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Tetrahedron 70 (2014) 8879e8884

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Tetrahedron

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

Base mediated synthesis of a-aminated aroyl/acetylnaphthalenesthrough [4þ2] annulations

Surjeet Singh a, Ismail Althagafi b, Pratik Yadav a, Rahul Panwar a, Abhinav Kumar c,Ramendra Pratap a,*

aDepartment of Chemistry, University of Delhi, North Campus, Delhi 110007, IndiabDepartment of Chemistry, Umm Alqra University, Makkah, Saudi ArabiacDepartment of Chemistry, University of Lucknow, Lucknow, Uttar Pradesh 226009, India

a r t i c l e i n f o

Article history:Received 31 May 2014Received in revised form 27 September 2014Accepted 29 September 2014Available online 5 October 2014

Keywords:NaphthaleneAnnulationKetenedithioacetalAcridine

* Corresponding author. Tel./fax: þ91 2766664drapratap@gmail.com (R. Pratap).

http://dx.doi.org/10.1016/j.tet.2014.09.0890040-4020/� 2014 Elsevier Ltd. All rights reserved.

a b s t r a c t

We have developed a base promoted simple, efficient and alternative approach for the synthesis of 4-amino-3-aroyl//heteroaroyl/acetyl-2-methylsulfanyl-naphthalene-1-carbonitriles by reaction of easilyaccessible 3,3-bis(methylthio)-1-aryl/heteroaryl/acetylprop-2-en-1-one and 2-cyanomethyl-benzoni-trile. Reaction of 1-(2-halo/methoxy-phenyl)-3,3-bis(methylthio)prop-2-en-1-one and 2-cyanomethyl-benzonitrile under basic conditions also afforded 6-(methylthio)-7-oxo-7,12-dihydrobenzo[c]acridine-5-carbonitrile along with usual product. Structure of the synthesized product has been confirmed by singleX-ray crystallography.

� 2014 Elsevier Ltd. All rights reserved.

1. Introduction

Arylketones are well known for their use as a building block forthe synthesis of various pharmaceutical and biologically importantcompounds.1 They are also in use for dye, fragrance and agro-chemical industries.2 a-Aminoaryl-arylketone and closely relatedskeletons are reported as antitubulin agents3 and also exhibit betteranti-proliferative activity against human cancer cell than colchi-cine.4 Functionalized a-aminated-diarylketones were used as anintermediate for synthesis of various natural products and bi-ologically important compound, such as derivatives of quinazo-lines,5 new class of homocamptothecins,6 2-(aminoalkyl)-2,3,3a,8-tetrahydrodibenzo[c,f]isoazole[2,3-a]azepine derivatives,7

azaisoflavones,8 central benzodiazepine receptor9 and pyrazolecontaining class of GluN2C/GluN2D selective antagonist.10 Thesecompounds were also used for the synthesis of various compoundspossessing electrochemical and photophysical properties.11 a-Aminoaryl-arylketones were generally synthesized by Friedele-Crafts acylation.12 For monoacylation, protection of amine group isnecessary and also requires excess of Lewis acid. In literature,limited methodologies are available for synthesis of a-amino aryl-ketones, such as Ru (II) catalyzed intermolecular ortho amidation of

6; e-mail address: ramen-

aromatic ketones,13 Pd-catalyzed carbonylative cross-coupling fol-lowed by hydrogenation,14 Cu-catalyzed synthesis of aryl aminesfrom aryl halides and ammonia.15 1-Amino-2-aroylnaphthaleneswere also synthesized by reaction of 1-amino-naphthalene-2-carbonitrile and aryl magnesium halide (Grignard reagent).16 Ear-lier literature procedures require expensive metal catalysts, harshreaction conditions and moisture sensitive reagents, which gave usimpetus to develop new protocol for synthesis of highly function-alized 1-amino-2-aroyl-naphthalene.

Recently, we have developed a new precursor 2-(1-cyano-2,2-bis(methylthio)vinyl)benzonitrile for the synthesis of 1-amino-2-aroyl/acetylnaphthalenes. Reaction of 2-(1-cyano-2,2-bis(methylthio)vinyl)benzonitrile with various acetophenones/ac-etone under basic conditions involves (5þ1) annulation to afford1-amino-2-aroyl/acetylnaphthalenes in good to moderate yields(Scheme 1).17

2. Result and discussion

In search of an alternative route to achieve excellent yield, weplanned to use 3,3-bis(methylthio)-1-aryl/heteroaryl/acetylprop-2-en-1-one as a precursor (Scheme 1).18 These precursors are wellexplored by Ila and co-worker for the construction of polycyclicaromatic system.19 The required precursor 3,3-bis(methylthio)-1-aryl/heteroaryl/acetylprop-2-en-1-ones was synthesized by re-action of various acetophenones, acetone or cyclopropylmethyl

CN

CN

R CH3

ONH2

R

O

SMeCN

NH2

R

O

SMeCN

CN

CN

MeS SMe

SMeMeS

HR

O

Recently established approach [5+1 annulation approach]

Proposed alternative approach [4+2 annulation approach]

+

Yield 65-94%

Yield 41-81%

Scheme 1. (5þ1) versus (4þ2) annulations approach for synthesis of a-amino-2-aroyl-naphthalenes.

