A general and efficient synthesis of 3,6-diazabicyclo[3.2.1]octanes

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A general and efficient synthesis of 3,6-diazabicyclo[3.2.1]octanes
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  A general and efficient synthesis of 3,6-diazabicyclo[3.2.1]octanes Rakesh K. Singh, a,† Sanjay Jain, a, * ,‡ Neelima Sinha, a,‡ Anita Mehta, a Fehmida Naqvi b and Nitya Anand a, * a  Medicinal Chemistry Division, New Drug Discovery Research, Ranbaxy Laboratories Limited, R&D II, Plot # 20, Sector-18,Udyog Vihar Industrial Area, Gurgaon 122 001, India b  Department of Chemistry, Jamia Millia Islamia, New Delhi 110 015, India Received 28 October 2005; revised 18 January 2006; accepted 10 February 2006Available online 3 March 2006 Abstract —A convenient and efficient synthesis of   N  6 -substituted 3,6-diazabicyclo[3.2.1]octanes ( 6a – c ) has been achieved starting fromsuitably substituted lactams, which were converted to nitroenamines followed by reductive cyclization to afford 3,6-diazabicyclo[3.2.1]-octane-2-ones in good yields. These bicyclic lactams were then reduced to the corresponding 3,6-diazabicyclo[3.2.1]octanes and convertedto the required  N  3 ,  N  6 -disubstituted 3,6-diazabicyclo[3.2.1]octanes ( 7a – h ), which were screened for  a 1 -adrenoceptors antagonistic activities. q 2006 Elsevier Ltd. All rights reserved. 1. Introduction Lactams have been the subject of much study in thislaboratory for creation of molecular diversity, a usefulsource of leads for potential bioactive agents/intermedi-ates, 1,2 through conversion to reactive intermediates such aslactim ethers, lactim thioethers and lactam acetals, whichundergo facile reaction with both nucleophiles andelectrophiles and also with bifunctional reagents. In ourstudies directed to the design of conformationally con-strained prototypes incorporating the essential structuralfeatures of important pharmacophores, 3 we were interestedin the synthesis of 3,6-diazabicyclo[3.2.1]octanes ( 6 ).A literature survey revealed that 6-methyl-3,6-diazabicyclo[3.2.1]octane  6a  (Fig. 1) has been reportedonce as a conformationally rigid ethylenediamine systemsfrom 2-azabicyclo[2.2.1]hept-5-ene via ozonolysis of thedouble bond to a dialdehyde followed by reductiveamination using benzylamine. 4 But this method has severallimitations: (a) ozonolysis is not a very convenient reactionto carry out, (b) reductive amination was carried out inpresence of sodium cyanoborohydride, which duringworkup generate hydrogen cyanide gas, and (c) poor yields(18–40%). In this paper, we wish to report a convenient andefficient synthesis of 3,6-diazabicyclo[3.2.1]octanes fromreadily available 5-oxopyrrolidine-3-carboxylic acid methylester. This method also provides an easy access to thesubstitution at the N-3, N-6 and C-4 centre. 