann. Chem. 1984, 38; (b) Haimova, M. A.; Ognyanov, V. I.; Mollov, N. M. Synthesis 1980, 845. 15. (a) Cobas, A.; Guitian, E.; Castedo, L. J. Org. Chem. 1993, 58, 3113; (b) Maruyama, W.; Naoi, M. J. Neurol. 2002, 249, 116. 16. Dominguez, E.; Martinez de Marigorta, E.; Carillo, L.; Fananas, R. Tetrahedron 1991, 47, 9253. 17. (a) Brooks, J. R.; Harcourt, D. N.; Waigh, R. D. J. Chem. Soc., Perkin Trans. 1 1973, 1, 2588; (b) Haraoka, M.; Yamagishi, H.; Marutani, M.; Mukai, C. Tetrahedron Lett. 1984, 25, 5169. ndez, L. J.; C lez, M. G.; Bravo, R. D. Tetrahedron Lett. 2012, 18. Me anepa, A. S.; Gonza 53, 688. 19. Cho, W. J.; Min, S. Y.; Le, T. N.; Kim, T. S. Bioorg. Med. Chem. Lett. 2003, 13, 4451. 20. Matsui, T.; Sugiura, T.; Nakai, H.; Iguchi, S.; Shigeoka, S.; Takada, H.; Odagaki, Y.; Nagao, Y.; Ushio, Y.; Ohmoto, K.; Iwamura, H.; Yamazaki, S.; Arai, Y.; Kawamura, M. J. Med. Chem. 1992, 35, 3307. 21. Cho, W. J.; Yoo, S. J.; Chung, B. H.; Choi, B. G.; Cheon, S. H.; Whang, S. H.; Kim, S. K.; Kang, B. H.; Lee, C. O. Arch. Pharm. Res. 1996, 19, 321. 22. Fosset, M.; DeWeille, J. R.; Green, R. D.; Antomarchi, H. S.; Lazdunski, M. J. Biol. Chem. 1988, 263, 7933. 23. Ray, P.; Wright, J.; Adam, J.; Boucharens, S.; Black, D.; Brown, A. R.; Epemolu, O.; Fletcher, D.; Huggett, M.; Jones, P.; Laats, S.; Lyons, A.; de Man, J.; Morphy, R.; Sherborne, B.; Sherry, L.; Straten, N.; Westwood, P.; York, M. Bioorg. Med. Chem. Lett. 2011, 21, 1084. 24. Li, S. W.; Nair, M. G.; Edwards, D. M.; Kisliuk, R. L.; Gaumont, Y.; Dev, I. K.; Duch, D. S.; Humphreys, J.; Smith, G. K.; Ferone, R. J. Med. Chem. 1991, 34, 2746. 25. Van, H. T.; Yang, S. H.; Khadka, D. B.; Kim, Y. C.; Cho, W. J. Tetrahedron 2009, 65,10142. 26. Le, T. N.; Cho, W. J. Chem. Pharm. Bull. 2008, 56, 1026. 27. Le, T. N.; Cho, W. J. Bull. Korean Chem. Soc. 2007, 28, 763.

28. 29. 30. 31. 32. 33.

34. 35. 36. 37. 38.

39. 40.

41.

42. 43. 44.

45.