S. Singh et al. / Tetrahedron 70 (2014) 8879e88848880

ketone and carbon disulphide and methyl iodide under basic con-dition at low temperature (Scheme 2).18

Table 2Synthesis of a variety of 4-amino-3-aroyl/acetyl/heteroaroyl-2-methylsulfanylnapthalene-1-carbonitrilesa,b,c

CN

CN SMeCN

NH2

R

O3

MeS SMe

R

O KOH/DMSO

1

2

MeS SMe

R

OH3C

R

OCS2/MeI

1

NaH/THF

Scheme 2. Synthesis of 3,3-bis-methylsulfanyl-1aryl/heteroaryl/acetylprop-2-en-1-one [Precursor was synthesized by reported literature procedure].18

We have chosen 3,3-bis(methylthio)-1-phenylprop-2-en-1-one1 and 2-cyanomethylbenzonitrile 2 as model substrate to screenvarious reaction conditions (Table 1). We have started our in-vestigation by stirring the mixture of 3,3-bis(methylthio)-1-phenylprop-2-en-1-one 1 and 2-cyanomethylbenzonitrile 2 for2 h in tetrahydrofuran (THF) in presence of sodium hydride andobtained 65% of the desired product 3a (entry 1, Table 1). While useof N,N-dimethylformamide (DMF) in lieu of THF provides 77% yield(entry 2, Table 1). Then we have used potassium hydroxide andsodamide as base in DMF separately and obtained the product in

Table 1Optimization of reaction conditionsa

Base / SolventTime

SMeCN

NH2

MeS SMe

OO

CN

CN

1 2 3a

Entry Base Solvent Time (h) Yieldb,c (%)

1 NaH THF 2 652 NaH DMF 2 773 KOH DMF 2 754 NaNH2 DMF 2 705g KOH DMSO 2 946 NaH DMSO 2 907 NaNH2 DMSO 2 858 KOH DMSO 1 88d

9 KOH DMSO 2 89e

10 KOH DMSO 2 86f

a All reactions performed by stirring 1 (1.0 mmol), 2 (1.0 mmol) and Base(2.0 mmol) in 5.0 mL of solvent at room temperature.

b Yields are reported after purification by recrystallization or columnchromatography.

c Room temperature was ranging from 25 to 30 �C.d Reaction was performed at 70

�C.

e 3.0 equiv of KOH was used.f 4.0 equiv of KOH was used.g Bold row shows the best reaction conditions.

moderate yield (entry 3 and 4, Table 1). Further attempt was madeby using potassium hydroxide as a base in dimethyl sulfoxide(DMSO) and afforded the product in excellent yield (94%) in 2 h(entry 5, Table 1). This result encourages us to screen other bases inDMSO. Then model reactionwas performed in DMSO using sodiumhydride and sodamide as base and afforded 90% and 85% of thedesired product, respectively (entry 6 and 7, Table 1). Then reactionof 1 and 2 was performed in DMSO in presence of KOH at 70 �C for1 h and obtained 88% of desired product. Reaction of 1 and 2 wascarried out by using excess of base (3 and 4 equiv) and observed thelowering in yield (entry 9 and 10, Table 1), probably due to someside reaction.

Thus, stirring of an equimolar mixture of 3,3-bis(methylthio)-1-aryl/heteroaryl/acetylprop-2-en-1-one and 2-cyanomethylbenzonitrile 2 in DMSO using KOH as base for twohours followed by required work-up provides the desired product3-aroyl/acetyl-4-amino-2-(methylthio)-1-naphthonitriles in ex-cellent yields. It was observed that various functional groupspresent in phenyl ring of ketenedithioacetal adversely affect theyield or product. We observed that reaction of 3,3-bis(methylthio)-1-(4-acetylphenyl)prop-2-en-1-one with 2-cyanomethylbenzonitrile 2 under similar conditions gave moderate yield of 3-(4-acetylphenyl)-4-amino-2-(methylthio)-1-naphthonitrile probablydue to some side reactions of additional acetyl group in the phenylring. Under optimized reaction conditions 3,3-bis(methylthio)-1-(thiophen/furan-2-yl)prop-2-en-1-ones react with 2 and providesexcellent yield (91e92%) of the product (Table 2).