2. Results and discussion Aretrosyntheticanalysisofcompound 6 (Scheme1)indicatedthe possibility of constructing 3,6-diazabicyclo[3.2.1]octanesring through reductive cyclization of a nitroenamine of type II, which could in turn be obtained from lactam I, byactivation of the amide group followed by condensation withnitroalkane.1-Methyl-5-oxopyrrolidine-3-carboxylic acid methyl ester 1a  and 1-(2-methoxyphenyl)-5-oxopyrrolidine-3-carboxylicacid methyl ester  1b , prepared from itaconic acid following 0040–4020/$ - see front matter q 2006 Elsevier Ltd. All rights reserved.doi:10.1016/j.tet.2006.02.030Tetrahedron 62 (2006) 4011–4017 NHNR 1 R 6a ;   R = Me, R 1  = H 6b ; R = R 1  = Me 6c ;   R = 2-OMeC 6 H 4 , R 1  = H 1346 Figure 1. Keywords : 3,6-Diazabicyclo[3.2.1]octanes; Lactams; Itaconic acid; Nitro-enamine; Reductive cyclization; RBx 2258. *  Corresponding authors. Tel.: C 91 20 25126161; fax: C 91 20 25171329;e-mail addresses: sanjay.sjain@gmail.com; nityaanand@satyam.net.in † Present address: Department of Pediatrics, Brown Medical School,Kilguss Research Centre, Women and Infant Hospital, Providence, RI02903, USA. ‡ Present address: Medicinal Chemistry Division, New Chemical EntityResearch, Lupin Research Park, 46/47A, Village Nande, Taluka Mulshi,Pune 411 042, India.  the procedure described in the literature, 1d,5 were chosen asthe starting material for the synthesis of 3,6-diazabicyclo-[3.2.1]octanes ( 6 ). The lactam  1a  was treated withLawesson’s reagent to give the corresponding thiolactam 2a  in almost quantitative yields. The thiolactam  2a  wasconverted to methylthioimonium iodide  3a  with excessmethyl iodide in 96% yield, which on condensation withnitromethane in DMF and excess of triethylamine yieldedthecorrespondingnitroenamine 4a in45%yield(Scheme2).The nitroenamine  4a  appeared to be thermodynamicallystable as the  E  -isomer as shown by NMR studies; irradiationof the olefinic proton resulted in 11% NOE enhancement forthe  N  -methyl protons. Catalytic transfer hydrogenation of nitroenamine  4a  over 10% Pd–C in presence of ammoniumformate in MeOH at reflux, resulted in reduction of both thedouble bond and the nitro group followed by in situcyclization to furnish 6-methyl-3,6-diazabicyclo[3.2.1]-octan-2-one  5a  in 70% yield. Finally, this bicyclic lactam 5a  was subjected to LAH reduction in THF at reflux, whichafter chromatographic purification afforded 6-methyl-3,6-diazabicyclo[3.2.1]octane ( 6a ) in 68% yield (Scheme 2).Analogously, the corresponding 4,6-dimethyl analogue  6b and 6-(2-methoxyphenyl) analogue  6c  were synthesized in53 and 57% yield, respectively, by using the appropriatelactams and nitroalkanes. Compound  6b  (R 1 Z CH 3 ) wasisolated as a mixture of diastereoisomers of unassignedrelative configuration.In the light of the likely benefits of restricted flexibility 6 onthe pharmacokinetic properties of bioactive agents, various3-substituted 6-(2-methoxyphenyl)-3,6-diazabicyclo-[3.2.1]octanes ( 7a – h ) were prepared because of the structural analogy of 6-(2-methoxyphenyl)-3,6-diazabicyclo[3.2.1]octane nucleus ( 6c ) with 1-(2-methoxyphenyl)piperazine the structural unit present inRBx 2258 (entry 9, Table 1), the analogue RBx 2258, 7 NHNR'RNRNRCO 2 R"R'H 2 NONRR'O 2 NCO 2 R"OCO 2 R" IIIIIIIV NHNR'R 6 Scheme 1.  