Le, T. N.; Cho, W. J. Chem. Pharm. Bull. 2006, 54, 476. Le, T. N.; Cho, W. J. Chem. Pharm. Bull. 2005, 53, 118. Khadka, D. B.; Cho, W. J. Bioorg. Med. Chem. 2011, 19, 724. Kiselev, E.; Dexheimer, T. S.; Pommier, Y.; Cushman, M. J. Med. Chem. 2010, 53, 8716. Alexander, V. B.; Vladimir, T. A.; Vladimir, V. M.; Artem, S. D. Tetrahedron Lett. 2005, 46, 8439. (a) Majumder, P. L.; Guha, S.; Sen, S. Phytochemistry 1999, 52, 1365; (b) Papadakis, D. P.; Salemink, C. A.; Alikaridis, F. J.; Kephalas, T. A. Tetrahedron 1983, 39, 2223; (c) Kim, J. P.; Kim, W. G.; Koshino, H.; Jung, J.; Yoo, I. D. Phytochemistry 1996, 43, 425. Li, E.; Zhang, F.; Niu, S.; Liu, X.; Liu, G.; Che, Y. Org. Lett. 2012, 14, 3320. Larock, R. C.; Yum, E. K.; Doty, M. J.; Sham, K. K. C. J. Org. Chem. 1995, 60, 3270. Morimoto, K.; Hirano, K.; Satoh, T.; Miura, M. J. Org. Chem. 2011, 76, 9548. Georg, G. I. The Organic Chemistry of b-Lactams; VCH: New York, NY, 1992; and references cited therein. (a) Ojima, I.; Shimizu, N.; Qiu, X.; Chen, H.-J. C.; Nakahashi, K. Bull. Soc. Chim. Fr. 1987, 649; (b) Hatanaka, N.; Abe, R.; Ojima, I. Chem. Lett. 1981, 10, 1297; (c) Ojima, I. Acc. Chem. Res. 1995, 28, 383; (d) Xu, J. Tetrahedron 2012, 68, 10696. (a) Alcaide, B.; Almendros, P.; Alonso, J. M. J. Org. Chem. 2004, 69, 993; (b) Alcaide, B.; Almendros, P.; Aragoncillo, C. Chem. Rev. 2007, 107, 4437. (a) Deshmukh, A. R.; Bhawal, B. M.; Krishnaswamy, D.; Govande, V. V.; Shinkre, B. A.; Jayanthi, A. Curr. Med. Chem. 2004, 11, 1889; (b) Alcaide, B.; Almendros, P. Curr. Med. Chem. 2004, 11, 1921; (c) Palomo, C.; Aizpurua, J. M.; Ganboa, I.; Oiardide, M. Curr. Med. Chem. 2004, 11, 1837; (d) Alcaide, B.; Almendros, P.; Cabrero, G.; Ruiz, M. P. Chem. Commun. 2007, 4788; (e) Kamath, A.; Ojima, I. Tetrahedron 2012, 68, 10640; (f) Dekeukeleire, S.; D’hooghe, M.; Vanwalleghem, M.; Brabandt, W. V.; De Kimpe, N. Tetrahedron 2012, 68, 10827. (a) Alcaide, B.; Almendros, P.; Luna, A.; Torres, M. R. Adv. Synth. Catal. 2010, 352, 621; (b) Alcaide, B.; Almendros, P. Chem. Rec. 2011, 11, 311; (c) Alcaide, B.; Almendros, P. Beilstein J. Org. Chem. 2011, 7, 622. Singh, P.; Bhargava, G.; Kumar, V.; Mahajan, M. P. Tetrahedron Lett. 2010, 51, 4272. Raj, R.; Mehra, V.; Singh, P.; Kumar, V.; Bhargava, G.; Mahajan, M. P.; Handa, S.; Slaughter, L. Eur. J. Org. Chem. 2011, 2697. (a) Anand, A.; Bhargava, G.; Kumar, V.; Mahajan, M. P. Tetrahedron Lett. 2010, 51, 2312; (b) Singh, P.; Mehra, V.; Anand, A.; Kumar, V.; Mahajan, M. P. Tetrahedron Lett. 2011, 52, 5060; (c) Mehra, V.; Singh, P.; Kumar, V. Tetrahedron 2012, 68, 8395; (d) Singh, P.; Raj, R.; Bhargava, G.; Hendricks, D. T.; Handa, S.; Slaughter, L. M.; Kumar, V. Eur. J. Med. Chem. 2012, 58, 513. Bhargava, G.; Anand, A.; Mahajan, M. P.; Saito, T.; Sakai, K.; Medh, C. Tetrahedron 2008, 64, 6801.