Entry R Yield (%)

3a C6H5 94 (gram scale yield 91%)3b p-CH3$C6H4 873c p-OCH3$C6H4 853d p-Br$C6H4 84 (gram scale yield 82%)3e m-Br$C6H4 723f p-Ac$C6H4 503g 2-Furyl 91 (gram scale yield 86%)3h 2-Theinyl 923i 1-Naphthyl 833j 2-Naphthyl 873k CH3 633l Cyclopropyl 65

a All reactions were performed by stirring 1 (1 mmol), 2 (1 mmol) and KOH(2.0 mmol) in DMSO (5.0 mL) at room temperature for 2 h.

b Yields are reported after recrystallisation or purification by columnchromatography.

c Room temperature was ranging between 25 and 30 �C.

Further scope of reactionwas tested by using 4,4-bis(methylthio)but-3-en-2-one and 1-cyclopropyl-3,3-bis(methylthio)prop-2-en-1-one as a precursor. Their reaction with 2 under basicconditions provides corresponding product in moderate yields(63e65%), probably due to some side reaction of acetyl or cyclo-propyl group. The competence of the optimized reaction conditionswere checked on large scale (up to 2.0 gm) for the synthesis of var-ious functionalized naphthalene and obtained in good yield(82e91%).

S. Singh et al. / Tetrahedron 70 (2014) 8879e8884 8881

Interestingly, reaction of 3,3-bis(methylthio)-1-(4-fluoro/chlor-ophenyl)prop-2-en-1-ones and 2-cyanomethylbenzonitrile undersimilar reaction conditions afforded 4-amino-2-(methylthio)-3-(4-(methylthio)benzoyl)-1-naphthonitrile 4 along with usual product4-amino-3-(4-fluoro/chlorobenzoyl)-2-(methylthio)-1-naphthonitrile 3m and 3n. It is clear that product 4 was formed bynucleophilic substitution reaction of fluoro/chloro group present inphenyl ring by in situ generated methylthio nucleophile (Scheme3). Mechanistically, reaction will initiate with ipso attack of meth-ylthio nucleophile at carbon bearing fluoro or chloro group withformation of intermediate X followed by loss of halide ion to affordthe product 4. Presence of bulky group in phenyl ring will not fa-cilitate the ipso attack and so 3d don’t react with methylthionucleophile.

SMeCN

NH2 O

SMeCN

NH2 O

X SMe

3 4

O

MeS SMe

X

CN

CN

KOH/DMSO

2

1 3m) X=F; 50% and 4; 33%3n) X=Cl; 57% and 4; 29%

SMeCN

NH2 O

XS

+

SCH3-X

probableintermediate

X

Scheme 3. Synthesis of 4-amino-3-(4-chloro/fluorobenzoyl)-2-(methylthio)-1-naphthonitrile 3m, 3n and 4-amino-2-(methylthio)-3-(4-(methylthio)benzoyl)-1-naphthonitrile 4.

S.N X Temp (oC)

Time hrs

Yield 3(%)

Yield 5(%)

Yield 6(%)

1 F RT 2 35(3o) 20 152 F RT 30 10(3o) 28 253 F 100 2 ---- 30 274 OMe RT 2 50(3p) ---- 185 OMe RT 24 32(3p) ---- 306 OMe 100 2 ---- ---- 477 Cl RT 2 73(3q) ---- ----8 Cl RT 24 55(3q) trace 109 Cl 100 2 ---- trace 4510 Br RT 2 65(3r) ---- ----11 Br 100 2 ---- ---- 38

Scheme 4. Synthesis of 4-amino-3-(2-halo/methoxybenzoyl)-2-(methylthio)-1-naphthonitrile 3oer, 4-amino-2-(methylthio)-3-(2-(methylthio)benzoyl)-1-naphthonitrile5 and 6-(methylthio)-7-oxo-7,12-dihydrobenzo[c]acridine-5-carbonitrile 6.

O

H2N

SMeCN

X NH

O SMeCN

3

6

DMSO / KOH100 oC/ 30-45 Minutes

XYield (%)

EntryFClBrOCH3

1234

71686874

6

O

NH

SMeCN

X

H

-HXBase

Y

Scheme 5. Proposed mechanism for the synthesis of 6-(methylthio)-7-oxo-7,12-dihydrobenzo[c]acridine-5-carbonitrile 6 from 3.

In order to explore the effect of functional group at ortho posi-tion of phenyl ring, we have chosen the precursors 1-(2-fluoro/chloro/bromo/methoxy-phenyl)-3,3-bis(methylthio)prop-2-en-1-ones,18 and performed the reaction under similar conditions. 1-(2-Fluorophenyl)-3,3-bis(methylthio)-prop-2-en-1-one 1 on reactionwith 2 afforded two more products apart from usual product 3o.One of the product isolated was 4-amino-2-(methylthio)-3-(2-(methylthio)benzoyl)-1-naphthonitrile (yield, 20%) formed by nu-cleophilic replacement of fluoro group by in situ generated meth-ylthio nucleophile, and other product 6-(methylthio)-7-oxo-7,12-dihydrobenzo[c]acridine-5-carbonitrile (yield, 15%) formed byintramolecular CeN bond formation reaction from 3o under basicconditions (Scheme 4). We have observed that, reaction of 1-(2-fluorophenyl)-3,3-bis(methylthio)prop-2-en-1-one with 2 at100 �C afforded mixture of 5 (yield, 30%) and 6 (yield, 27%) withcomplete consumption of 3o. If reaction of other precursors 1-(2-chloro/bromo/methoxy-phenyl)-3,3-bis(methylthio)prop-2-en-1-ones was carried out under basic condition at room temperature,only 6-(methylthio)-7-oxo-7,12-dihydrobenzo[c]acridine-5-carbonitrile 6 also isolated along with usual product 3per. Ifsame reaction was performed at 100 �C, exclusively formation ofproduct 6 occurs in moderate yield (38e47%).