Retrosynthetic approach to 3,6-diazabicyclo[3.2.1]octanes ( 6 ). NHNR 1 RNROOCH 3 ONROOCH 3 SNROOCH 3 H 3 CSINROOCH 3 R 1 O 2 NONHNR 1 R 1a ;   R = Me 1b ;   R = 2-OMeC 6 H 4 (i)(iii)(iv) 2a ;   R = Me; 98% 2b ;   R = 2-OMeC 6 H 4 ; 91% 3a ;   R = Me; 96% 3b ;   R = 2-OMeC 6 H 4 ; 90% 4a ;   R = Me, R 1  = H; 45% 4b ; R = R 1  = Me; 36% 4c ;   R = 2-OMeC 6 H 4 , R 1  = H; 45% 5a ;   R = Me, R 1  = H; 70% 5b ; R = R 1  = Me; 35% 5c ;   R = 2-OMeC 6 H 4 , R 1  = H; 70% 6a ;   R = Me, R 1  = H, 68% 6b ; R = R 1  = Me, 53% 6c ;   R = 2-OMeC 6 H 4 , R 1  = H, 57%(ii)(v) Scheme 2.  Reagents and conditions: (i) Lawesson’s reagent, THF, rt, 3 h; (ii) CH 3 I, PhMe or PhH, rt, 24 h; (iii) R 1 CH 2 NO 2 , Et 3 N, DMF, rt, 24 h;(iv) HCOONH 4 , 10% Pd–C, MeOH, reflux, 7–10 h; (v) LAH, THF, reflux, 18 h.  R. K. Singh et al. / Tetrahedron 62 (2006) 4011–4017  4012  which has shown good  a 1 -adrenoceptor blocking activityand appear promising for the treatment of benign prostatichyperplasia (BPH) is in phase II clinical trials.The compounds  7a – h  (Table 1) were prepared starting from1-(3-halopropyl)dicarboximides ( 9 ), which in turn wereprepared by condensing various a , u -dicarboximides ( 8 ) and1-bromo-3-chloropropane according to the proceduredescribed in literature. 7 The compounds  9  werethen condensed with 6-(2-methoxyphenyl)-3,6-diazabi-cyclo[3.2.1]octane ( 6c ) in presence of K  2 CO 3  in DMF at60–70  8 C to give 1-[6-(2-methoxyphenyl)-3,6-diazabi-cyclo[3.2.1]octan-3-yl]-3-[  N  -( a , u -dicarboximido)]pro-panes  7a – h  in good yields (Table 1). Compounds  6b – c  and 7a – h  are hitherto unknown in the literature and theirstructures were confirmed on the basis of elemental andspectroscopic analysis.Receptor binding assays were performed for native  a 1 -adrenoreceptors. Rat submaxillary and liver membranepreparations were used to assess the affinity for  a 1A  and  a 1B subtypes, respectively. 8 Aliquots of membrane protein(100–200  m g) were incubated in a final volume of 250  m Lassay buffer (50 mM Tris, 0.5 mM EDTA at pH 7.4) with0.5 nM [ 3 H]prazosin for 60 m at 28  8 C. Reaction wasstopped by rapid filtration on Millipore filters. Filters weredried and bound radioactivity counted. Non-specific bindingwas determined in the presence of 0.3 mM prazosin. Proteinwas assayed according to the method of protein estimation 9 with minor modifications. All the newly synthesizedanalogues of RBx 2258 were screened for  a 1A  inhibition.However, none of these compounds have shown anyremarkable activity. 