In order to confirm the probable intermediate for 6, reactionwascarried out for 24e30 h at room temperature and it was observedthat amount of 3oer decrease with increase in concentration of 5(only for entry 2, Scheme 4) and 6. This result concludes that re-quired precursor for product 6 is 3oer rather than 5. To furtherconfirm the proposed route, we have stirred 3oer in DMSO usingKOH as a base for 30e45 min and obtained 6-(methylthio)-7-oxo-7,12-dihydrobenzo[c]acridine-5-carbonitrile 6 in 68e74% yield(Scheme 5). Mechanistically, reaction initiates with intramolecularnucleophilic attack of amino group at carbon bearing halogen or

methoxy group followed by loss of hydrogen halide or methanol toafford 6 (Scheme 5).

Probably, formation of 3 is initiated with nucleophilic sub-stitution of either methylthio group by attack of carbanion gener-ated in situ from 2-cyanomethylbenzonitrile to afford 2-(1-cyano-2-(methylthio)-4-oxo-4-arylbut-2-enyl)benzonitrile. Under basic

S. Singh et al. / Tetrahedron 70 (2014) 8879e88848882

condition 2-(1-cyano-2-(methylthio)-4-oxo-4-arylbut-2-enyl)ben-zonitrile will loss the proton and enolate forms, which can exist aseither E-isomer (intermediate C) or Z-isomer (intermediate A).Formation of isolated product can be described by using Z-isomerenolate. Reaction involves Z-isomer and enolate attack throughcarbon at CN-2, with formation of intermediate B. Intermediate Bon tautomerization, provides the desired product 3 (Scheme 6). Weproposed that regioselectively, sterically less hindered and ther-modynamically more stable Z enolate forms as an intermediate toafford the desired product. In order to prove the mechanistic route,we attempted to isolate the proposed intermediate, but failed.Reaction was performed by using low equivalent of base to avoidthe cyclization of proposed intermediate A, but desired product andleft starting material obtained. On the basis of these experiments,we concluded that, as soon as enolate forms, it undergoes cycliza-tion through CN-2 immediately to afford 3.

CN

CN

MeS SMe

HO

R

SMe

O

R

CNCN

SMe

O

R

CN

NH

HSMe

O

R

CN

NH23 B

KOHNC NC H

KOH

CN O

NC

RO

NC

R

NC

SMe

OK

R

CN

NA

SMe SMe

K K

Z-isomer

CN-1CN-2

H

SMe

OK

R

NC

NC

CE-isomer

X

Scheme 6. Mechanistic approach synthesis for 4-amino-3-aryl-2- methylsulfanyl-naphthalene-1-cabonitriles.

2.1. X-ray structural analysis

The structure of one of the products 3n has been confirmed byX-ray crystallography (Fig. 1).20 The compound 3n crystallize in P21/c space group having eight molecules in themonoclinic unit cell.The two fused rings of the naphthalene are almost planer withdihedral angle of 3.48� between them. The fused naphthalene andthe chlorophenyl rings are perpendicular with respect to each otherand the dihedral angle between the planes formed by the naph-thalene and the chlorophenyl rings is 82.44� and due to this fact,

Fig. 1. ORTEP diagram of 3n at 30% probability with atom numbering scheme. Onlyone molecule of the asymmetric unit comprising of two molecules is presented andwater molecules have been omitted for clarity.

there is no intramolecular hydrogen bonding between 1� amineand the carbonyl oxygen O1 exist.

3. Conclusions

In conclusion, we have developed a metal free, simple andhighly efficient one pot [4þ2] cycloaromatization route for thesynthesis of 4-amino-3-aroyl/heteroaroyl/acetyl-2-methylsulfanyl-naphthalene-1-cabonitriles. This reaction is atom economic andrequires very mild reaction condition. This reaction involves onepot inter and intramolecular CeC bond formation reaction. Thisreaction provides excellent yield in comparison with recentlyestablished 5þ1 annulations approach for their synthesis. All therequired precursors are easily accessible. This reaction has beenperformed on gram scale with excellent yield successfully. In manycases, column chromatographic purification was not required.Along with desired product, formation of 4-amino-2-(methylthio)-3-(4-(methylthio)benzoyl)-1-naphthonitrile, 4-amino-2-(methyl-thio)-3-(2-(methylthio)benzoyl)-1-naphthonitrile and 6-(methyl-thio)-7-oxo-7,12-dihydrobenzo[c]acridine-5-carbonitrile are alsoan exciting result.

4. Experimental

4.1. General

Commercial available reagent and solvent purchased by sigmaAldrich and Alfa Aesar and used without further purification, IRspectra were recorded on a PerkineElmer AX-1 spectroscopy inwave number (cm�1). The 1H NMR (400 MHz) and 13C NMR(100 MHz) recorded in CDCl3 solution with reference of tetrame-thylsilane and coupling constant J reported in Hertz, internal signalpatterns reported as a m, multiplet; dd double doublet; t, triplet;d, doublet; s, singlet. Mass spectra was performed by ESIMSspectrometer.

Intensity data for the yellow coloured crystal of 3nwas collectedat 298(2) K on a OXFORD CrysAlis diffractometer system equippedwith graphite monochromated Mo Ka radiation l¼0.71073 �A. Thefinal unit cell determination, scaling of the data, and corrections forLorentz and polarization effects were performed with CrysAlisRED.21 The structures were solved by direct methods (SHELXS-97)22 and refined by a full-matrix least-squares procedure based onF2.23

4.2. General procedure for the synthesis of 4-amino-3-aroyl-2-(methylthio)-naphthalene-1-carbonitrile (3aer, 4, 5 and 6)

A mixture of 1-aryl/alkyl-3,3-bis-methylsulfanyl-propenone(1.0 mmol), 2-cyanomethyl-benzonitrile (1 mmol, 142.0 mg), andpowdered KOH (2 mmol, 112.0 mg) in dry DMSO (5 mL) was stirredat room temperature for 2 h. Completion of reactionwas monitoredby TLC. After completion, reaction mixture was poured onto ice-water with constant stirring and then neutralized with 10% HCl.The precipitate obtained was filtered, washed with water and driedover dry sodium sulfate. Many compounds were purified by re-crystallization in dry methanol. Some compounds were purifiedthrough column chromatography using 15% ethylacetate in hexaneas an eluent. Characterization data for some of the synthesizedcompounds are reported earlier.17

4.2.1. 4-Amino-3-(3-bromobenzoyl)-2-(methylthio)-1-naphthonitrile(3e). A mixture of 1-(3-bromophenyl)-3,3-bis(methylthio)prop-2-en-1-one (301.0 mg, 1.0 mmol), 2-cyanomethyl-benzonitrile(142.0 mg, 1.0 mmol), and powdered KOH (112.0 mg, 2.0 mmol) indry DMSO (5.0 mL) was stirred at room temperature for 2 h. Aftercompletion, reaction mixture was poured onto ice-water with

S. Singh et al. / Tetrahedron 70 (2014) 8879e8884 8883

constant stirring followed by neutralization with 10% HCl. Theprecipitate obtained was filtered, washed with water, dried andpurified through column chromatography using 15% ethylacetate inhexane as an eluent to obtain 82% (323.0 mg) of 3e. Brown solid, Rf(20% ethylacetateehexane) 0.25, mp: 161e163 �C; IR (KBr): 3367,2922, 2206,1609,1236 cm�1; 1H NMR (400MHZ, CDCl3): d 2.35 (3H,s, eSeCH3), 5.53 (2H, br s, eNH2), 7.28 (1H, t, J¼8.0 Hz, ArH),7.53e7.63 (2H, m, ArH), 7.64e7.69 (1H, m, ArH), 7.70e7.77 (1H, m,ArH), 7.83e7.88 (2H, m, ArH), 8.20 (1H, d, J¼8.0 Hz, 1H, ArH); 13CNMR (100 MHz, CDCl3): d 20.5, 104.5, 117.1, 119.2, 121.6, 121.7, 122.9,126.0, 127.1, 127.6, 130.1, 130.3, 131.5, 134.5, 136.1, 140.5, 140.7, 145.9,195.4; HRMS (ESI) calculated for C19H13BrN2OS, 397.0005 (MHþ);found for m/z, 397.0003.