3. Conclusion In conclusion, a convenient and new approach for thesynthesis of 3,6-diazabicyclo[3.2.1]octanes ( 6 ) has beenaccomplished. The key step of the synthesis involvescatalytic hydrogenation, accompanied with spontaneouscyclization, of the nitroenamine  4 . These nitroenamine canbe conveniently prepared in large quantities from readilyavailable starting materials. In addition, various confor-mationally constrained analogues of RBx 2258 have beensynthesized. However, derivatives of our novel 6-(2-methoxyphenyl)-3,6-diazabicyclo[3.2.1]octane ringsystems have not shown any activity against  a 1 -adrenor-eceptors. The lack of activity against  a 1 -adrenoceptors maybe probably due to steric hindrance of the methylene bridgein the ligands–receptor interaction. 4. Experimental4.1. General Melting points were recorded on a Bu¨chi B-540 meltingpoint apparatus. Compounds were routinely checked fortheir purity on silica gel 60 F 254  TLC plates and their spotswere visualized by exposing them to iodine vapor, UV lampor by spraying the plates with Dragendorff’s or KMnO 4 reagents. IR spectra ( y max  in cm K 1 ) were recorded on PerkinElmer Paragon-1000PC instrument and NMR (300 MHz)spectra were recorded on Bruker 300-DRX instrument assolutions using TMS as internal standard, and chemicalshifts are expressed in  d  units. Mass spectra were recorded Table 1 . Preparation of 3-substituted 6-(2-methoxyphenyl)-3,6-diazabi-cyclo[3.2.1]octanes ( 7a – h ) NNMeO 6c , K 2 CO 3 DMF60-70 o C15-18 hRef. 7 8 9 ; X = Cl, Br 7a − h NHOONOOXNOO Entry Product Yield(%) a 1 NNMeONOO 7a 782 NNMeONOO 7b 703 NNMeONOOHH 7c 674  NNMeONOOEtMe 7d 545 NNMeONOOO 2 NCl 7e 716 NNMeONOO 7f  647  NNMeONSOOO 7g 458 NNMeONOOMeMe 7h 469 NNOONOMe RBx 2258 — a The yieldsare based on productsisolatedby columnchromatography oversilica gel.  R. K. Singh et al. / Tetrahedron 62 (2006) 4011–4017   4013  on API-3000 LCMS/MS using direct inlet system underpositive ion electrospray ionization source. Elementalanalyses were carried out with a Perkin Elmer 2400analyzer and values found were within  G 0.4% of theoretical values. 4.2. General method of lactam 14.2.1. 1-Methyl-5-oxopyrrolidine-3-carboxylic acidmethyl ester (1a).  This was prepared according to theliterature method 1d,5 starting from itaconic acid in 87%yield as a thick oil;  y max  (CH 2 Cl 2 ) 1736, 1689 cm K 1 ;  d H (CDCl 3 ) 2.67–2.71 (m, 2H), 2.87 (s, 3H), 3.26 (m, 1H),3.56–3.76 (m, 2H), 3.76 (s, 3H);  m  /   z  158 (M C 1). Anal.Calcd for C 7 H 11 NO 3  (157.17): C, 53.49; H, 7.05; N, 8.91.Found: C, 53.52; H, 6.99; N, 9.05%. 4.2.2. 1-(2-Methoxyphenyl)-5-oxopyrrolidine-3-carb-oxylic acid methyl ester (1b).  To a cooled ( K 5  8 C)solution of MeOH (100 mL), freshly distilled thionylchloride (13.09 g, 0.11 mmol) was added dropwise over aperiod of 0.5 h, after addition was completed the resultingmixture stirred at the same temperature for 0.5 h. To this 1-(2-methoxyphenyl)-5-oxopyrrolidine-3-carboxylic acid 5a (23.5 g, 0.10 mmol) was added portion wise, at the sametemperature, stirred for another 0.5 h and then temperaturewas allowed to rise to 25–30  8 C and then stirred for 3 h.MeOH was removed completely under reduced pressure.The residue was dissolved in CHCl 3  (200 mL) and washedwith 20% aq NaHCO 3  (3 ! 50 mL), water (1 ! 50 mL),brine (1 ! 25 mL), dried (Na 2 SO 4 ) and filtered. The filtratewas concentrated under reduced pressure to give  1b  as whitepowder, yield 23.8 g (96%), mp 82–83  8 C;  y max  (KBr) 3000,2960, 1729, 1690, 1593, 1503, 1414 cm K 1 ;  d H  (CDCl 3 )2.74–2.94 (m, 2H), 3.35–3.46 (m, 1H), 3.77 (s, 3H), 3.85(s, 3H), 3.94–3.97 (d,  J  Z 7.7 Hz, 2H), 6.94–7.00 (m, 2H),7.24–7.30 (m, 2H);  d C  (CDCl 3 ) 174.4, 170.0, 153.9, 126.5,125.0, 121.4, 121.0, 114.1, 56.3, 50.6, 42.5, 36.0, 31.1;  m  /   z 250 (M C 1). Anal.Calcd for C 13 H 15 NO 4 (249.26): C, 62.64;H, 6.07; N, 5.62. Found: C, 63.00; H, 6.13; N, 5.29%. 4.3. General method of thiolactam 24.3.1. 1-Methyl-5-thioxopyrrolidine-3-carboxylic acidmethyl ester (2a).  This was prepared according to theliterature method 1d starting from  1a  in 98% yield as a thick oil;  y max  (CH 2 Cl 2 ) 1736, 1210 cm K 1 ;  d H  (CDCl 3 ) 3.26(s, 3H), 3.31–3.35 (m, 3H), 3.74 (s, 3H), 3.90–3.97 (m, 1H),4.04–4.09 (m, 1H);  m  /   z  174 (M C 1). Anal. Calcd forC 7 H 11 NO 2 S (173.23): C, 48.53; H, 6.40; N, 8.09. Found: C,48.20; H, 6.55; N, 8.00%. 4.3.2. 1-(2-Methoxyphenyl)-5-thioxopyrrolidine-3-car-boxylic acid methyl ester (2b).  To a solution of lactam 1b  (23.65 g, 95 mmol) in dry THF (100 mL) was addedLawesson’s reagent (19.19 g, 47.5 mmol) portion wiseunder stirring at 25–30  8 C and resulting reaction mixturestirred for 4–5 h at same temperature. THF was removedunder reduced pressure to obtain a viscous residue, whichwas dissolved in EtOAc (200 mL), washed with 10%NaHCO 3  (5 ! 50 mL), brine (30 mL), dried (Na 2 SO 4 ) andfiltered. The filtrate was concentrated under reducedpressure to give the thiolactam  2b  as off white powder,yield 22.91 g (91%), mp 92–93  8 C;  y max  (CH 2 Cl 2 ) 1738,1585, 1210 cm K 1 ;  d H  (CDCl 3 ) 3.47–3.50 (m, 3H), 3.78(s, 3H), 3.84 (s, 3H), 4.17–4.27 (m, 2H), 7.01–7.06 (m, 2H),7.26–7.39 (m, 2H);  d C  (CDCl 3 ) 197.9, 174.4, 158.9, 126.5,125.6, 125.0, 121.1, 114.5, 59.5, 56.0, 50.8, 48.5, 36.5;  m  /   z 266 (M C 1). Anal. Calcd for C 13 H 15 NO 3 S (265.33): C,58.85; H, 5.70; N, 5.28. Found: C, 59.03; H, 5.86; N, 5.02%. 4.4. General procedure for compounds 34.4.1. 3-Methoxycarbonyl-1-methyl-5-methylthio-3,4-dihydro-2  H  -pyrrolium iodide (3a).  A solution of thethiolactam  2a  (17.3 g, 100 mmol) and methyl iodide(70.95 g, 500 mmol) was stirred at 25–30  8 C for 2 h, theformation of a yellow precipitate indicates the formation of the methylthioimonium iodide. The excess of methyl iodidewas removed under reduced pressure, the residue taken upin dry benzene, stirred for 10 min, the solid, which separatedout was filtered, washed well with dry benzene and dry etherand dried under vacuum over P 2 O 5  to give  3a  as pale yellowsolid, yield 30.24 g (96%), mp 104–106  8 C;  y max  (KBr)2363, 2344, 1735, 1617 cm K 1 ;  d H  (CDCl 3 ) 2.94 (s, 3H),3.45 (s, 3H), 3.68–3.74 (m, 1H), 3.80 (s, 3H), 3.94–4.02 (m,1H), 4.26 (dd,  J  Z 10.2 Hz, 1H), 4.45 (dd,  J  Z 4.5 Hz, 1H),4.79 (t,  J  Z 11.1 Hz, 1H);  m  /   z  189 (M C 1). Anal. Calcd forC 8 H 14 INO 2 S (315.17): C, 30.49; H, 4.48; N, 4.44. Found: C,30.59; H, 4.56; N, 4.50%. 