4.2.2. 3-(4-Acetylbenzoyl)-4-amino-2-(methylthio)-1-naphthonitrile(3f). A mixture of 1-(4-acetylphenyl)-3,3-bis(methylthio)prop-2-en-1-one (266.0 mg, 1.0 mmol), 2-cyanomethyl-benzonitrile(142.0 mg, 1.0 mmol), and powdered KOH (112.0 mg, 2.0 mmol) indry DMSO (5.0 mL) was stirred at room temperature for 2 h. Aftercompletion, reaction mixture was poured onto ice-water withconstant stirring and neutralized with 10% HCl. The precipitateobtained was filtered, washed with water, dried and purifiedthrough column chromatography using 30% ethylacetate in hexaneas an eluent to obtain 50% (180.0 mg) of 3f; Rf (40% ethyl-acetateehexane) 0.37, light yellow solid, mp: 160e162 �C; IR (KBr):3369, 2924, 2208, 1624, 1259 cm�1; 1H NMR (400 MHz, CDCl3):d 2.33 (3H, s, eSeCH3), 2.61 (3H, s, eCOeCH3), 5.65 (2H, br s,eNH2), 7.55e7.65 (1H, m, ArH), 7.72e7.79 (3H, m, ArH), 7.87 (1H, d,J¼8.8 Hz, ArH), 7.98 (2H, d, J¼8.8 Hz, ArH), 8.21 (1H, d, J¼8.8 Hz,ArH); 13C NMR (100 MHz, CDCl3): d 20.6, 26.8, 104.7, 117.0, 119.2,121.7,121.7,126.1,127.2,128.5,129.0,130.4,134.6,140.0,140.8,142.6,146.2, 196.3, 197.3; HRMS (ESI) calculated for C21H16N2O2S,361.1005 (MHþ); found for m/z, 361.0981.

4.2.3. 4-Amino-3-(cyclopropanecarbonyl)-2-(methylthio)-1-naphthonitrile (3l). A mixture of 1-cyclopropyl-3,3-bis(methylthio)prop-2-en-1-one (188.0 mg, 1.0 mmol), 2-cyanomethyl-benzoni-trile (142.0 mg, 1.0 mmol), and powdered KOH (112.0 mg,2.0 mmol) in dry DMSO (5.0 mL) was stirred at room temperaturefor 2 h. Completion of reaction was monitored by TLC. After com-pletion, reaction mixture was poured onto ice-water with constantstirring followed by neutralization with 10% HCl. The precipitateobtained was filtered, washed with water, dried and purifiedthrough column chromatography using 15% ethylacetate in hexaneas an eluent to obtain 65% (183.0 mg) of 3l; Rf (20% ethyl-acetateehexane) 0.32, Brown solid, mp: 166e168 �C; IR (KBr):3363, 2925, 2204, 1642, 1241 cm�1; 1H NMR (400 MHz, CDCl3):d 1.05e1.14 (2H, m, eCH2e), 1.31e1.37 (2H, m, eCH2e), 2.56 (3H, s,eSeCH3), 2.59e2.68 (1H, s,eCHe), 5.94 (2H, br s,eNH2), 7.51e7.58(1H, m, ArH), 7.65e7.73 (1H, m, ArH), 7.81 (1H, d, J¼8.5 Hz, ArH),8.14 (1H, d, J¼8.5 Hz, ArH); 13C NMR (100 MHZ, CDCl3): d 13.9, 20.4,24.3, 103.8, 117.3, 120.8, 121.7, 121.8, 126.0, 126.8, 130.2, 134.1, 141.4,145.5, 206.0; HRMS (ESI) calculated for C16H14N2OS, 283.0900(MHþ); found for m/z, 283.0905.

4.2.4. 4-Amino-3-(2-fluorobenzoyl)-2-(methylthio)-1-naphthonitrile(3o). A mixture of 1-(2-fluorophenyl)-3,3-bis(methylthio)prop-2-en-1-one (242.0 mg, 1.0 mmol), 2-cyanomethyl-benzonitrile(142.0 mg, 1.0 mmol), and powdered KOH (112.0 mg, 2.0 mmol) indry DMSO (5.0 mL) was stirred at room temperature for 2 h. Aftercompletion, reaction mixture was poured onto ice-water with con-stant stirring and neutralized with 10% HCl. The precipitate obtainedwas filtered, washed with water, dried and purified through columnchromatography using 15% ethylacetate in hexane as an eluent toobtain 35% (117.0 mg) of 3o. Two other products 4-amino-2-(methylthio)-3-(2-(methylthio)benzoyl)-1-naphthonitrile (yield,

20%) and 6-(methylthio)-7-oxo-7,12-dihydrobenzo[c]acridine-5-carbonitrile (yield, 15%) was also isolated along with usual product3o; Rf (20% ethylacetateehexane) 0.28, yellow solid, mp:190e192 �C; IR (KBr): 3375, 2927, 2210, 1606, 1274 cm�1; 1H NMR(400 MHz, CDCl3): d 2.30 (3H, s, eSeCH3), 6.05 (2H, br s, eNH2),7.04e7.11 (1H, m, ArH), 7.15e7.20 (1H, m, ArH), 7.43e7.62 (3H, m,ArH), 7.70e7.76 (1H, m, ArH), 7.87 (1H, d, J¼8.0 Hz, ArH), 8.17 (1H, d,J¼8.0 Hz, ArH); 13C NMR (100 MHz, CDCl3): d 20.3, 104.5, 116.5 (d,JCeF¼22.0 Hz), 117.1, 120.0, 121.8, 121.9, 124.2 (d, JCeF¼3.8 Hz), 126.1,127.0, 129.0 (d, JCeF¼9.6 Hz), 130.5, 130.5, 134.1 (d, JCeF¼8.6 Hz),134.5, 141.6, 146.8, 160.7 (d, JCeF¼262.2 Hz), 193.7; HRMS (ESI) cal-culated for C19H13FN2OS, 337.0805 (MHþ); found for m/z, 337.0805.