4.4.2. 3-Methoxycarbonyl-1-(2-methoxyphenyl)-5-methylthio-3,4-dihydro-2  H  -pyrrolium iodide (3b).  Thiswas obtained in 90% yield as creamish-white powder byreacting methyl iodide with thiolactam  2b  according to theprocedure described for compound  3a ; mp 139–141  8 C; y max  (KBr) 2951, 1792, 1573, 1497 cm K 1 ;  d H  (CDCl 3 ) 2.84(s, 3H), 3.66 (m, 1H), 3.82 (s, 3H), 3.90 (s, 3H), 4.28–4.29(m, 1H), 4.58–4.68 (m, 1H), 4.72–4.80 (m, 2H), 7.04–7.15(m, 2H), 7.48–7.54 (m, 2H);  m  /   z  281 (M C 1). Anal. Calcdfor C 14 H 18 INO 3 S (407.27): C, 41.29; H, 4.45; N, 3.44.Found: C, 41.05; H, 4.65; N, 3.03%. 4.5. General procedure for compounds 44.5.1. 1-Methyl-5-nitromethylene-pyrrolidine-3-carb-oxylic acid methyl ester (4a).  To a stirred solution of   3a (7.88 g, 25 mmol) in dry DMF (50 mL), dry Et 3 N (2.78 g,27.5 mmol) and distilled nitromethane (7.63 g, 125 mmol)were added under nitrogen atmosphere. The reactionmixture was stirred at 25–30  8 C for 12 h. DMF and excessof nitromethane were removed under reduced pressure togive a crude product, which was purified by columnchromatography over silica gel (230–400 mesh) usingCHC1 3 –MeOH (98/2) as eluent to afford nitroenamine  4a as yellow solid, yield 2.27 g (45%), mp 76–78  8 C;  y max (KBr) 1733, 1590, 1359 cm K 1 ;  d H  (CDCl 3 ) 2.87 (s, 3H),3.23–3.33 (m, 1H), 3.63–3.69 (m, 3H), 3.73 (s, 3H), 3.84–3.89 (m, 1H), 6.63 (s, 1H);  d C  (CDCl 3 ) 174.8, 161.5, 102.1,57.5, 51.0, 46.1, 35.5, 33.5;  m  /   z  201 (M C 1). Anal. Calcd forC 8 H 12 N 2 O 4  (200.19): C, 48.00; H, 6.04; N, 13.99. Found: C,47.98; H, 6.22; N, 14.10%. 4.5.2. 1-Methyl-5-(1-nitroethylidene)-pyrrolidine-3-carboxylic acid methyl ester (4b).  This was obtained in36% yield as thick oil by reacting nitroethane with  3a  R. K. Singh et al. / Tetrahedron 62 (2006) 4011–4017  4014  according to the procedure described for compound  4a ;  y max (CH 2 Cl 2 ) 1738, 1581, 1376 cm K 1 ;  d H  (CDCl 3 ) 2.31 (s, 3H),3.14 (s, 3H), 3.18–3.28 (m, 1H), 3.57–3.60 (m, 3H), 3.72 (s,3H), 3.77–3.88 (m, 1H);  d C  (CDCl 3 ) 174.9, 154.1, 111.5,57.6, 50.6, 46.5, 35.8, 32.9, 10.8;  m  /   z  215 (M C 1). Anal.Calcd for C 9 H 14 N 2 O 4  (214.22): C, 50.46; H, 6.59; N, 13.08.Found: C, 50.55; H, 6.51; N, 13.17%. 4.5.3. 1-(2-Methoxyphenyl)-5-nitromethylene-pyrro-lidine-3-carboxylic acid methyl ester (4c).  This wasobtained in 45% yield as thick yellow oil by reactingnitromethane with  3b  according to the procedure describedfor compound  4a ;  y max  (CH 2 Cl 2 ) 2948, 1728, 1570, 1506,1351 cm K 1 ;  d H  (CDCl 3 ) 3.40–3.50 (m, 1H), 3.79 (s, 3H),3.84 (s, 3H), 3.85–3.92 (m, 3H), 4.03–4.23 (m, 1H), 6.38(s, 1H), 6.99–7.04 (m, 2H), 7.35–7.40 (m, 2H);  d C  (CDCl 3 )174.6, 153.7, 145.5, 129.1, 117.7, 114.6, 113.5, 103.5, 57.5,56.1, 50.7, 45.5, 29.9;  m  /   z  293 (M C 1). Anal. Calcd forC 14 H 16 N 2 O 5  (292.29): C, 57.53; H, 5.52; N, 9.58. Found: C,57.39; H, 5.65; N, 9.88%. 4.6. General procedure for compounds 54.6.1. 6-Methyl-3,6-diazabicyclo[3.2.1]octan-2-one (5a). To a solution of nitroenamine  4a  (3.0 g, 15.0 mmol) andammonium formate (18.9 g, 300 mmol) in MeOH (80 mL)was added 10% Pd–C (2.25 g, wet) and the resultingreaction mixture was refluxed under stirring for 10 h. Aftercompletion of reaction, reaction mixture was cooled to25–30  8 C and filtered through Celite bed, washed withMeOH (2 ! 5 mL) and the combined filtrate was concen-trated under reduced pressure to afford crude product, whichwas dissolved in CHCl 3  (10 mL). To this 10% NH 3 –CHCl 3 (10 mL) was added and stirred for 0.5 h at 25–30  8 C, solidseparated out was filtered off and filtrate was concentratedunder reduced pressure to obtain an oily residue, which waspurified by column chromatography over silica gel (100–200 mesh) using CHCl 3 –MeOH (99.5/0.5) / (98/2) aseluent to afford bicyclic lactam  5a  as thick oil, yield1.48 g (70%);  y max  (CH 2 Cl 2 ) 1682 cm K 1 ;  d H  (CDCl 3 ) 2.03–2.16 (m, 2H), 2.58 (s, 3H), 2.85 (br s, 1H), 3.01–3.11(m, 2H), 3.36 (br s, 1H), 3.24 (d,  J  Z 11.5 Hz, 1H), 3.48 (d,  J  Z 11.2 Hz, 1H), 5.92 (br s, 1H);  d C  (CDCl 3 ) 179.9, 63.6,51.8, 49.2, 39.5, 35.8, 30.6;  m  /   z  141 (M C 1). Anal. Calcd forC 7 H 12 N 2 O (140.18): C, 59.98; H, 8.63; N, 19.98. Found: C,59.73; H, 8.56; N, 19.80%. 4.6.2. 4,6-Dimethyl-3,6-diazabicyclo[3.2.1]octan-2-one(5b).  This was obtained in 35% yield as thick oil from  4b according to the procedure described for compound  5a ;  y max (CH 2 Cl 2 ) 1680 cm K 1 ;  d H  (CDCl 3 ) 1.58 (d,  J  Z 6.3 Hz, 3H),1.92 (br s, 3H), 2.49 (s, 3H), 2.79 (br s, 2H), 3.28–3.38 (m,2H), 5.30 (br s, 1H);  d C  (CDCl 3 ) 179.8, 67.5, 52.2, 48.6,39.5, 36.3, 27.9, 17.1;  m  /   z  155 (M C 1). Anal. Calcd forC 8 H 14 N 2 O (154.21): C, 62.31; H, 9.15; N, 18.17. Found: C,62.57; H, 8.99; N, 18.06%. 4.6.3. 6-(2-Methoxyphenyl)-3,6-diazabicyclo[3.2.1]-octan-2-one (5c).  This was obtained in 70% yield as thick oil from  4c  according to the procedure described forcompound  5a ;  y max  (CH 2 Cl 2 ) 1685 cm K 1 ;  d H  (CDCl 3 ) 2.04–2.11 (m, 2H), 2.97 (br s, 1H), 3.28–3.33 (m, 1H), 3.55–3.72(m, 3H), 3.83 (s, 3H), 4.62 (br s, 1H), 5.40 (br s, 1H),6.60–6.69 (m, 4H);  d C  (CDCl 3 ) 179.6, 146.7, 130.3, 121.5,119.1,115.0,114.3,63.5,56.1,51.9,48.7,39.0,30.2; m  /   z 233(M C 1). Anal. Calcd for C 13 H 16 N 2 O 2  (232.28): C, 67.22; H,6.94; N, 12.06. Found: C, 67.25; H, 6.89; N, 11.96%. 4.7. General procedure for compounds 64.7.1. 6-Methyl-3,6-diazabicyclo[3.2.1]octane (6a).  