4.2 .5 . 4-Amino-3-(2-methoxybenzoyl)-2-(methylthio)-1-naphthonitrile (3p). A mixture of 1-(2-methoxyphenyl)-3,3-bis(methylthio)prop-2-en-1-one (254.0 mg, 1.0 mmol), 2-cyanomethyl-benzonitrile (142.0 mg, 1.0 mmol), and powderedKOH (112.0 mg, 2.0 mmol) in dry DMSO (5.0 mL) was stirred atroom temperature for 2 h. After completion, reaction mixture waspoured onto ice-water with constant stirring followed by neutral-izationwith 10% HCl. The precipitate obtained was filtered, washedwith water, dried and purified through column chromatographyusing 20% ethylacetate in hexane as an eluent to obtain 50%(174.0 mg) of 3p along with 6-(methylthio)-7-oxo-7,12-dihydrobenzo[c]acridine-5-carbonitrile (yield, 18%); Rf (20% ethyl-acetateehexane) 0.23, yellow solid, mp: 179e181 �C; IR (KBr):3367, 2923, 2206, 1600, 1276 cm�1; 1H NMR (400 MHz, CDCl3):d 2.27 (3H, s, eSeCH3), 3.67 (3H, s, eOeCH3), 5.93 (2H, br s, eNH2),6.84e6.98 (2H, m, ArH), 7.39e7.49 (2H, m, ArH), 7.52e7.60 (1H, m,ArH), 7.66e7.74 (1H, m, ArH), 7.86 (1H, d, J¼8.7 Hz, ArH), 8.14e8.19(1H, m, AreH); 13C NMR (100 MHz, CDCl3): d 20.2, 55.8, 104.1, 111.8,117.4,120.3,121.5, 121.7, 121.9, 125.9,126.8,129.7, 130.0, 130.8,133.8,134.2, 141.8, 146.3, 158.6, 196.0; HRMS (ESI) calculated forC20H16N2O2S, 349.1005 (MHþ); found for m/z, 349.1005.

4.2.6. 4-Amino-3-(2-chlorobenzoyl)-2-(methylthio)-1-naphthonitrile(3q). A mixture of 1-(2-chlorophenyl)-3,3-bis(methylthio)prop-2-en-1-one (257.0 mg, 1.0 mmol), 2-cyanomethyl-benzonitrile(142.0 mg, 1.0 mmol), and powdered KOH (112.0 mg, 2.0 mmol) indry DMSO (5.0 mL) was stirred at room temperature for 2 h. Aftercompletion, reaction mixture was poured onto ice-water withconstant stirring followed by neutralization with 10% HCl. Theprecipitate obtained was filtered, washed with water, dried andpurified through column chromatography using 15% ethylacetate inhexane as an eluent to obtain 73% (257.0 mg) of 3q; Rf (20% eth-ylacetateehexane) 0.29, yellow solid, mp: 174e176 �C; IR (KBr):3351, 2923, 2205, 1608, 1277 cm�1; 1H NMR (400 MHz, CDCl3):d 2.22 (3H, s, eSeCH3), 6.51 (2H, br s, eNH2), 7.19e7.25 (2H, m,ArH), 7.32e7.38 (1H, m, ArH), 7.39e7.45 (1H, m, ArH), 7.56e7.63(1H, m, ArH), 7.70e7.7 (1H, m, ArH), 7.90 (1H, d, J¼8.0 Hz, ArH), 8.15(1H, d, J¼8.0 Hz, ArH); 13C NMR (100 MHz, CDCl3): d 20.3, 105.1,117.1, 118.4, 121.8, 121.9, 126.0, 126.4, 127.1, 129.9, 130.8, 130.8, 131.7,132.6, 134.6, 140.5, 142.4, 148.6, 196.0; HRMS (ESI) calculated forC19H13ClN2OS, 353.0510 (MHþ); found for m/z, 353.0510.