To astirred suspension of pulverized lithium aluminum hydride(2.96 g, 78 mmol) in dry THF (5 mL), a solution of bicycliclactam  5a  (2.73 g, 19.5 mmol) in dry THF (10 mL) wasadded under N 2  atmosphere at 25–30  8 C and the resultingreaction mixture was refluxed under stirring for 18 h. Aftercompletion of reaction, reaction mixture was cooled to K 5  8 C and cautiously decomposed with water (15 mL).After stirring for 1 h at 25–30  8 C, the reaction mass wasfiltered, washed with THF, the filtrate was collected anddried over Na 2 SO 4 , and filtered. The solvent was evaporatedto yield crude product, which was purified by columnchromatography over silica gel (100–120 mesh) usingCHC1 3 –MeOH (95/5) as eluent to afford 1.68 g (68%) of 6-methyl-3,6-diazabicyclo[3.2.1]octane ( 6a ) as a paleyellow oil;  y max  (CH 2 Cl 2 ) 2908, 2805, 1490 cm K 1 ;  d H (CDCl 3 ) 1.65–1.78 (m, 2H), 1.85–1.95 (m, 1H), 2.20–2.25(m, 2H), 2.31 (s, 3H), 2.58–2.70 (m, 1H), 2.75–2.90(m, 4H);  d C  (CDCl 3 ) 64.5, 54.3, 52.7, 51.5, 37.8, 36.9, 33.1; m  /   z 127(M C 1).Anal.CalcdforC 7 H 14 N 2 (126.20):C,66.62;H, 11.18; N, 22.20. Found: C, 66.75; H, 11.22; N, 21.95%. 4.7.2. 4,6-Dimethyl-3,6-diazabicyclo[3.2.1]octane (6b). This was obtained in 53% yield as thick oil from bicycliclactam  5b  according to the procedure described forcompound  6a ;  y max  (CH 2 Cl 2 ) 2890, 2800, 1495 cm K 1 ;  d H (CDCl 3 ) 1.38 (d,  J  Z 7.2 Hz, 3H), 1.95 (br s, 3H), 2.18–2.22(m, 2H), 2.30 (s, 3H), 2.45–2.50 (m, 1H), 2.70–2.85(m, 2H), 3.22–3.30 (m, 1H);  d C  (CDCl 3 ) 69.2, 54.8, 52.7,49.2, 38.1, 36.7, 31.4, 18.6;  m  /   z  141 (M C 1). Anal. Calcd forC 8 H 16 N 2  (140.23): C, 68.52; H, 11.50; N, 19.98. Found: C,68.25; H, 11.38; N, 20.10%. 4.7.3. 6-(2-Methoxyphenyl)-3,6-diazabicyclo[3.2.1]-octane (6c).  This was obtained in 57% yield as pale yellowoil from bicyclic lactam  5c  according to the proceduredescribed for compound  6a ;  y max  (CH 2 Cl 2 ) 2900, 2815,1498 cm K 1 ;  d H  (CDCl 3 ) 1.78–1.82 (m, 2H), 1.94–1.99(m, 1H), 2.30 (br s, 1H), 2.62–2.67 (d,  J  Z 9.6 Hz, 1H),2.79–2.93 (dd,  J  Z 9.9 Hz, 2H), 3.29–3.32 (d,  J  Z 9.6 Hz,1H), 3.60–3.65 (q,  J  Z 4.8 Hz, 1H), 3.78 (s, 3H), 4.21–4.24(t,  J  Z 5.4 Hz, 1H), 6.67–6.73 (m, 2H), 6.82–6.88 (m, 2H); d C  (CDCl 3 ) 146.5, 130.3, 121.9, 119.3, 115.6, 114.2, 63.6,56.2, 53.9, 51.5, 50.0, 35.3, 31.9;  m  /   z  219 (M C 1). Anal.Calcd for C 13 H 18 N 2 O (218.29): C, 71.53; H, 8.31; N, 12.83.Found: C, 71.68; H, 8.11; N, 12.80%. 4.8. General procedure for compounds 74.8.1. 1-{3-[6-(2-Methoxyphenyl)-3,6-diazabicyclo-[3.2.1]oct-3-yl]propyl}piperidine-2,6-dione (7a).  A mix-ture of 1-(3-chloropropyl)piperidine-2,6-dione (0.834 g,4.4 mmol), 6-(2-methoxyphenyl)-3,6-diazabicyclo[3.2.1]oc-tane ( 6c , 0.863 g, 3.96 mmol, 0.9 equiv), K  2 CO 3  (0.303 g,2.2 mmol, 0.5 equiv) and KI (0.146 g, 0.88 mmol, 0.2 equiv)in DMF (15 mL) was heated at 60–70  8 C under stirring for  R. K. Singh et al. / Tetrahedron 62 (2006) 4011–4017   4015
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