4.2.7. 4-Amino-2-(methylthio)-3-(2-(methylthio)benzoyl)-1-naphthonitrile (5). A mixture of 1-(2-fluorophenyl)-3,3-bis(methylthio)prop-2-en-1-one (242.0 mg, 1.0 mmol), 2-cyanomethyl-benzonitrile (142.0 mg, 1.0 mmol), and powderedKOH (112.0 mg, 2.0 mmol) in dry DMSO (5.0 mL) was stirred at100 �C for 2 h. After completion, reaction mixture was poured ontoice-water with constant stirring and neutralized with 10% HCl. Theprecipitate obtained was filtered, washed with water, dried andpurified through column chromatography using 20% ethylacetate inhexane as an eluent to obtain 30% (109.0 mg) of 5 along with 6-(methylthio)-7-oxo-7,12-dihydrobenzo[c]acridine-5-carbonitrile

S. Singh et al. / Tetrahedron 70 (2014) 8879e88848884

(yield, 27%); Rf (20% ethylacetateehexane) 0.24, yellow solid, mp:200e202 �C; IR (KBr): 3367, 2924, 2206, 1630, 1247 cm�1; 1H NMR(400 MHz, CDCl3): d 2.33 (3H, s, eSeCH3), 2.51 (3H, s, eSeCH3),4.88 (2H, br s, eNH2), 6.99e7.99 (1H, m, ArH), 7.20e7.26 (1H, m,ArH), 7.37 (1H, d, J¼8.2 Hz, ArH), 7.43e7.49 (1H, m, ArH), 7.55e7.63(1H, m, ArH), 7.68e7.76 (1H, m, ArH), 7.85 (1H, d, J¼8.2 Hz, ArH),8.19 (1H, d, J¼8.2 Hz, ArH); 13C NMR (100 MHz, CDCl3): d 15.6, 20.3,104.6, 117.2, 120.6, 121.6, 121.7, 123.4, 125.0, 126.0, 127.0, 130.1, 131.8,132.5, 134.5, 136.0, 141.1, 143.1, 146.0, 196.8; HRMS (ESI) calculatedfor C20H16N2OS2, 365.0777 (MHþ); found for m/z, 365.0775.

4.3. 6-(Methylthio)-7,12-dihydrobenzo[c]acridine-5-carbon-itrile (6)

This product was isolated during the synthesis of 3oer. Thisproduct was also synthesized by stirring 3oer (0.5 mmol) in DMSO(4.0 mL) using KOH (56.0 mg, 1.0 mmol) as a base at 100 �C for30e45 min. After completion, reaction mixture was poured ontoice-water with constant stirring followed by neutralization with10% HCl. The precipitate obtained was filtered, washed with water,dried and purified through column chromatography using 30%ethylacetate in hexane as an eluent to obtain 68e74% of 6; Rf (40%ethylacetateehexane) 0.30, yellow solid, mp: 274e276 �C; IR (KBr):3325, 2925, 2206, 1624, 1274 cm�1; 1H NMR (400 MHz, DMSO):d 2.67 (3H, s, eSeCH3), 7.36 (1H, s, ArH), 7.74e8.17 (6H, m, ArH),8.84e8.90 (1H, m, ArH), 11.79 (1H, br s,eNHe); 13C NMR (100MHz,DMSO): d 20.6, 104.1, 115.9, 117.3, 118.3, 121.5, 123.2, 123.5, 123.8,124.4, 125.5, 127.3, 131.5, 133.0, 133.4, 139.0, 141.5, 148.3, 175.4;HRMS (ESI) calculated for C19H12N2OS, 317.0743 (MHþ); found form/z, 317.0743.

Acknowledgements

Authors thank Council of Scientific and Industrial Research(CSIR, New Delhi) and Department of Science and Technology (DST,New Delhi) Delhi for financial support. S.S. thank Council of Sci-entific and Industrial Research (CSIR, New Delhi) and P.Y. and S.N.S.thank University Grants Commission (UGC, New Delhi) for researchfellowship. Authors thank University of Delhi for providing re-search funding and instrumentation facility.

Supplementary data

1H and 13C spectra of the entire synthesized compound areprovided in ESD. Supplementary data related to this article can befound at http://dx.doi.org/10.1016/j.tet.2014.09.089.

References and notes

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20. Crystal data for 3n (CCDC 999668): C19H13ClN2OS, FW¼368.82, Monoclinic, P21/c, a¼18.1345(7) �A, b¼7.6901(3) �A, c¼26.7377(14) �A, b¼99.348(4)� , V¼3679.2(3) �A3, T¼298(2) K, Z¼8, m, mm�1¼0.335, dcalc, g cm�3¼1.332, R1 [I>2s(I)]¼0.0834, wR2¼0.2137, R1 [all data]¼0.1068, wR2¼0.2282, S¼1.145. ‘CCDC containsthe supplementary crystallographic data for this paper. These data can beobtained free of charge from The Cambridge Crystallographic Data Centre viawww.ccdc.cam.ac.uk/data_request/cif’.

21. CrysAlis CCD, RED version 1.711.13, copyright 1995e2003, Oxford DiffractionPoland Sp.

22. Sheldrick, G. M. SHELXS97, Program for Crystal Structure Solution; University ofG€ottingen: G€ottingen, Germany, 1997.

23. Sheldrick, G. M. SHELXL97, Program for Crystal Structure Refinement; Universityof G€ottingen: G€ottingen, Germany, 1997.